literature review of oral cancer

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Peer-reviewed

Research Article

The cost of oral cancer: A systematic review

Contributed equally to this work with: Rejane Faria Ribeiro-Rotta, Eduardo Antônio Rosa, Vanessa Milani, Nadielle Rodrigues Dias, Ana Laura de Sene Amâncio Zara

Roles Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation School of Dentistry, Universidade Federal de Goiás (UFG), Goiânia, Goiás, Brazil

Roles Conceptualization, Data curation, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review & editing

Roles Investigation, Writing – review & editing

Roles Conceptualization, Methodology, Supervision, Validation, Writing – review & editing

¶ ‡ DM and ENS also contributed equally to this work.

Affiliation Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

Roles Conceptualization, Investigation, Methodology, Supervision, Validation, Writing – review & editing

Affiliation Universidade de Brasília (UnB), Brasília, Federal District, Brazil

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing – original draft, Writing – review & editing

• Rejane Faria Ribeiro-Rotta, 
• Eduardo Antônio Rosa, 
• Vanessa Milani, 
• Nadielle Rodrigues Dias, 
• Danielle Masterson, 
• Everton Nunes da Silva, 
• Ana Laura de Sene Amâncio Zara

• Published: April 21, 2022
• https://doi.org/10.1371/journal.pone.0266346
• Peer Review
• Reader Comments

Although clinical and epidemiological aspects of oral cancers (OC) are well-documented in the literature, there is a lack of evidence on the economic burden of OC. This study aims to provide a comprehensive systematic assessment on the economic burden of OC based on available evidence worldwide. A systematic review was conducted. The population was any individual, who were exposed to OC, considered here as lip (LC), oral cavity (OCC), or oropharynx (OPC) cancer. The outcome was information on direct (medical and non-medical) and indirect (productivity loss and early death) costs. The data sources included Scopus, Web of Science, Cochrane, BVS, and NHS EED. A search of grey literature (ISPOR and INAHTA proceedings) and a manual search in the reference lists of the included publications were performed (PROSPERO no. CRD42020172471). We identified 24 studies from 2001 to 2021, distributed by 15 countries, in 4 continents. In some developed western countries, the costs of LC, OCC, and OPC reached an average of Gross Domestic Product per capita of 18%, 75%, and 127%, respectively. Inpatient costs for OC and LC were 968% and 384% higher than those for outpatients, respectively. Advanced cancer staging was more costly (from ~22% to 373%) than the early cancer staging. The economic burden of oral cancer is substantial, though underestimated.

Citation: Ribeiro-Rotta RF, Rosa EA, Milani V, Dias NR, Masterson D, da Silva EN, et al. (2022) The cost of oral cancer: A systematic review. PLoS ONE 17(4): e0266346. https://doi.org/10.1371/journal.pone.0266346

Editor: Antoine Eskander, University of Toronto, CANADA

Received: October 3, 2021; Accepted: March 19, 2022; Published: April 21, 2022

Copyright: © 2022 Ribeiro-Rotta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All data files are available from the Figshare database (accession number https://figshare.com/s/f7eb4990efeb5021f131 ).

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Detection of oral cancer does not demand elaborate screening tests such as breast, prostate, and colon cancers. Oral cancer can be easily and effectively detected early with oral inspection during routine dental consultations and integrated in primary care [ 1 ]. To achieve this goal, current efforts must include target programs to educate high-risk persons and primary care providers about the main aspects of early detection [ 2 ]. Oral cancer staging plays an important role in survival rate, with early-stage (I and II) and advanced-stage (III and IV) lesions having a 5-year survival rate of 80% and 50% or less, respectively [ 3 ]. Additionally, advanced stages require more aggressive combined interventions, and consequently more expensive treatments. There are also equity concerns about oral cancers, since they asymmetrically affect different population groups and countries. Older, heavier male users of tobacco and alcohol, and people from low socioeconomic strata, as well as those who have a poor dietary intake are populations who are at a high risk of developing oral cancer [ 4 ]. Regarding geographical locations, the highest incidence rates occur in three low- and middle-income countries (Pakistan, Brazil, and India) [ 4 ]. There is also a growing incidence of oral and oropharynx cancer among young patients (<45 years), particularly in Africa, the Middle East, and Asia [ 5 ].

Although clinical and epidemiological aspects of oral cancers are well-documented in the literature, there is a lack of evidence on the economic burden of oral cancers worldwide. Cost-of-illness studies can provide information on the monetary consequences of a disease or condition, including healthcare costs and productivity losses, and its impact on societal or public health expenditure [ 6 ]. This information can be used to estimate avoidable costs if policies/programmes are implemented to reduce the prevalence of this disease. When available, it also can inform costs stratified by stages of the disease. In the United Kingdom, average treatment cost for oral cancer can range from I$ 3,343 in the early stages to I$24,890 in the advanced stages [ 7 ]. Cost-of-illness can also be used to inform priority setting, by providing estimates of how big a problem is in terms of costs [ 8 ]. Moreover, gathering information on costs may encourage decision makers to implement strategies for detecting and screening populations at high-risk of developing oral cancer, particularly by comparing costs at different stages of the disease. To the best of our knowledge, up to now there are no systematic reviews that synthesize evidence on the economic burden of oral cancer. The objective of this study is to provide a comprehensive systematic assessment of the economic burden of oral cancer based on available evidence worldwide.

A systematic review of studies revealing the costs of lip cancer (LC), oral cavity cancer (OCC), and oropharyngeal cancer (OPC) was conducted, taking into account any cost perspective (societal, third-party players, public systems). The method used was guided by the concepts of the Joanna Briggs Institute (JBI) [ 9 ] and in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [ 10 ]. A systematic review protocol can be found as a preprint on Research Square ( https://www.researchsquare.com/article/rs-34637/v1 ). This protocol was reformulated, and the final version can be found in Prospero (CRD42020172471).

Problem specification

What is the economic burden of oral cancer, including direct and indirect costs?

The question was framed using the acronym PEO (Population, Exposure, Outcome), which was used to define the search strategy. The population (P) considered for publication searching was any individual (human) or groups of individuals, without restriction of age, sex, race, or socioeconomic status, who were exposed (E) to oral cancer, considered here as LC, OCC, or OPC. The outcome (O) required from the publications was information on direct (medical and non-medical) and indirect (productivity loss and early death) costs.

Eligibility criteria

Original studies on the cost of oral cancer, which included direct and/or indirect costs, or that provided estimates per patient (average cost or by clinical stage) or economic burden as percentage of GDP or national healthcare expenditure were included in the review. No language or year of publication restriction was established.

Publications that met the following criteria were excluded:

• Types of study such as: editorial, letters to the editor, systematic and non-systematic reviews of the literature, meta-analyses, case reports, case series, clinical trials.
• Studies that estimated specific item components of oral cancer cost (e.g., only surgery or medication, etc).
• Studies that addressed specific analyses, such as cost-effectiveness, cost-utility, cost-benefit, cost-minimization.

Information sources

A systematic literature search was carried out through a comprehensive search of databases in PubMed, Scopus, Web of Science, BVS (Biblioteca Virtual em Saúde) and NHS Economic Evaluation Database up to March 31, 2021. We also manually searched the references of the articles included for additional studies. Additionally, our search was supplemented by gray literature, with the search of abstracts of conference proceedings from annual meetings of the following societies: International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and International Network of Agencies for Health Technology Assessment (INAHTA) [ 11 ] (accessed March 31, 2021).

Design of search strategy

To identify relevant cost-of-illness studies for LC, OCC, and OPC, appropriate disease-related MeSH terms were used (Additional file 1, available via https://figshare.com/s/f7eb4990efeb5021f131 ). To determine the search strategy, descriptors were selected by building a table (concept mapping). The table rows were allocated for each item of the acronym PEO and the columns for PubMed controlled vocabulary terms (Medical Subject Headings–MeSH), their subcategories (entry terms; see also), and uncontrolled vocabulary (free terms) usually obtained from titles and abstracts of the main publications, books, and gray literature on the research theme. After the PubMed MeSH controlled vocabulary tree was explored, terms were tested in the PubMed database and the most relevant descriptors were selected, and a search strategy was built (Additional file 2, available via https://figshare.com/s/f7eb4990efeb5021f131 ). The search strategy defined for PubMed was adapted for searches in the other databases.

All publications identified in the databases were exported to the Mendeley Reference Manager (Mendeley®, Elsevier, version 1.19.5/20019) for duplicate removal. After that, all publications were exported to Rayyan® software (Rayyan QCRI, Qatar Computing Research Institute–Data Analytics) [ 12 ] for the selection process.

Selection process

The stages of the selection process included at least one reviewer from each of the following fields of knowledge: oral cancer (EAR; VM; NRD; RFRR); epidemiology (ALSAZ); and / or health economics (ENS). Three reviewers (EAR; VM; NRD) read the title and abstract of publications using the software Rayyan (Rayyan QCRI). Kappa statistic was calculated to assess agreement between reviewers, in pairs, in the eligibility stage, with a significance level of 5% (p<0.05). The scale of Kappa value interpretation was as following: <0 no agreement; 0–0.20 slight; 0.21–0.40 fair; 0.41–0.60 moderate; 0.61–0.80 substantial and 0.81–1.0 perfect. All studies identified were screened based on the eligibility criteria and were forwarded for full-text review. Contact with the authors was established for the screened studies not available in full text. Two reviewers (EAR; ENS) independently read the full text for inclusion. Additional reviewers (RFRR; ALSAZ) were consulted for consensus in case of disagreement between the first two (EAR; ENS). Reviewers underwent training prior to the publication selection process, which was performed using 100 screened publications.

Data collection

An instrument was built to extract the relevant data on cost methodologies, designs, and approaches, using Research Electronic Data Capture (REDCap) [ 13 ]. This instrument included the following variables:

• Study identification: first author; country; journal and year of publication.
• Main study design characteristics: type of study (cost-of-illness study or another type of study that provides cost-of-illness information of oral cancer); epidemiological approach (longitudinal or cross-sectional or case control); sample (number, age, type of cancer, cancer anatomical site and stage); retrospective or prospective data gathering; data source; perspective of the analysis (societal, government, health insurance provider, hospital); time horizon; presence of a control group (patients not affected by oral cancer); location/setting (country, state, or city); cost-of-illness based approach (prevalence-based or incidence-based); estimation of resources and costs (single study-based or model-based); assumptions adopted (structural or other assumptions underpinning the study); year of cost estimation; currency; sensitivity analysis; use of discount rate; funding sources; conversion; data source (primary or secondary database). The perspective of studies was defined as: i) societal, which includes direct and indirect costs and/or out-of-pocket costs from patient point of view; ii) government (public payer), includes direct costs only; iii) health insurance provider (private payer), which includes direct costs reimbursed by the private health insurers; and iv) hospital, which includes direct cost charged by just one hospital, unless the authors explicitly reported the government or health insurer perspectives.
• Type of cost estimated: direct healthcare costs (hospitalization, surgery, chemotherapy, radiotherapy, intensive care unit, emergency room, physical therapists, speech therapists, medication, laboratory tests, imaging diagnosis and follow-up); direct non-healthcare costs (social services and transportation costs), indirect costs (productivity loss, early death).
• Primary study outcomes: costs related to oral cancer in patients, reported in monetary units or economic burden as a percentage of Gross Domestic Product (GDP) or national healthcare expenditure.
• Additional outcome: if the studies provided a specific breakdown of costs, this information was reported as a secondary outcome (outpatient and inpatient costs; cost by clinical stage; primary and recurrent tumor cost). We also calculated the economic burden of OC at individual level, by dividing the OC costs per patient by the GDP per capita of the country under investigation. This measure would indicate how catastrophic those costs could be for an average citizen (GDP per capita).

Data extraction was carried out by at least two of four reviewers (ALSAZ; EAR; ENS; RFRR), in a double-blind process, and disagreements were decided by consensus.

Data synthesis

All studies meeting the eligibility criteria were included in the study and critically appraised using the Larg & Moss’s guide [ 14 ] for assessing cost-of-illness. This checklist includes three domains: analytical framework; methodology and data; analysis and reporting. The method for assessing quality of individual studies was done at both the outcome and study level, independently, and in duplicate (EAR, ENS), and discrepancies were resolved by consensus. We provided a global score for the quality of each study by calculating the total number of points rated as “yes” and “not applicable (NA)”. Percentage intervals were established for meeting the items of the quality assessment instrument applied to the included studies: >80%; between 79% and 50%; and less than 50%. The average and standard deviation (SD) of the scores were calculated. The average of the scores were compared between study design groups (longitudinal studies, cross-sectional and case control studies, and cross-sectional studies based on information system data) and by domains, using a one-way analysis of variance (ANOVA) (p<0.05), by Open-Source Epidemiologic Statistics for Public Health (OpenEpi), version 3.01 [ 15 ]. In this section, this was considered the risk of bias information obtained from each study.

To calculate the percentage of the burden of the cost of oral cancer, GDP per capita of the countries where the studies were carried out was considered and converted to International Dollars (I$) by Purchasing Power Parity—PPP (2019) [ 16 ].

The results were presented in narrative form, using the Synthesis Without Meta-Analysis (SWiM) reporting guideline [ 17 ], and the main results were presented in tables.

The search procedure is shown in the PRISMA flow diagram [ 10 ] ( Fig 1 ). The systematic literature search identified 12,391 potentially relevant articles. After removal of duplicates, 6,864 studies were screened for inclusion ( Fig 1 ). Following title and abstract review, full-text articles were assessed (n = 44) and excluded (n = 20) for the following reasons—they were not an oral cancer cost study, did not include a specific intervention cost, there was a head and neck cancer cost study that did not present oral cancer cost separately, only proceedings available and there were no abstracts. The author or co-authors were contacted by email for the nine studies which were unobtainable, and for which only the abstracts or the title was available. There was only one answer from all of these authors, stating that they had not published the full study. Overall, 24 studies met all the eligibility criteria and were included in the systematic review.

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In the eligibility stage, Kappa coefficient was 0.83 (perfect) between the EAS and VM reviewers; 0.78 (substantial) between EAS and NRD and 0.78 (substantial) between VM and NRD.

Study characteristics

The study characteristics are summarized in Tables 1 and 2 . The studies identified were published from 2001 to 2021 and distributed by continent as follows: Europe (n = 9), Asia (n = 7), America (n = 6), Oceania (n = 1), and 1 global study stratified by region and income of 195 countries. The study population size ranged from a minimum of 69 (Sri Lanka) [ 18 ] to a maximum of 62,265 (Korea) [ 19 ]. Four studies [ 20 – 22 ] estimated costs by procedures and not per individual. The studies included investigated a wide variety of anatomical sites of the head and neck region, using a non-standardized terminology to identify them ( Table 1 ).

https://doi.org/10.1371/journal.pone.0266346.t001

https://doi.org/10.1371/journal.pone.0266346.t002

The 24 included studies were stratified by study design, which revealed five longitudinal studies [ 23 – 27 ] with a time horizon varying from one to five years. Of the 18 cross-sectional studies, 10 were cost-of-illness [ 18 – 22 , 28 – 32 ], 8 cost analysis [ 33 – 40 ] and one was a case control study [ 41 ]. The 24 studies used primary and/or secondary data sources, of which four were based on information system data [ 20 – 22 , 28 ]. The most frequent perspective of the studies was hospital (n = 7) [ 21 , 32 , 33 , 35 , 37 – 39 ]. Two studies used estimation of resources and cost based on mathematical models [ 31 , 35 ] ( Table 2 ).

Quality assessment

The global quality score of the studies, considered as the percentage rate of compliance to the items of the quality evaluation instrument, was 47.8% (SD = 10.9). The quality score varied from 38% [ 20 , 32 ] to 66% [ 19 ] ( Table 3 ). Regarding the study designs, the average of quality scores was 49.1% (SD = 9.9) for longitudinal studies, 47.3% (SD = 5.8) for cross-sectional and case control studies, and 46.0% (SD = 7.2) for studies based on information system data. No statistically significant difference was found among the average scores by study design (p = 0.796). Considering all studies, the Analytical Framework domain had an average score of 68.8% (SD = 15.0), the Methodology and Data domain 42.9% (SD = 10.1), and the Analysis and Reporting domains 43.8% (SD = 16.1), presenting a statistically significant difference among the average scores (p<0.001). The average of the quality scores of cross-sectional studies and those studies based on system data differed among domains (respectively p<0.001 and p = 0.001). The Analytical Framework domain had the highest average score in each included publication, when compared to the other two domains.

https://doi.org/10.1371/journal.pone.0266346.t003

Cost components

Fourteen studies [ 18 , 19 , 21 – 23 , 25 – 27 , 32 , 34 , 35 , 37 , 39 , 41 ] evaluated all components of direct medical costs (surgery, chemotherapy, radiotherapy, follow-up, medications, exams), and only six [ 18 , 19 , 22 , 29 , 30 , 39 ] investigated non-medical costs. Regarding indirect costs, three studies [ 18 , 28 , 30 ] evaluated absenteeism costs, two evaluated both [ 19 , 29 ] absenteeism and early death, and one investigated early death costs [ 31 ]. None of them estimated presenteeism costs ( Table 4 ).

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Studies that met the inclusion criteria presented the estimates of oral cancer cost according to a wide variety of aspects: cost per patient, monthly cost, total cost in a period, cost per treatment or procedure, from the payer’s perspective, cost components, outpatient and inpatient cost, services, by International Classification of Diseases, Tenth Revision (ICD-10) separately or in aggregate, by disease stage, follow-up, and disease recurrence ( Table 5 ).

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The OC cost comparison among studies was not possible. The set of anatomical sites investigated varied widely, in addition to the different measurement and costing methods. Only one of the studies included presented costs, separately, related to the sites considered as oral cancer in this systematic review (lip, oral cavity, and oropharynx) [ 22 ]. Most of the studies investigated lip, oral cavity, and oropharynx cancers together with other types of cancers from head and neck region ( Table 5 ).

Only two studies [ 22 , 23 ] investigated the cost of lip cancer separately from other ICD-10. The cost of lip cancer was estimated at GBP5,790 pounds per patient, over a five-year follow-up in the UK. In Brazil, the total expenditure of lip cancer was I$22.7 million in the period of nine years, from which I$18.1 million for inpatient costs and I$4.6 million for outpatient costs [ 22 ] ( Table 5 ).

Three studies [ 23 , 26 , 35 ] showed the cost of oral cavity cancer per patient, estimated at GBP25,311 pounds in five years of follow-up in the UK [ 23 ]; EUR18,462 in two years of follow-up [ 26 ] in Italy; and EUR35,541 in a mathematical model estimated for 10 years in the Netherlands [ 35 ]. Two studies [ 20 , 30 ] estimated oral cavity cancer cost per hospitalization, by information system data, with an average of THB29,531 [ 20 ] for Thailand and EUR6,482 for Germany [ 28 ], both over a one-year follow-up. One Brazilian study presented the expenditure of oral cavity cancer, in 9 years, as I$257.1 million: on average I$139.1 million for inpatients and I$118.0 million for outpatients [ 22 ] ( Table 5 ).

Three studies [ 26 , 35 , 41 ] showed the cost of oropharynx cancer per patient, estimated at EUR24,253 euros after two years of follow-up in Italy [ 26 ], EUR35,642 in a probabilistic mathematical model estimated for 10 years [ 35 ] in the Netherlands, which presented the health state after year 2, after year 4 and after years 5–10, calculated from the date of the primary diagnosis, and USD134,454 over a period of two years in the USA [ 41 ]. Three studies [ 20 , 22 , 28 ] estimated oropharynx cancer per hospitalization, by information system data, with an average of THB26,331 [ 20 ] in Thailand and EUR4,268 in Germany [ 28 ], both over a one-year follow-up, and I$1,338 in Brazil over nine years [ 22 ] ( Table 5 ).

Only four studies showed the costs of OC by cost components (direct and indirect costs) [ 28 – 30 ]. In France (2018) [ 30 ], the direct medical cost of head and neck cancer was EUR49,954 per patient, considering outpatient and inpatient care, public hospitals services, and private for-profit hospitals services. The indirect cost was EUR2,989 per patient for disability and sick leave. In Germany (2008) [ 28 ], the direct medical cost of oral cancer was approximately EUR113 million, and the indirect cost was EUR18 million (sick leave). The direct medical cost of oropharyngeal cancer was approximately EUR83 million, and the indirect cost was EUR16 million (sick leave) [ 28 ]. In Iran [ 29 ], the cost of lip cancer, and for other and unspecified parts of tongue, the floor of the mouth, and buccal cancers was approximately USD27 million, USD5 million, and USD32 million for direct and direct non-medical and indirect costs, respectively [ 29 ]. The direct medical costs in Taiwan (2018) [ 27 ] were USD19,644 per patient and indirect costs for morbidity and mortality were USD1,286 and USD35,570 per patient, respectively, in a follow-up over 2.3 years ( Table 5 ).

The LC burden of cost was 18.3% of UK GDP per capita [ 23 ]. Regarding the OCC cost, the burden was 79.8%, 64.9%, and 79.8% of UK, Italian, and the Netherlands’ GDP per capita, respectively [ 23 , 26 , 35 ]. The OPC burden of cost was 85.2%, 80.3%, 215.0% of Italy, the Netherlands, and the USA GDP per capita, respectively [ 26 , 35 , 41 ] ( Table 6 ).

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Five studies showed outpatient and inpatient costs [ 22 , 23 , 25 , 30 , 41 ]. In general, inpatient costs are higher than outpatient costs, with a coefficient of variation of 93% [ 30 ] to 967.5% [ 23 ]. Outpatient costs exceeded inpatient costs in those studies in which chemotherapy and radiotherapy procedures were performed as outpatient costs [ 22 , 41 ] ( Fig 2A ).

Oral cancer burden of cost and difference of costs (%) according to types of patient care (A) and clinical stage of the disease (B). Difference (%) = [(inpatient cost–outpatient cost)/outpatient cost x 100]. Currency: Kim,2011: Pounds; Lairson, 2017, Rezapour, 2018, Amarasinghe, 2019, Zavras, 2002, Epstein, 2008: US dollars; Pollaers, 2019: Australian dollars; Lafuma, 2019: Euros; Milani, 2021: International dollars (million); Goyal, 2014: rupees.

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Regarding the resource quantification, most of the included studies used a top-down approach (18 studies), generally obtained by allocating portions of a known total expenditure to a specific disease stratified by type of cost. Only 6 studies relied on individual data (bottom-up approach), generally obtained by multiplying the unit costs by quantities.

Advanced staging was more expensive (from 21.9% to 373.3%) than early cancer staging [ 18 , 25 , 29 , 34 , 37 ], despite the lack of a clinical stage standard definition of the disease and the different sets of head and neck tumors studied ( Fig 2B ).

The treatment of recurrent squamous cell carcinoma of the floor of mouth, tongue, and alveolar trigone was 51% more expensive than the treatment of primary tumors, in a two-year follow-up study [ 25 ].

Our systematic review highlights the economic impact of oral cancer as a rising burden from a worldwide perspective. In a resource‐scarce healthcare environment, with an aging population and an increasing number of new diagnoses of oral cancer, this new knowledge is imperative in guiding resource allocation for oral cancer care provision and research funding. Deployment of interventions to improve outcomes for patients should be measured not only in terms of clinical outcome, but also in terms of economic impact. Furthermore, the analysis uncovers the large heterogeneity of cost of illness studies (COI) focused on oral cancer.

In some western countries, the economic burden of OCC and OPC is more than 60% of GDP per capita [ 23 , 26 , 35 ], reaching 215% of US GDP per capita (OPC) [ 41 ]. Considering that the GDP per capita corresponds to the average income of families [ 16 ], it is a cost that the individual cannot, in most cases, bear alone, and which requires the support of governments. Governments and health insurance providers are supposed to be the organizations supplying support to the population in order to face the high cost of chronic diseases. Nevertheless, oral cancer has a 90% chance of being cured, if detected early [ 42 , 43 ].

The development of effective public policies is crucial for reducing these health expenditures. Oral cancer is confirmed as a public health problem and was a concern of at least 17 countries on 4 continents, based on the studies included in this review.

The main characteristics that qualify a COI study are expressed in its methodological definition. These include, among other aspects, the epidemiological approach, costing method and data collection. Incidence-based COI studies should include both direct and indirect costs throughout the life course to outcome. Prevalence-based COIs also include direct and indirect costs over a given period from any stage of the disease. For an acute illness, these two approaches would estimate similar costs. However, for a chronic disease, such as oral cancer, longitudinal incidence-based studies would provide more accurate estimates of the costs of this disease overt time. Considering the costing method for identifying and measuring resources, the COI approach can be micro (bottom up) or macro costing (top down). Using the micro-costing method, costing components and items are measured at the most detailed level possible, with estimated costs per individual, and the selection of a representative sample is recommended to allow external validity or generalizability of the results to a broader population. In macro costing, the total aggregate cost is divided by the number of individuals and can be expressed as an average value. Generally, COI studies that use micro-costing are more accurate, but less generalizable. Regarding data collection, retrospective studies represent a challenge because the data are secondary, generally intended for other purposes (epidemiological or surveillance) and may not be sufficient for a COI study. Most of the studies included in this systematic review did not meet all the items of the instrument used for quality assessment.

Although the economic burden of oral cancer was substantial, this systematic review showed that the costs may be underestimated, and only one [ 19 ] of the 24 studies considered all components of cost-of-illness simultaneously. In addition, from the six studies that analyzed indirect costs [ 18 , 19 , 28 – 31 ], only three studies [ 19 , 29 , 31 ] included costs of early death related to the disease, which is one of the most expensive items for society [ 44 ]. Further longitudinal studies with higher quality are needed, not only methodologically, but in their data analysis and reporting of results. These studies should include, not only direct medical costs, but also direct non-medical and indirect costs, so that more accurate estimates can contribute to cost evaluation of health promotion and disease management programs.

The wide heterogeneity of COI studies was identified in both the aspects related to disease characterization and those related to economic issues. Regarding the disease, the main sources of heterogeneity were the characteristics of the samples; the lack of standardization in the definition of the clinical stage of the disease, and the different sets of head and neck tumors studied. The heterogeneity related to economic issues of the studies were found in their design, perspective, time horizon, sources of information, components and costing items, the health system of each country, currency, and reporting of cost results. The World Health Organization (WHO) recommendation is that the results of COI studies be reported in international dollars according to the PPP, to better support country-to-country comparisons of costs [ 45 ]. The development of protocols for the cost evaluation of oral cancer should be encouraged, as it has been by the Pan American Health Organization (PAHO) with the protocol for calculating the cost of hospital infections [ 46 ], since these analyses are complex and depend on the objectives of the studies. Protocols may contribute to the reduction of heterogeneity, favoring the comparison between different regions and health systems, in order to obtain a more accurate calculation of oral cancer cost.

In general, inpatient costs are higher than outpatient costs. However, this depends on the provision of health resources in each healthcare unit of the health system in each country. For example, in the USA [ 41 ], outpatient costs were higher than inpatient costs because most patients were treated with radiotherapy in outpatient care, which is one of the most expensive treatments for oral cancer management.

The costs of oral cancer in advanced clinical staging were higher than those at early stages, which occurred regardless of the heterogeneous characteristics of the studies. Most cases of oral cancer have been diagnosed in advanced staging for almost two decades [ 47 ] which in addition to compromising patient survival, determines high-cost treatments and suggests flaws in policies to promote preventive measures/strategies and early detection and diagnosis. This reinforces the importance of public policies that prioritize actions in the context of primary care, including health education for the population, qualification of professionals for the early detection of the disease, and the monitoring of the population at risk through opportunistic screening [ 7 , 48 ].

The main limitation of this review was the difficulty of finding average cost results per patient from cancer sites, defined here as oral cancer (ICD-10 C01-C06, C09, and C10). These difficulties are possibly associated with the presentation of study results as aggregate costs of head and neck cancer and, also as a result of the absence of an international standardization defining which anatomical sites should characterize oral cancer. The heterogeneity of studies in other aspects of the disease characteristics, method, and economic issues may also have impacted on our findings, which did not allow a meta-analysis.

Decision makers increasingly require economic evidence to inform health policies [ 49 , 50 ] and systematic reviews of economic evaluations (COI and cost-effectiveness) have grown accordingly [ 51 – 55 ]. This study provides a comprehensive and critical overview of the COI analyses conducted around the world, which highlights the magnitude of the financial impact of oral cancer on societal or public health expenditure. This evidence can contribute to priority setting, particularly in the context of scarce resources. Our results can also be used by several other key stakeholders, such as international organizations (WHO and World Bank), health insurance companies, and health providers (health facilities and health workers).

This systematic review can also provide relevant insights for the health technology assessment field, particularly for economic evaluation studies. COI studies represent the first step towards complete economic analysis (e.g., cost-effectiveness analysis) and can also support budgetary impact analysis, by identifying, measuring, and valuing costs related to a specific disease or health condition [ 56 ].

This systematic review shows that the economic burden of oral cancer is substantial and underestimated. The cost of LC, OCC, and OPC reach an average of 18%, 75%, and 127% of GDP per capita, respectively, in some western countries. Further high-quality COI studies are needed, especially with robust methodological design and those that include, in addition to direct medical costs, the direct non-medical and indirect costs. Standardization of the terminology of the types of cancer and clarity in reporting the sources of cost information are crucial to consider in the COI studies. Also, if COI studies present international dollars as the unit price to reflect the economic cost of goods, and allow inter-country comparison of costs, this could support policy makers to identify major cost drivers of oral cancer and to make decisions regarding a more effective public policy for the prevention of oral cancer.

Supporting information

S1 checklist. prisma 2020 checklist..

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• Published: 05 September 2022

Knowledge, attitudes, and practices of oral cancer prevention among dental students and interns: an online cross‑sectional questionnaire in Palestine

• Rola Muhammed Shadid 1 , 2 ,
• Mohammad Amid Abu Ali 3 &
• Omar Kujan 4  

BMC Oral Health volume  22 , Article number:  381 ( 2022 ) Cite this article

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Oral cancer is frequently characterized with an aggressive behavior and an unfavorable prognosis; however, it is generally associated with promising prognosis if detected early. Therefore, this study aimed to assess knowledge, practices, and attitudes toward oral cancer prevention among dental students and interns; and to investigate the factors that influence their practices of oral cancer screening or prevention.

Material and methods

A cross-sectional questionnaire-based survey was conducted between March and April of 2022 on the fourth- and fifth-year undergraduate dental students and interns in the College of Dentistry at Arab American University in Palestine. A 48-item questionnaire which has 4 sections: demographics, knowledge, practices, and attitudes toward oral cancer prevention and early detection was sent to all eligible participants (N = 570).

The response rate was 68.7% (N = 351). About 66.8% of the respondents had poor knowledge about oral cancer and its risk factors, and 85.5% had a poor practice of oral cancer early detection and prevention; however, the majority of the respondents (81.1%) had shown favorable attitudes toward oral cancer prevention. Interns had significantly better knowledge and attitude scores compared to the undergraduate dental students ( P  < 0.05). Lack of training, time, confidence, and effectiveness were stated among the barriers to oral cancer screening.

Conclusions

Most of the participants surveyed in this study appeared to lack adequate knowledge and skills in oral cancer prevention and early detection; however, they seemed to have good motivation and a good attitude toward oral cancer prevention training.

Peer Review reports

Lip and oral cavity cancers are considered a main global health problem representing the 16th most common neoplasm globally, with almost 377,713 new cases and about 177,757 deaths registered in 2020 [ 1 ]. However, most of the new cases of oral cancers are reported in the developing countries [ 2 ]. Kujan et al. based on GLOBOCAN 2012 projection, estimated that the number of new cases and the mortality rate of oral cancer will duplicate in the Middle East and North Africa (MENA) region, where most countries in this region are from the developing world, by the year 2030. This contrasts with the incidence and mortality rate of the oral cancer globally where it is estimated to increase by only 50% in the same time span [ 3 ].

In Palestine as part of the MENA region, the newly reported cases of oral cavity and oropharyngeal cancer were estimated at around 90 and the associated deaths were 35 in 2012 [ 4 ].

Squamous cell carcinoma has been found to be the most common type of the lip and oral cavity cancers representing about 90% [ 5 ], and it is regarded to be a multifactorial disease [ 6 , 7 ]. Heavy tobacco smoking, alcohol drinking, viral infection by human papilloma virus (HPV), and genetic instability are considered to be the main risk factors in the MENA region [ 7 , 8 , 9 , 10 , 11 ]. Dietary, occupational, and environmental risk factors might also contribute to oral cancer development [ 12 ]. However, tobacco smoking that is an endemic habit in the MENA region is considered the most significant risk factor. For example, the prevalence of tobacco smoking among the Palestinian male population is about 40% [ 12 ].

Oral cancers are most prevalent on the lower lip, lateral border of the tongue, and floor of the mouth. They affect mainly the middle-aged and elderly men with the highest occurrence in the sixth to eighth decades of life [ 3 ]. Although oral cancers are frequently characterized with an aggressive behavior and unfavorable prognosis [ 13 , 14 ], they are generally associated with promising prognosis if detected early [ 15 ]. These lesions can be prevented by either lessening exposure to risk factors or detection and surveillance of oral potentially malignant disorders [ 16 ]. Unfortunately, a recent systematic review demonstrated that oral cancers are commonly ignored by healthcare providers and the resulting delay in referrals is a major contributor to disease’s advanced stages [ 17 ]. General dental practitioners play a vital role in the prevention and early detection of oral cancer due to their forefront contact with patients [ 18 ].

Several studies worldwide investigated oral cancer awareness, knowledge, practices, and attitudes among qualified practicing and future dentists [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. Some of these studies revealed poor or inadequate level of knowledge, attitudes, or practices of oral cancer prevention [ 22 , 30 , 31 , 32 ], implying the need for improving the oral cancer curricula in undergraduate and graduate dental courses and for conducting more continuing education programs for healthcare professionals to improve the knowledge and attitudes toward oral cancer prevention and early detection.

Since the incidence of oral cancer is increasing in the MENA region [ 3 ] due to incremental trends of highly associated risk factors such as smoking and alcohol consumption [ 12 ], and owing to the vital role played by the general dental practitioners in the prevention and detection of oral cancer lesions at early stages, and because no study till now was conducted in Palestine to assess the dentist’s oral cancer awareness, this cross-sectional study aimed to assess the knowledge, practices, and attitudes toward oral cancer prevention among students and interns in the College of Dentistry at the Arab American University (AAUP); and to investigate the factors that influence their practices of oral cancer prevention or early detection.

This cross-sectional questionnaire-based study was conducted and reported in accordance with CHERRIES guidelines [ 33 ] between March and April of 2022, and targeted the fourth- and fifth-year undergraduate dental students and interns in the College of Dentistry at AAUP. A total of 511 undergraduate students and 59 interns were deemed as eligible participants. The study was approved by the Institutional Review Board (IRB), College of Dentistry, Arab American University (2022/A/3/N), and was conducted in agreement with the Declaration of Helsinki guidelines. All participants provided informed consent. The 48- item questionnaire used in the current study was established after reviewing previous studies [ 18 , 23 , 29 ], and it was pilot tested on a group of 20 undergraduate students and interns to verify its clarity and simplicity. The questionnaire content validity was evaluated by an expert in Oral Medicine and it was pre-validated in previous research work [ 18 ]. Reliability was assessed using the test–retest method in which 20 students and interns completed the questionnaire twice within two weeks. Outcomes of the two times were compared using Pearson’s correlation coefficient that has shown a significant stability coefficient suggesting a good test–retest reliability.

Regarding internal consistency between items in the survey, it was measured using the coefficient alpha "Cronbach’s alpha”. A Cronbach α = 0.785 was attained, entailing acceptable internal consistency.

The questionnaire was created online using Google Drive and a link was emailed and shared with all eligible participants in closed groups on social media. A cover letter accompanying the questionnaire explained the study aims, the methods of the study, and assured that the participation was voluntary, anonymous, and all information given would be confidential and used for research purposes only.

The questionnaire consisted of 47 close-ended questions and one open-ended question which were categorized into 4 sections: demographics, knowledge, practices, and attitudes toward oral cancer prevention and early detection. The first section included information about the demographics such as age, sex, and education level. The second section included questions about participants’ knowledge regarding oral cancer signs, symptoms, and risk factors (22 questions). A score of “1” was given for each correct answer on the questions, so the overall knowledge score ranged from 0–22. The current study used (13.2 /22) 60% as cut-off points [ 32 ], > 13.2 points was considered to have good knowledge and ≤ 13.2 points was considered to have poor knowledge of oral cancer.

The third part of the questionnaire included 12 questions about practices of oral cancer prevention and detection and one question about the claimed barriers for regular oral cancer screening. The best practice score was 12 while 7.2 represented a cut-off score; > 7.2 was regarded as good practice and ≤ 7.2 as poor practice.

In the final part of the questionnaire, participants were questioned about their attitudes and opinions about oral cancer prevention by responding to 10 statements using “strongly agree”, “agree”, “disagree”, and “strongly disagree”. A score of 1 designated positive attitude, while a score of 0 designated negative attitude, with 10 represented the maximum score. Six was set as cut-off score; > 6 was considered as a favorable attitude and ≤ 6 as unfavorable.

Statistical analysis

Responses were assembled using the Google Drive Excel document, and data were analyzed statistically using the Statistical Package for Social Sciences (SPSS), version 22.0. Descriptive statistics of the mean, standard deviation and percentages were calculated for all continuous variables. The level of statistical significance was considered at P  < 0.05.

The influence of sex and age on the knowledge, practice, and attitude scores was evaluated using independent samples t-test, and the influence of education level on the abovementioned variables was tested using One Way Analysis of Variance (ANOVA).

Of the 511 undergraduate dental students who were requested to participate, 351 completed the survey with a response rate of 68.7%; and 41 interns from 59 filled the survey with a 69.5% response rate. This represents an overall response rate of 68.8%. Most of the respondents were females (64.3%), ≤ 30 years old (94.1%), and undergraduate dental students (98.5%; Table 1 ).

Table 2 shows the number and percentage of undergraduate dental students and interns who correctly answered the knowledge questions. Table 3 shows the number and percentage of undergraduate dental students and interns who recognized high-risk factors for oral cancer. Table 4 reveals the number and percentage of undergraduate dental students and interns who claimed good practice and experience with oral cancer screening and referral at College of Dentistry. Table 5 demonstrates the number and percentage of undergraduate dental students and interns who exhibited positive attitudes toward oral cancer prevention.

Concerning the assessed knowledge of oral cancer and its risk factors, 66.8% of the respondents had a poor knowledge with an 11.86 (3.56) overall mean among the responding participants. About 85.5% of the responding participants had a poor practice of oral cancer prevention and early detection with an overall mean of 4.44 (2.75). However, most respondents (81.1%) had favorable attitudes toward oral cancer prevention with an overall mean of 7.48 (2.15) (Table 6 ).

Regarding if the participant’s age, sex, or education level had a significant effect on the level of knowledge, practice, and attitudes toward oral cancer prevention, an independent t-test and ANOVA showed that sex was significantly associated with oral cancer practice in the College of Dentistry at AAUP ( P  < 0.05). Male responders (4.94 ± 2.86) had better practice scores compared to females (4.16 ± 2.65). Education level was also significantly related to knowledge, practice, and attitudes toward oral cancer prevention in the College of Dentistry at AAUP ( P  < 0.05). Interns had significantly better knowledge (13.68 ± 2.43) and attitude scores (8.68 ± 1.68) toward oral cancer prevention compared to undergraduate dental students; however, fourth-year dental students had significantly better practice scores (4.93 ± 2.90) when compared to fifth-year students and interns (Table 7 ).

Regarding the perceived barriers to oral cancer screening among undergraduate dental students and interns at AAUP, more than half of the respondents (57.2%) believed that insufficient training was a barrier. Other claimed barriers included lack of time (19.3%), lack of confidence (12.9%), and lack of effectiveness (10.6%; Table 8 ).

This cross-sectional study sought to assess the knowledge, practices, and attitudes toward oral cancer prevention and early detection among students and interns in the College of Dentistry at AAUP; and to investigate the factors that influence their practices of oral cancer screening or prevention.

There was an 68.8% response rate, which is higher compared to other analogous studies from Saudi Arabia (56.4%, 54.2%) [ 27 , 32 ].

The current study revealed that the level of oral cancer knowledge among most of the surveyed participants is regarded as poor. This result is comparable to the results of previous studies conducted in Saudi Arabia [ 31 , 32 ], Kuwait [ 30 ] and United Arab Emirates [ 34 ], but it is in contrast to those of other studies in Saudi Arabia [ 18 , 28 ] and India [ 25 ] that revealed good to excellent knowledge of oral cancer and its associated risk factors among dental students and interns.

Regarding the level of the practice of oral cancer prevention and early detection, the present survey demonstrated a poor level of practice among the surveyed participants. This is in accordance with the results of a recent cross-sectional study in Saudi Arabia [ 32 ]; however, it is in contrary to the results of studies in India [ 25 ] and Brazil [ 24 ] that demonstrated good practices of oral cancer prevention and screening among undergraduate dental students. Might be the poor level of oral cancer knowledge in the current study justifies the poor level of practice among the responding participants.

In addition, the present study demonstrated that the attitude toward oral cancer prevention among the participants was favorable. This agrees with the results of other studies in Saudi Arabia [ 31 ], India [ 25 ] and Brazil [ 24 ], but contrasts with those of a recent cross-sectional study conducted in Saudi Arabia [ 32 ].

The current study concluded that the level of education positively affected the knowledge and attitude scores; since the interns in the College of Dentistry at AAUP had significantly better knowledge and attitude scores toward oral cancer prevention compared to the undergraduate dental students. This finding is in accordance with that demonstrated by Shubayr et al. [ 32 ], but it is in contrast to the results of a study in Turkey [ 19 ] that demonstrated no significant association between the year of study in the dental college and the level of knowledge of oral cancer risk factors.

Regarding the practice of oral cancer prevention and early detection, why fourth-year dental students had significantly better practice scores compared to fifth-year students and interns might be explained by their application of freshly educated topics since they start to take these topics at fourth-year level.

Concerning the perceived barriers to oral cancer prevention and screening among the undergraduate dental students and interns at AAUP, lack of training was the most prevalent, followed by lack of time, lack of confidence, and lack of effectiveness. These findings are in accordance with the results of a study [ 26 ] undertaken in Australia that reported that lack of training, confidence, time, and financial incentives were seen as barriers to performing oral mucosal screening to at least some degree by the responding participants. The lack of training could be managed by enhancing the dental undergraduate curricula and by making continuous educational programs and training on oral cancer prevention and early detection. In the United States, the CODA (Commission on Dental Accreditation) specifies that all USA dental students should be experienced in screening for head and neck cancer and in identification of its risk factors [ 35 ]. It is worth noting that the studies published before the recent modifications of the CODA academic standard had revealed that American dental students and dentists considered themselves undertrained in oral cancer screening and detection [ 20 , 21 ].

Undergraduate dental students in AAUP are sensitized to the subject of oral cancer starting from the third year of curriculum. During this year, the students in oral pathology course are exposed to risk factors and carcinogenesis of oral cancer and potentially malignant oral disorders. This course is given in the form of lectures, structured interactive sessions, and evaluation of histopathological slides. By the fourth and fifth years, the students in oral medicine courses get the theoretical basics of diagnosis and treatment of malignant and potentially malignant oral lesions in the form of lectures, structured interactive sessions, and seminars. These sessions are guided by oral medicine and oral surgery specialists. Clinically, the students in the fifth year have an oral medicine clinic where potentially malignant oral lesions and oral cancer cases are referred to and the students practice examining, diagnosing, and treating like these cases.

It appears that the present study is the first in Palestine to assess the knowledge, practice, and attitudes toward oral cancer prevention and early detection among future and current dentists.

This study gains its importance from being a cross-sectional, low-cost, and prompt method that provides useful information on the adequacy of the dental curriculum of oral cancer prevention in this dental school, and also gives insight into the need for continuous education programs to train students and practitioners in oral cancer prevention theoretically and practically.

However, caution should be taken when interpreting the results of the current study due to some methodological limitations. The study was a questionnaire-based survey and all data were self-reported and subjective; therefore, the responses may not appropriately reproduce the real levels of knowledge and attitudes. In addition, this study included only dental students and interns in the College of Dentistry at AAUP; this may limit the generalizability of the findings to all students and dentists practicing in Palestine. Finally, the relatively low response rate (68.8%) that could introduce a nonresponse bias should be taken into consideration. However, this study shed the light on the necessity of enhancing the educational undergraduate curricula and on conducting continuous training activities for dental students and dentists about oral cancer prevention and early detection both theoretically and practically. Numerous oral cancer screening cases should be part of dental students’ clinical requirements. Dental schools should be the leader in heading like these training programs for oral health providers; therefore, oral cancer cases will be early detected leading to an increase in oral cancer survival rates and a decrease of morbidity rates [ 36 , 37 ].

According to the findings of this survey, it was concluded that dental students and interns at Arab American University in Palestine appeared to have a good attitude and a good motivation toward oral cancer prevention and early detection. However, they lacked the adequate knowledge and training. Interns had higher knowledge and attitude scores toward oral cancer prevention compared to the undergraduate dental students. More efforts and further research are needed to fill the gap in oral cancer knowledge and training by enhancing the undergraduate curricula and by organizing periodic, continuous training activities for dental students and dentists with regard to oral cancer prevention and early detection at the AAUP College of Dentistry.

Availability of data and materials

The data that support the findings of this study are submitted with the manuscript.

Abbreviations

Arab American University

Middle East and North Africa

One way analysis of variance

Commission on dental accreditation

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Acknowledgements

The authors would like to take this opportunity to thank Dr. Nada H. M. Ahmed who shared her questionnaire that helped in making the current questionnaire and are grateful to Dr. Lubna Sabbah for helping in questionnaire’s distribution. The authors also thank all participants who took part in this survey.

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Department of Prosthodontics, College of Dentistry, Arab American University, P.O. Box: 240, Jenin, Palestinian Territory, Palestinian Territory

Rola Muhammed Shadid

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Department of Oral and Maxillofacial surgery, College of Dentistry, Arab American University, Jenin, Palestinian Territory

Mohammad Amid Abu Ali

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R.S. conceived, designed, implemented the study, completed the data collection, wrote the manuscript, and approved the final version. M.A. implemented the study and approved the final version. O.K. designed the study, reviewed, edited, and approved the final version. All authors read and approved the final manuscript.

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The study was approved by the Institutional Review Board (IRB), College of Dentistry, Arab American University (2022/A/3/N), and was conducted in agreement with the Declaration of Helsinki guidelines. Informed consent was obtained from all probable participants for contribution in the present study.

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Shadid, R.M., Abu Ali, M.A. & Kujan, O. Knowledge, attitudes, and practices of oral cancer prevention among dental students and interns: an online cross‑sectional questionnaire in Palestine. BMC Oral Health 22 , 381 (2022). https://doi.org/10.1186/s12903-022-02415-8

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oral cancer

Oral cancer in young adults: report of three cases and review of the literature

• R J Oliver 1 ,
• J Dearing 2 &
• I Hindle 3  

British Dental Journal volume  188 ,  pages 362–366 ( 2000 ) Cite this article

30 Citations

Metrics details

Oral cancer chiefly affects older adults.

In younger adults, oral cancer is often not considered because of its relative infrequency which may lead to late referral for treatment.

Young adult patients who develop oral cancer often are not exposed to the traditional risk factors of tobacco and alcohol.

Oral cancer in young adults is fortunately uncommon in the UK. However, since it is so rare, when cases present they are often misdiagnosed and inappropriately treated leading to delay in definitive treatment. This may, in turn, lead to a poorer prognosis for these patients. It is debatable if oral cancer in younger adults carries an inherently poor prognosis and presents with more aggressive tumours. Three cases of oral cancer in young adults, aged under 30 years are presented and the literature reviewed with respect to oral cancer in this group of patients.

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Slow to heal or slow to diagnose cancer?

Oral squamous cell carcinomas: state of the field and emerging directions

Malignant transformation of oral epithelial dysplasia in Southwest Finland

Oral cancer (ICD 141, 143-146) continues to be a serious problem in the UK with a steadily rising incidence in certain birth cohorts. 1 Despite this, oral cancer remains primarily a disease of older patients. Cases occurring in younger adults are uncommon, in the region of 1% of oral cancers in England and Wales; 2 arbitrarily a younger age group is referred to as less than 30 or 40 years. However, in the majority of reports as in the present, a group of otherwise apparently healthy young adult patients often without any of the usual risk factors for the development of oral cancer are identified. However, even when young patients have indulged in the risk factors of tobacco and alcohol, it is for considerably shorter periods compared with the older age group. Patients in this younger age group are claimed by some to have a more aggressive disease with a higher incidence of local recurrence or regional lymph node involvement after treatment and a higher mortality rate compared with older patients 3 , 4 while others do not support this notion. 5 , 6 , 7 , 8

We are reporting a series of cases of oral cancer occurring in three apparently healthy Caucasian adult patients aged 20, 24 and 26 years old who presented to one consultant in a 12-month period.

Case reports

A 26-year-old married male presented for routine examination with his general dental practitioner, complaining of a sore area on the left side of his tongue, present for about 1 week. There was no relevant medical history, and the patient was a non-smoker who drank around 10 units of beer per week. The practitioner diagnosed a traumatic ulcer, prescribed triamcinolone in carmellose and a chlorhexidine mouthwash. Reviewing the patient 1 week later, the ulceration was found to have healed, leaving an area of leukoplakia tender to palpation. At review 1 month later the white patch had become nodular and the patient was referred. At presentation 3 days later the symptoms of pain from the left side of the tongue continued, exacerbated by spicy foods but not relieved by empirical treatments received from the practitioner. Intraorally, a 25 mm diameter white, verrucous area extended from the left lateral margin of the tongue into the sublingual area which was tender to palpation. The tissue proximal to the lesion was erythematous and atrophic in appearance.

The lesion was biopsied and histopathological examination revealed a well differentiated squamous cell carcinoma. The patient underwent total excision of the lesion with reconstruction using a split skin graft. At 5-year follow-up the patient remained free from disease.

A 24-year-old married female was referred urgently having presented to her general medical practitioner complaining of a lump under her tongue of about 3 weeks duration. On presentation, she admitted to a lump on the right side of her tongue which had previously been asymptomatic but had begun to cause occasional discomfort as it increased in size. The lump was interfering with the patients ability to eat. Previous medical history revealed that the patient had undergone cervical diathermy to remove severely dysplastic cells, which had been diagnosed as CIN III (cervical intra-epithelial neoplasia grade III). Otherwise her medical history was clear, and the patient was teetotal but smoked up to 20 cigarettes per day. Extraoral examination revealed the presence of right hand side jugulodigastric lymphadenopathy. Intraorally there was evidence of swelling on the right lower lateral border of the tongue extending into the floor of the mouth, which was tender and indurated ( Figure 1 ). There was no fixation of the mass to the mandible. An incisional biopsy was performed and histopathologically demonstrated well differentiated squamous cell carcinoma.

Lesion on the right lateral border of the tongue of Case 2 (24-year-old female)

Bone scans and chest computed tomogram (CT) were clear. CT revealed two abnormal nodes in the right jugulodigastric region and one on the left which were needle biopsied; the left hand side node was negative but the right nodes showed metastatic squamous cell carcinoma. Following surgery and radiotherapy the patient was still alive and well with no evidence of recurrent disease more than 5 years after presentation. She subsequently gave birth to her first child.

A 20-year-old female, was referred by her general dental practitioner regarding a 20 mm by 3 mm asymptomatic ulcerative lesion on the right lateral border of the tongue. This had been present for 3 weeks and had gradually reduced in size. The patient was unaware of the lesion, which had never caused any symptoms. There was no relevant medical history. The patient consumed minimal alcohol and smoked up to 30 cigarettes per day. Her paternal uncle had died from laryngeal carcinoma. Intraorally an erosive lesion of the right lateral margin of the tongue with surrounding areas of hyperkeratinisation was noted. Incisional biopsy of the lesion was performed providing a histopathological diagnosis of erosive lichen planus with no evidence of neoplasia.

The patient was reviewed at monthly intervals. Six months post-biopsy she attended her general dental practitioner complaining of a lump on her tongue, was reassured and dismissed. A further 2 months later the patient attended her local accident and emergency department for treatment of a sudden haemorrhage from the right side of her tongue. The haemorrhage was arrested and the patient discharged with no advice to seek further assistance. Two days later she presented suffering from marked dysarthria and dysphagia. Extraoral examination revealed a tender, hard, enlarged right jugulodigastric lymph node. Intraoral examination demonstrated a large, tender, indurated ulcer on the right lateral border of the tongue ( Figure 2 ). The patient was admitted and incisional biopsy of the lesion was performed which histopathologically was squamous cell carcinoma. Magnetic resonance imaging (MRI) showed that the lesion extended mesially to the midline of the tongue, inferiorly to the muscles of the floor of the mouth and posteriorly to the fauces without tonsillar involvement. Isotope bone scan and chest CT were clear, but MRI demonstrated abnormalities in the right jugulodigastric lymph nodes.

Ulcerated lesion on the right lateral border of the tongue of Case 3 (20-year-old female) illustrating that the lesion was haemorrhaging prior to taking the biopsy

Despite radical surgery and radiotherapy the patient died 5.5 months after presentation.

Oral cancer in young adults is uncommon and therefore case reports claiming its aggressiveness can be regarded as little more than anecdotal because of insufficient numbers to prove this hypothesis scientifically. The incidence of oral cancer is increasing in some cohorts of patients towards the younger end of the group of patients who develop oral cancer (those more than 40 years); 1 the numbers of cases in young adults less than 40 years of age are so few it is not possible at the present time to say if the incidence in this age group is actually increasing. Clinical experience tells us that young adults presenting with and treated for this disease often have extensive primary tumours and develop recurrences locally or in regional lymph nodes, often succumbing to their disease rapidly. However, this is not always the case, as illustrated in the present series. Summarised data of previous studies of oral cancer in young adults is presented in Table 1 .

Sarkaria and Harari reviewed a total of 152 cases of oral cancer in patients less than 40 years of age reported in the literature. 3 These authors concluded from this significant number that 57% experienced failure above the clavicles and that 47% of patients died from their cancer.However, recent statistics reveal that the 5-year survival for oral cancer in general is in the region of 39%. 9

In contrast to the above review of 14 papers, 3 Rennie and McGregor reported a series of 13 cases of oral cancer in patients less than 40 years of age and concluded that younger patients had a prognosis similar to older patients. 8 However, the age range of this group was between 33 and 39 years, with 11 out of 13 cases being smokers, 11 out of 13 being drinkers including 2 alcoholics; only one of their cases neither consumed alcohol nor smoked and this patient was alive and well after 4 years. In a similar vein, Lipkin et al . presented a series of head and neck cancers which included 15 cases in the oral cavity. 10 These authors concluded that oral cancer in young adults could be associated with heavy smoking and alcohol consumption with an average consumption of 63 pack/years of tobacco. However, their cohort of patients was largely in the 35 to 40 year age group which some would not classify as truly 'young' adults.

Lund and Howard reviewed head and neck tumours in the under 35 year olds during a 22-year period which included 14 tumours of the tongue, 6 of the palate and 3 in the floor of the mouth. 4 Detailed data were only available for the tongue tumours, all of which were squamous cell carcinomas. These authors noted a delayed presentation of these patients who had often been falsely reassured by other practitioners prior to referral. This fact may have accounted for their reported 75% mortality rate in this group. Their report, however, concluded that there was no increase in the rate of presentation in the younger patients. Indeed, in Case 3 of the present series, the patient was dismissed on two occasions when it was likely the carcinoma was present.

In a review of squamous cell carcinomas of the upper aerodigestive tract, Burzynski et al . included nine cases of the oral cavity with only two patients who died of disease, 6 one patient was lost to follow-up and one died of other causes. These cases were all treated with surgery in the first instance. They reported that 91% of the whole group (23 patients) were current or previous tobacco users, however, data was not presented for the individual patients with oral cancer. Two of the patients in the present report were smokers, interestingly, both female. Smoking is strongly associated with the development of oral cancer in older patients 11 but is not generally considered to be a significant aetiological agent in patients of the younger age group despite many of the reported cases showing this habit in these patients.

Assuming smoking and alcohol not to be significant in the aetiology of oral cancer in the young, the genetic events underlying the disease are difficult to account for. The tumour suppressor gene, p53, has been extensively studied and is the most consistently altered gene in oral cancer to date where it is particularly associated with heavy smoking. 12 In oral cancer of the young, p53 mutations have been reported as being absent in non-smoking and non-drinking patients. 13 Many young patients with oral cancer have a history of smoking, as two of the cases in the present report, so for these p53 may play a role but in the remainder of patients there is likely to be some other, as yet undetermined, genetic change. An increased susceptibility to carcinogenic agents has been reported in younger adult patients who have developed oral cancer, the details of which are outside the scope of this article and have been reviewed in a recent paper. 14

A family history of oral cancer has been reported 15 and positive family history of other cancers has been reported for young patients with oral cancer but this was not considered to be significant. 16 Mork et al . recently reported a significantly increased odds ratios for developing head and neck squamous cell carcinoma in female patients, aged less than 45 years, who had first degree relatives with cancer. 14

The role of viruses, particularly human papilloma virus (HPV), in oral cancer development is a much researched and debated area of study. Miller and White concluded in a review of the literature that HPV was a relatively ubiquitous virus and that its demonstration in a significant number of normal oral mucosae as well as in oral cancer was an effect rather than a cause. 17 The link between HPV and cervical cancer, however, is stronger 18 and it could be speculated there was a link in Case 2 between the development of CIN and oral cancer caused by HPV.

Some studies 3 , 4 have claimed oral cancer in younger patients is more aggressive than in older patients and on the basis of this advocate more aggressive therapy. 3 However, others have not reported any significant difference between the two groups. 5 , 6 , 7 , 8 Von Doersten et al . using multivariate analysis investigated recurrence in head and neck cancer patients comprising nearly half of the oral cavity. 19 They concluded that there was no significant difference between recurrence in the younger age group (15 to 39 years old) compared with the older age group and that more aggressive treatment was not necessary. In patients less than 40 years of age with squamous cell carcinoma of the head and neck, including 21% of tumours in the mouth, Clarke and Stell reported crude survival 10% better in younger patients than older adults. 7

Interestingly, one of the patients of the present series (Case 3) had histologically proven lichen planus which clinically presented in an erosive form. There is considerable controversy within the literature over the cancerous potential of lichen planus. Barnard et al . presented a series of cases of patients who developed squamous cell carcinoma in existing lichen planus and reviewed previously reported cases. 20 These authors concluded that there was up to a 5% increase in the risk of developing carcinoma in lichen planus. Most reports of malignant change are in those lesions which are atrophic or erosive which could also be expected to be more susceptible to carcinogens. However, lesions of lichen planus occurring in the high risk sites of the lateral border of the tongue and floor of the mouth should still be regarded with some suspicion. Zhang et al . 21 recently concluded that if malignant transformation occurred in lichen planus the genetic changes that took place were different from those of other precancerous lesions such as leukoplakia.

Conclusions

Oral cancer occurring in young adults is not common but nevertheless should always be considered in such patients when they present with persistent ulceration, leukoplakia, erythroplakia or swellings with no obvious local cause, particularly in the high-risk sites of the tongue and floor of the mouth. For any such lesion, a 'fast-track' referral is recommended by telephone to the nearest specialist centre accompanied by a letter, usually sent with the patient. This will ensure prompt investigation and initiation of treatment which may increase the chances of successful treatment.

It remains unproven if oral cancer in younger patients is inherently more aggressive with a worse prognosis than the disease in older individuals. Personal encounters with such patients may be clouded by the potential emotional aspects of such a deadly disease occurring in younger patients.

With so few cases of oral cancer in younger adults it is still not possible to demonstrate a rising incidence. Improved registration of oral cancer should enable this aspect to be investigated further.

The aetiology of oral cancer in the younger adult remains unclear. It is likely there is some degree of genetic predisposition; genetic linkage studies of affected individuals and their families may prove useful investigating this. In some of the young adult patients, possibly those with an inherent genetic defect, smoking may have a role in the aetiology of oral cancer.

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Lecturer, Oral Surgery Unit, University Dental Hospital of Manchester, Higher Cambridge Street, Manchester, M15 6FH

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Senior Lecturer, Oral Surgery Unit, University Dental Hospital of Manchester, Higher Cambridge Street, Manchester, M15 6FH

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Oliver, R., Dearing, J. & Hindle, I. Oral cancer in young adults: report of three cases and review of the literature. Br Dent J 188 , 362–366 (2000). https://doi.org/10.1038/sj.bdj.4800481

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Received : 15 June 1999

Accepted : 22 November 1999

Published : 08 April 2000

Issue Date : 08 April 2000

DOI : https://doi.org/10.1038/sj.bdj.4800481

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Oral tongue cancer: literature review and current management.

Rodrigo Arrangoiz

Sociedad Quirurgica S.C., American British Cowdray Medical Center, Mexico

E-mail : aa

Fernando Cordera

Eduardo Moreno

Enrique Luque de Leon

Manuel Munoz

DOI: 10.15761/CRR.1000153

In 2018, it is estimated that about 51, 540 new cases of oral cavity and pharyngeal cancer will develop, which represent approximately 3-5% of all cancers in the United States. During the same time period it is estimated that there will be approximately 10, 030 deaths. Incidence rates are more than twice as high in men as in women (Male cases–37,160, Female cases–14,380). From 2006 to 2010 incidence rates remained stable in men and have decreased by 0.9% per year in women. Oral tongue cancer requires a multidisciplinary approach to treat it that includes a surgical oncologist, a medical oncologist, a radiation oncologist, speech therapists and physical rehabilitation as well as emotional support through the help of psychologists or social workers. In this review paper we will discuss current management of these complex tumor.

oral cancer, oral tongue cancer, squamous cell carcinoma, diagnosis and treatment of oral tongue cancer

Introduction

In 2018, it is estimated that about 51, 540 new cases of oral cavity and pharyngeal cancer will develop, which represent approximately 3-5% of all cancers in the United States [1,2]. During the same time period it is estimated that there will be approximately 10, 030 deaths [1,2]. Incidence rates are more than twice as high in men as in women (Male cases–37,160, Female cases–14,380) [1]. From 2006 to 2010 incidence rates remained stable in men and have decreased by 0.9% per year in women [1]. From 2005 to 2014, incidence rates decreased by more than 2% per year among blacks, but increased by about 1% per year among whites, largely driven by rising rates for a subset of cancers associated with human papillomavirus (HPV) infection that arise in the oropharynx.

Death rates have been decreasing over the past three decades; from 2006 to 2010, rates decreased by 1.2% per year in men and by 2.1% per year in women [1]. In 2018, it is estimated that 17,110 new cases of oral tongue cancer will occur, of this 12,490 will occur in men and 4620 will develop in women (one third of the cases will develop in women). The estimated death rate from oral tongue cancer in 2018 is 2,510 deaths (1750 in males and 760 in females) (Table 1) [1]. Most head and neck cancers present with metastatic disease at the time of diagnosis, with regional nodal involvement and distant metastatic disease in 43% and 10% of the cases, respectively [3].

Table 1. Estimated new cases and mortality for the year 2018 in the United States [1]

Head and neck cancer patients often develop second primary tumors, this is because they share common risk factors [4]. These second primary tumors develop at an annual rate of 3-7% and 50-75% of these new cancers are located in upper aero digestive tract or lungs [3].

Surgical anatomy of the oral cavity

• Boundaries of the oral cavity:
• Superior border-from the vermillion border to the junction of the hard and soft palates.
• Inferior border-from the vermillion border to the circumvallate papillae of the oral tongue.
• The lateral border-is the mucosa of the mouth up to the anterior tonsillar pillars.

The oral cavity includes the lips, buccal mucosa, upper and lower alveolar ridges, gingiva, retromolar trigone, floor of mouth, hard palate and the anterior two thirds of the tongue ("oral tongue”). The main lymphatic drainage is to level IA (submental triangle), IB (submandibular triangle) and II (upper deep jugular nodes) [5].

Tongue anatomy

The tongue which is located in the oral cavity and oropharynx is a mass of muscle that is almost completely covered by a thick mucous membrane. The primary function of the tongue is taste sensation, but it also assists with mastication, deglutition, articulation, and oral cleansing [6]. The complex innervation of this multifunctional organ is provided by five cranial nerves [7].

The embryologic origins of the tongue first appear at 4 weeks' gestation [7,8]. The first branchial arch is responsible for the development of the tongue derivatives. It gives rise to two lateral lingual swellings and one median swelling (known as the tuberculum impar) [7,8]. The two lateral lingual swellings grow over the tuberculum impar and merge, forming the anterior two thirds of the tongue [8]. Portions of the second, third, and fourth branchial arches give rise to the base of the tongue [9]. The intrinsic musculature of the tongue derives from occipital somites which give rise to myoblasts [8].

Macroscopically from anterior to posterior, the tongue has three surfaces: tip, body, and the base. The tip of the tongue is the highly mobile, pointed, anterior portion of the tongue. Behind to the tip lies the body of the tongue, which has a dorsal (superior) and a ventral (inferior) surfaces. The median sulcus of the tongue separates the body into left and right halves. The terminal sulcus is a V-shaped furrow that separates the body of the tongue from the base of the tongue. At the tip of this sulcus is the foramen cecum, a remnant of the proximal thyroglossal duct. The base of tongue contains the lingual tonsils, the inferior most portion of Waldeyer’s ring [7-9].

The body of the tongue derives its characteristic surface appearance from the presence of lingual papillae, which are projections of lamina propria covered with epithelium [6]. Four different types of lingual papillae exist: circumvallate (vallate), foliate, filiform, and fungiform [6]. The circumvallate papillae are flat, prominent papillae that are surrounded by troughs. There are approximately eight to 12 circumvallate papillae, located directly anterior to the terminal sulcus. The ducts of the lingual glands of von Ebner secrete lingual lipase into the surrounding troughs to begin the process of lipolysis [10]. On the lateral surface of the tongue foliate papillae are identified, they are small folds of mucosa. The filiform papillae are thin and long and they are the most abundant papillae in the tongue. They are located along the entire dorsum of the tongue, but they are not involved in taste sensation [6]. The mushroom shaped papillae and called the fungiform papillae. They are scattered most densely along the tip and lateral surfaces of the tongue. The human tongue has roughly 200 to 300 fungiform papillae.

Each circumvallate, foliate, and fungiform papilla contains taste buds (250, 1000, and 1600 taste buds, respectively) [6], innervated by multiple nerve fibers. All taste buds can perceive the five different taste qualities: salt, sweet, bitter, acid, and umami. The taste bud consists of a taste receptor, basal cell, and edge cell. When a taste molecule binds to a taste receptor, the receptor cell depolarizes, causing an influx of Ca++, which results in the release of an unidentified neurotransmitter [6]. Following the depolarization, the afferent neural pathway depends on the location of the taste bud that was stimulated. In the anterior two thirds of the tongue, the chorda tympani branch of the facial nerve (cranial nerve VII) is stimulated [6,11]. The lingual-tonsillar branch of the glossopharyngeal nerve (cranial nerve IX) relays taste information from the posterior third of the tongue [6,11].

The tongue has four intrinsic and four extrinsic muscles [7,9,11]. The muscles on each side of the tongue are separated by a fibrous lingual septum. The extrinsic muscles are so named because they originate outside the tongue and insert within it and the intrinsic muscles are within the substance of the organ and do not insert on bone. Though the muscles do not act in isolation, intrinsic muscles generally alter the shape of the tongue, whereas extrinsic muscles alter its position [7]. The extrinsic muscles of the tongue are the genioglossus, hyoglossus, styloglossus, and palatoglossus [7]. The hypoglossal nerve provides the motor innervation to all muscles of the tongue except the palatoglossus, which is supplied by the pharyngeal plexus [7,11].

The arterial supply to the tongue and floor of the mouth is derived from the dorsal lingual, sublingual, and deep lingual branches of the lingual artery [11]. The venous drainage of the tongue is into the lingual veins, which drain into the facial and retromandibular veins, which join to form the common facial vein.

The oral cavity is continuously, been exposed to inhaled and consumed carcinogens, and thus it is the most common site for the origin of malignant epithelial neoplasms in the head and neck region. The most common location for a malignant tumor of the oral cavity is the anterior two thirds of the tongue. Known carcinogens in the oral cavity include those present in tobacco, alcohol, and betel nuts. The relationship of human papilloma virus (HPV) with oral cancer is not as well established as in oropharyngeal cancers. Primary tumors of the oral cavity may arise from the surface epithelium, minor salivary glands, submucosal soft tissue, and tumors of dento-alveolar origin [11]. More than 90% of cancers in the oral cavity are squamous cell in origin and we will be focusing our review on these neoplasms.

Epidemiology

Malignant neoplasm of the tongue are by far more common in men than in women (66-95% of cases), this is similar to the rest of the oral cavity [1]. The incidence by gender varies depending on the anatomic location and has been changing due to the increase in the number of women who smoke. The male to female ratio is currently 3:1 [1]. The incidence of oral cavity and tongue cancer increases with age, especially after age 50. Most patients are between 50 and 70 years but can also occur in younger patients [3].

There are large differences in the incidence of oral cavity cancer among different geographical regions. The highest incidence of this disease is found in Asia and is believed to reflect the prevalence of certain risk factors, such as chewing betel nut [12,13] and the use of smokeless tobacco (snuff) [14]. In the United States, in urban areas the high incidence among men is thought to reflect exposure to snuff and alcohol. Among women in rural areas in the United States the increase risk of oral cavity cancer is associated with the use of smokeless tobacco (snuff) [1].

Etiology and risk factors

One of the most important risk factors for the development of squamous cell carcinoma (SCC) of the tongue is tobacco. Smoking cigarettes, cigars, or pipes; chewing tobacco; and using snuff are the single largest risk factors for all head and neck cancer including the tongue. Eighty-five percent (85%) of head and neck cancers are linked to tobacco use [15,16]. Secondhand smoke may also increase a person’s risk of developing a head and neck cancer [17].

Based on epidemiologic studies, cigar smoking is an important risk factors for oral cavity tumors and the only difference between cigarette smoking and cigar smoking is that it instigates a change in the usual anatomic location for these tumors [1,18]. The use of smokeless tobacco is also associated with an increased incidence of cancer of the oral cavity [1,2]. Chewing snuff is the leading cause of SCC of the oral cavity and oropharynx in India, part of Southeast Asia, China, and Taiwan, especially when consumed with betel containing areca nut [19].

Alcohol by itself is a risk factor for the development of tongue and oral cavity cancer, although it is less potent carcinogen than tobacco [20,21]. People who use tobacco and alcohol, these risk factors appear to be synergistic and result in a multiplicative increase in risk, 30 to 36 times higher for people who smoke and drink heavily [22].

Edentulous patients and poor oral hygiene can be risk factors for cancer of the oral cavity [23,24]. The use of mouthwashes that have high alcohol content could be a risk factor for tongue and oral cavity SCC (unproven) [24,25]. The consumption of the tea beverage, mate (consumed by South Americans), has been associated with an increased risk of cancer of the oral cavity [26] .

Epidemiologic studies suggest that the intake of vitamin A, β-carotene, and α -tocopherol may reduce the risk of developing oral cavity cancers [27-32]. Certain syndromes caused by inherited defects (mutations) in certain genes have a very high risk of developing cancer of the oral cavity and tongue. Fanconi anemia is a disease that can be caused by inherited defects in several genes that contribute to DNA repair. People with this syndrome often have hematologic problems an early age, which can lead to leukemia or aplastic anemia. They also have a risk of developing cancer of the oral cavity, especially tongue cancer [33,34]. Dyskeratosis congenita is a genetic syndrome that can cause aplastic anemia, skin rashes, and nail abnormalities of the hands and feet; they also increase the risk of developing oral cavity cancer [35,36].

Mechanisms of carcinogenesis

The development of tongue and oral cavity SCC is a multistep progression that involves changes related to specific genes, epigenetic events, and signal transduction within the cell [37]. Tobacco smoke contains agents that may act as mutagens. Also, tobacco smoke extract has been shown to activate the epidermal growth factor receptor (EGFR) in vitro and EGFR activation has been shown, in turn, to increase the production of prostaglandins, including PGE2 which may act in a positive feedback fashion by increasing EGFR signal transduction. Cyclin-D1 is frequently overexpressed in head and neck cancer and increased cyclin-D1 activity is a downstream event triggered by EGFR activation [38].

An important epigenetic event in the progression to cancer is the silencing of gene promoter regions through hypermethylation [39], which has been shown to affect the tumor suppressors p16, DAP-kinase, and E-cadherin. Also, the gene for retinoic acid receptor-beta (RAR-beta) is silenced by methylation of its promoter [40].

Genetic alterations that are present early in the course of carcinogenesis are mutations or deletions of chromosome 3p and 9p. Telomerase activation also occurs early in carcinogenesis. Mutations or deletions at chromosome 17p (involving the p53 tumor suppressor gene), and chromosome 13q and chromosome 18q generally are seen later in the process. Patients whose tumors contain HPV mRNA have a significantly lower rate of deletions of chromosomes 3p, 9p, and 17p, suggesting an alternate molecular mechanism in these patients. The viral proteins E6 and E7 have been shown to cause deregulation of the cell cycle by inactivating p53 and retinoblastoma protein, which may be the mechanism of HPV-mediated carcinogenesis [41].

In addition to deletions or mutations of individual genes, evidence exists demonstrating that numeric chromosomal imbalances, known as aneuploidy, may be a cause rather than a consequence of malignant transformation [42]. Aneuploidy may occur as a result of mutations in genes controlling chromosome segregation during mitosis and centrosome abnormalities.

The need for a rapid diagnosis and referral of patients to a skilled physician with expertise in the management of tumors of the head and neck is very important because early diagnosis can lead to a reduction in mortality [3]. The risk factors mention on the etiology section of this paper, including history of tobacco and alcohol use should be interrogated. Any adult patient with symptoms attributable to the upper aero digestive tract lasting more than two weeks or an asymptomatic cervical (neck) tumor should undergo a full examination with a high index of suspicion for malignancy [3].

The physical examination is the best way to detect lesions of the upper aero digestive tract. Often the initial assessment also indicates the severity and chronicity of the disease. Due to the frequent occurrence of synchronous primary tumors in patients with head and neck cancers (approximately 5%), a careful evaluation of the entire upper aero digestive tract is required at the time of diagnosis [43].

Tongue cancers usually cause symptoms related to the upper aero digestive tract, including changes in swallowing, speech, hearing and breathing. During the interrogation the physician must give emphasis to the following symptoms: tongue pain, non-healing ulcer on the tongue, and changes in the ability to form words. A complete physical examination should be performed on every patient with specific emphasis on the head and neck exam (inspection, palpation, otoscopic exam, indirect laryngoscopy, and when indicated nasopharyngolaryngoscopy) and a neurological exam with emphasis on cranial nerves V, through XII. The most common presenting complaint of patients with tongue tumors is a sore or lump. Cancer of the tongue mucosa may present as an indurated ulcer with raised edges (Figure 1) or as an exophytic growth. Bleeding from the surface of the lesion is a characteristic of malignancy and immediately raises suspicion for a neoplastic process. Approximately one third of the patients come in to the office with a neck lump [44].

Figure 1. Ulcerated lesion of the tongue

Biopsy of the tongue lesion can often be performed in the office or as an outpatient surgery depending on the anatomic site and patient preference. One can perform the biopsy in the office setting using a punch biopsy or using biopsy forceps (Figure 2). The biopsy should be obtained from the edge of the lesion, away from areas of obvious necrosis or excess keratinization.

Figure 2. Punch biopsy and forceps to perform the biopsy

Fine needle aspiration (FNA) is a useful diagnostic modality [45-47] for differentiating benign from malignant lymph nodes in the neck. A fine gauge needle (#23 gauge) makes multiple passes over the lesion while continues suction is applied. Suction must be released before removing the needle of the lesion. This procedure has a false negative rate of 7% [47]. Cytology is particularly useful to distinguish metastatic SCC from other malignant histology’s. However, a negative result should not be interpreted as " absence of disease" when the clinical scenario is highly suspicions for malignancy. A core needle biopsy should not be performed in a lump in the neck, with the exception of an already diagnosed lymphoma. Martin Hayes in a communication to the medical profession in general stated “not only to the needlessness but also to the possible harmfulness of excisional lymph node biopsy as the first or even as an early step in the diagnosis of cancer” [48]. Open biopsies should be done only when the diagnosis has not been made after extensive clinical evaluation and after at least two non-diagnostic FNA’s. The surgeon performing the open biopsy should be prepared to perform a definitive surgical treatment at that moment in time, which may involve a formal neck dissection if the diagnosis turns out to be a SCC.

Computed tomography (CT) is probably the most informative test in the evaluation of tumors of the oral cavity and tongue [49]. It can help define the extent of disease and the presence and extent of lymph node involvement. CT provides high spatial resolution, can discriminate between fat, muscle, bone and other soft tissues. CT out performs magnetic resonance imaging (MRI) in detecting bone erosion (Figure 3) [50], has a sensitivity of 100% and specificity of 85% [51]. MRI can provide accurate information on the size, location and extent of the tumor involvement of the soft tissues. It is not very reliable to provide information regarding bone extension, unless, there is full involvement of the medullary cavity. The MRI has a relatively higher sensitivity than CT but has lower specificity [49-52]. PET has been evaluated in primary and recurrent carcinomas of the head and neck. In a multicenter, prospective study of patients newly diagnosed with a tumor of the head and neck region the results were discrepant when PET was compared with CT in 43% of cases, and the therapeutic plan was altered in 14 % of patients [53]. PET should not be routinely used in the diagnosis or evaluation of patients with early tumors of the oral cavity.

Figure 3. CT of the head and neck showing bone erosion

Pathology and histologic grade of tongue and oral cavity tumors

Over 90% of head and neck cancers (including the oral cavity tumors) are SCC. The World Health Organization classifies squamous tumors of the head and neck in different histologic subtypes [54,55]:

-Conventional

- Verrucous

- Papillary

- Spindle Cell (Sarcomatoid)

- Acantholytic

- Adenosquamous

- Cuniculatum

Each of these variants can develop in any of the different regions of the head and neck with the exception of the Cuniculatum subtype, that only develops in the lining of the oral cavity [56]. Variants of SCC frequently arise within the mucosa of the upper aero digestive tract, accounting for up to 15% of SCCs in these areas. The most common variants include verrucous, exophytic or papillary, spindle-cell (sarcomatoid), basaloid and adenosquamous carcinoma. Each of these variants has a unique histomorphologic appearance, which raises a number of different differential diagnostic considerations, with the attendant clinically relevant management decisions. Stage for stage each one of these different subtypes of SCC has the same prognosis and are management identically.

Broder’s grading system was the first of the systems, which initiated quantitative grading of cancer. This classification system was based on the estimated ratio of differentiated to undifferentiated elements in the tumor. There are four histologic grades based on the amount of keratinization [56,57]:

• Well-differentiated tumor-> 75% keratinization.
• Moderately differentiated tumor-50-75% keratinization.
• Poorly differentiated tumor-25-50% keratinization.
• Anaplastic or undifferentiated tumor-< 25% keratinization.

Histologic grade is not a consistent predictor of clinical behavior. The characteristics that predict aggressive behavior include perineural infiltration, lymphatic invasion, and tumor extension beyond the capsule of the lymph nodes [56,58].

Immunohistochemical studies may be useful in poorly differentiated lesions to help make the diagnosis because SCC’s express epithelial markers such as cytokeratin’s. Squamous cells are immune-positive for certain cytokeratin’s such as AE1/AE3 and pancytokeratin’s. CK5/CK6 and p63 are also excellent markers for squamous differentiation [59].

Concept of field cancerization (field defect)

It is an important concept related to the natural history of oral cavity cancer. The term describes diffuse injury of the epithelium of the head and neck region, lung and esophagus resulting from chronic exposure to carcinogens [60]. Clinically field cancerization manifests by the frequent occurrence of abnormalities of the mucosa, such as leukoplakia and dysplasia, beyond the margins of an oral cavity cancer or second primary tumors in this field. The lifetime risk of a patient with oral cavity cancer to develop a new cancer is 20-40% [61].

TNM classification of tumors of the head and neck

The TNM staging system of the AJCC maintains uniformity in the staging of head and neck tumors and is based on the best estimate of the extent of disease prior to treatment (Tables 2-5). Assessment of the primary tumor is based on inspection and palpation when possible, by indirect mirror examination and direct endoscopy when necessary [62].

Table 2. TNM classification of oral cavity cancer - primary tumor (T) [62]

Table 3. TNM classification of oral cavity cancer - lymph nodes (N) [62]

Table 4. TNM classification of oral cavity cancer - distance metastasis (M) [62]

Table 5. Anatomical staging and prognostic groups [62]

The prognosis is strongly correlated with the stage of the disease at diagnosis. Survival of patients with stage I disease exceeds 80% [2]. For patients with locally advanced disease at the time of diagnosis (i.e., stage III and IV), survival drops below 40% [63]. The development of metastases in lymph nodes reduces the survival of a patient with a small primary tumor by 50% [2,3]. Most patients with head and neck cancers at the time of diagnosis are found to be stage III or IV [62,64].

Patterns of relapse

Despite aggressive treatment of the primary most relapses occur within the same region of the primary oral cavity tumor. Local and regional recurrences represent approximately 80% of primary treatment failures [65]. Distant metastases increase as the disease progresses and more frequently include the lungs, and to a lesser extent, bone and liver. This is a reason to use PET/CT for assessing the distant spread of the cancer in patients with disease recurrence of progression . In 10-30% of patients distant metastases are detected at the time of death [63].

Treatment options

Management of tongue cancers requires a multidisciplinary team made up of a surgical oncologist specialized in head and neck cancers, dentist, prosthodontist, plastic reconstructive surgeons, medical oncologist, radiation oncologist, speech therapist, fiscal rehabilitation therapist, social worker, and psychologist.

The treatment depends on the site, the extent of the primary tumor, and lymph node status, and may include [49,63,66]:

• Surgery alone.
• Radiation therapy alone.
• A combination of the above.

The best therapeutic approach for the primary tumor depends on the anatomic site. Most early cancers of the tongue can be treated equally well with surgery or radiation therapy, therefore the method chosen to treat the neck is based on the mode that has been selected for the primary tumor. When the primary tumor is treated with radiation, regional lymph nodes "at risk" are incorporated into the field of treatment [3]. Patient factors and experience should influence the choice of treatment. Due to the lower morbidity of primary surgical resection of oral tongue tumors compared to primary radiation therapy most international guidelines recommend surgery as the primary modality [67]. Larger cancers may require composite resections with reconstruction of the defect by pedicle flaps and often require adjuvant therapy with radiation and chemotherapy [68,69].

The classical surgical principles of oncology are applied to tongue cancers. Complete en bloc resection is necessary. Ensuring adequate margins can be challenging due to the important structures in this area [70]. The reconstruction after surgery is complex after resection of tumors of the tongue because the surgical procedure may have an important impact on speech and swallowing. Experienced surgeons should perform the decisions regarding the extent of resection. Prosthodontic rehabilitation is important, especially in the early stages of cancer, to ensure better quality of life.

For lesions of the oral tongue, surgery should revmove all macroscopic evidence of the disease keeping in mind the possibility of microscopic extension. If regional nodes are positive, cervical lymph node dissection is usually done in the same procedure. Neck dissection must be standardized (i.e. complete anatomical dissections, instead of random biopsies) in these situations to prevent incomplete surgery. Elective neck dissection is recommended for patients who have a oral cavity tumors with a minimum thickness of 4 mm [3], although some researchers believe that tumor thickness of 2-3 mm would be a more appropriate cut off [71,72] (Table 6).

Table 6. Thickness of oral cancer predicts survival and failure [72]

Supraomohyoid neck dissection is recommended in patients with a clinical stage N0 who are treated surgically. There is evidence of skip metastases through the levels of the neck [73] and in some cases just involving level IV without involving the first levels. Therefore some authors recommend extended supraomohyoid neck dissection [73]. Bilateral neck dissection is performed if the tumor is close to or abutting the midline.

Sentinel lymph node (SLN) biopsy is another new option to standard elective neck dissection for identifying an occult cervical metastasis in patients with an early (T1 or T2) oral tongue cancer in centers where expertise for this procedure exists [74,75]. Patients who are found to have metastatic disease in their SLN’s must undergo a completion neck dissection while those without a positive SLN can be observed with close follow up. The precision of the SLN biopsy for staging of the neck in early oral cavity cancer has been tested at length in multiple single-center trials and in two mutli-institutional studies against the reference standard of elective neck dissection with a pooled estimated sensitivity of 0.93 and negative predictive value ranging from 0.88 to 1 [74-79]. This is a technically demanding procedure that has a steep learning curve in which the success rate is dependent on the experience and expertise of the surgeon. Up to know a direct comparison with the policy of elective neck dissection is lacking [77], so we recommend using this procedure very selectively. For example, very early carcinomas of the oral cavity (T1 or may be T2), excluding floor of the mouth tumors because the accuracy in the studies we have up to date is inferior to other anatomical sites within the oral cavity such as the tongue [74,76], that have a tumor thickness less than 4 mm.

Radiation therapy for cancer of the oral cavity may be administered as external beam radiotherapy (EBRT) or interstitial implantation alone. It is difficult getting enough dose to primary with brachytherapy while still delivering adequate dose to the regional nodes, so for many sites using both modalities produces better control and better functional outcomes [80]. Small superficial cancers can be treated very successfully by local implantation using any of the various radioactive sources (intraoral cone therapy, or electrons) [81]. Larger lesions are frequently managed using external beam radiotherapy, which includes the primary site and regional lymph nodes (even if not clinically affected) [63]. Supplementation with interstitial radiation sources may be required to achieve adequate doses for bulky large primary tumors and / or lymph node metastases. A review of published clinical results of radical radiation therapy for head and neck tumors suggests a significant loss of local control when the administration of radiation therapy was prolonged, therefore, lengthening of standard treatment programs should be avoided whenever possible [82,83].

Radiation therapy with curative intent usually involves daily treatment for 6 to 7 weeks (total dose: 60-70 Gy) [67]. Although there is no loss of tissue with radiation therapy as with surgery, potential complications include dry mouth, tissue fibrosis, trismus, bone necrosis, hypothyroidism, and dysphagia [84-86]. Some of these problems are common and debilitating enough to require significant attention during treatment planning. Surgery often results in less morbidity in the oral cavity, while radiation therapy causes less morbidity in other regions such as the oropharynx, larynx and nasopharynx.

The definitive indications for postoperative radiotherapy are positive margins, multiple positive nodes with metastatic disease, and extra capsular nodal extension [66,87]. Less certain indications include lymphovascular space invasion, perineural spread, single encapsulated positive lymph node, and thick tumors [87]. Tumors with a thickness between 3 to 9 mm have 44% subclinical node positivity and a 7% local recurrence rate and tumors with a thickness greater than 9 mm thickness have 53% subclinical node positivity and a 24% local recurrence rate [87].

Postoperative radiotherapy (60 to 70 Gy in 6-7 weeks) reduces the rate of local and regional recurrence from 50-15% for tumors with pathologic features that predict a high local and regional failure rates [81,88,89]. The indications for postoperative radiotherapy are well established and are outlined in Table 7.

Table 7. Possible Indications for postoperative radiotherapy

Two randomized clinical trials were conducted to determine whether adding chemotherapy to radiation therapy improves local /regional control and survival in high-risk patients with head and neck cancers after definitive surgical resection. The results of these trials were published in 2004 [88,90] (Table 8).

Table 8. Results from the EORTC 22931 and RTOG 9501 Studies

In a comparative analysis of the two trials, the presence of extracapsular extension and / or microscopically involved surgical margins were the only risk factors for the positive impact that chemo radiation had over improved survival [91]. The adjuvant treatment for patients with oral tongue cancers is summarized in Table 9.

Table 9. Summary of adjuvant treatment of oral cavity cancers

Recently the results of the RTOG-0234 examining concurrent chemoradiotherapy and cetuximab in the postoperative treatment of patients with head and neck squamous cell carcinoma (HNSCC) with high-risk pathologic features was published [92]. The study recruited 238 patients were with stage III to IV HNSCC with gross total resection showing positive margins and/or extracapsular nodal extension and/or two or more nodal metastases. Patients were randomly assigned to 60 Gy radiation with cetuximab once per week plus either cisplatin 30 mg/m2 or docetaxel 15 mg/m2 once per week. With a median follow-up of 4.4 years, 2-year overall survival (OS) was 69% for the cisplatin arm and 79% for the docetaxel arm; 2-year disease-free survival (DFS) was 57% and 66%, respectively. DFS in this study was compared with that in the chemoradiotherapy arm of the RTOG-9501 trial, which had a hazard ratio of 0.76 for the cisplatin arm versus control (P=0.05) and 0.69 for the docetaxel arm versus control (P=0.01), reflecting absolute improvement in 2-year DFS of 2.5% and 11.1%, respectively. The delivery of postoperative chemoradiotherapy and cetuximab to patients with HNSCC is possible and tolerated with predictable toxicity. The docetaxel regimen shows favorable outcome with improved DFS and OS relative to historical controls and has commenced formal testing in a phase II/III trial (RTOG 1216).

The recommendations for follow-up are based on the risk of relapse, second primaries, treatment sequelae, and toxicities includes a history and physical (including a complete head and neck exam; mirror and fiberoptic examinations as clinically indicated every 1 to 3 months for the first year, every 2-6 months for the second year, every 4 to 8 months years 3 to 5, and every 12 months after 5 years. To facilitate this our group sees the patient every three months for the first five years. Post-treatment baseline imaging of the primary (and neck, if treated) is recommended within 6 months of treatment, further imaging is indicated based on signs and symptoms (but is not routinely recommended without worrisome manifestations). Chest imaging as clinically indicated for patients with a smoking history. If the neck was radiated, the NCCN guidelines recommend thyroid stimulating hormone (TSH) testing every 6 to 12 months. Smoking and alcohol counseling as clinically indicated [67].

Cancer of the oral tongue requires a multidisciplinary team approach to their management that includes a surgical oncologist, medical oncologist, radiation oncologist, dentist, oral maxillary surgeon, prosthodontist, rehabilitation therapists, rehabilitation speech therapist, as well as of emotional support by psychologists or social workers. Early referral to a center that has the expertise in the management of these complex tumors has been shown to improve outcomes and is highly encouraged.

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Editorial Information

Editor-in-chief.

Dung-Fang Lee University of Texas

Article Type

Review Article

Publication history

Received date: April 22, 2018 Accepted date: May 10, 2018 Published date: May 14, 2018

© 2018 Arrangoiz R. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Arrangoiz R, Cordera F, Caba D, Moreno E, de Leon EL, et al. (2018) Oral tongue cancer: Literature review and current management. Cancer Rep Rev 2: doi: 10.15761/CRR.1000153

Corresponding author

Rodrigo arrangoiz ms, md, facs.

Sociedad Quirurgica S.C. at the American Britihs Cowdray Medical Center, Av. Carlos Graef Fernandez # 154-515, Colonia Tlaxala, Delegacion, Cuajimalpa, Mexico, Tel: 1664 7200

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• Published: 27 May 2024

Patients’ satisfaction with cancer pain treatment at adult oncologic centers in Northern Ethiopia; a multi-center cross-sectional study

• Molla Amsalu 1 ,
• Henos Enyew Ashagrie 2 ,
• Amare Belete Getahun 2 &
• Yophtahe Woldegerima Berhe   ORCID: orcid.org/0000-0002-0988-7723 2  

BMC Cancer volume  24 , Article number:  647 ( 2024 ) Cite this article

Metrics details

Patient satisfaction is an important indicator of the quality of healthcare. Pain is one of the most common symptoms among cancer patients that needs optimal treatment; rather, it compromises the quality of life of patients.

To assess the levels and associated factors of satisfaction with cancer pain treatment among adult patients at cancer centers found in Northern Ethiopia in 2023.

After obtaining ethical approval, a multi-center cross-sectional study was conducted at four cancer care centers in northern Ethiopia. The data were collected using an interviewer-administered structured questionnaire that included the Lubeck Medication Satisfaction Questionnaire (LMSQ). The severity of pain was assessed by a numerical rating scale from 0 to 10 with a pain score of 0 = no pain, 1–3 = mild pain, 4–6 = moderate pain, and 7–10 = severe pain Binary logistic regression analysis was employed, and the strength of association was described in an adjusted odds ratio with a 95% confidence interval.

A total of 397 cancer patients participated in this study, with a response rate of 98.3%. We found that 70.3% of patients were satisfied with their cancer pain treatment. Being married (AOR = 5.6, CI = 2.6–12, P  < 0.001) and being single (never married) (AOR = 3.5, CI = 1.3–9.7, P  = 0.017) as compared to divorced, receiving adequate pain management (AOR = 2.4, CI = 1.1–5.3, P  = 0.03) as compared to those who didn’t receive it, and having lower pain severity (AOR = 2.6, CI = 1.5–4.8, P  < 0.001) as compared to those who had higher level of pain severity were found to be associated with satisfaction with cancer pain treatment.

The majority of cancer patients were satisfied with cancer pain treatment. Being married, being single (never married), lower pain severity, and receiving adequate pain management were found to be associated with satisfaction with cancer pain treatment. It would be better to enhance the use of multimodal analgesia in combination with strong opioids to ensure adequate pain management and lower pain severity scores.

Peer Review reports

Introduction

Pain is defined as an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage [ 1 ]. The prevalence of pain in cancer patients is 44.5-66%. with the prevalence of moderate to severe pain ranging from 30 to 38%, and it can persist in 5-10% of cancer survivors [ 2 ]. Using the World Health Organization’s (WHO) cancer pain management guidelines can effectively reduce cancer-related pain in 70-90% of patients [ 3 , 4 ]. Compared to traditional pain states, the mechanism of cancer-related pain is less understood; however, cancer-specific mechanisms, inflammatory, and neuropathic processes have been identified [ 5 ]. Uncontrolled pain can negatively affect patients’ daily lives, emotional health, social relationships, and adherence to cancer treatment [ 6 ]. Patients with moderate to severe pain have a higher fatigue score, a loss of appetite, and financial difficulties [ 7 ]. Patients fear the pain caused by cancer more than dying from the disease since pain affects their physical and mental aspects of life [ 8 ]. A meta-analysis of 30 studies stated that pain was found to be a significant prognostic factor for short-term survival in cancer patients [ 9 ]. Many cancer patients have a very poor prognosis. However, adequate pain treatment prevents suffering and improves their quality of life. Although the WHO suggested non-opioids for mild pain, weak opioids for moderate pain, and strong opioids for severe pain, pain treatment is not yet adequate in one-third of cancer patients [ 10 ].

Patient satisfaction with pain management is a valuable measure of treatment effectiveness and outcome. It could be used to evaluate the quality of care [ 11 , 12 , 13 ]. Patient satisfaction affects treatment compliance and adherence [ 12 ]. Studies have reported that 60-76% of patients were satisfied with pain treatment, and a variety of factors were found associated with levels of satisfaction [ 3 , 14 , 15 , 16 ]. Studies conducted in Ethiopia reported the prevalence of pain ranging from 59.9 to 93.4% [ 17 , 18 ]. These studies indicate that cancer pain is inadequately treated. Assessment of pain treatment satisfaction can help identify appropriate treatment modalities and further its effectiveness. We conducted this study since there was limited research-based evidence on cancer pain management in low-income countries like Ethiopia. Our research questions were: how satisfied are adult cancer patients with pain treatment, and what are the factors associated with the satisfaction of adult cancer patients with pain treatment?

Methodology

Study design, area, period, and population.

A multi-center cross-sectional study was conducted at four cancer care centers in Amhara National Regional State, Northern Ethiopia from March to May 2023. Those cancer care centers were found in the University of Gondar Comprehensive Specialized Hospital (UoGCSH), Felege-Hiwot Comprehensive Specialized Hospital (FHCSH), Tibebe-Ghion Comprehensive Specialised Hospital (TGCSH) and Dessie Comprehensive Specialized Hospital (DCSH). We selected these centers as they were the only institutions providing oncologic care in the region during the study period.

The UoGCSH had 28 beds in its adult oncology ward and serves 450 cancer patients every month. Three specialist oncologists and 12 nurses provide services in the ward. The FHCSH had 22 beds and provides services for 325 cancer patients every month. Two specialist oncologists, two oncologic nurses, and 7 comprehensive nurses provide services. The TGCSH had eight beds and serves 300 cancer patients every month. There were three specialist oncologists and four oncologic nurses at the care center. The cancer care center at DCSH had 10 beds. It serves 350 cancer patients every month. There was one specialist oncologist, three oncologic nurses, and three comprehensive nurses.

All cancer patients who attended those cancer care centers were the source population, and adult (18+) cancer patients who were prescribed pain treatment for a minimum of one month were the study population. Unconscious patients, patients with psychiatric problems, patients with advanced cancer who were unable to cooperate, and patients with oncologic emergencies were excluded from this study.

Variables and operational definitions

The outcome variable was patient satisfaction with cancer pain treatment, which was measured by the Lubeck Medication Satisfaction Questionnaire. The independent variables were sociodemographic (age, sex, marital status, monthly income, and level of education), clinical (site of tumor, stage of cancer, metastasis), cancer treatment (surgery, chemotherapy, radiotherapy), level of pain, and analgesia (type of analgesia, severity of pain, adequacy of pain treatment, adjuvant analgesic).

• Patient satisfaction

perceptions of the patients regarding the outcome of pain management and the extent to which it meets their needs and expectations. It was measured by a 4-point Likert scale (1 = strongly disagree, 2 = disagree, 3 = agree, 4 = strongly agree) using the LMSQ which has 18 items within 6 subscales that have 3 items in each (effectivity, practicality, side-effects, daily life, healthcare providers, and overall satisfaction) [ 19 ]. Final categorization was done by dichotomizing into satisfied and dissatisfied by using the demarcation threshold formula.

\((\frac{\text{T}\text{o}\text{t}\text{a}\text{l}\,\,\text{h}\text{i}\text{g}\text{h}\text{e}\text{s}\text{t}\,\,\text{s}\text{c}\text{o}\text{r}\text{e} - \text{T}\text{o}\text{t}\text{a}\text{l}\,\, \text{l}\text{o}\text{w}\text{e}\text{s}\text{t}\,\, \text{s}\text{c}\text{o}\text{r}\text{e} }{2}\) ) + Total lowest score [ 20 ]. The highest patient satisfaction score was 70 and the lowest satisfaction score was 26. A score < 48 was classified as dissatisfied, and a score ≥ 48 was classified as satisfied.

The Numeric rating scale (NRS) is a validated pain intensity assessment tool that helps to give patients a subjective feeling of pain with a numerical value between 0 and 10, in which 0 = no pain, 1–3 = mild pain, 4–6 = moderate pain, 7–10 = severe pain [ 21 ].

The Adequacy of cancer pain treatment was measured by calculating the Pain Management Index (PMI) according to the recommendations of the WHO pain management guideline [ 22 ]. The PMI was calculated by considering the prescribed most potent analgesic agent and the worst pain reported in the last 24 h [ 23 ]. The prescribed analgesics were scored as follows: 0 = no analgesia, 1 = non-opioid analgesia, 2 = weak opioids, and 3 = strong opioids. The PMI was calculated by subtracting the reported NRS value from the type of most potent analgesics administered. The calculated values of PMI ranged from − 3 (no analgesia therapy for a patient with severe pain) to + 3 (strong opioid for a patient with no pain). Patients with a positive PMI value were considered to be receiving adequate analgesia, whereas those with a negative PMI value were considered to be receiving inadequate analgesia.

Sample size determination and sampling technique

A single population proportion formula was used to determine the sample size by considering 50% satisfaction with cancer pain treatment and a 5% margin of error at a 95% confidence interval (CI). A non-probability (consecutive) sampling technique was employed to attain a sample size within two months of data collection period. After adjusting the proportional allocation for each center and adding 5% none response, a total of 404 study participants were included in the study: 128 from the University of Gondar Comprehensive Specialized Hospital, 99 from Dessie Comprehensive Specialized Hospital, 92 from Felege Hiwot Comprehensive Specialized Hospital, and 85 from Tibebe Ghion Comprehensive Specialized Hospital.

Data collection, processing, and analysis

Ethical approval.

was obtained from the Ethical Review Committee of the School of Medicine at the University of Gondar ( Reference number: CMHS/SM/06/01/4097/2015) . Data were collected using an interviewer-administered structured questionnaire and chart review during outpatient and inpatient hospital visits by four trained data collectors (one for every center). Written informed consent was obtained from each participant after detailed explanations about the study. Informed consent with a fingerprint signature was obtained from patients who could not read or write after detailed explanations by the data collectors as approved by the Ethical Review Committee of the School of Medicine, at the University of Gondar.

Questions to assess the severity of pain and pain relief were taken from the American Pain Society patient outcome questionnaire [ 24 ]. Patients were asked to report the worst and least pain in the past 24 h and the current pain by using a numeric rating scale from 0 to 10, with a pain score of 0 = no pain, 1–3 = mild pain, 4–6 = moderate pain, 7–10 = severe pain.

The Pain Management Index (PMI) based on WHO guidelines, was used to quantify pain management by measuring the adequacy of cancer pain treatment [ 25 ]. The following scores were given (0 = no analgesia, 1 = non-opioid analgesia, 2 = weak opioid 3 = strong opioid). Pain Management Index was calculated by subtracting self-reported pain level from the type of analgesia administered and ranges from − 3 (no analgesic therapy for a patient with severe pain) to + 3 (strong opioid for a patient with no pain). The level of pain was defined as 0 with no pain, 1 for mild pain, 2 for moderate pain, and 3 for severe pain. Patients with negative PMI scores received inadequate analgesia.

The pain treatment satisfaction was measured by the Lübeck Medication Satisfaction Questionnaire (LMSQ) consisting of 18 items [ 19 ]. Lübeck Medication Satisfaction Questionnaire (LMSQ) has six subclasses each consisting of equally waited and similar context of three items. The subclass includes satisfaction with the effectiveness of pain medication, satisfaction with the practicality or form of pain medication, satisfaction with the side effect profile of pain medication, satisfaction with daily life after receiving pain treatment, satisfaction with healthcare providers, and overall satisfaction. Satisfaction was expressed by a four-point Likert scale (4 = Strongly Agree, 3 = Agree, 2 = Disagree, 1 = Strongly Disagree). The side effect subclass was phrased negatively, marked with Asterix, and reverse-scored in STATA before data analysis.

Data were collected with an interviewer-administered questionnaire. The reliability of the questionnaire was assessed by using 40 pretested participants and the reliability coefficient (Cronbach’s alpha value) of the questionnaire was 91.2%. The collected data was checked for completeness, accuracy, and clarity by the investigators. The cleaned and coded data were entered in Epi-data software version 4.6 and exported to STATA version 17. The Shapiro-Wilk test, variance inflation factor, and Hosmer-Lemeshow test were used to assess distribution, multicollinearity, and model fitness, respectively. Descriptive, Chi-square and binary logistic regression analyses were performed to investigate the associations between the independent and dependent variables. The independent variables with a p-value < 0.2 in the bivariable binary logistic regression were fitted to the final multivariable binary logistic regression analysis. Variables with p-value < 0.05 in the final analysis were considered to have a statistically significant association. The strength of associations was described in adjusted odds ratio (AOR) at a 95% confidence interval.

Sociodemographic and clinical characteristics

A total of 397 patients were involved in this study (response rate of 98.3%). Of the participants, 224 (56.4%) were female, and over half were from rural areas ( n  = 210, 52.9%). The median (IQR) age was 48 (38–59) years [Table  1 ]. The most common type of cancer was gastrointestinal cancer 114 (28.7%). Most of the study participants, 213 (63.7%), were diagnosed with stage II to III cancer. The majority of the participants were taking chemotherapy alone (292 (73.6%)) [Table  2 ]. Over 90% of patients reported pain; 42.3% reported mild pain, 39.8% reported moderate pain, and 10.1% reported severe pain. Pain treatment adequacy was assessed by self-reports from study participants following pain management guidelines, and 17.1% of patients responded to having inadequate pain treatment. The majority of patients, 132 (33.3%), were prescribed combinations of non-opioid and weak opioid analgesics for cancer pain treatment. Only 34 (8.6%) cancer patients used either strong opioids alone or in combination with non-opioid analgesics.

Patients’ satisfaction with cancer pain treatment and correlation among the subscales

Most participants strongly agree (243, (61.2%)) with item LMSQ18 in the “overall satisfaction” subscale and strongly disagree (206, (51.9%)) for item LMSQ2 in the “side-effect” subscale respectively [Table  3 ]. The highest satisfaction score was observed in the side-effect subscale, with a median (IQR) of 10 (9–11) [Table  4 ].

Two hundred and seventy-nine (70.3%) cancer patients were found to be satisfied with cancer pain treatment (CI = 65.6−74.6%). The highest satisfaction rate was observed in the “side-effects” subscale, to which 343 (86.4%) responded satisfied [Fig.  1 ]. A Spearman’s correlation test revealed that there were correlations among the subscales of LMSQ; and the strongest positive correlation was observed between effectivity and healthcare workers subscale (r s = 0.7, p  < 0.0001). The correlation among the subscales is illustrated in a heatmap [Fig.  2 ].

Patient satisfaction with cancer pain treatment with each LMSQ subclass, n  = 397

A heatmap showing the Spearman correlation of each subclass of pain treatment satisfaction, n  = 397

Factors associated with patient satisfaction with cancer pain treatment

In the bivariable binary logistic regression analysis, marital status, stage of cancer, types of cancer treatment, severity of pain in the last 24 h, current pain severity, types of analgesics, and pain management index met the threshold of P-value < 0.2 to be included into the final multivariable binary logistic regression analysis. In the final analysis, marital status, current pain severity, and pain management index were significantly associated with patient satisfaction (P-value < 0.05). Married and single cancer patients had higher odds of being satisfied with cancer pain treatment compared to divorced patients (AOR = 5.6, CI, 2.6–12.0, P  < 0.001), (AOR = 3.5, CI = 1.3–9.7, P  = 0.017), respectively. The odds of being satisfied with cancer pain treatment among patients who received adequate pain management were more than two times greater than those who received inadequate pain management (AOR = 2.4, CI = 1.1–5.3, P  = 0.03). Patients who reported a lesser severity of current pain were nearly three times more likely to be satisfied with cancer pain treatment (AOR = 2.6, CI = 1.5–4.8, P  < 0.001) [Table  5 ].

The objective of the present study was to assess patients’ satisfaction with cancer pain treatment at adult oncologic centers. Our study revealed that most cancer patients (70.3%) have been satisfied with cancer pain treatment. This is consistent with studies done by Kaggwa et al. and Mazzotta et al. [ 16 , 26 ]. Whereas, it is a higher rate of satisfaction compared to other studies that reported 33.0% [ 27 ] and 47.7% [ 28 ] of satisfaction. The differences might be possibly explained by the use of different pain and satisfaction assessment tools, the greater inclusion (about 70%) of patients with advanced stages of cancer, the duration of cancer pain treatment, and the adequacy of pain management. In the current study, only 19.6% of patients have been diagnosed with stage IV cancer: patients should take treatment at least for a month, and over 80% of patients have received adequate pain management according to PMI. However, some studies have reported higher rates of satisfaction with cancer pain treatment [ 15 , 29 ]. The possible reason for the discrepancy might be the greater (over 40%) use of strong opioid analgesics in the previous studies. Strong opioids were prescribed only for 8.6% of patients in our study. Due to the complex pathophysiology, cancer pain involves multiple pain pathways. Hence, multimodal analgesia in combination with strong opioids is vital in cancer pain management [ 30 ]. Furthermore, the use of epidural analgesia could be another reason for higher rates of satisfaction [ 29 ].

Regarding satisfaction with subscales of LMSQ, about 80% of patients were satisfied with the information provided by the healthcare providers [ 27 ]. In our study; 67.8% of patients were satisfied with the education provided by healthcare providers about their disease and treatment. In contrast, a higher proportion of participants were satisfied with information provision in a study conducted by Kharel et al. [ 29 ]. Furthermore, we observed the lowest satisfaction rate in the daily life subscale. About 48% of cancer patients were not satisfied with their daily lives after receiving analgesic treatment for cancer pain.

Married and single (never married) cancer patients were found to have higher odds of being satisfied with cancer pain treatment as compared to divorced cancer patients. These findings could be explained by the presence of better social support from family or loved ones. Better social support can enhance positive coping mechanisms, increase a sense of well-being, and decrease anxiety and depression. It also improves a sense of societal vitality and results in higher patient’ satisfaction [ 31 , 32 ].

Patients who had a lower pain score were satisfied compared to those who reported a higher pain score, and this is supported by multiple previous studies [ 16 , 26 , 27 , 29 , 33 , 34 ]. This could be explained by the negative impacts of pain on physical function, sleep, mood, and wellbeing [ 35 ]. Moreover, higher pain severity scores could increase financial expenses because of unnecessary or avoidable emergency department visits; and has a consequence of dissatisfaction [ 23 ]. On the contrary, there are studies that state pain severity does not affect patients’ satisfaction [ 36 , 37 ].

Positive PMI scores were significantly associated with cancer pain treatment satisfaction. Patients who received adequate pain management were highly likely to be satisfied with cancer pain treatment. This finding is similar to that of a study done in Taiwan [ 38 ]. However, a study conducted by Kaggwa et al. has denied any association between PMI scores and cancer pain satisfaction [ 16 ].

Satisfaction with healthcare workers and effectivity of analgesics

This study showed that there was a moderately positive correlation between satisfaction with healthcare workers and satisfaction with patients’ perceived effectiveness of analgesics. This might be explained by a positive relationship between healthcare professionals and patients receiving cancer pain treatment. Healthcare providers who provide health education regarding the effectiveness of analgesics may improve patients’ adherence to the prescribed analgesic agent and improve patients’ perceived satisfaction with the effectiveness of analgesics. A systematic review showed that the hope and positivity of healthcare professionals were important for patients to cope with cancer and increase satisfaction with care [ 39 ]. Increased patient satisfaction with care provided by healthcare workers may change attitude of patients who accepted cancer pain as God’s wisdom or punishment and create a positive attitude toward the effectiveness of analgesics [ 40 ]. Another study supported this finding and stated that healthcare providers who deliver health education regarding the prevention of drug addiction, side effects of analgesics, timing, and dosage of analgesics improve patient attitude and cancer pain treatment [ 41 ].

Correlation of each subclass of cancer pain treatment satisfaction

A Spearman correlation was run to assess the correlation of each subclass of LMSQ using the total sample. There was strong positive correlation (r s = 0.5–0.64) between most of LMSQ subclass at p  < 0.01.

A cross-sectional study stated that the effectiveness of analgesic, efficacy of medication and patient healthcare provider communication were associated with patient satisfaction [ 42 ]. In this study, 58.2% of patients were satisfied with the practicability of analgesic medications. Comparable to this study, a cross-sectional study stated that patients who were prescribed convenient, fast-acting medications were more satisfied [ 43 ]. Another study stated that 100% of patients who received sufficient information on analgesic treatment and 97.9% of patients who received sufficient information about the side effects of analgesic treatment were satisfied with cancer pain management [ 44 ]. Patients who were satisfied with their pain levels reported statistically lower mean pain scores (2.26 ± 1.70) compared to those not satisfied (4.68 ± 2.07) or not sure (4.21 ± 2.21) [ 27 ]. This may be explained by the impact of pain on daily activity. Patients who report a lower average pain score may have a lower impact of pain on physical activity compared to those who report a higher mean pain score. Another study also supports this evidence and states that patients who reported a severe pain score and lower quality of life had lower satisfaction with the treatment received [ 45 ].

As a secondary outcome, only 16% of patients were diagnosed to have stage I cancer. This finding could indirectly indicate that there were delays in cancer diagnosis at earlier stage. Further studies may be required to underpin this finding.

In this study, baseline pain before analgesic treatment was not assessed and documented. As a cross-sectional study, we could not draw a cause-and-effect conclusion. Since questions that were used to measure oncologic pain treatment satisfaction were self-reported, answers to each question might not be trustful. The expectation and opinion of the interviewer also might affect the result of the study. These could be potential limitations of the study.

Conclusions

Despite the fact that most cancer patients reported moderate to severe pain, there was a high rate of satisfaction with cancer pain treatment. It would be better if hospitals, healthcare professionals, and administrators took measures to enhance the use of multimodal analgesia in combination with strong opioids to ensure adequate pain management, lower pain severity scores, and better daily life. We also urge the arrangement of better social support mechanisms for cancer patients, the improvement of information provision, and the deployment of professionals who have trained in pain management discipline at cancer care centres.

Data availability

Data and materials used in this study are available and can be presented by the corresponding author upon reasonable request.

Abbreviations

Adjusted Odds Ratio

Crude Odds Ratio

Confidence Interval

Dessie Compressive and Specialized Hospital

Felege-Hiwot Compressive and Specialized Hospital

Inter-quartile Range

Lubeck Medication Satisfaction Questionnaire

Numerical Rating Scale

Pain Management Index

Standard Deviation

Tibebe-Ghion Compressive and Specialized Hospital

University of Gondar Compressive and Specialized Hospital

World health organization

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Acknowledgements

We would like to acknowledge the University of Gondar Comprehensive Specialized Hospital, Tibebe-Ghion Comprehensive Specialized Hospital, Felege-Hiwot Comprehensive Specialized Hospital, Dessie Comprehensive Specialized Hospital. We would also want to acknowledge Ludwig Matrisch from the Department of Rheumatology and Clinical Immunology, Universität zu Lübeck, 23562 Lübeck, Germany for supporting us on the utilization of the Lübeck Medication Satisfaction Questionnaire (LMSQ) [email protected],

This study was supported by University of Gondar and Debre Birhan University with no conflict of interest. The support did not include publication charges.

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Molla Amsalu

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Henos Enyew Ashagrie, Amare Belete Getahun & Yophtahe Woldegerima Berhe

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‘’M.A. has conceptualized the study and objectives; and developed the proposal. Y.W.B., H.E.A., and A.B.G. criticized the proposal. All authors had participated in the data management and statistical analyses. Y.W.B, M.A., and H.E.A. have prepared the final manuscript. All authors read and approved the final manuscript.‘’.

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Amsalu, M., Ashagrie, H.E., Getahun, A.B. et al. Patients’ satisfaction with cancer pain treatment at adult oncologic centers in Northern Ethiopia; a multi-center cross-sectional study. BMC Cancer 24 , 647 (2024). https://doi.org/10.1186/s12885-024-12359-7

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Signs and Symptoms of Oral Cancer

Oral cancer is cancer of the mouth that affects the tissues in the throat, gums, lips, under the tongue, and at its base. This cancer doesn't always cause symptoms in the early stages, but cancer cells can spread quickly. If you develop symptoms, common signs of this condition include the development of growths, sores, or white patches in the mouth.  

This condition becomes especially dangerous if it spreads (or “metastasizes”) to other parts of the body—which happens in about 3% to 7% of oral cancer cases. Fortunately, most cases of oral cancer are treatable, as long as you receive a diagnosis and treatment in a timely manner.

Common Symptoms 

If oral cancer goes untreated, symptoms can get worse. As with other cancers, healthcare providers such as periodontists (dentists specializing in oral disease) or otolaryngologists (specialists in the ears, nose, and throat) stage the disease based on the severity of your condition and how far it’s spread.

Across these stages, the most common warning signs of oral cancer include:

• Persistent sores on the tissues of the mouth, gums, tongue, throat, or lips
• Red or white patches in the throat
• Numbness in parts of the mouth or tongue
• Bleeding in the gums, tongue, and lips
• Sore throat , hoarseness, or loss of voice
• Pain or difficulty with chewing, swallowing, or talking
• Feeling a lump in your neck
• Difficulty moving the tongue or jaw
• Jaw swelling

Stage 0 Symptoms

When staging oral cancer, healthcare providers follow classification systems, such as the TNM system set by the American Joint Committee on Cancer (AJCC). This system stages cancer from 0 to 4 (stage 4 being the most severe), based on three criteria: tumor growth (T), the extent of spread to the neck’s lymph nodes (N), and metastasis (M), or whether the cancer has spread to other parts of the body.   

Also known as carcinoma in situ, stage 0 is a pre-symptomatic stage of oral cancer, and there’s no spread of cancer cells to the lymph nodes (known as metastasic). Though there aren’t symptoms, healthcare providers can detect abnormal squamous cells—the cells that line the mouth, tongue, and throat. These cells have the potential to become cancerous (or “malignant”).        

Stage I Symptoms 

In the first stage of oral cancer, the tumors are less than 2 centimeters (cm) in diameter and are 5 millimeters (mm) or less deep. Malignant cells in this stage are found in the tissues of the mouth, lips, or throat but haven’t spread to surrounding tissues, lymph nodes, or organs in other parts of the body, such as the lungs.

Stage II Symptoms 

According to the AJCC, there are two definitions of stage II oral cancer. In these cases, the cancerous tumors are either between 2 and 4 cm in diameter and between 5 and 10 millimeters (mm) deep. In this stage, cancer cells haven’t started growing into other tissues, so they aren’t present in the lymph nodes or other organs. But you may start noticing symptoms that affect your mouth, throat, or lips.

Stage III Symptoms 

In stage III, oral cancer has advanced considerably, becoming prominent in the mouth and in some cases starting to spread to the lymph nodes. As with stage 2, there are two definitions:

• Tumors are larger than 4 cm in diameter in the mouth or the base of the tongue , with no sign of spread to lymph nodes or other parts of the body
• Tumors of any size in tissues surrounding the throat and spreading to one lymph node, which swells to 3 mm or less, but nowhere else  

If the oral cancer spreads to your lymph nodes, it can lead to symptoms like painful swallowing and feeling a lump in the neck.

Stage IV Symptoms 

If you have stage IV—the most advanced stage of oral cancer—the cancer has started to spread to surrounding tissues, lymph nodes, and more distant organs. In the TNM classification, this stage can cause one or more of the following:

• Tumors of any size that may or may not actively spread into surrounding tissues, such as the bones of the jaw or face, the voice box (larynx), muscles, sinuses , and skin on the face or nose affected. Swelling in a nearby lymph node is common.
• Tumors spread into tissues as well as one lymph node on the same or opposite side. The lymph node usually swells to over 3 cm in diameter.
• Tumors have spread not only to surrounding structures and lymph nodes but also to other parts of the body, such as the lungs.

When to Contact a Healthcare Provider 

If you suspect oral cancer, it’s critical to get help as soon as possible, as this disease can progress rapidly. Early detection of this condition vastly improves outcomes. In one study, 90% of those who detected the issue in stage I and got treatment were still alive five years later; this number dropped to 45% among those with stage IV.

If you experience any symptoms of oral cancer for longer than two weeks, call your healthcare provider. Persistent sores or swollen, discolored spots, lumps in the neck, and other typical signs of the condition can mean you need help.

Oral cancer can become a medical emergency due to complications or severe side effects of treatments. Call 911, if you experience any of the following:

• Worsening side effects from radiation or chemotherapy , such as nausea and vomiting
• Shortness of breath
• Severe headache
• Neck stiffness
• Bloody urine

Questions to Ask Your Provider

When seeking care for oral cancer, think about asking the periodontist or specialist the following questions:

• What stage of oral cancer do I have, and what does that mean for treatment?
• What side effects can I expect from treatment and what I can do about them?
• What lifestyle changes can I adopt to improve my outcome?
• Will I need to change what I eat because of my symptoms?
• Will I need surgery to treat oral cancer?

A Quick Review 

Oral cancer causes tumors or growths in the tissues of the mouth, tongue, gums, or throat. This condition, if left untreated, worsens over time and can cause cancer cells to spread to the lymph nodes, surrounding tissues, and distant organs. If you're experiencing symptoms of oral cancer, get medical care as soon as you can to improve symptoms and survival outcomes.

Frequently Asked Questions

What is the survival rate for oral cancer?

Several factors influence the survival rate of oral cancer, such as whether you receive treatment and how severe your condition is. Without treatment, the prognosis is poor.

In one study, 31% of those who had stage I without treatment survived after five years, something which only 12.6% of stage IV patients managed. But with timely treatment, the picture improves. At five years, studies found survival rates after five years were 90% for people in stage I and nearly 50% for stage IV.

How long can you have oral cancer without knowing?

The early stages of this cancer don’t always cause symptoms. Some types, such as verrucous carcinoma, progress more slowly, making it harder to detect earlier signs. But squamous cell oral carcinoma, the most common type, moves more quickly, spreading to the lymph nodes or surrounding tissues within as little as three months or less.

Can a dentist detect oral cancer?

Though specialists like periodontists or otolaryngologists (ear, nose, and throat doctors) guide the treatment of oral cancer, dentists can diagnose the condition. During routine cleanings and check-ups, dentists look for tumors, growths, or other symptoms. Dentists may also perform additional screening methods, such as using a screening light or using a dye to detect growths or other signs.

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Health-Related Quality of Life in Oral Cancer Patients: Scoping Review and Critical Appraisal of Investigated Determinants

Davide de cicco.

1 Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples “Federico II”, 80131 Naples, Italy; [email protected] (D.D.C.); [email protected] (C.S.); [email protected] (G.L.G.)

Gianpaolo Tartaro

2 Department of Multidisciplinary Medical, Surgical and Dental Specialties, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; [email protected] (G.T.); [email protected] (R.R.); [email protected] (G.C.)

Fortunato Ciardiello

3 Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; [email protected] (F.C.); [email protected] (M.F.)

Morena Fasano

Raffaele rauso, francesca fiore.

4 Department of Internal and Polyspecialist Medicine, A.O.U. “Luigi Vanvitelli”, 80131 Naples, Italy; [email protected]

Chiara Spuntarelli

Antonio troiano, giorgio lo giudice, giuseppe colella, associated data.

The data presented in this study are available on request from the corresponding author.

Simple Summary

Oral cancer may strongly impair patients’ quality of life. Huge efforts have been made during recent decades in trying to improve the treatment outcomes in terms of patients’ survival, self-perception, and satisfaction. Consequently, the investigation into health-related quality of life (HRQOL) became an established and worldwide practice. Hundreds of studies tried to clarify which could be the most important variables that impact HRQOL in head and neck cancer patients. However, such a complex topic may be influenced by a multitude of interconnected aspects and several controversies were reported. In this study the current literature was reviewed to identify all those possible sources of bias that may be encountered in trying to correlate HRQOL to patient-specific or disease/treatment-specific aspects. As a result, a list of recommendations was reported to enhance the evidence of future studies.

Background: health-related quality of life (HRQOL) represents a secondary endpoint of medical interventions in oncological patients. Our aim was to highlight potential sources of bias that could be encountered when evaluating HRQOL in oral cancer patients. Methods: this review followed PRISMA-ScR recommendations. Participants: patients treated for oral cancer. Concept: HRQOL assessed by EORTC QLQ-C30 and QLQ-H&N35/QLQ-H&N43. A critical appraisal of included studies was performed to evaluate the accuracy of data stratification with respect to HRQOL determinants. Results: overall, 30 studies met the inclusion criteria, totaling 1833 patients. In total, 8 sociodemographic (SDG) and 15 disease/treatment-specific (DT) HRQOL determinants (independent variables) were identified. The mean number of the independent variables was 6.1 (SD, 4.3)—5.0 (SD, 4.0) DT-related and 1.1 (SD, 1.8) SDG-related variables per article. None of the included papers considered all the identified determinants simultaneously. Conclusions: a substantial lack of evidence regarding HRQOL determinants was demonstrated. This strongly weakens the reliability of the reported findings due to the challenging presence of baseline confounding, selection, and omitted variable biases. The proposed approach recommends the use of further evaluation tools that gather more variables in a single score together with a selection of more homogeneous, reproducible, and comparable cohorts based on the identified baseline confounding.

1. Introduction

Patient-reported outcomes (PROs) provide precious information about troubles in everyday life and the perception of psychological and physical wellness from the patient’s perspective. Over recent decades, PROs have gained more relevance in treatment decision making, so much so that the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) consider them—including the quality of life—as a relevant end point to approve new therapies [ 1 , 2 , 3 ]. To approach such a complex topic as the quality of life in oncological patients, they commonly refer to health-related quality of life (HRQOL). A distinction between these concepts has been made to exclude influences from domains that are not related to the patient’s health status [ 4 ], at least theoretically.

The concept of “quality of life” was firstly introduced by Heckscher [ 5 ], and in 1977 was adopted as a “keyword” by the United States National Library of Medicine [ 6 ]. Since then, several definitions have been proposed [ 7 , 8 ]. The WHO defined quality of life as “individuals perceptions of their position in context of the culture and value systems in which they live and in relation to their goal, expectations, standards, and concerns” [ 9 ].

Head and neck tumors and their treatment may negatively affect patients’ HRQOL, which is considered an essential secondary outcome of treatment nowadays [ 10 , 11 ]. For this reason, having reliable evaluation tests is mandatory to better understand how and why specific medical interventions should be chosen and adapted according to individual needs. The quest towards the perfect quality of life evaluation test led researchers to understand some key points to be focused on: a test should be reproducible, sensitive, and easy to understand [ 12 ]. Questionnaires developed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Group are widely used in current literature to address these needs. A core questionnaire (EORTC QLQ-C30) is associated with site-specific validated modules (EORTC QLQ-H&N35/43), consisting of single- and multi-item scales that measure several head and neck symptoms [ 13 , 14 ].

HRQOL is a complex topic and needs to be analyzed taking into account every potential influencing factor. Various sociodemographic, disease-specific, and treatment-specific aspects have been recognized as affecting HRQOL [ 12 , 15 , 16 , 17 , 18 , 19 , 20 ]. Several researchers have investigated its intrinsic multidimensionality, concluding that HRQOL plays a role in treatment decision making, but none have verified what the relevant items are and how this feature is assessed. The scope of the present review was to highlight possible sources of bias that could be encountered when evaluating HRQOL in patients treated for oral cancer. The second aim was to lay the foundation of a standardized protocol for cohort selection, data collection, and stratification that could enhance knowledge in the field.

2. Materials and Methods

This study was conducted following recommendations by PRISMA for scoping reviews (see supplementary document Table S1 ). Description of primary objectives was carried out according to the JBI reviewer’s manual [ 21 ]: participants = patients treated for oral cancer; concept = HRQOL assessed by EORTC questionnaires; context = not specified).

A systematic search of published literature was performed in PubMed, EMBASE, and Scopus databases without limitations concerning the date of publication (last screening on 2 February 2021), based on the following search query: (oral cancer OR oral cancers OR tongue cancer OR tongue cancers OR mandible cancer OR cancer of floor of the mouth OR cancers of floor of the mouth OR fom cancer OR fom cancers OR palate cancer OR palate cancers OR palatal cancer OR palatal cancers OR cheek cancer OR cheek cancers OR buccal cancer OR buccal cancers OR gingival cancer OR gingival cancers) AND (quality of life OR health-related quality of life OR health related quality of life OR hrqol OR qol) AND eortc.

All results were exported to Endnote™ bibliographic management software (Clarivate™, Philadelphia, PA, USA). After duplicates removal, the study design filter was applied according to the inclusion/exclusion criteria reported in Table 1 . To minimize potential language selection biases, all non-English language papers were moved to the title and abstract screening phase if at least the abstract was reported in the English language. Two authors (D.D.C. and C.S.) independently screened retrieved articles by titles and abstracts. Eventual controversies were solved by the intervention of a third author (G.C.). Those papers considered relevant for the topic were selected for full-text reading and independently screened by two authors (D.D.C. and C.S.) following inclusion/exclusion criteria reported in Table 1 . Disagreements were solved by a third author (G.C.). The PRISMA search flow diagram reported in Figure 1 summarizes our strategy.

PRISMA search flow diagram.

Inclusion/exclusion criteria.

2.1. Data Extraction

According to the findings reported in screened studies and previously published reviews [ 12 , 16 , 20 ], those sociodemographic (SDG) and disease/treatment-specific (DT) variables that have been found to be linked to patients’ HRQOL were identified and listed.

The following information was retrieved from included studies: country; study design; characteristics of studied populations, such as sample size; SDG features—gender, age, marital status/family, comorbidity, smoke addiction, alcohol consumption, educational level, employment status; DT features—tumor site, tumor T stage, mandibular resection, extent of resection, surgical approach, neck dissection (ND), reconstruction, neoadjuvant radiotherapy (nRT) and adjuvant radiotherapy (RT), neoadjuvant chemotherapy (nCT) and adjuvant chemotherapy (CT), neoadjuvant chemoradiotherapy (nCRT) and adjuvant chemoradiotherapy (CRT), presence of synchronous lesions at baseline, recurrence or metachronous lesions developed before HRQOL evaluation, major postsurgical complications occurred, secondary surgery required. Additional information was retrieved during the appraisal of the included studies (as well as the use of further scoring systems).

2.2. Critical Appraisal

Included studies were evaluated and marked as follows:

• “Stratified” for each independent variable related to EORTC QLQ-C30 and/or EORTC QLQ-H&N35/43 *.
• “Homogeneous” for each independent variable when all the included cases were equal concerning that specific feature.
• “Excluded” or “not present in the sample” for each independent variable if the cases reporting that specific feature were excluded during cohort selection, or if that specific feature was not observed in the screened population.
• “Incomplete stratification” for each independent variable related to EORTC QLQ-C30 and/or EORTC QLQ-H&N35/43, in case of uneven or incomplete sample grouping rules.
• “Not stratified” for each independent variable that was reported but not related to EORTC QLQ-C30 and/or EORTC QLQ-H&N35/43.
• “Not available” for each independent variable that did not clearly describe or was not described in the sample features.

A color-coding system was applied as follows:

• GREEN: stratified, stratified by oral subsites, homogeneous, excluded, not present in the sample.
• YELLOW: incomplete stratification, incomplete stratification by oral subsites.
• LIGHT RED: not stratified, not stratified by oral subsites.
• RED: not available, not clear.

Included articles and independent variables were systematized and charted by using Microsoft ® Excel ® (v 2012, © 2021 Microsoft Corporation, Albuquerque, NM, USA).

* Specifically, for tumor site, “stratified” and “not stratified” were replaced by “stratified by oral subsites” and “not stratified by oral subsites”, respectively, given that differences were found among tumors located in different oral subsites about their influence on patients’ HRQOL.

The initial search yielded a total of 1655 studies. Firstly, 403 duplicated records were removed. Then, in accordance with the applied study design criteria ( Table 1 ), 547 records were excluded (488 conference abstracts, 1 conference review, 47 reviews, 6 books, 2 book chapters, 1 editorial, 2 short surveys). The remaining 705 records were screened by title and abstracts (including 37 non-English language papers), resulting in 223 articles that were considered relevant for the topic and selected for full-text reading. The online search finally yielded 25 articles that met inclusion/exclusion criteria. The screening of grey literature and citations of included studies revealed 5 more relevant papers. Thus, a total of 30 studies was included for the critical appraisal. The search strategy is summarized in the PRISMA flow diagram ( Figure 1 ). Although outside the scope of the adopted study design, reasons for the exclusion after full-text reading are summarized in Figure 2 and extensively reported in the supplementary document Table S2 . The most common reason for exclusion was related to the heterogeneity of the studied cohorts (or poor data stratification) regarding the tumor location.

Reasons for the exclusion of the screened articles.

According to previously published reviews [ 12 , 16 , 20 ] and included articles, we identified and drafted 23 potential determinants of HRQOL (see supplementary documents Tables S3 and S4 ). Almost all of them were considered as an independent variable for statistical analysis by at least one of the included studies, except for employment status, which was elsewhere advocated to influence HRQOL [ 22 , 23 ].

3.1. Study Design

A summary of data design, overall data stratification, and findings of included studies is reported in Table 2 . In total, 18 were cohort studies (15 prospective and 3 retrospective), 11 followed a cross-sectional design, and 1 was a case-control study. Of the relevant studies, 27 were conducted on a single-center population, three were multicenter studies (one prospective cohort, one retrospective cohort, and one cross-sectional study). The whole sample of this review comprised 1833 OC cases.

Study design and independent variables considered for data stratification and findings. Legend to Table 2 : ACE-27 = Adult Comorbidity Evaluation 27 score; ADM = acellular dermal matrix; BAMM = buccinator myomucosal flap; BOT = base of tongue; CRT = chemoradiotherapy; CT = chemotherapy; DCIA = deep circumflex iliac artery flap; FFF = free fibula flap; FOM = floor of the mouth; G8 = Geriatric 8 screening tool; HADS = Hospital Anxiety and Depression Scale; HNC = head and neck cancer; KFI = Kaplan–Feinstein index; MRND = modified radical neck dissection; ND = neck dissection; NOS = not otherwise specified; OC = oral cavity; OCC = oral cavity cancer; OP = oropharynx; OOP = oral cavity and oropharynx; OOPC = oral/oropharyngeal cancer; ORFFF = osteofasciocutaneous radial forearm free flap; OSCC = oral squamous cell carcinoma; PMMC = pectoralis major myocutaneous flap; RFFF = radial forearm free flap; RT = radiotherapy; SCAIF = supraclavicular artery island flap; SCC = squamous cell carcinoma; SND = selective neck dissection; STSG = split thickness skin graft.

3.2. Sociodemographic Variables (SDG)

A summary of data stratification by SDG variables is reported in Table 3 (for further features see supplementary document Table S3 ). In total, 8 of the 23 selected variables were related to SDG aspects. None of the included articles considered all SDG variables simultaneously during cohort selection or for data analysis.

Summary of data stratification by DT and SDG variables. Legend to Table 3 : Ex = excluded; H = homogeneous; IS = incomplete/inadequate stratification; ISOS = incomplete/inadequate stratification by oral subsites; na = not available; NP = not present; NS = not stratified; NSOS = not stratified by oral subsites; S = stratified; SOS = stratified by oral subsites. * Studies on patients treated by non-surgical therapies.

Gender was reported by 28 articles, and data stratification was performed by 10 [ 9 , 25 , 26 , 27 , 37 , 43 , 46 , 48 , 49 ].

Age was reported by 28 articles; data stratification was properly performed by six [ 9 , 26 , 27 , 46 , 49 ] and inadequately by two (which did not report age thresholds) [ 43 , 48 ]. One study investigated a homogeneous population for this variable [ 36 ].

Marital status/family was reported by six articles and data stratification was properly performed by four [ 25 , 27 , 33 , 43 ].

Comorbidity status was reported by seven articles, of which, data stratification was properly performed by four papers [ 25 , 26 , 33 , 46 ]. One study excluded patients affected by severe comorbidity status [ 27 ].

Smoking was reported by seven articles and data stratification was performed by one [ 27 ].

Alcohol consumption was reported by four articles and data stratification was performed by two [ 27 ].

Educational level was reported by four articles and data stratification was performed by two [ 27 , 33 ].

Employment status/annual income was reported by three articles and data stratification was performed by one [ 33 ].

3.3. Disease- and Treatment-Specific Variables (DT)

Summary of data stratification by DT variables is reported in Table 3 (for further information see supplementary document Table S4 ). In total, 15 of the 23 selected variables were disease- and treatment-related aspects, seven of which were linked to surgical procedures (see methods paragraph).

None of the included articles considered all DT variables simultaneously during cohort selection or data analysis.

Data from the included studies were adequately stratified by involved oral subsites in three papers [ 37 , 46 , 48 ] and incompletely/inadequately in five (which customarily grouped different oral subsites) [ 9 , 23 , 30 , 36 , 49 ]. Investigations performed by five studies were on homogeneous populations regarding this variable: on mobile tongue cancers in three [ 28 , 31 , 45 ], on lower lip cancers in one [ 38 ], and on buccal mucosa cancers in another [ 39 ].

Tumor stage was reported in 26 articles—data stratification was properly performed in three [ 9 , 36 , 46 ] and incomplete/inadequate stratification was performed in nine (which distinguished patients grouping different T stages together) [ 23 , 24 , 25 , 26 , 27 , 33 , 34 , 49 , 50 , 51 ]; in three studies the investigations were performed on homogenous populations regarding this variable: on pT3 of the mobile tongue in two [ 28 , 31 ] and on T4 of the buccal mucosal in the other [ 39 ].

Of the included studies, two were conducted on patients who had undergone medical treatments without surgery [ 45 , 49 ], thus marked as “not present” (NP) compared to all the surgery-related DT variables. The only exception was the study of Petruson et al. [ 45 ], which was marked as “not available” for “required secondary surgery” since the authors did not clearly define whether a part of the studied sample underwent a secondary surgery after definitive medical treatment.

Performed mandibular resection was overtly reported in 15 articles—data stratification was properly performed in three [ 23 , 36 , 46 ]; incomplete/inadequate stratification was performed in one (which compared no mandibular resection group to patients undergoing mandibular resection grouping together with those who received marginal and segmental resections) [ 24 ]; six studies clearly stated that none of the included cases underwent mandibular resection [ 28 , 31 , 38 , 39 , 45 , 49 ]; and in three studies, the investigated population homogeneously underwent segmental mandibular resection [ 29 , 40 , 48 ].

The extent of surgical resection was considered “stratified” only in those cases where the resected oral subsites were clearly identified. This variable was indicated in seven articles—according to this definition, none performed stratifications. Data from one study were considered incompletely/inadequately stratified due to the reported horizontal defect size (which partially defined the extent of surgical resection) [ 48 ]. In two studies, the investigated population homogeneously underwent the same resection: partial glossectomy in one [ 28 ] and partial pelviglossectomy in the other [ 31 ].

The surgical approach was indicated in seven articles; data stratification was properly performed in one [ 31 ]. In three studies, the investigated population homogeneously underwent transoral surgery [ 28 , 38 , 39 ].

The performed ND was indicated in 10 articles—data stratification was properly performed in one (it means that different standardized procedures [ 52 ] were separately investigated) [ 37 ] and incomplete/inadequate stratification was performed in six (mostly because the type of ND were not specified) [ 10 , 23 , 28 , 36 , 39 , 48 ].

The performed reconstruction was reported in 23 articles—data stratification was properly performed in five (means that each investigated reconstruction strategy—i.e., each type of free flap, each type of regional flap, each type of local flap, primary closure, and each type of graft was investigated separately from each other) [ 28 , 29 , 32 , 38 , 40 ], incomplete/inadequate stratification was performed in in seven [ 23 , 24 , 31 , 35 , 37 , 46 , 48 ], and the investigated populations homogeneously underwent the same reconstruction strategy in four studies (radial forearm free flap) [ 22 , 25 , 26 , 39 ].

The performed nRT was reported in 12 articles—data stratification was properly performed by one [ 35 ] and incomplete/inadequate stratification was performed by two (means that the authors did not define whether the radiotherapy was performed before or after surgery) [ 32 , 33 ]. In 1 study the investigated population homogeneously underwent nCRT [ 36 ]; 5 studies stated that none of the included cases underwent nRT [ 31 , 34 , 39 , 45 , 49 ].

The performed nCT was reported in eight articles—data stratification was properly performed by one [ 35 ]; incomplete/inadequate stratification was performed by another one (it means that authors did not define whether the radiotherapy was performed before or after surgery) [ 33 ]; in one study, the investigated population homogeneously underwent nCRT [ 36 ]; and five articles stated that none of the included cases underwent nCT [ 31 , 34 , 39 , 45 , 49 ].

The performed RT (both adjuvant or definitive) was reported in 26 articles—data stratification was properly performed by 10 [ 26 , 27 , 30 , 34 , 35 , 37 , 39 , 41 , 47 , 48 ]; incomplete/inadequate stratification was performed by two (this means that authors did not define whether radiotherapy was performed before or after surgery) [ 32 , 33 ]; and in 4 studies, the investigated population homogeneously underwent RT or CRT (both adjuvant or definitive) [ 22 , 28 , 45 , 49 ].

The performed CT (both adjuvant or definitive) was reported in 13 articles—data stratification was properly performed by four [ 30 , 34 , 37 , 39 ]; incomplete/inadequate stratification was performed by one (it means that authors did not define whether radiotherapy was performed before or after surgery) [ 33 ]; in three studies, the investigated population homogeneously underwent RT or CRT (both adjuvant or definitive) [ 28 , 45 , 49 ]; and one article overtly stated that none of the included cases underwent CT [ 35 ].

The presence or the absence of patients with synchronous lesions at baseline in the studied sample was overtly indicated in four articles—in one paper, those patients who presented synchronous lesions were excluded a priori [ 28 ], while the authors in two studies stated that these patients were not present in the studied population [ 31 , 49 ].

The presence or the absence of patients who developed metachronous neoplasms or disease relapse in the studied sample were indicated in 17 articles—data stratification was properly performed in two [ 39 , 46 ]; in eight papers, those patients who developed a relapse or a metachronous lesion were excluded from data analysis [ 24 , 26 , 34 , 36 , 42 , 48 , 50 , 53 ]; and the authors in another study overtly stated that these patients were not present in the studied population [ 31 ].

The presence or the absence of patients who experienced major post-surgical complications in the studied sample was reported in nine articles—data stratification was properly performed in one [ 32 ]; incomplete/inadequate stratification was performed in two (it means that an uneven definition of this variable was reported—e.g., partial and total flap loss not distinguished, major surgical complications NOS) [ 26 , 46 ]; in another paper, these patients were excluded from data analysis [ 48 ]; and the authors from three studies clearly stated no major post-surgical complications were observed in the investigated sample [ 28 , 31 , 38 ].

Patients who required secondary surgery for tumor relapse or reported major post-surgical complications were included in six articles—none performed data stratification regarding this variable; in one study, these patients were excluded from the data analysis [ 24 ]; and the authors from another study stated that no secondary surgery was performed in the investigated sample [ 31 ].

3.4. Descriptive Analysis

RT and gender were the most frequently considered among DT and SDG variables, respectively, followed by mandibular resection and reconstruction in the former group, and by age and comorbidity in the latter ( Figure 3 and Figure 4 ). Results also showed that these studies focused on the exclusion of patients who developed recurrences of metachronous lesions.

Overall stratification by DT variables. Legend to Figure 3 : CT = adjuvant/definitive chemotherapy; Ex = excluded; H = homogeneous; IS = incomplete/inadequate stratification; ISOS = incomplete/inadequate stratification by oral subsites; na = not available; nCT = neoadjuvant chemotherapy; ND = neck dissection; NP = not present; nRT = neoadjuvant radiotherapy; NS = not stratified; NSOS = not stratified by oral subsites; RT = adjuvant/definitive radiotherapy; S = stratified; SOS = stratified by oral subsites.

Overall stratification by SDG variables. Legend to Figure 4 : Ex = excluded; H = homogeneous; IS = incomplete/inadequate stratification; na = not available; NP = not present; NS = not stratified; S = stratified.

On average, only 5.0 (SD, 4.0) DT variables were considered by each included study, and 5.1 (SD, 3.8) for each case, as a result in the weighted average. However, these values dropped to 3.7 (SD, 3.8) and 3.8 (SD, 3.7) if just proper analysis, exclusions, and homogeneity were considered ( Table 3 , Figure 5 ).

Box plot representation of the considered independent variables during data analysis and cohort selection. Legend to Figure 5 : Ex = excluded; H = homogeneous; IS = incomplete/inadequate stratification; ISOS = incomplete/inadequate stratification by oral subsites; na = not available; nc = not clear; NP = not present; NS = not stratified; NSOS = not stratified by oral subsites; S = stratified; SOS = stratified by oral subsites.

On average, only 1.1 (SD, 1.8) SDG variables were considered by each included study, and 1.0 (SD, 1.9) for each case, as a result in the weighted average. Similar values were achieved considering only proper analysis, exclusions, and homogeneity ( Table 3 , Figure 5 ).

As mentioned above, surgery-related DT variables were considered as “not present” (NP) for those studies that investigated a non-surgical population [ 45 , 49 ]. Thus, they resulted in two of the most accurate analyses among the included studies ( Figure 6 ).

Summary of data stratification by both SDG and DT variables of the included studies. * Studies on patients treated by non-surgical therapies.

4. Discussion

Although this article was initially designed as a systematic review and a meta-analysis, in our opinion, outcomes would be meaningless due to the inhomogeneity of included studies and biases that might have occurred. As a result, we chose to investigate how closely potential influencing factors were evaluated, to highlight possible sources of bias that could be encountered assessing HRQOL in oral cancer patients.

4.1. Sociodemographic Variables

4.1.1. gender and age.

Among sociodemographic variables, gender and age were the most investigated ones. Most of the included studies found no differences concerning these variables [ 9 , 25 , 27 , 46 , 49 , 53 ]. Remarkably, Kovacs et al. [ 37 ] reported worse results in males regarding financial difficulties and cognitive and social functioning. This revealed an interesting food for thought, considering that household income derives most commonly from men.

Non-standardized thresholds were considered by investigating the potential influences of age. Moreover, it is noteworthy that during the last decades chronological age has progressively lost its relevance according to the comprehensive geriatric assessment (GCA) approach. An innovative concept of “psychological age” is gaining momentum in the field [ 54 , 55 ] and it was adapted to HNC patients by Pottel et al. [ 56 ], assessing the effectiveness of different health status screening tools. They found that Geriatric 8 (G8) represents the index of choice to identify patients in a GCA approach. Among included studies, Bozec et al. [ 27 ] performed a stratification using the G8 tool, finding a significant negative correlation between HRQOL and scores lower than 15.

4.1.2. Marital Status and Family

Marital status and family were investigated by four studies [ 25 , 27 , 33 , 51 ], all reporting no associations with questionnaires. However, Bozec et al. [ 27 ] found a negative correlation by stratifying the results of the EORTC QLQ-ELD14. This finding suggests the existence of covering effects from other variables that might impact QLQ-C30 and H&N35 strongly, hiding possible influences of the marital status and family conditions.

4.1.3. Comorbidity

Only a minority of the included studies investigated the influence of comorbidity on HRQOL. No correlations were found by three studies [ 25 , 33 , 46 ], while results from Bozec et al. [ 26 ] were retrieved from the analysis of questionnaires taken 6 months after surgery. As reported in the inclusion/exclusion criteria, these suggestions were not taken into account, since a great variability in HRQOL scores was reported in the literature during the first year after treatment.

It must be noted that different methods (even non-standardized and non-validated) were used to assess patients’ comorbidity status. In our opinion, it is strongly preferable to use one of the several scoring systems and scales widely adopted elsewhere in the literature, as well as the Kaplan–Feinstein Index (KFI)—which was developed to evaluate comorbidities in diabetes mellitus [ 57 ] and subsequently modified and validated by Piccirillo [ 58 ]—or the Adult Comorbidity Evaluation 27 (ACE-27) [ 59 ]—which also includes alcohol abuse.

4.1.4. Alcohol, Smoke, and Educational Level

The effects of alcohol consumption and smoking were investigated only by Bozec et al. [ 27 ], who found no correlations with HRQOL conversely to other findings reported in the literature [ 60 , 61 ]. To clarify the roles of smoking and alcohol consumption in determining HRQOL, the comparison to some control groups composed of teetotalers and non-smokers should be required. Unfortunately, it would be extremely challenging to obtain adequate sample sizes to allow them to be reliably compared. Smoking and alcohol intake are the main risk factors for the development of OCC [ 62 ].

The correlations between HRQOL and educational level were analyzed by Bozec et al. [ 27 ] and Huang et al. [ 33 ], both retrieving no associations.

Interesting results would be expected from an investigation into educational level in larger cohorts. In this regard, it might be preferred to achieve standardized subgroups by using validated evaluation tools, as well as the International Standard Classification of Education (ISCED) [ 22 ].

4.2. Disease- and Treatment-Specific Variables

4.2.1. cancer site.

Although HRQOL in HNC patients has gained great relevance during recent decades, most published studies still have not considered that cancer site might have a significant impact [ 34 , 37 , 42 , 46 , 50 , 63 ]. Indeed, the most common reason for exclusion in the screened articles was directly related to this aspect ( Figure 2 ). This potential source of bias is scantly contemplated concerning the HNC regions (e.g., oral cavity, oropharynx, larynx, etc.), and much less considering oral subsites.

Interestingly, findings reported by Kovacs et al. [ 37 ] demonstrated that cancers arising from different oral subsites differently affect HRQOL, while Pierre et al. [ 46 ] and van Gemert et al. [ 48 ] found no significant variations. Such controversies should be addressed by analyzing larger samples that allow performing a more reliable data stratification. At the same time, it must be highlighted that the cohort selection would overcome this issue by including more homogeneous cases, as performed by some included articles [ 28 , 31 , 38 , 39 , 45 ].

4.2.2. Cancer Stage

Most likely, the cancer stage represents one of the most challenging variables to correlate with HRQOL, since the multitude of baseline confounding must be considered. For example, compared to early-stage cancers, advanced stages require more frequently adjuvant therapies and they need more extensive surgeries, which may include a mandibular resection, implying more demanding reconstruction strategies. The appraisal of findings reported by Beck-Broichsitter et al. [ 24 ] and Becker et al. [ 23 ] provided a clear demonstration of possible controversies that could be encountered due to some omitted variable biases. The authors compared the same T-stage subgroups (Tis-2 vs. T3/4) and one found no significant differences, while the other reported worse results for almost all questionnaire items in advanced-stage cancers. Controversies like this are repeatedly presented in the screened papers, some reporting no differences [ 25 , 27 , 36 , 49 ], others reporting substantial ones [ 9 , 33 , 34 , 46 ].

In our opinion, the cancer stage could be considered in a wider context, including almost all baseline confounding. The only exception is represented by those middle-stage cancers that could or could not be eligible for adjuvant therapies based on clinical and histological features. Future studies will provide adequate piece of evidence to reliably correlate these variables.

4.2.3. Mandibular Resection

Although it has been previously stressed that mandibular resection strongly impairs patients’ HRQOL [ 16 , 64 ], the generic findings of included studies are inconsistent. Becker et al. [ 23 ] were the sole researchers reporting worse results in patients undergoing mandibular resection compared to those who did not. A mandibular resection group was also studied distinguishing marginal from segmental resections. Unsurprisingly, the former demonstrated better questionnaire results.

Like most of the selected variables, the controversies observed among included articles suggest the existence of baseline confounding. We suppose that the need for adjuvant therapies (particularly the RT), the reconstruction, the cancer stage, and the extent of surgical resection could be the most probable sources of bias, since the mandible involvement is commonly associated with advanced cancer stages.

4.2.4. Extent of Resection

Van Gemert et al. [ 48 ] were the sole researchers who stratified the studied sample according to the extent of resection (specifically in the horizontal size). Conversely to what was documented elsewhere [ 16 , 65 ], they reported minimal differences. Since the current knowledge in reconstructive techniques allows surgeons to adequately restore even complex and extended defects, the authors suggest that accurate and successful reconstructions could justify these findings. We agree with this hypothesis, despite the fact that surgical complications and secondary surgery must be excluded or carefully examined during data analysis to ensure the absence of possible omitted variable biases. Thus, influences from the aforementioned baseline confounding (see cancer stage paragraph) should be considered.

4.2.5. Surgical Approach

Within the included studies, the impact of the surgical approach on HRQOL was supposed to explain some of the findings. Ferri et al. [ 31 ] were the only ones who considered this variable for data analysis. They compared two different treatment protocols: transoral partial pelviglossectomy followed by a buccinator artery myomucosal flap versus a pull-through partial pelviglossectomy followed by various free flaps. Significantly better results were reported in the former group.

The comparison of different surgical protocols implies taking into account some baseline confounding. For example, the pull-through resection involves various deep structures of the mouth floor that can more likely be restored by using free flaps [ 66 ], as clearly recognized by the authors. The cancer stage, adjuvant therapies, and the extent of resection also represent possible baseline confounding variables, since the cancer extent might force the surgeon to choose more invasive surgical approaches.

As reported elsewhere in the literature, the surgical approach seems to impact HRQOL in treated patients. Although disease-free survival still represents the primary outcome, minimally invasive approaches should be considered whenever it is possible, in order to reduce post-operative morbidity [ 67 , 68 , 69 , 70 , 71 ].

4.2.6. Neck Dissection

Some contradictory results were retrieved from the included studies concerning the ND as an HRQOL determinant. Kovacs et al. [ 37 ] described progressively worse results comparing patients who did not receive ND to those treated by selective ND (lev. I–II) and those by type III modified radical ND. We agree with the authors’ opinion about the possibility of baseline confounding since patients undergoing ND most frequently even underwent adjuvant RT. Future studies comparing patients receiving RT/CRT only and those treated by surgery with neck dissection and adjuvant RT/CRT will probably clarify these doubts.

4.2.7. Reconstruction

Unsurprisingly, reconstruction was the most investigated among surgery-related variables. It is commonly believed that the quality of reconstruction is strictly associated with patients’ functional and aesthetic outcomes and post-treatment HRQOL [ 72 , 73 ]. Knowledge in reconstructive surgery has been taking great strides forward since free flaps were introduced for the restoration of head and neck defects [ 72 , 73 , 74 ]. Performing a systematic review of the literature on reconstructive strategies in patients not eligible for free flaps, we surprisingly highlighted a growing interest toward more conservative solutions over the last few years [ 75 , 76 , 77 ].

Despite the huge literature, reconstruction still raises disputes about which surgical reconstructive protocol is the best to restore oral defects [ 78 , 79 , 80 , 81 , 82 , 83 ]. Similarly, the findings reported by included studies showed widely controversial results. In this regard, it should be noticed that huge differences within the studied populations do not permit a reliable comparison of the observed outcomes. In our opinion, the evaluation of the impact of reconstructive procedures on HRQOL implies several risks of bias that must be considered. For instance, careful attention should be paid to patients who developed surgical complications, by excluding them or by performing an accurate sample stratification. Furthermore, the related complications may heavily impair the functional outcome, requiring a much longer recovery time, long-term rehabilitation programs, or even secondary surgery. Moreover, according to the chosen procedure, free flaps may lead to various donor site morbidity [ 84 , 85 ]. All these aspects should be considered for their potential effects on HRQOL.

Reconstruction strategies are mainly chosen according to the defect size and composition: small to moderate simple defects may benefit from reduced donor site morbidity by performing local flaps, while large and/or composite defects need free or regional flaps to be restored [ 75 , 86 ]. Therefore, the evaluation of the reconstruction as an HRQOL determinant should consider some baseline confounding variables, such as the cancer stage, the extent of resection, the mandibular involvement, and the adjuvant therapies. None of the included studies considered simultaneously all these independent variables during the data analysis. Conversely, many of them investigated various reconstructive procedures grouping different flaps together. In our opinion, a reliable comparison should firstly consider the studied flaps separately to minimize evitable biases.

4.2.8. Radiotherapy and Chemotherapy

Almost all the included studies agreed about the deteriorating effects of radiotherapy on HRQOL. Kovacs et al. [ 37 ] performed an accurate study comparing patients who received adjuvant RT, adjuvant CT, or adjuvant CRT. Interestingly, there were no significant differences between adjuvant RT and adjuvant CRT groups, which both demonstrated significant worse results compared to patients who did not undergo post-surgical therapies.

Some symptom-related items were found to be particularly affected: dry mouth, sticky saliva, and mouth opening were almost always impaired. These findings were in line with those already widely reported in the published literature [ 87 , 88 , 89 , 90 , 91 , 92 , 93 ].

The evaluation of HRQOL demonstrated less interest in studying the effects of neoadjuvant therapies and adjuvant CT alone. This could be attributed to the uncommon use of these treatment protocols in HNC and it would be interesting to investigate the existence of different influences on HRQOL between neoadjuvant therapies and post-surgical ones.

Further compelling aspects derive from the adopted RT technique. The accurate analysis performed by Huang et al. [ 33 ] underlined that the most recent 3D radiotherapy (3DRT) and the intensity-modulated radiotherapy (IMRT) result in a better impact on patients’ HRQOL, as largely accepted in the current literature [ 94 , 95 ]. Nevertheless, most included studies did not specify which techniques were used in the studied samples, producing a relevant source of bias.

As mentioned above, adjuvant therapies suffer from several baseline confounding factors that should be always considered during the data appraisal. Nonetheless, the trends in the reported findings overtly suggest that it can be considered as one of the main HRQOL influencing factors.

4.2.9. Synchronous Lesions, Recurrences, and Metachronous Lesions

Although rare, the presence of synchronous lesions in the oral cavity inevitably requires larger resective surgeries that negatively influence the HRQOL, but only three studies clearly excluded these patients [ 28 , 31 , 49 ].

On the other hand, it might appear obvious that a recurrence of previously treated tumors or the development of further cancers may strongly impair HRQOL, especially by affecting psychological status and symptoms [ 96 , 97 , 98 ]. Nevertheless, only 12 of the included papers considered this aspect during cohort selection [ 24 , 26 , 31 , 33 , 34 , 35 , 36 , 39 , 42 , 46 , 48 , 49 ]. Mair et al. [ 39 ] were the only ones who conducted an analysis to compare disease-free patients to those who developed a recurrence. Their results strongly support the initial hypothesis, but we should make a point to note the potential sources of bias that might be encountered. Indeed, progression-free survival strongly depends on the cancer stage, which also reflects the invasiveness of the adopted treatment.

4.2.10. Major Surgical Complications and Secondary Surgery

Only a minority of the included studies considered these variables. Girod et al. [ 32 ] investigated the differences between the reconstruction of OC defects by using split thickness skin graft and acellular dermal matrix. They stratified the results by surgical complications, distinguishing patients who experienced a graft failure from those with regular healing. No significant differences were found, but the small sample size and the missing stratification by other variables might have affected their results.

It is reasonable to believe that post-surgical complications and recurrences may impact the HRQOL. In our opinion, this might be related to the resulting functional and aesthetic impairments or to the need for secondary surgery, which may impair the psychological status and the symptoms [ 96 , 97 , 98 ]. The included studies did not investigate this relation and it could be an interesting food of thoughts for future studies.

4.2.11. Other Variables

The increasing knowledge in multidisciplinary management of oncological patients strongly highlights the relevance of the psychological status [ 99 ]. The HRQOL is considered useful not only to evaluate the quality of care interventions from the patient’s perspective but also to adjust clinical decision making by evaluating patients’ needs and additional interventions, such as psychological counselling [ 100 ]. The close relationship between psychological status and HRQOL was demonstrated to predict the quality of life in patients treated for HNC [ 101 ].

Expressions of poor psychological status were investigated among the included studies. Moubayed et al. [ 40 ] and Bozec et al. [ 27 ] observed a negative correlation between depression and HRQOL, as measured by using the Hospital Anxiety and Depression Scale (HADS), while Airoldi et al. [ 22 ] supported this observation after evaluating associations with the Dische Scale. In our opinion, obtaining information on patients’ psychological status is mandatory to avoid biases that could impair the reported observations. Stratifying results by using validated and standardized indexing systems could address this issue.

Dental restoration represents one of the most interesting fields in searching for treatment-related aspects that could improve the HRQOL in OC patients. Usually, dental status has been already impaired at baseline and not only in those who suffered from cancers involving the jaws. The dental prosthetic restoration (supported or not by implants) could be a deeply influencing factor in patients’ everyday life and HRQOL. The recovery of dental occlusion and a balanced mastication has been demonstrated to influence aesthetic outcomes, social parameters, swallowing and cognitive functions [ 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 ]. The published literature expressed highly significantly better results in patients undergoing micro-vascular mandibular reconstruction (mostly by using free fibula flap) with following implant-supported dental prosthetic rehabilitation compared to non-rehabilitated patients [ 108 , 109 , 110 , 111 , 112 ]. Unfortunately, most of these articles included non-oncological patients within the investigated population and did not meet the inclusion/exclusion criteria.

A potential limitation of this review could be the exclusion of papers that used other evaluation tools. We chose to select only those studies based on EORTC questionnaires because of the comprehensive insight given by the assessment of general (by the QLQ-C30 module) and specific (by the QLQ-H&N35/43 modules) features, addressing the widespread use of these questionnaires. Further studies could provide a comparison with other tools.

5. Conclusions and Recommendations for Future Studies

The number of controversies found in the current literature demonstrates a substantial lack of evidence regarding HRQOL determinants in HNC patients. Therefore, none of the potential influencing variables should be excluded from data analysis based on the authors’ opinion only.

Currently, many of the published articles considered a minority of potential determinants. The data analysis is commonly performed on the basis of each independent variable individually. By approaching such a complex and multidimensional aspect as the HRQOL in this way, the reliability of the reported findings might be strongly weakened due to several selection and omitted variable biases that could be encountered. Since the EORTC Quality of Life Group was founded in 1980, a standardized guideline for cohort selection is still lacking. Thus, the crucial task to avoid the described biases is charged to examiners’ knowledge only.

We strongly believe that almost all the identified determinants should be investigated. This implies that much larger samples and much more data must be collected. At the same time, particular attention should be paid to cohort selection to achieve better comparability among the studies. This scope will probably be attained by creating a shared and standardized online data set.

Considering the complex net of baseline confounding highlighted in this manuscript, a suitable strategy could be the use of further evaluation tools, scales, and indexes that condenses many variables in a single score. In our opinion, the benefits from this approach are twofold: a simplification of data analysis and a minimization of omitted variable biases. In this regard, an interesting investigation was performed by Tribius et al. [ 113 ] regarding the influence of sociodemographic variables on HRQOL in HNC patients. This study used an adapted version of a composite social class indicator [ 114 ] that considered three different sociodemographic variables (educational level, type of occupation, and household income) to differentiate the socio-economic status as high, moderate, or low. Other examples were reported within the discussion of this review (G8, ACE-27, KFI, HADS), but those were related to sociodemographic and psychological variables. To the best of our knowledge, no scoring systems that condense the selected DT-specific variables have been developed yet. Our recommendation for future research is to consider these features simultaneously, rather than individually, addressing the baseline confounding described above, and to select cohorts that are as homogeneous as possible. An example of this protocol is given by Ferri et al. [ 31 ] and Canis et al. [ 28 ], who performed some accurate cohort selections resulting in quite a small sample size, but one that was highly homogeneous and reproducible.

As observed by Borggreven et al. [ 25 ], patients usually present compromised HRQOL at the baseline, probably due to preexisting impairments related to comorbidity status or cancer diagnosis. We believe that this issue could be addressed by evaluating only the differences between baseline and post-treatment questionnaires in a longitudinal study design, rather than in absolute scores compared to a reference population in a cross-sectional fashion, even though the interquestionnaire analysis may highlight interesting insights [ 44 ].

As a result of this approach, more homogeneous, reproducible, and comparable cohorts will be expected, enhancing the level of evidence in the field.

Acknowledgments

We would like to thank Nicola Catena, who provided insight and expertise that greatly assisted the research, and Cecilia Moraci for providing us with writing assistance.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/cancers13174398/s1 , Table S1: PRISMA-ScR Checklist, Table S2: Reason for the exclusion after full-text reading, Table S3: Data extraction, SDG variables, Table S4: Data extraction, DT variables.

Author Contributions

Conceptualization, D.D.C.; methodology, D.D.C. and G.C.; software, D.D.C.; validation, G.T., F.C. and G.C.; formal analysis, D.D.C.; investigation, D.D.C., C.S. and A.T.; resources, R.R.; data curation, D.D.C. and C.S.; writing—original draft preparation, D.D.C., C.S. and G.L.G.; writing—review and editing, R.R., F.F., M.F., G.L.G. and A.T.; visualization, D.D.C. and M.F.; supervision, G.T., F.C., M.F. and F.F.; project administration, D.D.C.; funding acquisition, none. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Data availability statement, conflicts of interest.

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Role of Poor Oral Hygiene in Causation of Oral Cancer-a Review of Literature

Affiliation.

• 1 Dept. of Head and Neck Surgery, Tata Memorial Centre, Parel, Mumbai 400012 India.
• PMID: 30948897
• PMCID: PMC6414580
• DOI: 10.1007/s13193-018-0836-5

Oral squamous cell carcinomas (OSCC) are among the commonest cancers in South East Asia and more so in the Indian subcontinent. The role of tobacco and alcohol in the causation of these cancers is well-documented. Poor oral hygiene (POH) is often seen to co-exist in patients with OSCC. However, the role of poor oral hygiene in the etio-pathogenesis of these cancers is controversial. We decided to evaluate the available literature for evaluating the association of POH with OSCC. A thorough literature search of English-language articles in MEDLINE, PubMed, Cochrane Database of Systematic Reviews, and Web of Science databases was conducted, and 93 relevant articles were short-listed. We found that POH was strongly associated with oral cancers. It aids the carcinogenic potential of other known carcinogens like tobacco and alcohol. Even on adjusting for known confounding factors like tobacco, alcohol use, education, and socio-economic strata, presence of POH exhibits higher odds of developing oral cancer.

Keywords: Dental visits; Missing teeth; Mouth neoplasm; Oral cancer; Poor oral hygiene; Tooth brushing.

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• Volume 14, Issue 5
• Effectiveness of educational and psychological survivorship interventions to improve health-related quality of life outcomes for men with prostate cancer on androgen deprivation therapy: a systematic review
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• http://orcid.org/0000-0001-9268-5331 Sally AM Sara 1 ,
• http://orcid.org/0000-0001-8102-1871 Nicole Heneka 2 ,
• http://orcid.org/0000-0002-7541-3665 Anna Green 2 ,
• http://orcid.org/0000-0003-2369-6111 Suzanne K Chambers 2 , 3 ,
• http://orcid.org/0000-0002-1180-3381 Jeff Dunn 2 , 4 ,
• http://orcid.org/0000-0003-4154-8526 Victoria R Terry 1
• 1 University of Southern Queensland , Toowoomba , Queensland , Australia
• 2 University of Southern Queensland , Springfleld , Queensland , Australia
• 3 Australian Catholic University , Brisbane , Queensland , Australia
• 4 Prostate Cancer Foundation of Australia , St Leonards , New South Wales , Australia
• Correspondence to Sally AM Sara; sally.sara{at}unisq.edu.au

Objectives Androgen deprivation therapy (ADT), a common treatment for prostate cancer, has debilitating impacts on physical and psychological quality of life. While some interventions focus on managing the physical side effects of ADT, there is a paucity of interventions that also address psychosocial and educational needs. The objective of this systematic review was to identify psychological and educational survivorship interventions targeting health-related quality of life (HRQoL) outcomes in men on ADT.

Design A systematic review of randomised controlled trials.

Data sources Web of Science, Cochrane, EBSCO Host, PubMed, SCOPUS from inception (1984) to 28 January 2023.

Eligibility criteria for selecting studies Psychological and/or educational survivorship interventions targeting HRQoL outcomes for men on ADT; minimum 80% of participants on ADT; used a validated HRQoL outcome measure; published in English in a peer-reviewed journal.

Data extraction and synthesis Data extraction using pre-specified study criteria was conducted. Heterogeneity of eligible studies precluded a meta-analysis.

Results A total of 3381 publications were identified with eight meeting the criteria. Interventions were either psychological with a cognitive behavioural approach (n=4), or educational with (n=2) or without (n=2) psychoeducational components.

Two studies reported a statistically significant improvement using a specific HRQoL measure. Most studies were not adequately powered and/or included small sample sizes limiting the conclusions that can be drawn on effectiveness. The most effective interventions were (i) individually based, (ii) educational with a psychoeducational component, (iii) supplemented with information packages and/or homework and (iv) included personalised needs assessments.

Conclusion There is a paucity of literature reporting psychological and educational survivorship interventions targeting HRQoL outcomes for men on ADT. What is urgently needed are person-centred survivorship interventions that are flexible enough to identify and address individual needs, taking into account the impact ADT has on both physical and psychological quality of life.

PROSPERO registration number CRD4202230809.

• Prostatic Neoplasms
• Clinical Trial
• Health Education
• MENTAL HEALTH
• Nursing Care

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/ .

https://doi.org/10.1136/bmjopen-2023-080310

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STRENGTHS AND LIMITATIONS OF THIS STUDY

To our knowledge, this is the first systematic review of educational and psychological-related interventions aiming to improve or maintain health-related quality of life in men on androgen deprivation therapy.

The focus on randomised controlled trials ensures a review of the highest level of evidence in relation to the effectiveness of educational and/or psychological interventions.

A number of studies had small sample sizes, and some had very short follow-up times so findings may not have fully reflected the men’s experience over time.

Not all included studies were adequately powered, and two were powered for a pilot study only, so caution is needed in interpreting results.

Only studies published in English were included; hence, studies conducted in non-English speaking countries may have been missed.

Introduction/background

Prostate cancer is the second most commonly diagnosed cancer globally in men and a significant cause of morbidity and mortality. 1 Androgen deprivation therapy (ADT), also known as hormone therapy, describes a common form of prostate cancer treatment that blocks the production of the male androgen testosterone, a hormone that stimulates the growth of prostate cancer cells. By reducing the amount of testosterone circulating in the body, the growth of prostate cancer is slowed, inhibiting progression of the cancer and increasing survival. ADT is the mainstay treatment for metastatic prostate cancer and routinely used as adjuvant or neo-adjuvant treatment with radiation therapy for intermediate to high-risk localised and locally advanced disease. Although very effective in reducing disease progression, the side effect profile is debilitating with significant impact on physical, psychological, sexual and metabolic health. 2 3

Men undergoing ADT lose muscle mass and bone mineral density, increasing risk of falls and bone fractures, and are at greater risk of death from cardiovascular disease. 4 5 Moreover, men report a profound impact on health-related quality of life (HRQoL) from testosterone loss, in particular changes to mood and cognition, loss of sexual function and libido, hot flushes and physical changes such as genital shrinkage, weight gain and growth of breast tissue. Reports in the literature indicate that men on ADT have significantly lower HRQoL scores than other prostate cancer treatments such as brachytherapy, external beam radiation therapy (without adjuvant ADT) and radical prostatectomy. 6 In addition to treatment side effects, men undergoing androgen deprivation live with the knowledge that they have high-risk localised, locally advanced or metastatic prostate cancer. Rates of depression in men with prostate cancer are higher than the general population, and higher again in men treated with ADT. 7–9 Of further concern, men diagnosed with prostate cancer have a 70% higher risk of suicide when compared with the general population, with men undergoing ADT at increased risk of suicidal ideation. 7

Survivorship care is an essential component of quality cancer care. Prioritising quality of life and well-being across the cancer trajectory, survivorship care incorporates the psychological, physical, social, emotional, financial and spiritual effects of cancer, from the point of diagnosis through the rest of life. 10 Survivorship interventions target short and long-term physical and/or psychosocial effects of the cancer and treatment. 11 Placing men with prostate cancer at the centre of their care, prostate cancer survivorship interventions should be widely accessible and take into account educational, psychosocial and informational needs in addition to physical activity, exercise medicine and nutritional interventions. 12 13 Consistent with current trends in prostate cancer survivorship care, intervention development and delivery should be guided by contemporary best practice frameworks that support responsive and coordinated short and long-term survivorship care. 12 There is a plethora of studies reporting the benefits of exercise medicine on the physical and psychological well-being of men on ADT, including increased muscle strength and weight control, lessening of fatigue and improved emotional well-being and quality of life. These studies have been soundly reviewed and reported in a number of recent systematic reviews focusing on the benefits of exercise in managing ADT-related toxicities and supporting the view that referral to tailored exercise programmes should be considered standard of care when prescribing ADT for the treatment of prostate cancer. 14–16 Further systematic reviews report specifically on the positive impact of exercise on quality of life. 17 18 Similarly, there is evidence relating to the impact of lifestyle modification including exercise and nutrition on maintaining HRQoL in men on ADT. 19 20 Despite the success of these interventions, men on ADT report significant unmet informational and supportive care needs in relation to the impact of treatment for prostate cancer on their lives, including loss of masculinity, reduced sense of control, fear of death and dying, uncertainty around disease progression, insomnia, hot flushes, sexual dysfunction and mood changes. 21–23 Physical changes, growth of breast tissue, loss of hair and genital shrinkage can have a profound psychological effect with men feeling like their bodies have undergone a feminisation process causing embarrassment, grief and decreased self-esteem. 24

With an estimated 30% to 50% of men diagnosed with prostate cancer undergoing ADT at some stage in their treatment trajectory, 25 and with a growing number of prostate cancer survivors predicted over the next few decades, 26 there is a critical need clinically for interventions that aim to improve overall health and HRQoL for men undergoing androgen deprivation, in addition to the benefits delivered by exercise and nutritional programmes. 8 22 27 This requires a systematic review and synthesis of the evidence in relation to key components and modes of delivery of educational and psychological survivorship interventions that are effective in improving HRQoL outcomes with the view to informing future intervention design.

This systematic review of the literature aims to (1) identify educational and/or psychological survivorship interventions (‘interventions’) targeting health-related quality of life outcomes for men with prostate cancer on ADT and evaluate their effectiveness and (2) analyse the key components and modes of delivery of these interventions to inform future intervention design.

This systematic review of randomised controlled trials was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020 Statement. 28 The review protocol was prospectively registered with PROSPERO (ID # CRD42022308096). No patients or public were involved in the study design.

Eligibility criteria

Inclusion criteria.

Studies were included if they met the predetermined criteria for review: (1) compared an educational and/or psychological survivorship intervention targeting HRQoL outcomes for men on ADT with standard care or another intervention, (2) randomised controlled trial study design with at least 80% of participants on ADT, (3) used a validated HRQoL measure to report primary or secondary outcomes and (4) available in English and published in a peer-reviewed journal.

For the purposes of this review, HRQoL was defined as specific health characteristics (such as health status, fitness, well-being and satisfaction) while also taking into account general quality of life factors such as physical, psychological, social and environmental factors. 29 There are a variety of validated instruments designed to measure HRQoL, including those that measure HRQoL more generally, and those that are more disease-specific.

Exclusion criteria

Studies were excluded if they described (1) interventions for men on ADT that did not report on HRQoL outcomes or did not use validated HRQoL measures; (2) surgical, radiological or pharmaceutical interventions; (3) interventions using nutritional or dietary supplements or other ingestive therapies; (4) exercise and/or nutritional and dietary interventions; (5) complementary and alternative medicine (CAM) interventions; (6) case reports, conference abstracts, editorials and studies not of randomised controlled trial design; and (7) studies not reported in English or published in a peer-reviewed journal.

Information sources and search strategy

Five electronic databases and search platforms were searched using key search terms: Web of Science, Cochrane, EBSCO Host, PubMed and SCOPUS. A search strategy was created and refined with the assistance of a health research librarian at the University of Southern Queensland ( online supplemental material 1 ).

Supplemental material

Terms within each set were combined using the Boolean ‘OR’ operator, and the sets were combined using the ‘AND’ operator. Potential search terms were trialled and mapped to indexed medical subject headings terms including prostatic neoplasms, randomised controlled trial and survivorship. Key search terms included prostate cancer, androgen deprivation therapy, randomised controlled trial, quality of life, side effects and survivorship. Reference lists of included articles were also searched.

All searches were run from database inception to 28 January 2023.

Data collection, extraction and synthesis

Identified articles from each database were imported into EndNote. After removing duplicates, the remaining titles and abstracts were imported into COVIDENCE. Initially, 10% of papers were independently reviewed against the eligibility criteria by three authors to check the inter-rater reliability (SS, NH and AG). The remaining title and abstracts were equally distributed between the same three authors who undertook independent review. Any disagreements were resolved by discussion until consensus was reached.

Full-text versions of potentially eligible studies were reviewed and screened against the eligibility criteria by one author (SS) using a data extraction table. Articles identified as meeting the inclusion criteria were checked by a second reviewer (NH). There were no disputes to resolve.

Data extraction using pre-specified study criteria was conducted by one author (SS) and checked by a second author (NH). Data extraction included study setting; participant demographics; study characteristics; intervention type, aim and outcomes measured; and results. Intervention characteristics extracted included intervention type and mode of delivery; content and components; frequency and duration. Outcomes included patient-reported HRQoL outcomes such as emotional, physical, social and functional well-being in addition to anxiety, depression, self-management and prostate cancer-specific HRQoL outcomes.

Due to the heterogeneity of the eligible studies (ie, diversity in outcome measures, duration, modes of delivery and aims), a meta-analysis was not conducted. This review followed Popay et al .’s guidance on the conduct of narrative synthesis in systematic reviews. 30

Study risk of bias assessment

Risk of bias was assessed by the lead author (SS) and independently checked by a second author (NH) using the Critical Appraisal Skills Programme Randomised Controlled Trials Standard Checklist. 31 Although the overall quality of the included studies was sound, and all studies had a clear protocol and research aims, there were some differences in the way some methods were presented. However, there were no issues around quality that led us to exclude a study. A detailed summary of the quality appraisal results can be found in online supplemental material 2 .

Patient and public involvement

Study selection.

The initial searches identified 3378 unique records with an additional three articles identified through other sources. Following removal of duplicates and title and abstract screening, 251 articles were included for full-text review. Eight publications 32–39 met the pre-established eligibility criteria and were included in the review (refer figure 1 ).

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Flowchart of studies through the review process.

Study characteristics

All studies were published since 2004. Three studies were from the USA, 35 38 39 one from Denmark 33 and one each from Australia, 32 Scotland, 34 England 36 and Northern Ireland. 37 Two studies were conducted using web-based technology, 38 39 two were telephone-based 32 36 and four involved in-person sessions in outpatient settings. 33–35 37 Six studies reported 100% of participants on ADT 34–39 and the remaining two studies reported greater than 89% on ADT. 32 33 Refer to online supplemental table 1 for a summary of included studies.

A total of 656 men participated in the studies. Mean age of male participants across all studies ranged from 66.0 to 74.9 years, with an overall mean age of 69.2 (SD±2.6) years. Only four studies recorded time since diagnosis 32 36 38 39 which ranged from 2.1 to 6.6 years. Three studies included men with advanced prostate cancer, 32 34 39 three studies included men with either localised or advanced disease 33 35 36 and two studies did not report stage of disease at all. 37 38

All studies were described as randomised controlled trials and involved two arms (an intervention and a control). 32–39 Of the control arms across the eight studies, six were described as ‘Usual Care’, 33–38 one as ‘Minimally Enhanced Usual Care’ 32 and one as ‘Health Promotion Attention Control’. 39

All studies included as a primary or secondary outcome, a specific HRQoL measure comprising general health, cancer-related or disease-specific quality of life plus additional outcome measures such as anxiety, distress, depression, coping styles, fatigue, physical activity, hot flushes, night sweats, cognitive functioning, supportive care needs, disease knowledge and self-efficacy (refer online supplemental table 1 ). Several general and disease-specific instruments were used to measure HRQoL outcomes across the studies. Two studies 33 35 used the general health-related HRQoL Medical Outcome Study Short Form-12 (SF-12) 40 to measure the impact of health on everyday life. 29 Two studies 37 39 used the Functional Assessment of Cancer Therapy - General (FACT-G) 41 to measure cancer-related HRQoL. Two studies 34 36 used the European Organisation for Research and Treatment of Cancer Study Group on Quality of Life Questionnaire (EORTC QLQ-C30) 42 to assess themes relevant to people with cancer, and two studies 32 37 used the Functional Assessment of Cancer Therapy - Prostate (FACT-P) 41 to assess prostate cancer-specific HRQoL. In addition to using SF-12 to assess general HRQoL, one study used the Expanded Prostate Cancer Index Composite (EPIC) 33 to measure prostate cancer symptom-related HRQoL. All studies assessed participants at baseline and between 4 weeks and 9 months post intervention.

Intervention characteristics and outcomes

Interventions delivered tended to be either psychological 32 36 38 39 or educational, 35 37 with two educational interventions also including a psychoeducational component 33 34 (refer online supplemental table 2 and figure 2 ). For the purposes of this review, interventions delivering cognitive behavioural or relaxation therapy, or cognitive training delivered by a health professional were categorised as psychological interventions. Educational interventions included information about treatment and physical symptoms and side effect management (with no cognitive behavioural approaches) and were delivered primarily by nurses or in combination with other members of the healthcare team such as physical therapists, clinicians or trained facilitators

Matrix of outcomes and intervention characteristics.

Psychological interventions

There were four psychological interventions. 32 36 38 39 One involved cognitive behavioural stress management (CBSM) interventions, 39 one cognitive behavioural therapy, 36 one mindfulness-based cognitive therapy 32 and one computerised cognitive training. 38 The content of two interventions 36 39 included information on ADT side effects in addition to the cognitive approaches. Mode of delivery was web-based 38 39 or phone-based. 32 36 Two interventions were group-based 32 39 and two were individual only. 36 38 All four included homework in the form of a practice programme or diary, three had some degree of supervision 32 and one was a fully self-directed online package. 38

None of these psychological interventions demonstrated a statistically significant improvement on HRQoL measures but two studies showed an improvement in HRQoL-associated outcomes on symptom burden and depressive symptoms. 36 39 Notably, however one of these studies, 36 while powered to detect a clinically significant difference in hot flush and night sweat rating, reported a modest sample size in each arm. The authors of the other study 39 reported that the study was underpowered to detect significant intervention effects.

Educational interventions with psychoeducational component

There were two educational interventions that included a psychoeducational component. 33 34 Both interventions were individually based and delivered in person. They included explicit side effect management education and included written information packages. Both involved assessment of individual needs to enable delivery of a personalised, tailored intervention and involved a multidisciplinary approach (delivered by nurses and/or allied health professionals).

One study demonstrated a statistically significant improvement in HRQoL outcome on SF-12 (physical component summary p=0.002). 33 This study was both powered sufficiently and demonstrated a small to moderate effect size on prostate cancer-specific symptom bother and physical HRQoL. The second study 34 was powered for a pilot trial sample size and did not report effect size. While not demonstrating statistically significant HRQoL outcomes over time, this study did demonstrate statistically significant reduction in unmet supportive care needs in the intervention group at 3 months compared with control (p=0.002), with greatest improvements in the following domains of unmet needs: physical symptoms, fear of cancer spreading, fear of death and dying, changes in sexual feelings, informational needs and self-management.

Educational interventions with no psychoeducational component

There were two educational interventions with no psychoeducational content included. 35 37 Both interventions were individually based and involved in-person delivery sessions. The first was nurse-delivered and included an information booklet for participants to supplement the education session. 37 This intervention demonstrated a statistically significant improvement in HRQoL outcome in FACT-G (p<0.001) and FACT-P (p<0.001) between pre-test and post-test, with additional significant changes in emotional and functional well-being following FACT-P subscale analysis (p<0.01). 37 However, this study did not report power analysis or effect size and had a very short follow-up with the post-test questionnaire completed 4 weeks post intervention.

The second study involved multidisciplinary assessment and counselling on symptom management and was delivered by a dietitian, palliative care physician, and trainer. 35 There were no statistically significant differences between treatment arms for all primary and secondary outcomes nor did this study meet the recruitment target or report effect size.

Significant outcomes

Importantly, only two of the eight studies reported a statistically significant improvement using a specific HRQoL measure, namely FACT-G and FACT-P scales and the SF-12. One was a nurse-led educational intervention 37 and the other was a multidisciplinary educational intervention with psychoeducational components. 33 Both interventions were delivered in the individual setting, and included supplementary educational materials and specific information on the management of ADT side effects. 33 37 One additional study, 39 a CBSM web-based programme, reported a positive trend in functional well-being (p=0.06) and emotional well-being (p=0.07) on the FACT-G subscale.

Although only two studies showed statistically significant changes related to specific HRQoL outcomes, there were three studies that showed statistically significant improvement in associated outcomes such as symptom burden, anxiety and depressive symptoms and unmet supportive care needs. 34 36 39 Of these, 34 36 39 two were psychological interventions 36 39 and one was educational/informational in design and included psychoeducational components. 34

Irrespective of whether the statistically significant improvement was in HRQoL outcomes or an associated outcome, all five of these studies included homework or a supplementary information package and included specific information about ADT side effects. Four involved individual participation 33 34 36 37 and one was group-based. 39 Only two included individual needs assessment allowing for individual care planning and personalisation of the intervention for each participant. 33 34

This systematic review aimed to identify educational and psychological survivorship interventions targeting HRQoL outcomes for men with prostate cancer on ADT and analyse their key components, modes of delivery and their effectiveness in order to highlight any gaps in the literature and to inform future intervention design. Of the 3319 studies screened, only eight studies focused on addressing HRQoL issues for men on ADT. This small number of eligible studies indicates a lack of research into this area. Of note, the majority of included studies were not adequately powered and/or included small sample sizes limiting the conclusions that can be drawn on intervention effectiveness. Two reported small to moderate effect sizes in HRQoL outcomes 33 39 and three did not report effect sizes at all. 34 35 37 Consequently, caution needs to be applied when interpreting the findings including the studies that reported statistically significant changes.

The majority of included studies described interventions with cognitive-based psychological or psychoeducational components. Concerningly, only two studies demonstrated statistically significant improvements using a specific HRQoL measure. 33 37 One was a nurse-led educational intervention 37 which supports the evidence in the literature that nurse-led interventions lead to significant improvements in HRQoL. 43 The other was a multidisciplinary educational intervention with psychoeducational components. 33 Both interventions were delivered in the individual setting, and included supplementary educational materials and specific information on the management of ADT side effects.

In addition to the two studies reporting statistically significant HRQoL outcomes, a further three studies demonstrated significant associated outcomes that are likely to impact overall HRQoL, such as improvement in symptom burden, cancer-related depressive symptoms and supportive care needs. 33 34 36 37 39 Interestingly, what these five studies had in common was that they were clinician-led, primarily directed at individuals, included a supplementary information or homework package and included specific information about ADT side effects. All but one of the interventions demonstrating significant improvements were supervised which highlights the importance of participants feeling they are not alone by linking them to a person or team delivering the intervention. 44 45 Of note, only three of the eight studies were designed exclusively for men with metastatic prostate cancer. 32 34 39 We expected more given that men with advanced prostate cancer are recognised as being at risk of poorer psychosocial outcomes. 22 46 In our experience, studies focusing on men with metastatic cancer are harder to recruit for; however, retention rates may be higher if the mode of delivery caters for their needs, highlighting the importance for interventions to be designed so they can be tailored to men’s health and social needs, including modes of delivery that may lessen the impact of travel and appointment attendance. 22 43

Interestingly, no single intervention included cognitive behavioural approaches in addition to educational and psychoeducational aspects. This was unexpected as the literature indicates that multimodal approaches combining cognitive-behavioural and educational approaches addressing disease and treatment management information, side effect advice, stress management, and problem solving, goal setting and cognitive behavioural approaches have been shown to reduce distress and improve HRQoL outcomes in the cancer setting. 43 47–49 Surprisingly, across all eight studies, only two included individualised needs assessments enabling personalised care and tailoring of the intervention to each participant’s identified needs. 33 34 Both of these studies demonstrated a statistically significant outcome although only one showed a statistically significant change in a specific HRQoL outcome. 33 The other study 34 included a supportive care needs assessment which led to an individualised self-management plan, demonstrating an association between supportive care needs and HRQoL, with evidence in other studies that if supportive care needs are not met, HRQoL is impaired. 50 51 With a global trend towards personalised medicine and person-centred care, the design of future interventions addressing HRQoL for men on ADT should move away from a ‘one size fits all’ to an individualised approach. 12 52 Given the interplay between HRQoL and individual care needs it is vital that maintaining HRQoL should be a key goal in the delivery of person-centred survivorship care.

Until recently, models of care supporting the delivery of coordinated, accessible and personalised survivorship care have been missing from the prostate cancer setting. Since 2020, the Prostate Cancer Survivorship Essentials Framework 12 has provided a set of key domains that directly influence HRQoL in men with prostate cancer, yet when we reviewed the literature for examples of survivorship interventions that address these domains in the ADT setting (such as health promotion, vigilance, care coordination and personal agency), the results were sparse. Beyond exercise medicine and nutrition, there are very limited examples of effective survivorship interventions that address the informational, physical and psychological needs of men undergoing androgen deprivation. This void has implications clinically where psychological health issues can have a serious impact on HRQoL in men on ADT. Consequently, interventions that incorporate psychological care are paramount. 52 In addition, despite limited studies in this review demonstrating significant improvement educational interventions may have on HRQoL, education is a crucial component of health promotion and personal agency and access to personalised educational interventions should be considered a critical element of best practice survivorship care. For health professionals looking for examples of effective and accessible interventions they can translate and deliver into clinical practice, the lack of effective educational and psychological interventions is of concern.

This systematic review comparing intervention type, mode of delivery, content, duration and outcome suggests that the most effective characteristics of interventions aiming to improve HRQoL outcomes for men with prostate cancer on ADT are interventions that are (i) individually based, (ii) educational in design with a psychoeducational component, (iii) supplemented with home-based information packages with reading and/or activities and (iv) include personalised individual needs assessments. Cognitive-based psychological components may add to the effectiveness when delivered in conjunction with educational components but appear to be less effective when delivered as a standalone intervention. While we focused on studies that included a validated HRQoL measure, it is critical to remember that addressing factors such as anxiety, depression and fear of recurrence will impact on overall HRQoL. Ideally, interventions should commence early, aligning as close of possible to commencement of ADT, and include a multisession approach with ‘check in’ opportunities between men and their healthcare team when the side effects really start to take hold, recognising that informational and supportive care needs can vary over time. Supervised sessions that are individually tailored appear to have a higher chance of improving HRQoL. The inclusion of low-intensity psychological care with cognitive behavioural approaches should be considered in relation to future design, specifically in relation to stress and coping, problem solving and goal setting. 53

When designing interventions for men undergoing ADT, it is important that health professionals and researchers take into account the influence masculinity can have on health outcomes, and work to incorporate male preferences in terms of design and acceptability. 46 54 55 For example, a problem-solving approach can lead men to identify individual problems, explore solutions, set goals, test strategies and determine the best solution for them, with the ultimate goal to reduce or limit some of the sources of stress in their lives. 53 Competing demands between work, family and social commitments, and masculine ideals, such as stoicism and self-reliance can mean that men are reluctant to access services, and actively seek out support. 55 Interventions need to be accessible, men-centred and provide opportunities for targeted support tailored to the needs of the individual, using problem-solving approaches. In the clinical setting, consideration should also be given to access and equity with an increasing focus on technology. 56 At a minimum, interventions should include educational materials and information about the impact of ADT including side effect management, screening for distress and identification of problems and needs, leading to an individualised person-centred care plan. 57

Limitations

This review included studies published in English only due to financial costs and time factors relating to professional translation; hence, studies conducted in non-English speaking countries may have been missed. Web-based machine translation such as Google Translate was not employed due to concerns around evaluation of context, and degree of accuracy in the absence of word for word translation. 58 59

There were a number of studies with small sample sizes; some had very short follow-up times so findings may not have fully reflected the men’s experience over time. Moreover, not all the studies were adequately powered, and two were powered for a pilot study only, so caution is needed in interpreting results. Despite these limitations, to our knowledge, this is the first systematic review of educational and psychological-related interventions aiming to improve or maintain HRQoL in men on ADT.

It is well established that men on ADT often face severe decrements in quality of life. While there is a large body of literature describing the impact ADT has physically and psychologically, men still report significant unmet informational, educational and supportive care needs. There is limited evidence of interventions that effectively address these concerns. While there are many studies to mitigate ADT side effects using exercise, there is a scarcity of evidence evaluating the effectiveness of educational and psychological survivorship interventions on health-related quality of life, and what can be found appears to be hindered by small sample sizes and inadequate powering of studies. What is urgently needed are person-centred interventions that are flexible enough to identify and address individual needs, taking into account the impact ADT has on both physical and psychological quality of life.

When designing interventions for men undergoing ADT, it is imperative that health professionals and researchers incorporate men’s health behaviours, consider male preferences in terms of design and acceptability and incorporate cognitive behavioural approaches with educational and psychoeducational components. Interventions need to be accessible, use problem-solving approaches and provide opportunities for targeted support tailored to the needs of the individual. A one size fits all approach with no psychoeducational component or individual assessment is least likely to address HRQoL outcomes in a meaningful way.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

Acknowledgments.

The authors acknowledge the contribution of Ms Rowena McGregor, Health Librarian University of Southern Queensland, in the development of the literature search strategy.

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Contributors SS is the author responsible for the overall content as the guarantor. Planning for this paper was undertaken by SS, VT, SC, NH and JD. Data collection and management were undertaken by SS and reviewed by NH and AG. VT, JD, SC, NH and AG provided critical review of the article. All authors reviewed and gave final approval of the version to be published.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

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• Published: 24 May 2024

VER-Net: a hybrid transfer learning model for lung cancer detection using CT scan images

• Anindita Saha   ORCID: orcid.org/0000-0002-5780-9252 1 ,
• Shahid Mohammad Ganie   ORCID: orcid.org/0000-0001-9925-0402 2 ,
• Pijush Kanti Dutta Pramanik   ORCID: orcid.org/0000-0001-9438-9309 3 ,
• Rakesh Kumar Yadav   ORCID: orcid.org/0000-0002-0151-4981 4 ,
• Saurav Mallik   ORCID: orcid.org/0000-0003-4107-6784 5 &
• Zhongming Zhao   ORCID: orcid.org/0000-0002-3477-0914 6  

BMC Medical Imaging volume  24 , Article number:  120 ( 2024 ) Cite this article

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Lung cancer is the second most common cancer worldwide, with over two million new cases per year. Early identification would allow healthcare practitioners to handle it more effectively. The advancement of computer-aided detection systems significantly impacted clinical analysis and decision-making on human disease. Towards this, machine learning and deep learning techniques are successfully being applied. Due to several advantages, transfer learning has become popular for disease detection based on image data.

In this work, we build a novel transfer learning model (VER-Net) by stacking three different transfer learning models to detect lung cancer using lung CT scan images. The model is trained to map the CT scan images with four lung cancer classes. Various measures, such as image preprocessing, data augmentation, and hyperparameter tuning, are taken to improve the efficacy of VER-Net. All the models are trained and evaluated using multiclass classifications chest CT images.

The experimental results confirm that VER-Net outperformed the other eight transfer learning models compared with. VER-Net scored 91%, 92%, 91%, and 91.3% when tested for accuracy, precision, recall, and F1-score, respectively. Compared to the state-of-the-art, VER-Net has better accuracy.

VER-Net is not only effectively used for lung cancer detection but may also be useful for other diseases for which CT scan images are available.

Peer Review reports

Introduction

Lung cancer is one of the leading causes of cancer-related deaths globally. It is broadly classified as small and non-small-cell lung cancer [ 1 ]. Lung cancer is a significant contributor to cancer-related deaths worldwide, with the highest mortality rate among all types of cancer. According to the World Health Organization Footnote 1 , cancer is a significant contributor to global mortality, resulting in approximately 10 million fatalities in 2020, which accounts for roughly one out of every six deaths. WHO estimated that one in 16 people would be diagnosed with lung cancer worldwide by 2022. Figure  1 represents the incidence cases and deaths of cancers for both sexes and all age groups worldwide Footnote 2 . The x-axis represents the number of people, while the y-axis denotes the types of cancers. Amongst all cancers, lung cancer has a significantly higher mortality rate. Additionally, when considering the number of incident cases, lung cancer ranks second among all types of cancer.

Roughly one-third of cancer-related deaths can be attributed to tobacco usage, a high body mass index, alcohol consumption, inadequate consumption of fruits and vegetables, and a lack of physical activity [ 2 ]. In addition, international agencies for cancer research have identified several risk factors that contribute to the development of various cancers, including alcohol, dietary exposures, infections, obesity, radiation, and many more that contribute towards cancer diseases. Lung cancer is caused by the abnormal growth of cells that form a tumour and can have serious consequences if left untreated. Early detection and effective treatment can lead to successful cures for many forms of cancer. Also, it is crucial for improving the survival rate and reducing mortality [ 3 ].

Lung cancer is a respiratory illness that affects people of all ages. Symptoms of lung cancer include changes in voice, coughing, chest pain, shortness of breath, weight loss, wheezing, and other painful symptoms [ 4 ]. Non-small-cell lung cancer has various subtypes, including Adenocarcinoma, squamous cell cancer, and large cell carcinoma, and is frequently observed [ 5 ]. However, small-cell lung cancer spreads faster and is often fatal.

Over the decades, clinical pathways and pathological treatments for lung cancer have included chemotherapy, targeted drugs, and immunotherapy [ 6 ]. In hospitals, doctors use different imaging techniques; while chest X-rays are the most cost-effective method of diagnosis, they require skilled radiologists to interpret the images accurately, as these can be complex and may overlap with other lung conditions [ 7 ]. Various lung diagnosis methods exist in the medical industry that use CT (computed tomography), isotopes, X-rays, MRI (magnetic resonance imaging), etc. [ 8 , 9 ].

Manual identification of lung cancer can be a time-consuming process subject to interpretation, causing delays in diagnosis and treatment. Additionally, the severity of the disease infection may not be apparent on X-ray images.

Incident cases and mortality rate of different cancers

As artificial intelligence (AI) has advanced, deep learning has become increasingly popular in analyzing medical images. Deep learning is a technique that can automatically discover high dimensionality, as compared to the more intuitive visual assessment of images that is often performed by skilled clinicians [ 10 , 11 , 12 ]. Convolutional neural networks (CNNs) are promising for extracting more powerful and deeper features from these images [ 13 ]. Significant improvements have been achieved in the potential to identify images and extract features inside images due to the development of CNN [ 14 , 15 ]. Advanced CNNs have been shown to improve the accuracy of predictions significantly. In recent years, the development of computer-aided detection (CAD) has shown promising results in medical image analysis [ 16 , 17 ]. Deep learning techniques, particularly transfer learning, have emerged as a powerful technique for leveraging pre-trained models and improving the performance of deep learning models [ 18 ].

Transfer learning has gained significant attention and success in various fields of AI, including medical image diagnosis [ 19 ], computer vision [ 20 ], natural language processing [ 21 ], speech recognition [ 22 ], and many more. Transfer learning involves using pre-trained neural networks to take the knowledge gained from one task (source task) and apply it to a different but related task (target task) [ 23 ]. In transfer learning, a model pre-trained on a large dataset for a specific task can be fine-tuned on similar datasets for different tasks.

Transfer learning has recently shown much promise in making it easier to detect lung cancer from medical imaging data. Integrating transfer learning methodologies into pipelines for lung cancer detection has demonstrated enhanced accuracy and efficiency across multiple research investigations. It offers a practical and effective way to leverage existing knowledge and resources to develop accurate and efficient models for lung cancer detection. It starts with a pre-trained CNN model and fine-tunes its layers on a dataset of lung images. This allows the model to quickly learn to identify relevant features associated with lung cancer without requiring extensive labelled lung cancer images. The advantages of transfer learning for lung cancer detection are listed in Fig.  2 .

Advantages of transfer learning for lung cancer detection

In this paper, we employed different transfer learning models for lung cancer detection using CT images. We proposed a hybrid model to enhance the prediction capability of the pre-trained models. The key contributions of this paper are:

The original image dataset is resized into 460 × 460 × 3.

Random oversampling is applied to fuse synthetic images in the minority class.

Data augmentation is applied by applying shear_range, zoom_range, rotation_range, horizontal_flip, and vertical_flip.

Eight transfer learning models, viz. NASNetLarge, Xception, DenseNet201, MobileNet, ResNet101, EfficientNetB0, EfficientNetB4, and VGG19 are tried with the processed dataset.

A novel transfer learning model (VER-Net) is built by stacking VGG19, EfficientNetB0, and ResNet101. The outputs of all three models are individually flattened and concatenated afterwards.

Seven deep dense layers are added to optimize the performance of VER-Net.

The performance of VER-Net is validated on eight different matrices (accuracy, loss, precision, recall, F1-score, macro average, weighted average, and standard deviation) and compared with the other eight considered models.

The accuracy of VER-Net is compared with the state-of-the-art.

The rest of the paper is organized as follows. Similar recent research addressing identifying lung cancer through transfer learning is discussed in Sect. 2. The working principle, details of the dataset preparation, and considered transfer learning models are discussed in Sect. 3. Section 4 presents the details of the proposed stacking model, including architecture and parameters. Section 5 presents the proposed model’s experimental details, results, and performance analysis. Section 6 concludes the paper, mentioning the limitations of this study and future scopes.

Related work

Deep learning techniques provide reliable, consistent, and accurate results. Due to this, they are widely applied across multiple domains to solve real-world problems [ 24 , 25 , 26 , 27 ]. Researchers have carried out diverse literature that includes datasets, algorithms, and methodology to facilitate future research in the classification and detection of lung cancer. Some of the prominent attempts to detect lung cancer using transfer learning are discussed in this section.

Wang et al. [ 28 ] experimented with a novel residual neural network with a transfer learning technique to identify pathology in lung cancer subtypes from medical images for an accurate and reliable diagnosis. The suggested model was pre-trained on the public medical image dataset luna16 and fine-tuned using their intellectual property lung cancer dataset from Shandong Provincial Hospital. Their approach accurately identifies pathological lung cancer from CT scans at 85.71%. Han et al. [ 29 ] developed a framework to assess the potential of PET/CT images in distinguishing between different histologic subtypes of non-small cell lung cancer (NSCLC). They evaluated ten feature selection techniques, ten machine learning models, and the VGG16 deep learning algorithm to construct an optimal classification model. The VGG16 achieved the highest accuracy rate of 84.1% among all the models. Vijayan et al. [ 30 ] employed three optimizers with six deep learning models. These models included AlexNet, GoogleNet, ResNet, Inception V3, EfficientNet b0, and SqueezeNet. While evaluating the various models, their effectiveness is measured by comparing their results with a stochastic gradient, momentum, Adam, and RMSProp optimization strategies. According to the findings of their study, GoogleNet using Adam as the optimizer achieves an accuracy of 92.08%. Nóbrega et al. [ 31 ] developed the classification model using deep transfer learning based on CT scan lung images. Several feature extraction models, including VGG16, VGG19, MobileNet, Xception, InceptionV3, ResNet50, Inception-ResNet-V2, DenseNet169, DenseNet201, NASNetMobile and NASNetLarge, were utilized to analyze the Lung Image Database Consortium and Image Database Resource Initiative (LIDC/IDRI). Among all the algorithms, the CNN-ResNet50 and SVM-RBF (support vector machine– radial basis function) combination was found to be the most effective deep extractor and classifier for identifying lung nodule malignancy in chest CT images, achieving an accuracy of 88.41% and an AUC of 93.19%. The authors have calculated the other performance evaluation matrices to validate the proposed model. Dadgar & Neshat [ 32 ] proposed a novel hybrid convolutional deep transfer learning model to detect three common types of lung cancer - Squamous Cell Carcinoma (SCC), Large Cell Carcinoma (LCC), and Adenocarcinoma. The model included several pre-trained deep learning architectures, such as VGG16, ResNet152V2, MobileNetV3 (small and large), InceptionResNetV2, and EfficientNetV2, which were compared and evaluated in combination with fully connected, dropout, and batch-normalization layers, with adjustments made to the hyper-parameters. After preprocessing 1000 CT scans from a public dataset, the best-performing model was identified as InceptionResNetV2 with transfer learning, achieving an accuracy of 91.1%, precision of 84.9%, AUC of 95.8%, and F1-score of 81.5% in classifying three types of lung cancer from normal samples. Worku et al. [ 33 ] proposed a denoising first two-path CNN (DFD-Net) for lung cancer detection. During preprocessing, a residual learning denoising model (DR-Net) is used to remove the noise. Then, a two-path convolutional neural network was used to identify lung cancer, with the denoised image from DR-Net as an input. The combined integration of local and global aspects is the main emphasis of the two pathways. Further, the performance of the model was enhanced, and a method other than the traditional feature concatenation techniques was employed, which directly integrated two sets of features from several CNN layers. Also, the authors overcame image label imbalance difficulties and achieved an accuracy of 87.8% for predicting lung cancer. Sari et al. [ 34 ] implemented CAD system using deep learning on CT images to classify lung cancer. They used transfer learning and a modified ResNet50 architecture to classify lung cancer images into four categories. The results obtained from this modified architecture show an accuracy of 93.33%, sensitivity of 92.75%, precision of 93.75%, F1-score of 93.25%, and AUC of 0.559. The study found that the modified ResNet50 outperforms the other two architectures, EfficientNetB1 and AlexNet, in accurately classifying lung cancer images into Adenocarcinoma, large carcinoma, normal, and squamous carcinoma categories.

Overall, these studies show that transfer learning has the potential to improve how well medical imaging data can be used to find lung cancer. Using pre-trained deep neural networks can significantly reduce the need for large datasets and reduce training time, making them more accessible for clinical applications. However, more research is needed to find the best architecture for transfer learning and the best fine-tuning strategy for spotting lung cancer. Further studies can focus on improving the interpretability and generalization of transfer learning models for real-world applications.

Research methodology

The details of the requirements and experimental steps carried out in this paper are discussed in this section.

The proposed model follows seven phases of structure, as shown in Fig.  3 . After acquiring the chest CT scan images, they were preprocessed and augmented to make the experiment suitable. The processed dataset is divided into training, validation, and testing sets. Eight popular transfer learning models were executed based on this data. Among them, the top three were selected and stacked to build a new prediction model. The model was fine-tuned repeatedly to improve the classification accuracy while reducing the required training time. The model was trained and validated to classify three cancer classes and a normal class. Finally, the model was tested.

Framework of the proposed methodology

Dataset description

The chest CT images utilized in this study were obtained from Kaggle Footnote 3 . The dataset contains CT scan images of three types of lung cancers: Adenocarcinoma, Large cell carcinoma, and Squamous cell carcinoma. During the cancer prediction process, the lung cancer image dataset taken from Kaggle consists of 1653 CT images, of which 1066 images are used for training, 446 images for testing and the remaining 141 for validation purposes to determine the efficiency of the cancer prediction system. Class-wise samples of lung cancer CT images are depicted in Fig.  4 . The detailed distribution of the dataset in terms of the total images, number of images in each class, number of classes, and labelling in each category is elucidated in Table  1 .

Sample images from chest CT imaging dataset (a) large cell, (b) squamous cell, (c) adenocarcinoma, and (d) normal

Adenocarcinoma

Lung adenocarcinoma Footnote 4 is the most common form of lung cancer, accounting for 30% of all cases and about 40% of all non-small cell lung cancer occurrences. Adenocarcinomas are found in several common cancers, including breast, prostate and colorectal. Adenocarcinomas of the lung are found in the outer region of the lung in glands that secrete mucus and help us breathe. Symptoms include coughing, hoarseness, weight loss and weakness.

Large cell carcinoma

Large-cell undifferentiated carcinoma Footnote 5 lung cancer grows and spreads quickly and can be found anywhere in the lung. This type of lung cancer usually accounts for 10 to 15% of all cases. Large-cell undifferentiated carcinoma tends to grow and spread quickly.

Squamous cell carcinoma

Squamous cell carcinoma Footnote 6 is found centrally in the lung, where the larger bronchi join the trachea to the lung or in one of the main airway branches. Squamous cell lung cancer is responsible for about 30% of all non-small cell lung cancers and is generally linked to smoking.

The last category is the normal CT scan images.

Data preprocessing

To develop a robust and reliable automated system, data preprocessing plays a crucial role in the model-building process [ 35 , 36 , 37 ]. Preprocessing is an essential step to eliminate the distortions from the images. In this study, data preprocessing, image resizing, and data augmentation were used for better classification and detection of lung cancer, as discussed in the subsections below.

Image resizing

The loaded images are standardized and normalized using a standard scaler and min-max scaler as the normalization functions. The files are resized from 224 × 224 to 460 × 460 using a resize function. The classes undergo label encoding, i.e., 0 for class Adenocarcinoma, 1 for class Large cell carcinoma, 2 for class Normal and 3 for class Squamous cell carcinoma.

Data augmentation

Random oversampling was applied afterwards to add randomly duplicate examples in the minority class by adding additional images to the classes containing fewer samples in the dataset. Initially, the dataset comprised 1000 images, with each class containing 338, 187, 260 and 215 images. The final dataset after oversampling contains 1653 images, with each class containing 411, 402, 374 and 466 images, as shown in Table  2 .

After that, data augmentation was applied by applying shear_range = 0.2, zoom_range = 0.2, rotation_range = 24, horizontal_flip = True, and vertical_flip = True. Finally, the dataset is split into training, testing and validation in 64.48%, 26.98% and 8.52%, respectively. After the preprocessing followed by the Train-test split, the data is fed to models for training.

Transfer learning models

Transfer learning models play a significant role in healthcare for medical image processing [ 23 , 31 ]. Medical imaging technologies, such as X-rays, CT scans, MRI scans, and histopathology slides, generate vast amounts of visual data that require accurate and efficient analysis. Transfer learning enables the utilization of pre-trained models trained on large datasets from various domains, such as natural images, to tackle medical image processing tasks [ 28 ]. The transfer learning models that are considered in this experiment are described in this section.

NasNetLarge

Google created the NasNetLarge [ 38 ], a neural architecture search network designed for powerful computational resources. This model addresses the issue of crafting an ideal CNN architecture by formulating it as a reinforcement learning challenge. NasNetLarge introduces an approach where a machine assists in designing neural network architecture and constructing a deep neural network without relying on traditional underlying models that concentrate on tensor decomposition or quantization techniques. Notably, NasNetLarge demonstrated exceptional performance in the ImageNet competition, showcasing its state-of-the-art capabilities. The model is tailored to a specific image input size of 331 × 331, which remains fixed and unmodifiable.

The unique advantages of NasNetLarge are:

Efficient architecture design using neural architecture search.

Achieves state-of-the-art performance on various image classification tasks.

Good balance between accuracy and computational efficiency.

The Xception architecture is a popular and strong convolutional neural network through various significant principles, including the convolutional layer, depth-wise separable convolution layer, residual connections, and the inception module [ 39 ]. Additionally, the activation function in the CNN architecture plays a crucial role, where the Swish activation function has been introduced to enhance the conventional activation function. The foundation of Xception is rooted in the Inception module, which effectively separates cross-channel correlations and spatial relationships within CNN feature maps, resulting in a fully independent arrangement.

The unique advantages of Xception are:

Deep and efficient convolutional neural network architecture.

Achieves high accuracy on image classification tasks.

Separable convolutions reduce the number of parameters and operations.

DenseNet201

DenseNet201 [ 40 ] is a CNN with 201 layers. It is based on the DenseNet concept of densely connecting every layer to every other layer in a feedforward manner, which helps improve the flow of information and gradient propagation through the network. It is a part of the DenseNet family of models, designed to address the problem of vanishing gradients in very deep neural networks. The output of densely connected and transition layers can be calculated using Eq.  1 and Eq.  2 .

where H i is the output of the current layer, f is the activation function, and [ H 0 , H 1 , H 2 , …, H i−1 ] are the outputs of all previous layers concatenated together. Also, W i+1 is the set of weights for the convolutional layer, BN is the batch normalization operation, f is the activation function, and W i+1 is the output of the transition layer.

The unique advantages of DenseNet201 are:

Dense connectivity pattern between layers, allowing for feature reuse.

Reduces the vanishing gradient problem and encourages feature propagation.

Achieves high accuracy while using fewer parameters compared to other models.

MobileNet [ 38 ] is a popular deep neural network architecture designed for mobile and embedded devices with limited computational resources. The architecture is based on a lightweight building block called a MobileNet unit, which consists of a depth-wise separable convolution layer followed by a pointwise convolution layer. The depth-wise separable convolution is a factorized convolution that decomposes a standard convolution into a depth-wise convolution and a pointwise convolution, which reduces the number of parameters and computations. The output of a MobileNet unit and inverted residual block can be calculated using Eq.  3 to Eq.  7 .

where X is the input tensor, DW is the depth-wise convolution operation, Conv 1 × 1 is the pointwise convolution operation, σ is the activation function, BN is the batch normalization operation, and Y is the output tensor. Also, X in is the input tensor, X is the output tensor of the bottleneck layer, Conv 1 × 1 and DW are the pointwise and depthwise convolution operations.

The unique advantages of MobileNet are:

Specifically designed for mobile and embedded vision applications.

Lightweight architecture with depth-wise separable convolutions.

Achieves a good balance of accuracy and model size, making it ideal for resource-constrained environments.

Residual Neural Networks (ResNets) are a type of deep learning model that has become increasingly popular in recent years, particularly for computer vision applications. The ResNet101 [ 41 ] model allows us to train extremely deep neural networks with 101 layers successfully. It addresses the vanishing gradient problem by using skip connections, which allow the output of one layer to be added to the previous layer’s output. This creates a shortcut that bypasses the intermediate layers, which helps to preserve the gradient and makes it easier to train very deep networks. This model architecture results in a more efficient network for training and provides good performance in terms of accuracy. Mathematically, the residual block can be expressed as given by Eq.  8

where x is the input to the block, F is a set of convolutional layers with weights W i , and y is the block output. The skip connection adds the input x to the output y to produce the final output of the block.

The unique advantages of ResNet101 are:

Residual connections that mitigate the vanishing gradient problem.

Permits deeper network architecture without compromising performance.

It is easy to train and achieves excellent accuracy.

• EfficientNetB0

EfficientNetB0 [ 42 ] is a CNN architecture belonging to the EfficientNet model family. These models are specifically crafted to achieve top-tier performance while maintaining computational efficiency, rendering them suitable for various computer vision tasks. The central concept behind EfficientNet revolves around harmonizing model depth, width, and resolution to attain optimal performance. This is achieved through a compound scaling technique that uniformly adjusts these three dimensions to generate a range of models, with EfficientNetB0 as the baseline. The network comprises 16 blocks, each characterized by its width, determined by the number of channels (filters) in every convolutional layer. The number of channels is adjusted using a scaling coefficient. Additionally, the input image resolution for EfficientNetB0 typically remains fixed at 224 × 224 pixels.

The unique advantages of EfficientNetB0 are:

Achieve state-of-the-art accuracy on image classification tasks.

Use a compound scaling method to balance model depth, width, and resolution.

A more accurate and computationally efficient architecture design.

EfficientNetB4

The EfficientB4 [ 43 ] neural network, consisting of blocks and segments, has residual units and parallel GPU utilization points. It is a part of the EfficientNet family of models, designed to be more computationally efficient than previous models while achieving state-of-the-art accuracy on various computer vision tasks, including image classification and object detection. The CNN backbone in EfficientNetB4 consists of a series of convolutional blocks, each with a set of operations, including convolution, batch normalization, and activation. The output of each block is fed into the next block as input. The final convolutional block is followed by a set of fully connected layers responsible for classifying the input image. The output of a convolutional block can be calculated using Eq.  9 .

where x i−1 is the input to the current block, W i is the set of weights for the convolutional layer, BN is the batch normalization operation, f is the activation function, and y i is the block output.

Being in the same family, EfficientB4 shares the advantages of EfficientNetB0.

Visual Geometry Group (VGG) is a traditional CNN architecture. The VGG19 [ 44 ] model consists of 19 layers with 16 convolutional layers and three fully connected layers. The max-pooling layers are applied after every two or three convolutional layers. It has achieved high accuracy on various computer vision tasks, including image classification, object detection, and semantic segmentation. One of the main contributions of the VGG19 network is the use of very small convolution filters (3 × 3) in each layer, which allows for deeper architectures to be built with fewer parameters. The output of the convolutional layers can be calculated using Eq.  10 .

where x is the input image, W is the weight matrix of the convolutional layer, b is the bias term, and f is the activation function, which is usually a rectified linear unit (ReLU) in VGG19. The output y is a feature map that captures the important information from the input image.

The unique advantages of VGG19 are:

Simple and straightforward architecture.

Achieves good performance on various computer vision tasks.

Its simplicity and ease of use make it a favourite among educators.

Proposed VER-Net model

To find out the best-performing models among the ones discussed in the previous section, we ran them and assessed their performance individually. Among them, VGG19 and EfficientNetB0 were the best performers in all metrics. However, EfficientNetB4 and ResNet101 competed with each other to take the third spot. In some metrics, EfficientNetB4 did better, while in some, ResNet101 was better. Nevertheless, we picked ResNet101 over EfficientNetB4 because it has better testing accuracy and precision, which is crucial for detecting life-threatening diseases like cancer. Therefore, we stacked VGG19, EfficientNetB0, and ResNet101 in our proposed VER-Net model. The complete algorithm for this procedure is shown in Algorithm 1.

Model Architecture

The architecture of the proposed VER-Net model is shown in Fig.  5 . The input shape is 460 × 460 × 3, which is mapped to four classes as output. We used three different dense layers for three stacked transfer learning models in the model. Thereafter, the same convolution layers of 7 × 7 × 1024 for all three and three different max-pooling layers are used. The outputs are flattened before sending to three 3 fully connected layers (1024 × 512 × 256). The three outputs of these connected layers are then concatenated using majority voting, and accordingly, the classified outputs are generated. The architectural description of VER-Net is shown in Table  3 .

VER-Net’s architecture

Model parameters

The details of hyperparameters settings for VER-Net are listed in Table  4 . In Table  5 , the details of data augmentation are listed. Here, we used the RandomFlip and RandomRotation functions available in TensorFlow.Keras for data augmentation.

Experiment, results and performance analysis

In this section, the experimental details, including system setup and evaluation metrics, are covered. Also, the results are elaborately presented, and the performance of the proposed model is extensively assessed.

Experimental system setup

The experiment was conducted on a Dell workstation with a Microsoft Windows environment. Python was used to program on the Anaconda framework. The details of the system are given in Table  6 .

Evaluation Metrics

Evaluation metrics are used to assess the performance of a model on a problem statement. Different evaluation metrics are used depending on the problem type and the data’s nature. In this study, the experimental findings for the presented models are evaluated using various performance metrics, summarised in Table  7 .

VER-Net model implementation

After background and designing the VER-Net model, we implemented it. The results are discussed in the following.

Confusion matrix

The classification performance of VER-Net is evaluated using a confusion matrix, as shown in Fig.  6 . Since there are four output classes, the confusion matrix is a 4 × 4 matrix. Every column in the matrix represents a predicted class, whereas every row represents an actual class. The principal diagonal cells denote the respective classes’ correct predictions (TP). Besides the TP cell, all other cells in the same row denote TN. For example, in the first row, except the first column, five of the Adenocarcinoma were falsely classified as large cell carcinoma, and four were categorized as Squamous cell carcinoma. So, 9 (5 + 0 + 4) are TN classifications for the Adenocarcinoma class. Similarly, all other cells in the same column denote FP besides the TP cell. For example, in the first column, except the first row, four Large cell carcinoma, four normal cells, and 21 Squamous cell carcinoma are falsely classified as Adenocarcinoma. So, 29 (4 + 4 + 21) FN classifications exist for the Adenocarcinoma class. The rest of the cells denote FN predictions.

Confusion matrix of VER-Net

Accuracy and loss of VER-Net

The accuracy and loss of our VER-Net model are plotted in Figs.  7 and 8 , respectively. The x-axis denotes the number of epochs (100), while the y-axis reflects accuracy in Fig.  7 and loss in Fig.  8 . The training curve suggests how well VER-Net is trained. It can be observed that both accuracy and loss for validation/testing converge approximately after 20 epochs. It is further noticed that the model did not exhibit significant underfitting and overfitting upon hyperparameter tuning. In our experiment, we tried with different epoch numbers (40, 60, 100, and 200). We got the best results with 100 epochs.

Training and validation/test accuracy VER-Net model

Training and validation/test loss VER-Net model

Performance analysis of VER-Net

In this section, we exhaustively analyze the performance of VER-Net model. For this, we adopted a comparative analysis approach. We compared VER-Net with other transfer learning models and the results of similar research works.

Comparing VER-Net with other transfer learning models

First, we compare the performance of VER-Net with the individual transfer learning models, mentioned in Sect. 3.4. All the models were trained and tested on the same dataset and validated with the same parameters.

Figures  9 and 10 present the accuracy and loss comparisons. VER-Net and VGG19 both achieved the highest accuracy of 97.47% for training, but for testing, VER-Net emerged as the sole highest accuracy achiever with 91%. NASNetLarge got the lowest accuracy on both occasions, with 69.51% and 64% training and testing accuracy, respectively. Similar to accuracy, VER-Net and VGG19 both managed the lowest loss of 0.07% for training, and VER-Net was the sole lowest loss achiever with 0.34%. Here also, NASNetLarge performed worst on both occasions with 0.66% and 0.80% training and testing loss, respectively.

Accuracy comparison of the proposed ensemble method (VER-Net) with other transfer learning models

Loss comparison of the proposed ensemble method (VER-Net) with other transfer learning models

Table  8 notes all classes’ precision, recall and F1-score values to compare VER-Net with other models. The macro average of these metrics for all four classes is shown in Fig.  11 . For all three instances, i.e., precision, recall and F1-score, VER-Net outperformed with 0.920, 0.910, and 0.913, respectively. VGG19 and EficientNetB0 emerged as the second and third-best performers, whereas NASNetLarge was the worst performer with 0.693, 0.645, and 0.645 for precision, recall and F1-score, respectively.

In Fig.  12 , VER-Net is compared with others in terms of weighted average for precision, recall and F1-score. Here, we used a uniform weight of 1.5 for all classes. Like the macro average, VER-Net was the top performer for all three metrics, followed by VGG19 and EficientNetB0, and NasNetLarge was the worst performer. As shown in Table  8 , NasNetLarge classifies the non-cancerous cells with 100% accuracy; in fact, it performs the best among all models but performs very poorly for the cancerous cells.

Macro average comparison of VER-Net and other models

Weighted average comparison of VER-Net and other models

To assess the performance variations of VER-Net, we calculated the standard deviation to calculate the mean-variance across the classes for precision, recall and F1-score. A lower value suggests that the model is effective for all classes equally. In contrast, a higher variation suggests bias to a certain class. From Fig.  13 , it can be observed that VER-Net has the lowest variations for recall and F1-score of 0.062 and 0.04, respectively. However, as an exception in the case of precision, VER-Net is bettered by DenseNet201 with a margin of 0.042 variations. This can be reasoned as VER-Net attained 100% precision for the Normal class. Nevertheless, VER-Net has significantly lower variance across three metrics than DenseNet201.

Standard deviation for precision, recall and F1-score of all classes

Comparing VER-Net with literature

In the previous section, we established the superiority of VER-Net over other established transfer learning models. To prove the ascendency of VER-Net further, we compared it with the results of some similar recent experiments, available in the literature pertaining to detecting lung cancer based on CT scan images using transfer learning methods. A comparative summary is given in Table  9 .

The above experiments and results clearly show that the proposed VER-NET performed well in detecting lung cancer in most of the performance testing. It is the overall best performer among the nine transfer learning models. One of the reasons for this is that we incorporated the best three models (considered in this experiment) into the VER-NET. Besides, we optimally designed the VER-NET architecture for its best performance. Furthermore, to make the model more generalized, we generated additional synthetic lung cancer images in addition to the original image dataset.

To balance the dataset, we performed image augmentation, which might make slight changes in the real images. So, the performance of VER-Net might vary little on a balanced real dataset where there is no need for synthetic augmentation. The images were generated with 64 × 64 pixels, which is insufficient for the analysis of medical images. For cancer cell detection based on cell images, high-resolution images are crucial.

Since VER-Net is an ensembled model comprising three transfer learning, it is obvious that it should increase the computational complexity, requiring longer for training. However, this should not be a discouraging factor in a lifesaving application like cancer detection, where accuracy and precision matter most.

Conclusions and future scope

Incorporating transfer learning into lung cancer detection models has shown improved performance and robustness in various studies. In this paper, we concatenated three transfer learning models, namely, VGG19 + EfficientNetB0 + ResNet101, to build an ensembled VER-Net model to detect lung cancer. We used CT scan images as input to the model. To make VER-Net effective, we conducted data preprocessing and data augmentation. We compared the performance of VER-Net with eight other transfer learning models. The comparative results were assessed through various performance evaluation metrics. It was observed that VER-Net performed best in all metrics. VER-Net also exhibited better accuracy than similar empirical studies from the recent literature.

Here, we incorporated the three top-performing transfer models in the hybrid VER-Net architecture. Further experimentation can be done on this ensembling approach. For example, other models can be tried in different combinations. Also, transfer learning models of different families can be tried.

We plan to extend the use of the VER-Net model for identifying lung cancer where only chest X-ray images are available. Furthermore, this model can also be applied to assess the severity of lung cancer if the patient is already infested. Considering the success of VER-Net in detecting lung cancer, it can be used for other diseases where CT scan images are useful to identify the disease.

Data availability

No datasets were generated or analysed during the current study.

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ZZ is partially funded by his startup fund at The University of Texas Health Science Center at Houston, Houston, Texas, USA.

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Department of Computing Science and Engineering, IFTM University, Moradabad, Uttar Pradesh, India

Anindita Saha

AI Research Centre, Department of Analytics, School of Business, Woxsen University, Hyderabad, Telangana, 502345, India

Shahid Mohammad Ganie

School of Computer Applications and Technology, Galgotias University, Greater Noida, Uttar Pradesh, 203201, India

Pijush Kanti Dutta Pramanik

Department of Computer Science & Engineering, MSOET, Maharishi University of Information Technology, Lucknow, Uttar Pradesh, India

Rakesh Kumar Yadav

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA

Saurav Mallik

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AS: Conceptualization, Data curation, Methodology; SMG: Formal analysis, Methodology, Validation, Visualization, Prepared figures, Writing - original draft, Writing - review & editing; PKDP: Investigation, Formal analysis, Validation, Prepared figures, Writing - original draft, Writing - review & editing; RKY: Supervision, Writing - review & editing; SM: Validation, Writing - review & editing; ZZ: Supervision, Funding, Writing - review & editing.

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Saha, A., Ganie, S.M., Pramanik, P.K.D. et al. VER-Net: a hybrid transfer learning model for lung cancer detection using CT scan images. BMC Med Imaging 24 , 120 (2024). https://doi.org/10.1186/s12880-024-01238-z

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Received : 25 November 2023

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DOI : https://doi.org/10.1186/s12880-024-01238-z

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