case study for proton beam therapy

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• Published: 20 March 2022

Successful treatment with proton beam therapy for a solitary sternal metastasis of breast cancer: a case report

• Yojiro Ishikawa   ORCID: orcid.org/0000-0002-4613-0332 1 , 2 ,
• Motohisa Suzuki 1 ,
• Hisashi Yamaguchi 1 ,
• Ichiro Seto 1 ,
• Masanori Machida 1 ,
• Yoshiaki Takagawa 1 ,
• Keiichi Jingu 2 ,
• Yasuyuki Kikuchi 1 &
• Masao Murakami 1  

Journal of Medical Case Reports volume  16 , Article number:  111 ( 2022 ) Cite this article

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Breast cancer infrequently metastasizes to the sternum as solitary metastasis. We experienced successful treatment with proton beam therapy for a case of sternal metastasis of breast cancer. This case demonstrates for the first time the role of proton therapy in the treatment of oligometastatic sternal metastasis with limited tolerance of normal tissue due to previous photon irradiation.

Case presentation

A 40-year-old Japanese female presented with lumpiness in her left breast. The patient was diagnosed with breast cancer (cT1N0M0, cStage IA) and underwent partial mastectomy with axillary lymph node dissection. After the mastectomy, the patient received radiation therapy with 50 Gy in 25 fractions for initial irradiation of the left breast. After the initial irradiation of 50 Gy, the patient received 10 Gy in five fractions of a sequential boost for the tumor bed to a total dose of 60 Gy. Although the patient was administered tamoxifen after radiation therapy, solitary sternal metastasis occurred 6 months after radiation therapy. She refused chemotherapy and requested proton beam therapy for her sternal metastasis. The daily proton beam therapy fractions were 2.5 relative biological effectiveness, receiving a total dose of 70 Gy relative biological effectiveness. An acute side effect of grade 2 dermatitis according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. occurred during proton beam therapy, but there was no acute or late complication of more than grade 3. At 3 years after proton beam therapy, the patient remains in complete remission without surgery or chemotherapy.

Discussion and conclusion

Proton beam therapy for solitary sternal metastasis of breast cancer is considered to be a therapeutic option.

Peer Review reports

Bone metastasis of breast cancer generally tends to be multiple. However, breast cancer rarely metastasizes to the sternum as solitary metastasis [ 1 ]. Management of metastatic breast cancer (MBC) is based on systemic treatment, while the role of local therapy remains controversial.

Proton beam therapy (PBT) is effective because protons have excellent dose localization according to the Bragg peak compared with photons and are biologically equivalent to conventional X-ray treatment for cancer [ 2 , 3 , 4 , 5 ]. In general, bone metastases are multiple metastases and are not an indication for PBT. We herein report the achievement of successful treatment with proton beam therapy for a solitary sternal metastasis of breast cancer. This case demonstrates for the first time the role of proton therapy in the treatment of oligometastatic sternal metastasis with limited tolerance of normal tissue due to previous photon irradiation.

One year before presentation to our hospital, a 40-year-old Japanese female presented to another hospital with lumpiness in her left breast. The patient had no medical history or family history of breast or ovary cancer. There was no history of drinking or smoking. At the previous hospital, a core needle biopsy revealed invasive ductal carcinoma, estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2-negative with a Ki-67 index of 23%. On the basis of the examination results, the patient was diagnosed with early breast cancer (cT1N0M0, cStage I) and underwent partial mastectomy with axillary lymph node dissection. After the mastectomy, the patient received radiation therapy (RT) with 50 Gray (Gy) in 25 fractions as initial irradiation for the left breast. After the initial irradiation of 50 Gy, she received 10 Gy in five fractions of a sequential boost for the tumor bed to a total dose of 60 Gy (Fig. 1 ). Tamoxifen was administered after RT.

Dose distribution of radiation therapy. The left breast after partial mastectomy was treated with 50 Gy

At 6 months after RT, she presented with a dull pain in her chest wall. Positron emission tomography–computed tomography (PET–CT) revealed uptake of 18F-2-fluoro-2-deoxy- d -glucose (FDG) in the sternum [maximum standardized uptake value (SUV max ) of 4.5] (Fig. 2 ). Because the patient had a history of breast cancer and FDG-PET results showed a low possibility of malignant disease other than breast cancer, biopsy examination was omitted. The diagnosis was sternal metastasis of breast cancer. The patient had an Eastern Cooperative Oncology Group Performance Score of 1.

Positron emission tomography–CT revealed uptake of 18F-2-fluoro-2-deoxy- d -glucose in the sternum (maximum standardized uptake value of 4.5)

Although the patient was recommended chemotherapy and RT for bone metastasis of the sternum, she refused to receive chemotherapy and RT owing to concerns about damage caused by these therapies. She and her family requested PBT for her bone metastasis of the sternum. Treatment with the aromatase inhibitor and luteinizing-hormone-releasing hormone agonists was also started at the previous hospital.

The patient was informed of the option of receiving PBT as an alternative to RT. It was difficult to use definitive RT of more than 60 Gy for the metastasis because the sternal metastasis was located close to the initial field of RT. We also considered stereotactic radiotherapy or volumetric modulated arc therapy for her bone metastasis. However, we did not select these therapies because of the increased risk of radiation-induced cardiotoxicity by X-ray treatment.

We gave the patient an explanation about late complications after PBT. She agreed to receive PBT in favor of tumor control despite late complications. The PBT system at our institute (Proton beam system, Mitsubishi, Tokyo, Japan) uses synchrotron and scattering methods. The gross tumor volume (GTV) included the bone metastasis of the sternum. The clinical target volume (CTV) was defined as GTV plus 0.5-cm margins and the whole sternum. We determined the CTV on the basis of the margins that surgery is performed on a solitary sternal metastasis. The planning target volume (PTV) was CTV plus 0.5-cm margins. The daily PBT fractions were 2.5 relative biological effectiveness (RBE) for PTV that received a total dose of 70 Gy RBE in 28 fractions. The overall treatment duration was 41 days. After initial irradiation of 50 Gy RBE in 20 fractions (Fig. 3 ), the patient received 20 Gy RBE in 8 fractions of a sequential boost for the sternal metastasis alone to a total dose of 70 Gy RBE (Fig. 4 ). The dosimetric comparison between PBT and photon beam therapy is shown in Table 1 and Figure 5 .

Dose distribution of initial proton beam therapy (PBT) in an axial field ( a ) and a coronal field ( b ). The daily PBT fractions were 2.5 relative biological effectiveness (RBE) for PTV, receiving a total dose of 50 Gy RBE. The gross tumor volume was 16.21 cm 3 . The clinical target volume was 60.44 cm 3 , and the planning target volume was 147.31 cm 3

Dose distribution of boost proton beam therapy in an axial field ( a ) and a coronal field ( b ). The patient received 20 Gy relative biological effectiveness (RBE) in five fractions of a sequential boost for the sternal metastasis alone to a total dose of 70 Gy RBE. The gross tumor volume was 16.21 cm 3 . The clinical target volume was 29.89 cm 3 , and the planning target volume was 70.96 cm 3

Dose distribution for proton beam therapy ( a ) and photon beam therapy ( b ). Photon beam therapy shows a dose distribution of 70 Gy in 28 fractions by intensity-modulated radiation therapy (IMRT). With the IMRT, a high-dose area was seen on the heart (white arrow), and a low-dose area was spread to the bilateral lungs (yellow arrow)

The acute side effect of grade 2 dermatitis according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. occurred during PBT (Fig. 6 ), but there was no acute or late complication higher than grade 3. Four months after PBT, the patient became aware of pain near the radiation field after exercising.

Macroscopic findings of the chest on the final day of proton beam therapy. The acute side effect in skin was grade 2 dermatitis according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Although the symptoms resolved in about a month, the hormone therapy was continued. At 3 years after PBT, the patient remains in complete remission without surgery or chemotherapy (Fig. 7 ).

Positron emission tomography 3 years after proton beam therapy (PBT). PBT resulted in the disappearance of high uptake of fluorodeoxyglucose in the sternum

The timeline for the present case is shown in Fig. 8 .

Timeline for intervention and clinical outcome

Metastatic breast cancer is difficult to cure. The main treatment for MBC is systemic therapy, and the role of local therapy remains controversial. There are rare cases where only a few metastases occur in MBC. Bone metastases are the most common metastases of breast cancer. Patients with solitary bone metastasis account for approximately half of all breast cancer patients [ 6 ]. Sternal metastasis from breast cancer can occur as a result of direct spread from involved intramammary nodes or isolated intramanubrial bone metastases [ 7 ]. Kozumi et al. reported that the incidence of metastasis in the sternum was 34% in patients with solitary bone metastasis [ 1 ]. Solitary sternal metastasis can remain solitary and confined to the sternum for a long time because the blood in the sternum lacks communication to the paravertebral venous plexus flow [ 8 , 9 ].

Cancer status with fewer than five metastatic or recurrent lesions and with controlled primary lesions can be considered as “oligo-metastases” or “oligo-recurrence” [ 10 ]. The term “oligo-metastases” was first reported in 1995 by Hellman and Weichselbaum [ 11 ]. Several retrospective studies showed that patients with oligo-metastases who received local therapy had a good prognosis. The overall survival rate in those patients was 82% at 10 years and 53% at 20 years [ 12 ]. It is reasonable to consider that our case was oligo-recurrence of a solitary sternal metastasis with a good prognosis.

In current guidelines for and reports on palliative radiation therapy for patients with breast cancer, a single fraction of 8–10 Gy or 20 Gy in 4–5 fractions is recommended for patients with poor performance status (PS), and 30 Gy in 10 fractions or 50 Gy in 25 fractions is recommended for patients with good PS [ 13 , 14 , 15 ].

It is difficult to cure bone metastases with radiation therapy at doses less than 50 Gy. Li et al. reported that a single fraction of RT with 20 Gy for sternal metastases in oligometastatic breast cancer was beneficial for local disease control. In their study, in-field control was achieved in nine of ten patients at a median follow-up of 32 months; however, they also reported that seven of the ten patients had distant relapse after RT, and the median time to distant relapse was 11 months. Kamiyoshihara et al. also reported a severe complication after radiation therapy for sternal metastasis. Although there was no detailed information about the radiation therapy in their report, aortic hemorrhage due to mediastinal infection occurred in one patient after irradiation for sternal metastasis [ 16 ].

We experienced successful treatment with PBT for a case of sternal metastasis of breast cancer. It is not surprising that bone metastasis is controlled well locally by PBT; however, no case similar to our case was found in the English literature in a PubMed search (available at http://www.ncbi.nlm.nih.gov/pubmed/ ) using “breast cancer” and “sternal metastasis” connected with “proton beam therapy” as index words. This is the first report of successful treatment with proton beam therapy for sternal metastasis from breast cancer.

Because this study was a case study, it is difficult to define the indication for PBT for solitary sternal metastasis of breast cancer. However, it is possible that some patients with solitary sternal metastasis of breast cancer were treated only by surgery, chemotherapy, or radiation therapy despite being potential candidates for PBT. PBT for solitary sternal metastasis of breast cancer is considered to be a therapeutic option.

Availability of data and materials

The data include individual patient data, but the data are available from the corresponding authors upon reasonable request.

Abbreviations

18F-2-fluoro-2-deoxy- d -glucose

Intensity-modulated radiation therapy

Management of metastatic breast cancer

Magnetic resonance imaging

• Proton beam therapy

Positron emission tomography–computed tomography

Performance status

Radiation therapy

Relative biological effectiveness

Maximum standardized uptake value

Volumetric modulated arc therapy

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Department of Radiation Oncology, Southern Tohoku Proton Therapy Center, 7-172, Yatsuyamada, Koriyama, Fukushima, 963-8052, Japan

Yojiro Ishikawa, Motohisa Suzuki, Hisashi Yamaguchi, Ichiro Seto, Masanori Machida, Yoshiaki Takagawa, Yasuyuki Kikuchi & Masao Murakami

Department of Radiation Oncology, Tohoku University Graduate School of Medicine, 1-1, Seiryo-chou, Aoba-ku, Sendai, Miyagi, 980-8574, Japan

Yojiro Ishikawa & Keiichi Jingu

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All listed authors contributed to the original manuscript. YI is the main radiation oncologist of this case and wrote the manuscript draft. MM and KJ coordinated and completed the manuscript. MY, IS MS, MM, TT, and YK supported proton beam therapy management. All authors have read and approved the manuscript of this case report.

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Correspondence to Yojiro Ishikawa .

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Ishikawa, Y., Suzuki, M., Yamaguchi, H. et al. Successful treatment with proton beam therapy for a solitary sternal metastasis of breast cancer: a case report. J Med Case Reports 16 , 111 (2022). https://doi.org/10.1186/s13256-022-03335-5

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Received : 26 October 2021

Accepted : 18 February 2022

Published : 20 March 2022

DOI : https://doi.org/10.1186/s13256-022-03335-5

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A, National number of PBT facilities identified from the Particle Therapy Co-operative Group 18 and number of National Cancer Database (NCDB) facilities from the Commission on Cancer. 19 B, Total number and percent of patients treated with PBT.

Percent (A) and count (B) of patients receiving PBT.

Proton beam therapy use by type of health insurance coverage. Percent of patients treated with PBT in group 1 (A) and group 2 (B); count of patients treated with PBT in group 1 (C) and group 2 (D).

Proton beam therapy use by age at diagnosis. Percent of patients treated with PBT in group 1 (A) and group 2 (B); count of patients treated with PBT in group 1 (C) and group 2 (D).

eTable 1. List of Topography Codes for the American Society for Radiation Oncology Group 1 Proton Beam Therapy Indication Cancer Types Based on the International Classification of Diseases for Oncology ( Third Edition , ICD-O-3 )

eTable 2. Trends in Use of PBT by ASTRO Model Policy Group 1 and Group 2 Cancer Sites, (NCDB 2004-2018)

eFigure 1. Number of Patients With Prostate Cancer Diagnosed With Prostate Cancer and Treated With Radiation Therapy Targeted to the Prostate, NCDB (2004-2018)

eFigure 2. Patients Treated With PBT (Percent and Count) by ASTRO Model Policy Groups and Median Zip Code Income Level Quintiles, NCDB (2004-2018)

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Nogueira LM , Jemal A , Yabroff KR , Efstathiou JA. Assessment of Proton Beam Therapy Use Among Patients With Newly Diagnosed Cancer in the US, 2004-2018. JAMA Netw Open. 2022;5(4):e229025. doi:10.1001/jamanetworkopen.2022.9025

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Assessment of Proton Beam Therapy Use Among Patients With Newly Diagnosed Cancer in the US, 2004-2018

• 1 Department of Surveillance and Health Equity Science, American Cancer Society, Atlanta, Georgia
• 2 Department of Radiation Oncology, Department of Radiation Oncology, Massachusetts General Hospital, Boston

Question   What were the patterns of proton beam therapy (PBT) use among groups of patients with different PBT indications in the US from 2014 to 2018?

Findings   In this cross-sectional study with 5 919 368 patients, PBT use increased nationally between 2004 and 2018 for both cancer sites for which PBT use is the recommended treatment modality (group 1) and for sites for which effectiveness of PBT over other radiotherapy modalities is still being investigated (group 2). Breast and prostate cancers are most frequently treated with PBT.

Meaning   The findings of this study suggest that PBT uptake varies by indication group and is most commonly used to treat cancers for which PBT effectiveness is still under study.

Importance   Proton beam therapy (PBT) is a potentially superior technology to photon radiotherapy for tumors with complex anatomy, those surrounded by sensitive tissues, and childhood cancers.

Objective   To assess patterns of use of PBT according to the present American Society of Radiation Oncology (ASTRO) clinical indications in the US.

Design, Setting, and Participants   Individuals newly diagnosed with cancer between 2004 and 2018 were selected from the National Cancer Database. Data analysis was performed from October 4, 2021, to February 22, 2022. ASTRO’s Model Policies (2017) were used to classify patients into group 1, for which health insurance coverage for PBT treatment is recommended, and group 2, for which coverage is recommended only if additional requirements are met.

Main Outcomes and Measures   Use of PBT.

Results   Of the 5 919 368 patients eligible to receive PBT included in the study, 3 206 902 were female (54.2%), and mean (SD) age at diagnosis was 62.6 (12.3) years. Use of PBT in the US increased from 0.4% in 2004 to 1.2% in 2018 (annual percent change [APC], 8.12%; P  < .001) due to increases in group 1 from 0.4% in 2010 to 2.2% in 2018 (APC, 21.97; P  < .001) and increases in group 2 from 0.03% in 2014 to 0.1% in 2018 (APC, 30.57; P  < .001). From 2010 to 2018, among patients in group 2, PBT targeted to the breast increased from 0.0% to 0.9% (APC, 51.95%), and PBT targeted to the lung increased from 0.1% to 0.7% (APC, 28.06%) ( P  < .001 for both). Use of PBT targeted to the prostate decreased from 1.4% in 2011 to 0.8% in 2014 (APC, −16.48%; P  = .03) then increased to 1.3% in 2018 (APC, 12.45; P  < .001). Most patients in group 1 treated with PBT had private insurance coverage in 2018 (1039 [55.4%]); Medicare was the most common insurance type among those in group 2 (1973 [52.5%]).

Conclusions and Relevance   The findings of this study show an increase in the use of PBT in the US between 2004 to 2018; prostate was the only cancer site for which PBT use decreased temporarily between 2011 and 2014, increasing again between 2014 and 2018. These findings may be especially relevant for Medicare radiation oncology coverage policies.

Proton beam radiotherapy (PBT) is a form of external beam radiation used in cancer care that provides the opportunity for better precision in dose delivery than other types of external beam radiotherapy. 1 Owing to its unique deposition characteristics, PBT is potentially superior to photon-based therapy for tumors with complex anatomy surrounded by critically sensitive tissues and for childhood cancers. 1 , 2 Proton beam radiotherapy was approved for treatment of cancer in 1988 and, since then, use of PBT has increased in the US. 3 However, evidence related to the efficacy and effectiveness of PBT varies by cancer site.

In clinical trials, PBT has demonstrated high efficacy (minimal toxic effects and local tumor control) for several rare tumors that are adjacent to critical tissues or structures and require high doses of radiation. 4 - 7 Proton beam radiotherapy is recommended for treatment of pediatric cancers, because minimizing late effects of radiation treatment (RT) is necessary, and in cancers where pituitary, visual, auditory, and intellectual functions might be disrupted because of RT.

High up-front capital investments and operating costs complicate the uptake of PBT. 8 Treatment cost to payers can be double the cost of photon-based radiotherapy depending on the indication, 9 - 12 and insurers may not cover treatments without clinical trial evidence to justify higher costs. 13 , 14 Lack of insurance coverage is a principal barrier for enrollment in trials evaluating PBT in cancer treatment. 8 , 9

The Centers for Medicare & Medicaid Services does not have a national coverage determination for PBT; instead, local coverage decisions specify conditions for payments. The first local coverage decision conditions for payment of PBT claims went into effect in 2009. 3 Commercial insurers and state Medicaid plans have disparate definitions for medical necessity and for indications still under study and are more restrictive than Medicare in covering PBT. 8 , 9

In the US, patient age and income are closely associated with health insurance coverage type. Adults aged 65 years and older are age-eligible for Medicare, and employment-based private health insurance is the main source of coverage for individuals younger than 65 years. Some individuals without access to employer-sponsored coverage are eligible for Medicaid coverage on the basis of income and other requirements determined by state policies. Other individuals can purchase health insurance coverage through the marketplace, with age informing premiums and income determining eligibility for subsidies. Therefore, age, income, and health insurance coverage type are major factors in access to PBT.

In 2014, the American Society of Radiation Oncology (ASTRO) categorized PBT clinical indications into group 1, for which health insurance coverage is recommended, and group 2, for which coverage is recommended only if additional clinical requirements are met. 15 The ASTRO considers use of PBT reasonable in instances in which sparing the surrounding healthy tissue cannot be adequately achieved with photon-based radiotherapy and PBT use is of added clinical benefit to the patient. The guidelines were updated in 2017. 16

Little is known about patterns of uptake of PBT according to clinical evidence used in the development of the ASTRO indications. In this study, we used national data to characterize changes in receipt of PBT by ASTRO-designated group 1 and group 2 indications as well as by patients’ age, health insurance type, and income.

Individuals newly diagnosed with cancer between 2004 and 2018 were identified from the National Cancer Database (NCDB), a hospital-based cancer registry jointly sponsored by the American College of Surgeons and the American Cancer Society that captures approximately 72% of all cancer cases in the US from more than 1500 facilities accredited by the American College of Surgeons’ Commission on Cancer. 17 This study followed the Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline for cross-sectional studies and was granted exemption from review by the institutional review board of the Morehouse School of Medicine in Atlanta, Georgia, because the study was a secondary analysis of deidentified data.

The proportion of PBT facilities in operation that are included in the NCDB was determined by combining publicly available information from the Particle Therapy Co-Operative Group 18 and the American College of Surgeons’ Commission on Cancer. 19 To account for PBT availability, only patients diagnosed at facilities where at least 5 patients received PBT between 2004 and 2018 or who were treated by a radiation oncologist who treated at least 5 patients with PBT were included (n = 7 129 898). Patients diagnosed with a cancer site, histologic type, and stage for which no other patients in the NCDB received PBT were excluded (n = 1 211 758).

We used the ASTRO Model Policies published in 2017 to retrospectively classify patients into group 1 and group 2 according to cancer type and RT anatomic target (eTable 1 in the Supplement ). 16 Group 1 included patients treated for ocular tumors, head and neck tumors (including mouth, parotid gland, tonsil, oropharynx, nasopharynx, pyriform sinus, hypopharynx, and paranasal sinuses), central nervous system tumors (including cerebral meninges, brain, spinal cord, and other central nervous system sites), hepatocellular carcinoma, skull and spine tumors, and rhabdomyosarcoma (relevant histologic codes pooled from several different primary sites). 20 Group 2 included patients treated for prostate, lung, breast, esophagus, pelvic (including colorectal, anal, uterine, cervical, and testicular) tumors, abdominal (including stomach, pancreas, and kidney) tumors, and thoracic lymphomas. These patients were treated while clinical evidence for medical necessity was accruing.

Self-identified race and ethnicity were ascertained from patients’ medical records. We present patient characteristics to indicate the diversity of the study population.

Data analysis was performed from October 4, 2021, to February 22, 2022. Patient characteristics were compared between indication groups, using χ 2 statistics. To characterize patterns in PBT use, annual percent change (APC) was calculated by fitting a least-squares regression to the natural logarithm of PBT use rates, using diagnosis year as the independent variable. Changes in patterns (structural breaks) were identified by using the additive outliers method. 21 Trends in PBT use through time overall, by ASTRO indication group, cancer site, age group, health insurance coverage type, and patients’ residence zip code median income quintiles were evaluated. All analyses were performed using SAS, version 9.4 (SAS Institute Inc). Statistical significance was set at a 2-sided threshold of α = .05.

Of the 5 919 368 patients eligible to receive PBT included in the study, 3 206 902 were female (54.2%) and 2 711 238 were male (45.8%) ( Table ). Mean (SD) age at diagnosis was 62.6 (12.3) years. Group 1 cancer sites were less common than group 2 sites. Patients diagnosed with group 2 cancer sites were more likely to be older (group 1, 58.7 [17.4] vs group 2, 63.5 [12.8] years), female (group 1, 445 063 [42.7%] vs group 2, 2 761 839 [56.6%]), reside in high-income areas (≥$69 000: group 1, 263 320 [25.5%] vs group 2, 1 394 908 [28.8%]), and have Medicare coverage (group 1, 395 628 [38.8%] vs group 2, 2 156 993 [45.0%]). Self-reported race and ethnicity for group 1 vs group 2 were Asian and Pacific Islander (39 576 [3.9%] vs 150 381 [3.1%]), Black (121 178 [11.8% vs 594 935 [12.3%]), Hispanic (77 055 [7.5%] vs 237 918 [4.9%]), White (776 497 [75.6%] vs 3 799 907 [78.8%], and other (American Indian, Aleutian, Inuit, and 2 or more races: 12 792 [1.2%] vs 41 231 [0.9%]).

Of the 30 PBT facilities in clinical operation during the study period, 19 (63.3%) reported data to the NCDB. The NCDB captures RT (including PBT) that occurs outside of the reporting facility, and 14 477 patients (40.2%) treated with PBT received RT outside the reporting facility. Both the number of PBT facilities ( Figure 1 A) 18 , 19 and use of PBT among patients in NCDB ( Figure 1 B) increased nationally from 0.4% in 2004 to 1.2% in 2018 (APC, 8.12%; P  < .001).

Use of PBT increased significantly among patients in group 1, from 0.4% in 2010, to 2.2% in 2018 (APC, 21.97; P  < .001), and in group 2 from 0.03% in 2014 to 0.1% in 2018 (APC, 30.57; P  < .001) ( Figure 2 A). In 2018, 1876 patients (2.2%) diagnosed with group 1 cancers received PBT, compared with 3760 patients (0.9%) with group 2 cancers ( Figure 2 A). Most (3760 [66.7%]) patients treated with PBT in 2018 were treated for group 2 cancers ( Figure 2 B).

Use of PBT for group 1 cancers increased significantly among patients with every type of insurance coverage between 2010 and 2018 (APC, 20.89 for private insurance, 22.78 for uninsured, 21.01 for Medicaid, and 28.80 for Medicare; P  < .001 for all) ( Figure 3 A). In 2018, 1039 patients (3.0%) with private coverage who were diagnosed with group 1 tumors received PBT. Use of PBT in patients in group 2 increased between 2014 and 2018 among those with all types of insurance coverage (APC, 32.04 for private insurance, 28.24 for Medicare, 53.01 for Medicaid, and 51.31 for the uninsured; P  < .001 for all) ( Figure 3 B). In 2018, although most patients who received PBT for group 1 cancers had private insurance (1039 of 1876 [55.4%]) ( Figure 3 C), Medicare was the most common coverage type among patients treated with PBT for group 2 cancers (1973 of 3760 [52.5%]) ( Figure 3 D).

Use of PBT for treatment of all group 1 cancer sites increased significantly between 2010 and 2018 (eTable 2 in the Supplement ). Use of PBT increased most rapidly for head and neck tumors (APC, 52.0%), and central nervous system was the cancer type most frequently treated with PBT among group 1 indications in 2018 (821 patients). Among group 2 cancers, use of PBT increased between 2010 and 2018 for all cancer sites except prostate. From 2010 to 2018, among patients in group 2, PBT targeted to the breast increased from 0.0% to 0.9% (APC, 51.95%), and PBT targeted to the lung increased from 0.1% to 0.7% (APC, 28.06%) ( P  < .001 for both). Use of PBT targeted to the prostate decreased from 1.4% in 2011 to 0.8% in 2014 (APC, −16.48%; P  = .03) then increased to 1.3% in 2018 (APC, 12.45; P  < .001). Use of PBT increased most rapidly for breast cancer, and breast was the group 2 cancer site most frequently treated with PBT in 2018. Use of PBT for prostate cancer decreased between 2011 and 2014 and increased between 2014 and 2018 (eTable 2 in the Supplement ). The decrease in PBT use for prostate cancer was not parallel with the decrease in the number of patients diagnosed with prostate cancer or treated with RT in NCDB, which started earlier, in 2008, and at a slower pace (eFigure 1 in the Supplement ). Even with the significant decrease in PBT use for prostate cancer after 2011, prostate was the second most frequently treated group 2 cancer site with PBT in 2018 (eTable 2 in the Supplement ).

Use of PBT for group 1 cancers increased significantly in every age group between 2010 and 2018 for patients in group 1 and between 2014 and 2018 for those in group 2 ( Figure 4 ). In 2018, 258 children (14.8%) diagnosed with group 1 cancers received PBT ( Figure 4 A). Most patients treated with PBT for group 1 indications in 2018 were diagnosed between ages 40 and 64 years (692 of 1876 [36.9%]) ( Figure 4 C); ages 65 to 74 years was the most common age group treated with PBT for group 2 indications in 2018 (1488 of 3760 patients [39.7%]) ( Figure 4 D).

Use of PBT increased significantly in every income level between 2010 and 2018 for patients in group 1 and between 2014 and 2018 for those in group 2 (eFigure 2A and 2B in the Supplement ). Most patients who received PBT for treatment of both group 1 and group 2 cancers in 2018 resided in high-income areas (eFigure 2C and 2D in the Supplement ).

In this large, comprehensive cross-sectional study, PBT use among patients newly diagnosed with cancer increased within the US between 2004 and 2018. There was a sharp increase in the number of patients treated for group 1 indications after 2010 and the number in group 2 after 2014. The increase in the total number and percent of patients treated with PBT is partly due to the increase in the number of PBT facilities in the US. 3 , 18

The sharp increase in the number of patients treated with PBT targeted to anatomic sites recently included in the ASTRO Model Policies as group 1 indications could be owing to increasing adherence to mounting clinical evidence for medical necessity, even before the ASTRO guidelines were published, or owing to patients’ enrollment in the clinical trials that generated the medical evidence used to develop the Model Policies. Despite the rarity of cancer sites included in group 1 indications, more than 30% of patients treated with PBT in 2018 conformed with the ASTRO Model Policies group 1 indications.

For all group 2 indications, the ASTRO Model Policies state that additional clinical data are needed for appropriate coverage policies to be developed. In addition, patients treated under the Coverage with Evidence Development paradigm should be covered by the insurance carrier as long as the patient is enrolled in an institutional review board–approved clinical trial. However, a principal barrier for enrollment in clinical trials is health insurance coverage. 8 Although Medicare covers all indications currently under study, 8 , 9 private insurers vary greatly in their criteria for PBT coverage, even for group 1 indications, and Medicaid coverage varies by state. 22 , 23

Private insurance was the most common type of coverage among patients treated with PBT for group 1 indications. Most patients treated with PBT for group 2 indications had Medicare coverage, consistent with the higher incidence of group 2 cancers in adults older than 65 years. 24

Nearly 15% of children diagnosed with group 1 tumors were treated with PBT in 2018, and age 40 to 64 years was the most common age group treated with PBT for group 1 indications. In contrast, approximately 6% of pediatric patients and approximately 1% of patients of all other ages diagnosed with group 2 cancers were treated with PBT. Most patients with group 2 cancers treated with PBT were older adults (aged 65-74 years), who are age-eligible for Medicare coverage.

Sociodemographic differences in PBT use over time might be partly due to the most commonly diagnosed cancer types in group 1 and group 2. Cancers affecting the central nervous system, which is the cancer most frequently treated with PBT for group 1 indications, is the second most commonly diagnosed childhood cancer. 24 Prostate, lung, and breast cancer—the nonskin cancers with the highest incidence in the US population 24 —were the most common target anatomic sites among patients receiving PBT for group 2 indications. The median age at diagnosis for prostate and lung cancer is older than 65 years. 24 Thus, the Medicare program covers PBT for most of these patients.

The number of patients treated with PBT targeted to the prostate decreased sharply after 2011. Although the incidence of prostate cancer decreased following the 2008 and 2012 United States Preventive Services Taskforce recommendations against prostate specific antigen–based screening, 24 , 25 it does not fully explain the decrease in PBT use targeted to the prostate between 2011 and 2014. Changes in health insurance coverage 26 and publications around the time of the decrease, including a comparative effectiveness study showing that patients with prostate cancer who received PBT had a higher rate of gastrointestinal problems and did not have significantly improved outcomes compared with patients treated with intensity-modulated RT, 27 may have contributed to the decrease. However, not all studies reported increased toxic effects with PBT. 13

Proton beam therapy is considered reasonable in instances in which sparing the surrounding healthy tissue cannot be adequately achieved by photon-based radiotherapy and is of added clinical benefit to the patient. With the development of injectable biodegradable rectal spacers that significantly reduced radiation-induced toxic effects, 28 , 29 PBT may not be of added clinical benefit to the patient with prostate cancer in terms of rectal toxic effects. To our knowledge, no study has shown a clear clinical benefit for PBT in prostate cancer, and PBT for primary treatment of prostate cancer is recommended by the ASTRO only within the context of a prospective clinical trial or registry. 13 , 14 , 16 , 30 , 31

In contrast to those with prostate cancer, the number of patients receiving PBT targeted to the breast and lung increased significantly between 2010 and 2016, without a similar increase in incidence. 24 Similar to prostate cancer, there is no consensus on the use of PBT for the treatment of breast 1 , 12 , 16 , 32 - 36 or lung 37 - 55 cancers. In addition, the increasing demand for PBT can be attributed, in part, to marketing by PBT facilities and patient support groups advocating for PBT. 56 , 57 However, the high number of patients treated with PBT for group 2 indications does not necessarily indicate overuse of a therapy with unproven benefits. It is possible that a large proportion of patients receiving PBT are enrolled in clinical trials or registry studies aimed at evidence development.

For adults younger than 65 years, who are not age-eligible for Medicare, private insurance approval can be a barrier for enrollment in clinical trials necessary to develop evidence-based coverage policies. 8 , 9 , 22 , 23 Moreover, in July 2019, with the goal of reducing Medicare spending and improving quality of care, the Centers for Medicare & Medicaid Services proposed to test an episode-based payment model for radiation oncology, citing evidence of overuse of expensive new therapies. 58 Continuous monitoring of how insurance coverage policies affect both PBT use and enrollment in clinical trials that generate medical evidence for the role of PBT in treating group 2 cancers will be vital. 9

This study has limitations. These limitations include the lack of information on some qualifying characteristics listed by the ASTRO Model Policies for PBT treatment, especially among group 2 indications; lack of information about treatment recommendations and the decision-making process; clinical trial enrollment or relevant outcomes of PBT, including toxic effects and lasting effects of treatment; and lower prostate cancer capture in the NCDB (58% of patients with prostate cancer are captured in the NCDB compared with 72% of all patients with newly diagnosed cancer). 17 As of 2018, 66% of PBT facilities in the US reported to the NCDB, and the NCDB captures RT, including PBT, received at facilities other than the reporting facility. 59 Therefore, it is likely that changes in PBT captured in the NCDB are representative of national patterns. However, for patients treated outside of NCDB facilities, information about treating facility type is unavailable. Therefore, evaluation of the patterns of PBT uptake by facility type, volume, or distance was not possible. Because the NCDB includes information on first-course treatment for incident cancers only, data on use of PBT for recurrent disease or reirradiation are not available. Monitoring PBT use will be important for future research. Nonetheless, the NCDB implements stringent data quality, standardization, and ascertainment methods, and patients included in the NCDB are similar to patients included in population-based databases. 17

This study provides useful information about national patterns in uptake of PBT by ASTRO indications by health insurance coverage and patient characteristics. The number of patients receiving PBT increased between 2004 and 2018, including a larger proportion of patients being treated for group 1 indications. Despite the variability in criteria for PBT coverage among insurance providers, the number of patients with private insurance who are treated with PBT for group 1 indications has increased, especially among pediatric patients. Adoption of the ASTRO Model Policies by private and public insurers could facilitate access to patients for whom evidence suggests PBT is superior to photon-based RT. Furthermore, adoption of the policies could help resolve lack of evidence for medical necessity for group 2 indications by requiring that patients treated for group 2 indications, who are most frequently insured by Medicare, be enrolled in clinical trials.

Accepted for Publication: March 8, 2022.

Published: April 27, 2022. doi:10.1001/jamanetworkopen.2022.9025

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2022 Nogueira LM et al. JAMA Network Open .

Corresponding Author: Leticia M. Nogueira, PhD, MPH, Department of Surveillance and Health Equity Science, American Cancer Society, 250 Williams St, Atlanta, GA 30067 ( [email protected] ).

Author Contributions : Dr Nogueira had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Yabroff and Efstathiou contributed equally to the work.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Nogueira, Yabroff, Efstathiou.

Drafting of the manuscript: Nogueira, Efstathiou.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Nogueira.

Obtained funding: Efstathiou.

Administrative, technical, or material support: Efstathiou.

Supervision: Efstathiou.

Conflict of Interest Disclosures: Dr Yabroff reported serving on the Flatiron Health Equity Advisory Board, with all honoraria donated to the American Cancer Society. Dr Efstathiou reported receiving fees from Blue Earth Diagnostics, Boston Scientific, AstraZeneca, Genentech, Merck, Roivant Pharma, Myovant Sciences, Janssen, and Bayer Healthcare outside the submitted work. No other disclosures were reported.

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Proton Therapy Case Studies – Gynecologic Cancers

Proton beam radiation therapy is an FDA-approved treatment modality. Proton beam therapy directs a beam of protons (positively charged subatomic particles) at the radiation target, where they deposit the bulk of their energy in the last few millimeters of their range; tissue beyond the tumor receives very little radiation dose because of the absence of exit dose. Given the physical characteristics of protons (no exit dose), proton beam therapy helps save vital organs that are close to the tumor.

Case 1| UTERINE CARCINOSARCOMA WITH EXTENDED FIELDS TO PARA-AORTIC NODES

Patient is a 60-year-old woman with postmenopausal woman with a history of FIGO stage IIIC1 (grade 3 carcinosarcoma of the uterus, 75% myometrial invasion (MMI), no lymphovsacular space invasion (LVSI), 2/2 lymph nodes involved. She was treated with total abdominal hysterectomy and bilateral salpingo-oopherectomy with pelvic lymph node dissection and 6 cycles of adjuvant Carbo/Taxol.

Treatment: Given her high grade and aggressive histology, decision was made to use the extended field to cover para-aortic nodes. She was treated with 55 Gy (45 Gy pelvis + 10 Gy boost)

Case 2 | RECURRENT ENDOMETRIAL CANCER IN PARAAORTIC NODE

Patient Case

Patient is a 76-year-old woman with a hx of breast ca and stage IIIC1 high grade uterine carcinosarcoma initially diagnosed in 2013 treated with total abdominal hysterectomy, bilateral salpingo-oopherectomy, and lymph node dissection. Pathology demonstrated <50% myometrial invasion, lymphovascular space invasion and evidence of 6/6 involved right pelvic lymph nodes and 2/5 involved left pelvic lymph nodes). She went on to receive 6 cycles of chemotherapy followed by external beam radiation with intensity modulated radiation therapy (IMRT) to 45 Gy and vaginal brachytherapy 7 Gy x 3. She then had a biopsy proven recurrence in a para-aortic node 4 years later.

She was treated with proton therapy due to prior radiation to reduce dose to organs at risk.

Case 3 | RE-IRRADIATION IN THE SETTING OF METASTATIC CERVICAL CANCER TO ENLARGING LYMPH NODE

A 63 year old woman presented with squamous cell carcinoma of the cervix that was metastatic to the para-aortic and pelvic lymph nodes. She completed chemoradiation with external beam to 45 Gy with a pelvic boost to 65 Gy along with weekly cisplatin. This was followed by a brachytherapy boost to the cervix, 700cGy in 1 fraction. She then had five cycles of adjuvant chemotherapy with carboplatin/paclitaxel. She returned to clinic with biopsy proven recurrent disease in an enlarging left iliac node two years later, compressing the obturator nerve. She was started with carboplatin/taxol/avastin.

Radiation Treatment

She received proton therapy in order to minimize dose to organs at risk (OARs). The patient had already showed signs of radiation toxicity with sacral insufficiency. Thus, proton radiation would be able to minimize additional dose to OARs including sacral nerves and bowel.

In this case, due to the lymph node pressure on the obturator nerve and the patient’s developing symptoms, obturator sparing using proton therapy was advantageous. Using a three beam technique.

Case 4 | RECURRENT ENDOMETRIAL CANCER IN PRIOR PORT SITES

Patient is a 60 y.o. post-menopausal woman with a history of FIGO Stage IB (Grade 1) endometrioid endometrial carcinoma s/p total laparoscopic hysterectomy/bilateral salpingo-oopherectomy and sentinel lymph node dissection. Pathology was significant for 76% myometrial invasion, no lymphovascular space invasion, negative margins, hormone positive with concern for isolated tumor cells vs benign mesothelial cells on ultra-staging for the bilateral sentinel lymph nodes. She then received adjuvant external beam radiation (45 Gy in 25 fractions) to the pelvis and high dose rate brachytherapy to the vaginal cuff (10 Gy in 2 fractions) because of high-risk features including isolated tumor cells, and loss of mismatch repair proteins. She presented with recurrence two years later, in two port sites, one in each the right and left abdomen. She underwent resection of both nodules.

Protons were used for boost after initial photon plan: Right side was treated with 45 Gy + 19.8 Gy; Left side 45 Gy + 14.4 Gy. The use of protons allowed for additional sparing of bowel dose to reduce toxicity due to her prior radiation.

Case 5 | PRIOR RADIATION FOR COLORECTAL CANCER, NEW DIAGNOSIS OF SERIOUS CARCINOMA

Patient is a 76-year-old woman with a history of colorectal cancer s/p chemoradiation in 2007 (records unavailable) and FIGO stage IIIC1 uterine serous carcinoma treated with hysterectomy and bilateral salpingo-oopherectomy two years prior. Pathology demonstrated >50% myometrial invasion, lymphovascular space invasion and, cervical stromal invasion. Additionally, 1 out of 6 lymph nodes were involved in the right obturator chain. She received 6 cycles of adjuvant carboplatin/paclitaxel.

Treatment:   She received proton therapy due to her prior radiation for her colorectal cancer in 2007. She was treated with 4000cGy in 20 fractions to the pelvic lymph nodes alone with 2400cGy x 6 fractions vaginal cylinder brachytherapy to the full vaginal length.

Case 6 | PRIOR HISTORY OF COLORECTAL CANCER WITH OSTOMY, NEWLY DIAGNOSED ENDOMETRIAL CANCER

Patient is a 74-year-old woman with a history of multifocal colorectal cancer managed with near-total proctocolectomy (permanent ostomy) with adjuvant chemoradiation to 50.4Gy in 2001 (records unavailable) and a remote supracervical hysterectomy. She presented twenty years later with a 4cm localized endometrioid adenocarcinoma at the vaginal apex.

Treatment: Given her prior radiation plan, proton therapy was recommended to minimize dose to organs at risk. She was treated with an SIB plan (SIB is simultaneous integrated boost, so a smaller volume will get a higher dose per fraction). The pelvic lymph nodes, vagina, parametrium, and ovaries received 40 Gy, the inguinal lymph nodes received 44 Gy, and the gross residual disease at the vaginal apex received 50 Gy. Using protons, we were able to dose escalate in the definitive treatment setting while protecting small bowel as well as the ostomy.

Proton Therapy Gynecologic Experts

Akila viswanathan, md, mph.

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Proton Therapy Case Study

Pediatric proton therapy center, treating a mandible tumor.

P.J., a 10-year-old girl who came to the Cancer Center for a second opinion, P.J. presented with a tumor measuring 3.7 x 3.5 x 7.7 cm in her right mandible. A biopsy of the tumor that had been performed at another hospital revealed that it had histologic characteristics of both Ewing sarcoma and osteosarcoma, making initial diagnosis challenging. The team at CHOP, after performing another biopsy, classified the tumor as Ewing sarcoma. The disease had metastasized to P.J.’s bone marrow. In early 2010, P.J. had six cycles of five-drug chemotherapy. Because local control is an important component of treatment for this disease, the Cancer Center team consulted with David C. Stanton, D.M.D., M.D., F.A.C.S., an oral and maxillofacial surgeon in CHOP’s Division of Dentistry. Stanton determined that given the tumor’s size and location, complete resection would be difficult. He recommended radiation therapy instead.

“If she had positive margins after the resection, she would have had to get radiation anyway,” says Rochelle Bagatell, M.D. , chief of the solid tumor section at the Cancer Center and P.J.’s oncologist. “And the surgery was expected to be quite disfiguring.”

Radiation oncologist and medical director of the Roberts Proton Therapy Center Zelig Tochner, M.D., evaluated P.J.’s case and was quick to recommend proton therapy. Two key factors made P.J. an excellent candidate for this extremely precise form of radiation: her age (younger patients, because they are still growing, are more susceptible to radiation’s harmful effects) and the location of her tumor. “With conventional radiation, she would have a lot of issues down the road with lack of salivary function,” says Bagatell. “What proton therapy enabled us to do was to limit the toxicity to the mouth, salivary glands and bony structures.”; P.J. received 31 proton treatments at the Roberts Center, and eight additional cycles of chemotherapy. Throughout her treatment, she had round-the-clock access to CHOP’s renowned subspecialists in dentistry, speech therapy, gastroenterology and other fields, who provided critical support when she experienced difficulty eating and opening her mouth —complications that are common among patients who receive radiation to the jaw. Bagatell believes these complications may have been worse with conventional radiation, and that P.J. will be spared many of the late effects she would likely have experienced with conventional radiation — including problems with chewing, swallowing and bone growth— because proton therapy was used to target radiation directly at her tumor while minimizing damage to nearby healthy tissue. This therapy appears to have left the other side of her mouth and jaw virtually unaffected.

“If she had gotten conventional radiation therapy, she probably would have had significant issues on both sides,” says Bagatell. “Proton therapy allowed us to focus on the area that needed to be focused on and avoid toxicity to other areas.”

• Case report
• Open access
• Published: 14 September 2022

Proton beam therapy for the isolated recurrence of endometrial cancer in para-aortic lymph nodes: a case report

• Kaname Uno 1 , 2 , 3 ,
• Masato Yoshihara   ORCID: orcid.org/0000-0001-5811-3137 1 , 2 ,
• Sho Tano 1 , 2 ,
• Takehiko Takeda 1 ,
• Yasuyuki Kishigami 1 &
• Hidenori Oguchi 1  

BMC Women's Health volume  22 , Article number:  375 ( 2022 ) Cite this article

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Proton beam therapy penetrates tumor tissues with a highly concentrated dose. It is useful when normal structures are too proximate to the treatment target and, thus, may be damaged by surgery or conventional photon beam therapy. However, proton beam therapy has only been used to treat recurrent endometrial cancer in a few cases; therefore, its effectiveness remains unclear.

Case presentation

We herein report a case of the isolated recurrence of endometrial cancer in the para-aortic lymph nodes in a 59-year-old postmenopausal woman that was completely eradicated by proton beam therapy. The patient was diagnosed with stage IIIC2 endometrial cancer and treated with 6 courses of doxorubicin (45 mg/m 2 ) and cisplatin (50 mg/m 2 ) in adjuvant chemotherapy. Fifteen months after the initial therapy, the isolated recurrence of endometrial cancer was detected in the para-aortic lymph nodes. The site of recurrence was just under the left renal artery. Due to the potential risks associated with left kidney resection due to the limited surgical space between the tumor and left renal artery, proton beam therapy was administered instead of surgery or conventional photon beam therapy. Following proton beam therapy, the complete resolution of the recurrent lesion was confirmed. No serious complications occurred during or after treatment. There have been no signs of recurrence more than 7 years after treatment.

Conclusions

Proton beam therapy is a potentially effective modality for the treatment of recurrent endometrial cancer where the tumor site limits surgical interventions and the use of conventional photon beam therapy.

Peer Review reports

Proton beam therapy (PBT) is one of the most effective and widely used particle therapies because of its ability to penetrate tumor tissues with a highly concentrated dose [ 1 ]. The superiority of PBT is particularly useful when normal structures are too proximate to the treatment target and, thus, may be damaged by surgery or conventional photon beam therapy [ 2 , 3 ]. Although the effectiveness of PBT for cervical cancer has been demonstrated in clinical studies [ 4 , 5 ], its utility for the treatment of endometrial cancer remains unclear [ 6 ]. We herein report a case of the isolated recurrence of endometrial cancer in the para-aortic lymph nodes that was completely eradicated with PBT.

A 59-year-old postmenopausal woman (gravida 3, para 3) was referred to our hospital with an abnormal endometrial cytology and thickening. Her medical history included obesity and partial thyroidectomy for thyroid cancer at the age of 49 years. Her social and family histories were unremarkable. An internal examination revealed that the uterus was the size of a goose egg, transvaginal ultrasonography showed an enlarged uterus with thickening of the endometrium to 19.5 mm, and deep myometrial invasion was suspected. Laboratory results showed elevated serum cancer antigen (CA) 125 and CA19-9 levels (129 and 117 U/mL, respectively). An endometrial Pap smear revealed suspected adenocarcinoma (Fig.  1 a), while biopsy results confirmed the existence of endometrioid adenocarcinoma. Magnetic resonance imaging of the abdomen revealed a local, space-occupying lesion arising from the anterior uterine wall, while positron emission tomography/computed tomography (PET/CT) showed the abnormal accumulation of 2-deoxy-2-(18F)fluoro- d -glucose (FDG) in the uterine corpus with a maximum standardized uptake value (SUVmax) of 16.9 as well as in the bilateral iliac and para-aortic lymph nodes (SUVmax = 4.1) (Fig.  1 b).

An endometrial Pap smear strongly indicated adenocarcinoma (at 20 × magnification, scale bar: 100 μm) ( A ). Positron emission tomography/computed tomography detected the abnormal accumulation of 2-deoxy-2-(18F)fluoro- d -glucose in the uterine corpus (SUVmax = 16.9) and para-aortic lymph nodes (SUVmax = 4.1) ( B ). The histopathological finding of endometrial carcinoma was compatible with grade 1 adenocarcinoma of the uterus (at 20 × magnification, scale bar: 100 μm) ( C ) and metastasis to the para-aortic lymph nodes (at 4 × magnification, scale bar: 500 μm) ( D )

The patient underwent extended hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic and para-aortic lymphadenectomy below the renal veins. A histopathological examination revealed grade 1 endometrioid carcinoma of the uterine corpus (Fig.  1 c), with myometrial invasion of > 50% and metastases of the bilateral iliac and para-aortic lymph nodes (Fig.  1 d). According to the International Federation of Gynecologists and Obstetricians guidelines, the lesion was diagnosed as stage IIIC2 endometrial cancer. After surgery, adjuvant therapy with six courses of doxorubicin (45 mg/m 2 ) and cisplatin (50 mg/m 2 ) successfully inhibited disease progression.

The clinical course of the patient is shown in Fig.  2 . Elevated levels of CA125 and CA19-9 gradually decreased and normalized after surgery and adjuvant chemotherapy. However, fifteen months after the initial surgery, serum CA125 and CA19-9 levels spontaneously increased, and the recurrence of endometrial cancer in the para-aortic lymph nodes was confirmed by the abnormal accumulation of FDG (SUVmax = 19.44) on a PET/CT scan (Fig.  2 , 3 a, b). The recurrent site in the para-aortic lymph nodes was located just under the left renal artery. Due to the potential influence of the proximal left kidney to limit the surgical resection of the tumor, the patient chose to undergo PBT at an advanced medical center that specializes in radiology. Thirty-six days after the diagnosis of recurrence, PBT was performed at a total dose of 68.2 GyE at 2.2 GyE per fraction (Fig.  3 c) for 51 days. No serious complications were observed during PBT. Serum CA125 and CA19-9 levels immediately decreased to within normal ranges of 8 and 9 U/mL, respectively, after PBT. The complete resolution of the recurrent lesion was confirmed in follow-up PET/CT (Fig.  3 d). The patient did not receive any additional treatment after PBT. Complications related to PBT, including dermatitis, nausea, anemia, and leukopenia, did not occur after treatment. Careful follow-ups after PBT were performed every three months and involved a physical examination, transvaginal ultrasound, and laboratory tests (including CA125 and CA19-9). Follow-up CT was performed at least every 6 months. CA125 and CA19-9 levels have remained stable within normal ranges after treatment. The condition of the patient is good 7 years after PBT with no signs of recurrence.

The 3-year clinical course of the patient from the initial diagnosis is highlighted by serum levels of cancer antigen (CA) 125 and CA19-9. AP, doxorubicin, and cisplatin therapy

Positron emission tomography/computed tomography (PET/CT) scans before proton beam therapy (PBT) ( A ). A solid tumor with the abnormal accumulation of 2-deoxy-2-(18F)fluoro- d -glucose (SUVmax = 19.44) was observed adjacent to the left renal vein ( B ). A dose distribution curve of the axial and sagittal sections C orange, purple, pink, green, yellow, sky blue, and dark blue lines in the circle represent doses of 5225, 4950, 4400, 3850, 2250, 1650, and 550 cGyE, respectively, which were delivered to the patient over the course of the PBT regimen. PET/CT scans of the para-aortic lesion after PBT ( D ). The recurrent para-aortic lesion was completely eradicated

All cytology and pathological images were obtained with an Olympus BX51 microscope (Olympus, Tokyo, Japan) with 4 × , 10 × , 20 × , 40 × UPlanSApo objective lenses (Olympus), which equipped with a DP27 digital camera (Olympus) and model U-TV0.5XC-3 TV system (Olympus) on upper site of the microscope. These images were captured by the digital ruler of image analysis software cellSens standard version 1.16 (Olympus). All images were adjusted automatically about white balance and resolution in the software.

Discussion and conclusions

Protons are widely recognized to possess physical and biological properties that are superior to photons for conventional use [ 1 , 3 ]. Protons are large positively-charged particles that penetrate tissues to various depths and deposit most of their energy in targeted tissues, which is referred to as the Bragg peak [ 7 ]. The physical properties of protons may maximize tumor-focused radiation and minimize effects on the surrounding tissues. In addition, the relative biological effectiveness of protons reaches 1.1 or potentially higher in the distal part of the spread-out Bragg peak [ 1 ]. Despite the theoretical concerns of damage to adjacent normal tissues associated with its greater biological effect, a large retrospective study repudiated the higher risk of secondary malignancies in patients who have undergone PBT than in those who have undergone photon therapy [ 8 ]. Although its use in clinical applications remains challenging because of the equipment required and associated costs, PBT provides an ideal radiation regimen based on its physical and biological features.

Since 1954, when the medical use of protons was initially reported, PBT has been applied to various parts of the body, including the uvea, skull base, and spine [ 1 , 9 , 10 ]. In the gynecological field, the clinical use and efficacy of PBT have mainly been reported for cervical carcinoma [ 3 , 4 , 5 ], low-grade endometrial stromal sarcoma [ 11 ], and solitary recurrent epithelial ovarian cancer [ 12 ]. Only one case report of the vaginal recurrence of endometrial carcinoma treated with PBT is available in the literature, which describes the complete regression of the tumor; however, there was a complication of grade 1 cystitis. This case report indicated the potential efficacy of PBT for recurrent endometrial cancer [ 6 ]. Unlike vaginal recurrence, curative radiation therapy is not widely recommended for the recurrence of endometrial cancer in the para-aortic lymph nodes. The number of patients with endometrial cancer has recently been increasing worldwide [ 13 ]. Recurrence has been detected in approximately 20% of patients with endometrial cancer [ 14 ]. Therefore, the number of patients with recurrent endometrial cancer has also been increasing [ 13 ]. Recurrent endometrial cancer often occurs in lymph nodes [ 14 , 15 ]. Therefore, the careful consideration of treatment strategies for recurrent endometrial cancer in para-aortic lymph nodes is essential to improve the prognosis and quality of life of patients during the treatment. In the present case, PBT effectively eradicated the isolated recurrence of endometrial cancer in the para-aortic lymph nodes adjacent to the left renal vein, the location of which impeded surgical interventions. Due to the limitations associated with conventional photon therapy, PBT was considered to be the preferred choice for our patient at that time.

No case reports in gynecological cancer have reported severe complications related to PBT. Previous studies reported transient low-grade cystitis or fever only as complications [ 6 , 12 ]. A randomized phase IIB trial of esophageal cancer revealed that PBT was associated with fewer complications than intensity-modulated radiation therapy using conventional photons [ 16 ]. A systematic review of esophageal cancer showed that PBT has the potential to not only improve patient outcomes, but also reduce complications [ 17 ]. Since PBT maximizes tumor-focused radiation and minimizes effects in the surrounding tissues, there are very few case reports of complications related to the suppression of bone marrow [ 18 ]. In the present case, there were no signs of the suppression of bone marrow during or after PBT. Therefore, PBT is associated with fewer complications than conventional photon treatments, which is beneficial.

To the best of our knowledge, this is the first case report to describe the successful treatment of the isolated distant recurrence of endometrial cancer by PBT, which may be regarded as a potentially effective treatment modality for recurrent endometrial cancer where the tumor location limits the application of surgery or conventional photon beam therapy. PBT is associated with fewer complications than conventional radiotherapy. The further accumulation of cases and additional trials are needed to establish the effectiveness of PBT for recurrent endometrial cancer as well as uterine cervical cancer.

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Abbreviations

• Proton beam therapy

Cancer antigen

Positron emission tomography/computed tomography

Fluoro- d -glucose

Standardized uptake value

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The authors appreciate affiliated institutions for supporting the management of the case with patience and knowledge. This manuscript conforms to the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) network guidelines.

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Kaname Uno, Masato Yoshihara, Sho Tano, Takehiko Takeda, Yasuyuki Kishigami & Hidenori Oguchi

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KU and MY elaborated the study concept, interpreted the data, and made the manuscript. TT, ST, and YK participated in designing the study and planned the investigation. HO drafted the study design and supervised all of the work. All authors have approved the final manuscript.

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Uno, K., Yoshihara, M., Tano, S. et al. Proton beam therapy for the isolated recurrence of endometrial cancer in para-aortic lymph nodes: a case report. BMC Women's Health 22 , 375 (2022). https://doi.org/10.1186/s12905-022-01961-1

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Article Contents

Introduction, materials and methods, conflict of interest, acknowledgement, data availability, presentation at a conference, clinical trial registration number.

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Proton beam therapy for muscle-invasive bladder cancer: A systematic review and analysis with Proton-Net, a multicenter prospective patient registry database

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Masayuki Araya, Hitoshi Ishikawa, Kentaro Nishioka, Kazushi Maruo, Hirofumi Asakura, Takashi Iizumi, Masaru Takagi, Masao Murakami, Haruhito Azuma, Wataru Obara, Hidefumi Aoyama, Hideyuki Sakurai, Proton beam therapy for muscle-invasive bladder cancer: A systematic review and analysis with Proton-Net, a multicenter prospective patient registry database, Journal of Radiation Research , Volume 64, Issue Supplement_1, June 2023, Pages i49–i58, https://doi.org/10.1093/jrr/rrad027

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To assess the safety and efficacy of proton beam therapy (PBT) for muscle-invasive bladder cancer (MIBC), we examined the outcomes of 36 patients with MIBC (cT2-4aN0M0) who were enrolled in the Proton-Net prospective registry study and received PBT with concurrent chemotherapy from May 2016 to June 2018. PBT was also compared with X-ray chemoradiotherapy in a systematic review (X-ray (photon) radiotherapy). The radiotherapy consisted of 40–41.4 Gy (relative biological effectiveness (RBE) delivered in 20–23 fractions to the pelvic cavity or the entire bladder using X-rays or proton beams, followed by a boost of 19.8–36.3 Gy (RBE) delivered in 10–14 fractions to all tumor sites in the bladder. Concurrently, radiotherapy was given with intra-arterial or systemic chemotherapy of cisplatin alone or in combination with methotrexate or gemcitabine. Overall survival (OS), progression-free survival (PFS) and local control (LC) rates were 90.8, 71.4 and 84.6%, respectively, after 3 years. Only one case (2.8%) experienced a treatment-related late adverse event of Grade 3 urinary tract obstruction, and no severe gastrointestinal adverse events occurred. According to the findings of the systematic review, the 3-year outcomes of XRT were 57–84.8% in OS, 39–78% in PFS and 51–68% in LC. The weighted mean frequency of adverse events of Grade 3 or higher in the gastrointestinal and genitourinary systems was 6.2 and 2.2%, respectively. More data from long-term follow-up will provide us with the appropriate use of PBT and validate its efficacy for MIBC.

Bladder cancer is a malignant tumor that develops from the bladder’s urothelial mucosa, and the age-adjusted incidence rate per 100 000 Japanese population in 2018 was 7.2 (12.6 in males and 2.8 in females). It is more common in the elderly, with >90% of patients being over the age of 60 [ 1 ]. According to the degree of invasion of the lesion, it is roughly classified as non-muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC), and the standard treatment varies greatly between the two. The treatment policy for NMIBC is to preserve the bladder through trans-urethral resection of the bladder tumor (TURBT) and intravesical instillation therapy, whereas surgical total cystectomy is the standard treatment for MIBC [ 2 , 3 ]. In the past, definitive radiotherapy was rarely chosen for MIBC patients; however, in many studies, combined modality therapy (CMT) that consists of maximal TURBT followed by chemoradiotherapy in appropriately selected MIBC patients demonstrated favorable outcomes. According to recent systematic reviews, meta-analyses and propensity score matching analyses [ 4–6 ], CMT treatment outcomes are comparable to surgery. CMT is currently listed as a recommended Category 1 option in the guidelines for patients who are ineligible for radical surgery due to co-morbidities or advanced age or who wish to preserve the bladder. The majority of CMT radiotherapy is X-ray (photon) radiotherapy (XRT).

Particle therapy is a treatment method that uses accelerated particles to irradiate lesions (mainly protons and carbon ions). Because particle beams emit energy at a specific depth based on incident energy and then rapidly decay (Bragg peak phenomenon), the exit dose is reduced compared with XRT, resulting in a higher dose concentration. Takaoka et al . studied selective bladder-preserving therapy with proton beam therapy (PBT) for cT2-3N0M0 muscle-invasive cancer and found a 5-year cumulative overall survival (OS) rate and progression-free survival (PFS) rate of 82 and 77%, respectively. Furthermore, a favorable result of 2% late non-hematologic toxicity of Grade 3 or higher was reported [ 7 ]. It is hypothesized that the particle therapy could deliver a higher dose to the tumor without increasing the dose to nearby organs at risk, such as the small intestine and bladder. However, because there has been no randomized controlled trial comparing XRT and particle beam therapy, there is insufficient evidence to support the safety and efficacy of particle beam therapy for bladder cancer.

Particle beam therapy is covered by Japanese national health insurance for some conditions, such as pediatric tumors, bone and soft tissue tumors and localized prostate cancer, but bladder cancer is not yet covered by national health insurance and is performed as advanced medical care. Because the cost burden on patients increases significantly in advanced medical care when compared with medical care covered by health insurance, conducting a randomized controlled trial to compare XRT and particle therapy for bladder cancer is difficult. As a result, the Japanese Society for Radiation Oncology (JASTRO) began a prospective registry study in May 2016 to prospectively register all patients receiving PBT in Japan. We present the treatment outcomes of bladder cancer patients enrolled in this study through June 2018 as well as a systematic literature review to assess the utility of particle therapy for bladder cancer.

Systematic examination

Protocol for searching.

A systematic search of the PubMed online database was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [ 8 ]. Because the current bladder cancer guidelines did not mention particle therapy and no search formula was available, we used the National Institutes for Quantum Science and Technology library to search English literature on CMT for MIBC published between January 2000 and September 2020. Because PBT is the only particle beam therapy used to treat bladder cancer in Japan, only reports on PBT were searched. Table 1 displays the search terms and formulas. The systematic review team also conducted a manual search.

The terms and formulae for systematic search

TIAB = title/abstract, MeSH = medical subject headings.

Article selection criteria

The population, intervention, comparison and outcome (PICO) framework was used to define the inclusion criteria for the literature. We defined the population as MIBC without metastasis (Clinical Stages II and III, T2-4aN0M0 according to the seventh edition of the UICC TNM classification); the intervention as PBT with concurrent chemotherapy; the comparison as XRT with concurrent chemotherapy and the outcome as OS rate, PFS rate, local control (LC) rate, bladder preservation rate (BPR) and frequency of urogenital (GU) and gastrointestinal (GI) Grade 3 or higher adverse events. Because we expected to find a limited number of articles on XRT and PBT for MIBC, we decided to include both retrospective and prospective clinical trials that reported at least one of the PICO outcomes. When multiple publications from a single institution were reported, only the most recent or most relevant study’s outcome data were included. The number of patients required for each study was set at 10. Case reports, proceedings, preclinical studies and review articles were not considered.

As part of the primary screening, two radiation oncologists from the systematic review team independently checked the titles and abstracts of the extracted literature and chose articles that met the selection criteria. The full texts of the articles chosen after the primary screening were checked as part of the secondary screening, and only those that met the selection criteria were accepted. Documents where there was a disagreement about inclusion or exclusion were resolved through team discussions.

Data extraction

A group of two members of the systematic review team extracted data. A third member was consulted to resolve the discrepancy (H.I. or M.A.). When OS, PFS and LC were not explicitly stated in the text, they were calculated based on the total number of patients, the size of the risk set at each time point and the censoring rate. The following parameters were extracted from the articles: number of patients, age, gender, clinical stage, OS rates at 1–3 years, PFS rates at 1–3 years, LC rates at 1–3 years, CMT, BPR, complete response rate and the frequency of Grade 3 or higher GU and GI adverse events.

Registry data analysis

From May 2016 to June 2018, patients with primary bladder cancer were prospectively enrolled in the ‘Proton-Net’ Japanese proton therapy multicenter database system in which a total of 13 facilities are participating. Patients with histopathologically or clinically diagnosed MIBC without metastasis at any site are eligible for inclusion in PBT as advanced medical care in Japan. Therefore, the inclusion criteria for this study were patients diagnosed with urothelial cell carcinoma, MIBC (cT2-4aN0M0), who had undergone PBT with concurrent chemotherapy as a curative treatment, and who had no other concurrent cancer irrespective of age and performance status. Computed tomography and bone scintigram were commonly used for staging, but positron-emission tomography was not mandatory.

PBT was carried out using a treatment protocol based on the unified treatment policy established by the urologic cancer working group subcommittee of the Japanese Society of Radiation Oncology’s Particle Therapy Committee (JASTRO). The relative biological effectiveness (RBE) value of 1.1 was used for the PBT treatment planning. Following 40–41.4 Gy (RBE) irradiation of the pelvic cavity or the entire bladder in 20–23 fractions with proton beams or X-rays, local lesions were boosted with proton beams using the following treatment protocol: (i) the treatment protocol for cases not adjacent to the GI tract was 33–36.3 Gy (RBE) in 10–11 fractions to all tumor sites in the bladder (total dose of 73.0–77.7 Gy (RBE) in 30–34 fractions) and (ii) for cases near the GI tract, the treatment protocol was 19.8–25.2 Gy (RBE) in 11–14 fractions (total dose of 59.8–66.6 Gy (RBE) in 31–37 fractions). As a dose constraint for organ at risk, the total dose to 2 cc of the intestine was allowed up to 60 Gy (RBE) in equivalent dose in 2 Gy fraction. At every treatment session of proton boost, the bladder was filled with urine or sterilized water to keep moderately full bladder.

Since there is no clear evidence of prophylactic pelvic irradiation for MIBC, the decision to perform pelvic irradiation was left to the discretion of the facility. In case pelvic irradiation was administered, the four-field technique of anteroposterior–posteroanterior and opposing lateral fields was used. Each field was set to include the tumor, the bladder and pelvic lymph nodes (internal iliac, external iliac, obturator and presacral lymph nodes). Proton beams were not used for pelvis irradiation in all patients because of the limitations on the field size. For X-ray therapy, high-energy X-rays of ≥6 MV energy were commonly used.

Endpoints and statistical analysis

OS, PFS, LC and treatment-related Grade 3 or higher late toxicity after proton therapy for MIBC were all evaluated in this study.

CT scans and urine cytology were examined every 3–4 months for 2 years after treatment and every 3–6 months thereafter, in accordance with the bladder cancer study's follow-up policy, with additional cystoscopy and biopsy performed if bladder recurrence was suspected.

The time span between the first day of PBT and the date of death or the last follow-up visit was defined as the follow-up period. OS defined an event as death from any cause. PFS defined an event as death from any cause or any signs of cancer progression. In the case of LC, an event was defined as any sign of superficial or invasive recurrences in the bladder. The time from the start of PBT to the date of the events or the last follow-up visit was used to calculate the survival function for each outcome using the Kaplan–Meier method and log-rank test. A P -value of <0.05 was considered to be statistically significant. The treatment-related late toxicity of Grade 3, defined as complications occurring 3 months after the completion of PBT, was assessed using the Common Terminology Criteria for Adverse Events (version 4.0). Prior approval was obtained from each center's ethics committee for this multicenter database prospective registry study, and all patients provided written informed consent in accordance with the Helsinki Declaration. This study has been registered with the UMIN-clinical trials registry under the study number UMIN000022917.

Systematic review

A flow diagram that outlines the selection process is shown in Fig. 1A (XRT) and Fig. 1B (PBT).

Flow diagrams of the selection process for X-ray radiotherapy ( A ) and PBT ( B ).

A total of 1375 articles on XRT were extracted via systematic search, with an additional 7 articles added via hand search. Primary screening excluded 1330 articles, and secondary screening was performed on the remaining 52. Thirty four of these were eliminated for the reasons outlined in Fig. 1A , and 18 were eventually chosen [ 9–26 ].

In terms of PBT, a systematic search yielded 135 articles. In the primary screening, 123 articles were eliminated, and the remaining 12 articles were subjected to secondary screening. Only two articles reported clinical outcomes, and because they were from the same institution and overlapped in the analysis subjects, only one was chosen [ 7 ]. We determined that meta-analysis was impossible due to the scarcity of articles reporting the results of PBT.

Table 2 provides a summary of the articles chosen. The 3-year OS, PFS and LC outcomes of XRT were 57–84.8%, 39–78% and 51–68%, respectively. The frequency of Grade 3 or higher adverse events ranged from 0 to 41% for GU and from 0 to 9.1% for GI, with weighted means of 6.2 and 2.2%, respectively. On the other hand, PBT demonstrated 90% in OS and 80% PFS after 3 years, with the frequency of GU and GI Grade 3 or higher adverse events being 2.9 and 0%, respectively.

Summary of literature review of XRT and PBT for bladder cancer

Abbreviations: WP = whole pelvis, OA = overall, BPR = bladder preservation rate, CR = complete response rate, GU = genitourinary, NA = not assessed, PTX = paclitaxel, 5FU = 5-fluorouracil, FP = cisplatin plus 5FU, GEM = gemcitabine.

Of 43 MIBC patients who were registered in Proton-Net, 36 patients from three facilities were studied. Tables 3 and 4 summarize the patient characteristics. The median age of these patients was 70.5 years (range: 48–87), and the median follow-up period was 41.4 months (range: 3.2–54.9).

Characteristics of the patients with MIBC from the registry dataset

ECOG = Eastern Cooperative Oncology Group.

Characteristics of treatment from the registry dataset

CDDP = cisplatin, MTX = methotrexate, GEM = gemcitabine.

According to the protocol, 27 patients received a total dose of 73–77.7 Gy (RBE) in 30–34 fractions, but 9 patients received a total dose of 59.8–66.6 Gy (RBE) in 30–37 fractions because their lesions were located close to the GI tract. The other patient was initially treated using the protocol close to the GI tracts. However, additional irradiation was required due to a suspected residual tumor, resulting in a final dose of 70 Gy (RBE) in 35 fractions. In 33 of the 36 patients, pelvic irradiation with X-ray was performed; 3 patients received whole-bladder irradiation with PBT alone, which was followed by PBT boost to the lesion sites in all cases. Twenty patients were given intra-arterial chemotherapy, while the remaining 16 were given systemic chemotherapy.

Recurrence was observed in 13 patients (36.1%), with 7 patients (19.4%) having local recurrences and 6 patients (16.7%) having metastatic lesions. The data entered from the registry data showed four patients with distant metastasis and two with regional lymph node metastasis. At the time of the last observation, three patients (8.3%) were dead; two died of cancer progression, while the other died of intercurrent disease with no sign of recurrence. After local recurrence in the bladder, one patient underwent radical cystectomy. The 3-year OS, PFS and LC rates of the 36 patients in this study were 90.8% (95% CI: 74.0–96.9), 71.4% (95% CI: 53.3–83.5) and 84.6% (95% CI: 66.8–93.3), respectively ( Fig. 2 ). In univariate analysis, operability, the presence of hydronephrosis and prophylactic pelvic irradiation were factors associated with OS ( P  = 0.010, <0.001, <0.001, respectively), while the presence of hydronephrosis, T stage and prophylactic pelvic irradiation were factors associated with PFS ( P  = 0.044, =0.006, <0.001), but there were no factors associated with LC ( Table 5 ).

Kaplan–Meier curves showing the probabilities of OS ( A ), PFS ( B ) and LC ( C ). The solid line indicates the estimated value, and the upper and lower dotted lines represent the upper and lower limits of 95% confidence interval, respectively.

Univariate analyses of risk factors for progression

Significant P-values are shown in bold typeface.

Only one case (2.8%) experienced Grade 3 urinary tract obstruction as a result of treatment, but no severe GI adverse effects were observed. The Grade 1–2 toxicities data were not collected in Proton-Net and, therefore, are unavailable.

Using prospective nationwide registry data, this study assessed the clinical efficacy of PBT as a CMT that consists of maximal TURBT, which was followed by chemoradiotherapy as a definitive bladder preservation therapy for patients with Stages II and III MIBC. The 3-year OS and PFS rates in the study were 90.8 and 71.4%, respectively, and no Grade 3 or severe GI adverse effects were observed. The results of the largest study on PBT for MIBC were previously published by a Tsukuba group, and the outcomes of 70 Stages II and III MIBC patients treated with CMT using PBT until 2015 (before the start of the nationwide registry) were reported [ 7 ]. In their study, the 3-year OS and PFS rates were 92 and 80%, respectively, with no Grade 3 GI toxicity. As a result, the prospective registry data in this study appear to replicate the clinical outcomes of feasibility and efficacy reported in the previous study.

There have been no randomized trials comparing PBT to XRT as CMT for patients with Stages II–III MIBC. As a result, we attempted SR to compare the clinical outcomes of the treatments. As a result of our systematic review, the 3-year outcomes of XRT-based CMT were 57–84.8% in OS, 39–78% in PFS and 51–68% in LC, and Grade 3 or higher GI adverse events ranged from 0 to 9.1%, with a weighted mean of 2.2% ( Table 2 ). The dose of irradiation to bladder tumors is critical in radiotherapy to completely eradicate tumor cells, but it is known that there are dose dependencies in the severity and incidence of late adverse effects on adjacent organs at risk. The proton beams have a physical property in radiotherapy for deep-sheeted tumors. While X-rays exhibit the characteristic of depth dose buildup, proton beams can be stopped at a specific depth in the body to impart a maximal radiation dose to the target during treatment. Furthermore, because they can be stopped at a specific depth in the body during treatment, a favorable dose distribution of the proton beams can be obtained by smaller numbers of beam ports than used for X-rays and that could explain why we obtained favorable results regarding the toxicity outcomes of prospective registry data in previous and current studies of PBT for MIBC [ 27 , 28 ]. As a result, PBT can deliver sufficient dose to control the bladder tumor without increasing the risk of adverse events in normal tissues such the GI tracts and the normal bladder. PBT’s safety in treating patients with Stages II–III MIBC may thus be confirmed.

In terms of the efficacy of using protons in CMT for MIBC, this study found that the 3-year OS and LC rates after PBT were ~90%, which appears to be superior to other outcomes after CMT using X-rays. In this study, seven (19.4%) patients experienced local recurrence, and the recurrence rate appears to be lower than in previous XRT-based CMT protocols (ranging from 11 to 43%) [ 29 ]. Furthermore, the previous and our studies’ 3-year LC rates of PBT were 80 and 84.6%, respectively, but the corresponding rate after XRT-based CMT ranged from 51 to 68% ( Table 2 ). Because dose escalation is a reasonable approach to bladder tumor control, the higher irradiation dose (77.7 Gy (RBE)) given by PBT compared with the standard dose (60–70 Gy) in other studies may contribute to the high LC rate [ 6–26 ]. In this study, patients were treated with two protocols, a high-dose group and a low-dose group, depending on whether the lesion was close to the GI tract. However, this analysis did not confirm an oncologic outcome advantage in the high-dose group, which is farther from the GI tract. Since prior studies have suggested improved LC with increasing doses, the reason this difference was not significant in the present analysis may be due to the small number of cases. This study included T3b–T4 diseases (30.6%), multifocal tumors (27.8%) and the presence of tumor-related hydronephrosis (11.1%), all of which have been identified as risk factors for recurrence after CMT in Stages II–III MIBC patients [ 29 ]. Similarly, in this analysis, hydronephrosis was associated with OS and PFS, and T stage with PFS. On the other hand, tumor volume and size are known to be significant predictors of tumor control [ 29 , 30 ], and the median diameter of the bladder tumors in the study was 3.0 cm (ranging from 1.0 to 5.9 cm). As a result, although the effectiveness of proton beams on CMT for MIBC may be confirmed, the relatively small size of tumors may influence our preferable results. In this analysis, some factors (especially, tumor size and pelvic irradiation) had very small sample sizes for each stratum, so the analysis results should be interpreted carefully.

The usefulness of PBT for various urological cancers has been confirmed, particularly in the step-by-step treatment of prostate cancer [ 31–34 ], but publications on PBT studies for bladder cancer have only come from a Tsukuba group [ 7 , 27 , 35 ]. As a result, SR for PBT for MIBC in this study must be immature. Despite this significant limitation, the California Protons Cancer Therapy Center and the Texas Center for Proton Therapy, as well as a number of Japanese PBT institutes, have begun to use protons for MIBC [ 36 ]. Although randomized trials or matched-pair analyses are required to validate the efficacy of PBT, a rapid increase in the number of PBT facilities around the world will be able to alleviate the concern in the future. Furthermore, there are some limitations to our research. Because the nationwide registry was begun in 2016, and only patients treated in the first 2 years were analyzed in the study, the number of patients in the obtained data was relatively small ( n  = 37). However, PBT was performed on all MIBC patients in accordance with JASTRO's treatment policy, and data from them were collected prospectively. As a result, we will be able to obtain more reliable and larger registry data in the coming years. Second, patient and treatment characteristics, such as chemotherapy regimen and use of prophylactic nodal irradiation, were inconsistent, despite the fact that a previous Japanese multi-institutional study found that the type of chemotherapy administered had no effect on LC or OS rates [ 37 ]. Future research using the continuous nationwide registry will address these issues and provide a detailed indication and treatment method for PBT for MIBC.

PBT is expected to provide at least the same toxicity as XRT-based CMT for Stages II-III MIBC while improving survival. More detailed data from long-term follow-up will provide us with an appropriate use of protons and will validate the efficacy of PBT as a CMT for MIBC.

This work was supported by Hokkaido University (Functional enhancement promotion expenses by the Ministry of Education, Culture, Sports, Science and Technology) and AMED under Grant Number JP16lm0103004.

The authors would like to thank Enago ( www.enago.jp ) for the English language review.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Sperling Prostate Center

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• October 19, 2021
• Other Treatments

A Case Study of Recurrent Prostate Cancer after Proton Beam Therapy

By: dr. dan sperling.

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• Prostate Cancer Diagnosis

Note that when PSA is rising after any form of radiation, include brachytherapy, it is assumed that PCa is back—though only a biopsy proves it. In any case, such recurrence rates have not persuaded insurers that proton beam is worth the extra cost. Discouraged patients often resign themselves to another choice. The National Association for Proton Therapy has a website for coaching patients on strategies they can implement to appeal a denial decision. Generating an effective appeal takes tenacity and a big commitment to do the research and documentation needed to mount a campaign. For someone who’s already dealing with a cancer diagnosis, the effort may not be worth it.

When the National Cancer Institute (NCI) publishes a case study in prostate cancer (PCa) treatment, it’s an experience in very respectable clinical detail. An example is the 2015 analysis of one man’s recurrent PCa following primary (first) prostate cancer treatment with proton beam radiation. The study, “Upgrading Prostate Cancer Following Proton Beam Therapy,” [iv] includes co-author Dr. Peter Pinto, a name that might be familiar to many of you.

The purpose of the authors is to discuss the physical effects of radiation on prostate tissue, and how this could make it challenging to distinguish recurrence on biopsy. In a sense, this case study is a cautionary tale, and I’ll explain why.

The patient was 45 years old when he was diagnosed with PCa. His PSA was 8.6 ng/mL, and his Gleason score was 4+3. He was determined to be stage T1c, meaning he was considered to have disease still localized within the gland. He looked like a very good candidate for radiation therapy – in his case, proton beam.

Effects of radiation

A lot of people assume that radiation kills cancer quickly, but this is not the case. Unlike thermal ablation such as focal laser ablation , which destroys cancer at the time of treatment, radiation acts on the DNA of cancer cells over time, making it difficult for the cells to reproduce themselves. Healthy cells are less susceptible to the effects of radiation, though the scatter effect of all radiation can also do some harm to normal cells.

The more radiation you give, the greater the effects. This is called a dose-dependent response, and the authors inform us that radiation-induced effects “can be heterogeneous among a single tumor and patients. These changes can be so pronounced that they can affect assessment of residual disease.” This is what I take to be the main point of this article: the changes in tissue due to exposure to radiation can make it difficult to accurately diagnose recurrence.

Here’s what happened

His PSA reached a nadir (lowest point) of 3.2 ng/mL at 3 months after treatment. Then it began to rise, eventually reaching 9.39 at 21 months. Meanwhile, the patient had a 12-core TRUS biopsy at 18 months. It was diagnosed as negative for PCa, only showing the unusual cell formations typical of radiated prostate tissue. But something wasn’t adding up, so he was sent for a multiparametric MRI (mpMRI) of the prostate – the same type of imaging we do at our Center – which the NCI excels at.

Not surprisingly, the mpMRI scan found two suspicious areas in the prostate plus what appeared to be invasion of the seminal vesicles; however, there was no evidence at that point of PCa in the lymph nodes or bone. A 6-core targeted biopsy into the suspicious lesions found “all six targeted cores demonstrating high-grade disease (five cores with Gleason 4 + 5 = 9 disease) with perineural and seminal vesicle invasion.”

The patient then underwent a salvage robotic prostatectomy and extended removal of 33 lymph nodes. Examination of the entire prostate specimen showed that the whole gland as “atrophied” from radiation effect, and was found to have “multifocal Gleason 5+5 disease with extracapsular extension and seminal vesicle invasion.” PCa was found in two of the lymph nodes. There is some hopeful news for this patient: At 1 and 3 months post-surgery, his PSA was stable at 0.07 ng/mL.

Important take-aways

Here the important points I gained from this article:

• It appears that proton beam radiation affects tissue in ways similar to other forms of radiation, though more research is needed
• When examining recurrent PCa in radiated glands, one must be aware that some tumor areas will show radiation effects while others may not. The authors advise against grading the affected areas, and only grading the non-affected areas.
• The reason to grade the non-affected areas is because PCa tumors that escape radiation’s effects tend to come back more aggressive than the parent tumor, as demonstrated by Gleason grade and changes in the DNA itself (called ploidy)
• If recurrence is suspected, it’s better to wait a year to biopsy tissue, because “it is believed tumor regression continues for 6-12 months after radiation treatment” (remember: radiation does not kill cancer quickly) so at 1 year, if what a biopsy finds looks like cancer, it probably IS cancer.

Although this article is a single case study, the in-depth tissue analysis of the surgical specimen helps explain why the biopsy at 18 months was inconclusive for cancer: the changes brought about by radiation made it challenging to characterize the cells under the microscope. On the other hand, the mpMRI detected tumor clusters with significant (high grade) characteristics, and the targeted biopsy harvested large enough samples to distinguish radiation effect from active tumor.

There is, of course, a place for radiation therapy in the toolkit we use against prostate cancer, especially for nonsurgical candidates with multifocal disease. It is still a very good option for appropriate patients. However, articles like this case study help make us aware that the cancer-destroying power of radiation is based on a completely different action, and even proton beam cannot completely spare non-PCa cells.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

[i] Kubeš J, Haas A. Vondrá?ek V, Andrlik M et al. Ultrahypofractionated Proton Radiation Therapy in the Treatment of Low and Intermediate-Risk Prostate Cancer-5-Year Outcomes. Int J Radiat Oncol Biol Phys. 2021 Jul 15;110(4):1090-1097. [ii] Takagi M, Demizu Y, Terashina K, Fujii O et al. Long-term outcomes in patients treated with proton therapy for localized prostate cancer. Cancer Med. 2017 Oct;6(10):2234-2243. [iii] Takagi M, Demizu Y, Fujii O, Terashima K et al. Proton therapy for localized prostate cancer: long-term results from a single-center experience. Int J Radiat Oncol Biol Phys. 2021 Mar 15;109(4):964-974. [iv] Logan JK, Rais-Bahrami S, Merino MJ, Pinto PA. Upgrading prostate cancer following proton beam therapy. Urol Ann. 2015 Apr-Jun;7(2):262-4.

About Dr. Dan Sperling

Dan Sperling, MD, DABR, is a board certified radiologist who is globally recognized as a leader in multiparametric MRI for the detection and diagnosis of a range of disease conditions. As Medical Director of the Sperling Prostate Center , Sperling Medical Group and Sperling Neurosurgery Associates , he and his team are on the leading edge of significant change in medical practice. He is the co-author of the new patient book Redefining Prostate Cancer , and is a contributing author on over 25 published studies. For more information, contact the Sperling Prostate Center .

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• Published: 22 October 2012

The clinical case for proton beam therapy

• Robert L Foote 1 ,
• Scott L Stafford 1 ,
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Over the past 20 years, several proton beam treatment programs have been implemented throughout the United States. Increasingly, the number of new programs under development is growing. Proton beam therapy has the potential for improving tumor control and survival through dose escalation. It also has potential for reducing harm to normal organs through dose reduction. However, proton beam therapy is more costly than conventional x-ray therapy. This increased cost may be offset by improved function, improved quality of life, and reduced costs related to treating the late effects of therapy. Clinical research opportunities are abundant to determine which patients will gain the most benefit from proton beam therapy. We review the clinical case for proton beam therapy.

Summary sentence

Proton beam therapy is a technically advanced and promising form of radiation therapy.

X-rays have been used to treat cancer since 1895. Advances in x-ray therapy over the years include development of linear accelerators that produce high-energy x-rays for deeper penetration. Blocking techniques were developed to contour the beam to conform to the size and shape of the tumor target. Multiple beams and angles are used to adapt the dose to the tumor and to reduce the dose to healthy organs. Advances in imaging have allowed for improved tumor delineation. Four-dimensional imaging allows measurement of motion of both tumor and normal structures during treatment. Changes in tumor size and shape during treatment can be corrected for use of adaptive radiotherapy techniques. Faster and more powerful computers allow for more accurate dose calculations and the delivery of intensity modulated x-ray beams and volumetric arc therapy. Improved patient and organ immobilization devices, along with imaging during treatment to detect patient, organ, and tumor motion (image-guided radiotherapy), enhance the accuracy of treatment delivery.

These advances were accomplished without performing conventional prospective clinical trials. The administration of concurrent radiation-sensitizing chemotherapy and biologically targeted agents has been found to improve both disease control and survival for many cancer patients.

The likelihood of tumor control through radiation therapy is related to the dose delivered to the tumor, and the likelihood of severe organ injury is related to dose to the organ and volume of the organ exposed to radiation [ 1 ]. A balance always exists between cure and risk of severe complications. The challenge in using high-energy x-rays to treat cancer is that the x-rays pass through the thickness of the body, depositing an entrance and an exit dose to healthy organs. The dose to healthy organs limits the dose that can be safely administered to the tumor. Radiation oncologists constantly strive to find the optimal balance between a high-enough dose to prevent cancer recurrence and a low-enough dose to avoid injury to healthy organs.

Proton beam therapy offers an option for obtaining that balance. Hospital- or clinic-based proton beam facilities have been in existence since 1990. Currently, 11 proton beam facilities are in operation in the United States (Figure 1 ) and 26 are operational in 13 other countries (Russia, Switzerland, Sweden, England, France, South Africa, Canada, Germany, Japan, Italy, China, South Korea, and Poland) (Figure 2 ). Eighteen proton beam facilities are under construction in Switzerland, Czech Republic, Austria, Italy, China, Germany, Taiwan, Russia, Slovak Republic, Sweden, and the United States.

Proton beam treatment facilities that are operational or under construction in the United States. CDH indicates Central Dupage Hospital; IU, Indiana University; MGH, Massachusetts General Hospital; OKC, Oklahoma City; U, University; UCSF, University of California, San Francisco.

Proton beam treatment facilities that are operational or under construction outside the United States.

Protons are positively charged subatomic particles that are massive compared with x-rays. The biologic effects of protons and x-rays on cells are similar since both are sparsely ionizing with a relatively small linear energy transfer. However, the way protons interact with matter provides advantages compared with x-rays. As protons enter the body, they deposit a very low entrance dose. The depth of proton penetration is dependent on kinetic energy and, hence, the higher the energy, the deeper is the penetration. When the proton arrives at its target, it delivers the dose and stops, thereby eliminating an exit dose. This physical advantage serves to lower the dose to healthy organs both superficial and deep to the tumor, thus reducing the risk of injury. It also allows administration of a higher dose to the tumor, potentially reducing the recurrence rate without increasing the complication rate and leading to better organ function and quality of life. This result can lead to an avoidance of costs associated with treating recurrent tumors and damaged organs. This effect is particularly important in young children with a high likelihood of cure who are strongly susceptible to the long-term effects of x-ray therapy and in patients with cancers located adjacent to critical healthy organs, such as the eye, brain, brainstem, spinal cord, lung, heart, liver, bowel, and kidneys.

• Clinical review

Ocular (choroidal) melanoma

Treatment options for patients with ocular melanoma include 1) enucleation, 2) suturing of a radioactive plaque to the eye overlying the melanoma, and 3) proton beam therapy. No differences in survival between treatments have been reported in prospective clinical trials [ 2 , 3 ]. Advantages of the radioactive plaque and proton beam therapy are preservation of the eye and vision. In a phase 3 study performed to compare the radioactive plaque with helium ion therapy (helium ions contain 2 protons), there were fewer recurrences of the melanoma in those patients treated with helium ions (0% vs 13.3%) [ 3 ]. The proportion of patients who required enucleation because of melanoma recurrence or complications was less when they were treated with helium ion therapy (9.3% vs 17.3%). The proportion of eyes with visual acuity greater than 20/40 was the same with both treatments (21%-23%).

The Mayo Clinic experience with radioactive plaques has been reported [ 4 ]. The recurrence rate is 8%; the enucleation rate is 8%. The proportion of patients with visual acuity greater than 20/40 is 22%. Several large series of patients treated with proton beam therapy have been reported, confirming low recurrence rates (3%-4%) and low enucleation rates (9.4%-11%), with visual acuity greater than 20/40 in 44.8% [ 5 – 9 ]. Of these series, the larger ones included 1,406 patients treated in France [ 8 ]; 2,435 patients in Switzerland [ 9 ]; and 2,815 patients in Boston, Massachusetts [ 7 ]. A phase 3 study conducted by the Massachusetts Eye and Ear Infirmary compared 2 different dose levels of proton beam therapy, 50 Gy and 70 Gy [ 10 ]. No differences were noted in outcome, with recurrence rates of 2% to 3% and enucleation rates of 4% to 5%.

Proton beam therapy has a number of advantages over radioactive plaques, including 1) localization requires 1 or no surgery, depending on technique, 2) no hospital stay is needed, yet treatment is still completed in 5 calendar days, 3) more patients are eligible for proton beam therapy than radioactive plaque therapy because of the ability to treat larger tumor sizes and tumors surrounding the optic nerve, and 4) medical staff have no radiation exposure.

Skull base chordoma

Skull base chordomas are rare tumors that are difficult to completely remove surgically. Doses of radiation therapy are limited because of the adjacent brain, brainstem, cranial nerves, and spinal cord structures. At Mayo Clinic, with a combination of aggressive surgical debulking, 3-dimensional (3-D) conformal x-ray therapy, and Gamma Knife radiosurgery, the 5-year tumor control rate was 32% in 25 patients [ 11 ]. At the Paul Scherrer Institute in Switzerland, with a combination of surgical debulking and scanning proton beam therapy, the 5-year tumor control rate was 81% in 42 patients [ 12 ]. The incidence of symptomatic temporal lobe injury at Mayo Clinic was 10% vs 6% with scanning proton beam therapy at the Paul Scherrer Institute [ 11 , 12 ]. At the Harvard Cyclotron Laboratory, 290 patients with skull base chordomas were treated with scattered proton beams [ 13 ]. The 5-year tumor control rate was 73%, with an 8% incidence of temporal lobe injury. It appears from these data that proton beam therapy is more effective than x-ray therapy in producing a greater probability of long-term tumor control without increasing the risk of temporal lobe injury.

Lung cancer

Standard treatment for locally advanced, inoperable non–small cell lung cancer includes a combination of chemotherapy and x-ray therapy. Median survival is about 17 months, with 50% of the patients having severe toxicity related to treatment (60 Gy of x-ray therapy) [ 14 , 15 ]. Results of phase 3 studies using combined x-ray therapy (60–64 Gy) and chemotherapy report long-term survivors (3–5 years) in 15% to 18% with a 40% to 80% recurrence rate and 48% to 53% of patients having serious or life-threatening toxicity (ie, esophagitis and pneumonitis) [ 14 , 15 ]. The North Central Cancer Treatment Group (including Mayo Clinic) performed a phase 1 dose-escalating trial and found that, by increasing the x-ray therapy dose to 74 Gy, the median overall survival was favorable at 40 months and the recurrence rate was reduced to 15%, but the serious, life-threatening toxicity continued to be high at 54% [ 16 ]. The MD Anderson Cancer Center performed a phase 2 dose-escalating trial using proton beam therapy and confirmed that 74 Gy resulted in a favorable median overall survival (29.4 months) and decreased the recurrence rate to 20% [ 17 ]. In addition, the incidence of serious toxicity was reduced with proton beam therapy and included dermatitis (11%), esophagitis (11%), and pneumonitis (2%). These results suggest that there is an opportunity to take advantage of dose escalation with proton beam therapy to prolong survival; lower the recurrence rate; decrease the risk of serious, life-threatening toxicity; and intensify chemotherapy. A recently completed phase 3 study comparing a modest dose increase from 60 Gy to 74 Gy of x-ray therapy failed to demonstrate improved survival with 74 Gy [ 18 ]. The assumed reason for this lack of benefit was death due to higher doses of x-ray therapy affecting the heart and lungs adversely [ 19 ]. This outcome suggests that further dose escalation with x-rays will not be feasible. Massachusetts General Hospital and MD Anderson Cancer Center are nearing completion of a phase 3 clinical trial comparing x-rays to protons in the treatment of locally advanced non–small cell lung cancer.

Hodgkin lymphoma in children, adolescents, and young adults

Hodgkin lymphoma (HL) is a curable hematogenous malignancy that affects primarily children and young adults and in which consolidation x-ray therapy is often used after chemotherapy for treatment of initially involved lymph node groups. Survivors of HL have an excessive amount of secondary malignancy (SM), with a 15-year risk of about 15%. Although x-ray therapy may improve outcomes in HL, it may increase the risk of SM, particularly breast, lung, and thyroid cancers and hematogenous cancers. The risk of radiation-induced cancers is proportional to the dose delivered. Using a proton beam treatment planning system, we compared the distribution of proton dose to x-ray dose in patients with HL treated with x-ray therapy at Mayo Clinic. We found that the integral dose of exposure radiation to the patient was reduced by at least 50% with the use of scattered or scanned proton beams compared with 3-D or intensity modulated x-ray beams. This reduction predicts that the risk of radiation-induced cancers would be reduced by at least 50%.

A study from Massachusetts General Hospital of 1,450 patients treated with proton beam therapy at the Harvard Cyclotron Laboratory appears to support this conclusion [ 20 ]. A subset of the patients (n=503) was matched to similar patients identified in the Surveillance Epidemiology and End Results cancer registry who were treated with x-ray therapy (n=1,591). SM was reported in 12.8% of the patients treated with x-ray therapy compared with 6.4% in patients treated with proton beam therapy (adjusted hazard ratio, 2.73; 95% confidence interval, 1.87-3.98; P <.0001). These data substantiate what we would have predicted by evaluating the x-ray vs proton beam dosimetry. Other investigators have similarly concluded that proton beam therapy may reduce the risk of SM by up to 50% in comparison with x-ray therapy [ 21 ].

Similarly, cardiac irradiation during HL x-ray therapy has been associated with an increased risk of coronary artery disease and valvular dysfunction [ 22 , 23 ]. Therefore, a substantial reduction in health care costs, lost productivity, morbidity, death, and human suffering in HL survivors could be realized with the use of proton beam therapy.

Esophageal and gastroesophageal junction cancers

The current standard of care for locally advanced esophageal cancer is concurrent chemotherapy and x-ray therapy with or without surgical resection. The 5-year overall survival rate is 20% to 30%. The incidence of treatment-related toxicity that is severe or worse is 33% [ 24 ]. Irradiation of the heart has been shown to increase the risk of a myocardial perfusion abnormality [ 25 ]. A recent review of the Mayo Clinic experience found that the incidence of non–cancer-related deaths within the first year after treatment was 8% following chemotherapy and x-ray therapy without surgery, 33% following preoperative chemotherapy and x-ray therapy, and 20% following postoperative chemotherapy and radiation therapy. The majority of these deaths were due to cardiopulmonary toxicity. The risk of cardiac toxicity due to x-ray therapy is dependent on the dose delivered and the volume of heart exposed to radiation [ 1 ]. Through comparative treatment planning analysis of x-ray and proton beams, we found that the dose delivered to one-third the volume of the heart was reduced from 75% of the dose prescribed to the tumor with conventional x-ray therapy to 58% with intensity modulated x-ray therapy and to just 9% with proton beam therapy. This finding suggests that cardiac-related morbidity and death could potentially be reduced by using proton beam therapy to treat esophageal cancer.

Pediatric cancers

Great advances have been made in the treatment of pediatric cancers. Currently, 85% of pediatric cancer patients are cured, although 65% of long-term survivors have chronic health conditions, with death from a SM or other treatment-related event occurring in 20% [ 26 – 32 ]. Despite the increased use of chemotherapy in the management of pediatric cancers, x-ray therapy has an important role in the treatment of approximately 50% of children with cancer, particularly children with brain tumors. However, although x-ray therapy is effective in many children, their quality of life is frequently compromised by late effects of x-ray therapy.

In pediatric practice, the relatively large volume of the body exposed to low doses of x-ray therapy is frequently clinically relevant in relation to long-term effects. Treatment complications include neurocognitive deficits, hearing loss, pituitary dysfunction, hypothyroidism, cardiac dysfunction, pulmonary disease, diminished vertebral body growth, scoliosis, gastrointestinal tract dysfunction, infertility, and SM. The marked reduction in dose to the body and healthy organs associated with proton beam therapy may be used to reduce the extent of the harmful low-dose x-ray effect and thus may be clinically beneficial in pediatric radiation oncology practice.

Medulloblastoma is the second most common pediatric brain tumor. This tumor classically develops in the posterior fossa with frequent metastases along the craniospinal axis, and thus craniospinal axis x-ray therapy is a vital component of treatment. Once considered incur-able, the 5-year overall survival rate is now in excess of 65% following treatment with a combination of surgery, x-ray therapy, and chemotherapy. This rate raises concerns regarding long-term, treatment-associated adverse effects.

Of utmost concern are the neuropsychological effects of x-ray therapy to the central nervous system, including impaired neurocognitive development and behavioral disorders. These effects are dose and volume dependent. There is evidence—from whole-brain irradiation for leukemia—of a dose–response effect on long-term neuropsychological effects [ 33 ]. In a recent study of children treated for medulloblastoma, Grill et al. [ 34 ] showed a significant correlation between full-scale IQ scores and x-ray dose, with mean scores of 84.5, 76.9, and 63.7 for 0, 25, and 35 Gy, respectively. A dose–response curve relating the probability of neuropsychological sequelae to brain dose has been derived from an analysis of the medical literature [ 33 ]. Mulhern et al. [ 35 ] prospectively examined the neuropsychological functioning of children with medulloblastoma treated in the POG 8631/CCG 923 study. They found that children treated with 23.4 Gy craniospinal axis x-ray therapy had less neuropsychological toxicity than those treated with 36 Gy.

Long-term effects from x-ray therapy for pediatric cancers include hypoplasia of soft tissue and bone. In children treated with abdominal x-ray therapy for Wilms tumor, 19.6% were reported to have clinically significant long-term orthopedic deficits [ 36 ]. There is evidence that the severity of these effects is dose related [ 37 ]. Other long-term effects include hearing loss; primary hypothyroidism; thyroid cancer; cardiomyopathy, especially when x-ray therapy is combined with anthracycline chemotherapy; cardiac valvular disease; early onset coronary artery disease; infertility related to pelvic x-ray therapy; and secondary osteosarcoma related to x-ray therapy for Ewing sarcoma, retinoblastoma, or medulloblastoma.

The goal of clinicians is not only to eradicate the primary tumor, but also to minimize the risk of radiation-induced cancers over the lifetime of these children. The observation that many of the late effects of x-ray therapy appear to be dose dependent provides the rationale for proton beam therapy reducing some of the effects that result from exposing structures outside the tumor target volume to radiation.

Comparison of treatment plans using proton, conventional x-ray, or intensity modulated x-ray beams has showed improved dose distributions with proton beams, with modeling estimating a 2-fold reduction or more in risk of a radiation-induced cancer for a child with rhabdomyosarcoma and an 8- to 15-fold decrease for a child with medulloblastoma (due to larger treatment volume) [ 38 ]. A study comparing the risk of radiation-induced cancer following spinal irradiation for childhood medulloblastoma after various radiation delivery techniques found the highest lifetime risk of SM with intensity modulated x-ray therapy (30%) and the lowest risk with intensity modulated proton therapy (4%) (Table 1 ) [ 39 ]. These studies underscore the concern with using x-ray therapy in the treatment of pediatric cancers.

Table 2 illustrates a comparison of 3 radiation therapy treatment delivery techniques for a child with medulloblastoma [ 40 ]. The substantial sparing of healthy tissue is apparent in proton beam therapy of the posterior fossa and spinal axis.

A recent publication from Sweden projected decreased health care expenses using proton beam therapy in the treatment of pediatric medulloblastoma [ 41 ]. The initial cost of proton beam therapy (€10,217.90) was approximately 2.5 times the initial cost of x-ray therapy (€4,239.10). However, the cost of treating adverse events related to x-ray therapy (€33,857.10) was 8 times greater than the cost of treating adverse events related to proton beam therapy (€4,231.80). Considering both initial cost of treatment and the cost of treating adverse events related to the treatment, x-ray therapy was 2.6 times more costly than proton beam therapy (€38,096.20 vs €14,449.70). The additional costs related to treating adverse events associated with x-ray therapy were due to IQ loss, hearing loss, growth hormone deficiency, hypothyroidism, osteoporosis, and SM.

Dosimetric and clinical studies have demonstrated the benefits of proton beam therapy compared with x-ray therapy in reducing dose and harm to healthy organs in children with retinoblastoma, medulloblastoma, pelvic soft tissue sarcoma, bone sarcoma, and orbital rhabdomyosarcoma [ 42 , 43 ].

Breast cancer

The meta-analysis of the Early Breast Cancer Trialists’ Collaborative Group demonstrated improved 5-year tumor control and improved 15-year breast cancer and overall mortality rates with the use of adjuvant x-ray therapy [ 44 ]. The therapy was used in the clinical setting of breast-conserving and postmastectomy treatment. However, x-ray therapy was associated with an excess of SM (lung cancer relative risk [RR], 1.61 P =.0007]; esophageal cancer RR, 2.06 P =.05]; leukemia RR, 1.71 P =.04]; soft tissue sarcoma RR, 2.34 P =.03]; contralateral breast cancer RR, 1.18 P =.002]) and non–breast cancer deaths (any non–breast cancer RR, 1.12 P =.001]; pulmonary embolism RR, 1.94 P =.02]; heart disease RR, 1.27 P =.0001]; lung cancer RR, 1.78 P =.0004]; and esophageal cancer RR, 2.4 P =.04]). The non–breast cancer deaths reduce the efficacy of x-ray therapy by 20%. In patients with positive axillary lymph nodes undergoing postmastectomy chest wall and nodal x-ray therapy, 30% die of noncancer-related deaths. If the morbidity and death due to SM and cardiopulmonary disease could be reduced or eliminated, the overall survival advantage for women treated with x-ray therapy would be further improved, along with reduction in human suffering and health care costs. The risk of cardiotoxicity is increasingly important in light of the cardiotoxicity associated with anthracycline and, more recently, trastuzumab treatment, which are mainstays in modern adjuvant medical therapy for breast cancer.

We developed 3 treatment plans for a cohort of women with left-sided stage I breast cancer who were undergoing breast-conserving therapy at Mayo Clinic with lumpectomy and breast irradiation. The first plan used conventional x-ray therapy to the entire breast, with an electron boost to the tumor cavity; the second used passively scattered proton beams; and the third used actively scanned proton beams. Compared with the x-ray and electron boost plan, the 2 proton beam plans substantially reduced all measures of lung dose. For example, the mean total lung dose was reduced by 71% using the passively scattered beams and by 81% using the actively scanned beams. Both proton beam plans eliminated the dose to the contralateral lung. The 2 proton beam plans also reduced all measures of dose to the heart. For example, the mean total heart dose was reduced by 75% with the passively scattered beams and by 99% with the actively scanned beams. The mean dose to the contralateral breast was reduced with the proton beam plans compared with the x-ray and electron beam plan—by 88% using the passively scattered beams and by 96% using the actively scanned beams. In addition, the 2 proton beam plans reduced the mean dose to the entire body by 37% for the passively scattered proton beams and by 54% for the actively scanned proton beams.

A similar dosimetric study of women undergoing postmastectomy chest wall and regional lymph node irradiation at Mayo Clinic revealed similar advantages to protons compared with x-rays. Other investigators have confirmed these findings [ 45 – 49 ]. Lundkvist et al. [ 50 ] have demonstrated that proton beam therapy is cost-effective in women with left-sided breast cancer and risk factors for cardiac disease, on the basis of a lower cost per quality-adjusted life-year. Cost-effectiveness will be further improved when investigators also include the cost reductions associated with a reduced incidence of radiation-induced malignancy and pulmonary disease. It is hypothesized that proton beam therapy will be most cost-effective in young women with left-sided breast cancer; in women with a long life expectancy; and in women with risk factors for cardiopulmonary disease, a desire to avoid mastectomy, and indications for postmastectomy chest wall and nodal irradiation.

Current clinical trials are evaluating the safety, efficacy, and cosmetic outcome of partial breast irradiation compared with whole breast irradiation. Should these trials document a meaningful clinical advantage to partial breast irradiation, Taghian et al. [ 48 ], Kozak et al. [ 49 , 51 ], and Bush et al. [ 52 , 53 ] have demonstrated that partial breast irradiation using proton beam therapy is safe, effective, and technically feasible; provides excellent tumor coverage; and improves healthy tissue (heart and lung) sparing, including nontarget breast tissue, when compared with partial breast irradiation using conventional x-rays and electron beams. In addition, it is less expensive than intracavitary and interstitial brachytherapy.

Prostate cancer

The treatment of prostate cancer with proton beam therapy is controversial. Current treatment options include prostatectomy, brachytherapy, and intensity modulated x-ray therapy, all of which are less costly than proton beam therapy.

Prospectively randomized clinical trials have demonstrated that higher doses of x-ray therapy result in improved survival and lower doses to the rectum and bladder result in lower risks of complications. A phase 3 study funded by the NHS Trust randomly assigned 225 men with prostate cancer to 2-dimensional (2-D) or 3-D conformal x-ray therapy [ 54 ]. The results of this study proved the principle that reducing the radiation dose to the rectum and bladder by using 3-D conformal techniques reduces the incidence of ≥grade 2 bowel toxicity (from 18% with 2-D to 8% with 3-D) and bladder toxicity (from 23% with 2-D to 20% with 3-D). A phase 3 dose-escalation study conducted by MD Anderson Cancer Center randomly assigned 301 patients to 70 Gy using 2-D x-ray therapy vs 78 Gy using 3-D conformal x-ray therapy [ 55 , 56 ]. This study proved that a higher dose of x-ray therapy results in fewer recurrences (79% 5-year freedom from biochemical failure with 78 Gy vs 69% with 70 Gy). The ≥grade 2 bowel and bladder toxicity was 14% (bowel) and 20% (bladder) for 2-D compared with 21% (bowel) and 9% (bladder) for 3-D x-rays.

The reduced recurrence rate using a higher dose has been confirmed by another phase 3 clinical trial conducted by the Netherlands Cancer Institute, in which 664 men were randomly assigned to 68 Gy vs 78 Gy using 3-D conformal x-ray therapy [ 57 ]. The 5-year freedom from biochemical failure was increased from 53% with 68 Gy to 66% with 78 Gy. The ≥grade 2 bowel toxicity was 27% with 68 Gy and 32% with 78 Gy; the ≥grade 2 bladder toxicity was 41% with 68 Gy and 39% with 78 Gy. Intensity modulated x-ray therapy has been administered to a dose as high as 81 Gy in 561 men with prostate cancer at Memorial Sloan-Kettering Cancer Center, with ≥grade 2 bowel toxicity of just 1.6% and ≥grade 2 bladder toxicity of 12% [ 58 ]. Loma Linda University Medical Center has reported the results of treating 1,255 men with prostate cancer to 74 Gy using proton beam therapy [ 59 ]. The 5-year freedom from biochemical failure was 75%, with 3.5% ≥grade 2 bowel toxicity and 5.4% ≥grade 2 bladder toxicity.

Finally, Massachusetts General Hospital and Loma Linda University Medical Center conducted a phase 3 dose-escalation study in 393 patients with prostate cancer using a combination of x-rays with a proton beam boost to the prostate gland [ 60 ]. Patients were randomly assigned to 70.2 Gy or 79.2 Gy. There was a significant improvement in the 5-year freedom from biochemical failure rate in men randomly assigned to 79.2 Gy (80%) compared with those randomly assigned to 70.2 Gy (61%) ( P <.0001). This improvement in recurrence rate with higher dose was obtained without significantly increasing the risk of ≥grade 2 bowel toxicity (9% with 70.2 Gy vs 18% with 79.2 Gy) or bladder toxicity (20% with 70.2 Gy vs 21% with 79.2 Gy). Only 2% of patients in both treatment arms had late severe (≥grade 3) genitourinary toxicity and 1% of patients in the high-dose arm had late ≥grade 3 gastrointestinal tract toxicity [ 61 ]. A cost-effectiveness study suggested that proton beam therapy may be cost-effective in young men with intermediate-risk prostate cancer who have longer life expectancy [ 62 ].

In summary, direct evidence shows that the higher the dose of radiation administered, the lower the risk of prostate cancer recurrence. Direct evidence also shows that lower doses to the rectum and bladder are associated with a lower risk of complications. Indirect evidence shows that with highly conformal techniques (intensity modulated x-ray therapy or proton beam therapy), the dose can be further escalated without increasing the risk of bowel or bladder toxicity and, in fact, with a lower risk of harm than with conventional 2-D and 3-D x-ray therapies. A phase 3 study comparing high-dose intensity modulated x-ray therapy with proton beam therapy was recently opened to patient accrual.

One way of drastically reducing the cost of proton beam therapy compared with intensity modulated x-ray therapy and bringing it more in line with prostatectomy and brachytherapy is to reduce the number of treatments from 40 to 45 administered over 8 or 9 weeks to 5 treatments administered in 1 week [ 63 ]. This regimen would be far more convenient for patients and reduce their time off work and their out-of-pocket expenses. Clinical trials evaluating the safety and efficacy of hypofractionated proton beam therapy should be designed and conducted.

Head and neck cancer

Evidence exists that patients with head and neck cancer may benefit from proton beam therapy by increasing the dose to the cancer to reduce recurrence risk and by reducing the dose to the salivary glands, mandible, and maxilla to lower the risk for dry mouth, dental caries, dental extractions, and osteoradionecrosis [ 64 – 67 ]. The risk of osteoradionecrosis has been shown to be associated with the total dose and the dose per treatment received by the mandible, with a 0% risk for less than 54 Gy at 1.8 Gy per treatment and a 9.8% risk for 54 Gy or greater at 1.8 Gy per treatment [ 68 ]. We evaluated a cohort of consecutive patients at Mayo Clinic undergoing postoperative adjuvant x-ray therapy for tongue cancer. We planned that each patient would receive intensity modulated x-rays and actively scanned proton beams. All measures of mandibular dose were significantly reduced in the patients receiving actively scanned proton beams. For example, the mean volume of the mandible receiving 54 Gy with intensity modulated x-ray beams was 61% (range, 37%-90%) compared with 26% (range, 6%-51%) with actively scanned proton beams ( P =.002). Furthermore, the mean parotid dose was reduced from 33.1 Gy (range, 24.2-44.1 Gy) with intensity modulated x-ray beams to 19.3 Gy (range, 9.6-32.6 Gy) with actively scanned proton beams ( P =.002), thereby significantly reducing the risk of xerostomia [ 69 ].

Other cancers

Potential advantages of proton beam therapy exist for rectal and anal cancers (lower dose to bowel, bladder, and hips); gastric, pancreatic, and hepatobiliary cancers (lower dose to liver, small bowel, heart, lungs, kidneys, and spinal cord); and bone and soft tissue sarcomas. Improved hematologic tolerance may allow dose intensification of chemotherapy given concurrently with proton beam therapy for thoracic, gastrointestinal tract, and other cancers [ 17 ].

Take home points

Mayo Clinic is a national provider of health care with clinics and hospitals in Arizona, Florida, Georgia, Iowa, Minnesota, and Wisconsin caring for more than 13,000 new cancer patients annually. The most common types of cancer treated with radiation therapy at Mayo Clinic are breast cancer (15%), lung cancer (12%), prostate cancer (11%), gastrointestinal tract cancers (10%), and head and neck cancer (5%). In 2002, the Department of Radiation Oncology participated in a departmental exercise to review its status and determine its future direction. As a result of this exercise, the implementation of a charged particle therapy program became a top priority.

There is always a dilemma for large medical practices on the timing for the implementation of new technologies. Health technology assessment is the systematic evaluation of properties, effects, or other impacts of health technology. The main purpose of a health technology assessment is to inform decision making for policy decisions related to technology in health care. The assessment may address the direct and intended consequences of technologies, as well as their indirect and unintended consequences. Historically, the emphasis has been on technology assessment among hospitals, health systems, and health plans. The most common form of technology assessment has focused around pharmaceuticals through pharmacy and therapeutics committees [ 70 ]. However, in recent years the interest has been increasing in technology assessment around devices and procedures. For example, 64-slice computed tomography, positron emission tomography, da Vinci robots, health information technology systems, and telemonitoring programs have undergone technology assessments commonly. Typically, the goal of these committees is to weigh the benefits and costs and conduct analyses of return on investment of new technologies. This evaluation also allows health systems to identify priorities for investment.

We recognize the need to generate, evaluate, integrate, and manage knowledge and information related to proton beam therapy. To transform the cancer care delivery process and to be trusted and affordable through the reduction of harm and cost to patients and society, health care providers will need to define which patients benefit the most from proton beam therapy and to define outcomes (tumor control, overall survival, patient-reported function and quality of life, and cost-effectiveness) prospectively in controlled clinical trials and registries.

Abbreviations

Hodgkin lymphoma

Relative risk

Secondary malignancy

3-dimensional

2-dimensional.

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The effectiveness and safety of proton beam radiation therapy in children and young adults with Central Nervous System (CNS) tumours: a systematic review

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A Correction to this article was published on 05 March 2024

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Central nervous system (CNS) tumours account for around 25% of childhood neoplasms. With multi-modal therapy, 5-year survival is at around 75% in the UK. Conventional photon radiotherapy has made significant contributions to survival, but can be associated with long-term side effects. Proton beam radiotherapy (PBT) reduces the volume of irradiated tissue outside the tumour target volume which may potentially reduce toxicity. Our aim was to assess the effectiveness and safety of PBT and make recommendations for future research for this evolving treatment.

A systematic review assessing the effects of PBT for treating CNS tumours in children/young adults was undertaken using methods recommended by Cochrane and reported using PRISMA guidelines. Any study design was included where clinical and toxicity outcomes were reported. Searches were to May 2021, with a narrative synthesis employed.

Thirty-one case series studies involving 1731 patients from 10 PBT centres were included. Eleven studies involved children with medulloblastoma / primitive neuroectodermal tumours (n = 712), five ependymoma (n = 398), four atypical teratoid/rhabdoid tumour (n = 72), six craniopharyngioma (n = 272), three low-grade gliomas (n = 233), one germ cell tumours (n = 22) and one pineoblastoma (n = 22). Clinical outcomes were the most frequently reported with overall survival values ranging from 100 to 28% depending on the tumour type. Endocrine outcomes were the most frequently reported toxicity outcomes with quality of life the least reported.

Conclusions

This review highlights areas of uncertainty in this research area. A well-defined, well-funded research agenda is needed to best maximise the potential of PBT.

Systematic review registration.

PROSPERO-CRD42016036802.

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Introduction

Central Nervous System (CNS) tumours account for approximately 25% of all childhood neoplasms. Improvements in multimodality treatment regimens including surgical resection, focal and craniospinal radiotherapy (RT) and chemotherapy, have led to the 5-year overall survival rate of around 75% for this group of tumours in UK children [ 1 ]. Conventional RT (photon RT), which uses photon (x-ray) beams to target cancer cells, has made a significant contribution to survival, however it is associated with long-term adverse effects resulting from damage to adjacent healthy tissue which can lead to long-term cognitive, developmental and behavioural dysfunction [ 2 , 3 , 4 ]. These are caused by a combination of the direct and indirect impact of the tumour itself and also patient and treatment related parameters. There has been increasing interest in the potential of proton beam therapy (PBT) to reduce these late adverse events. Compared to photon RT, PBT is associated with smaller volumes of non-target irradiated normal tissue [ 5 , 6 , 7 , 8 , 9 ] largely due to the near complete elimination of exit dose [ 10 ]. Based on modelling assumptions from dosimetric studies, PBT has been adopted as the primary RT treatment modality for selected paediatric CNS tumours in several healthcare systems worldwide. In turn it is assumed that the radiodosimetric advantage of PBT will translate into improved clinical benefits such as a reduction in neuro-psychological sequalae and a lower incidence of radiotherapy induced second tumours.

The utility of systematic reviews to summarise research evidence in a non-biased, reproducible and transparent way is well established. Our initial scoping review identified three published systematic reviews that had investigated the effectiveness of PBT [ 11 , 12 , 13 ]. In all three, searches were up to 2014, meaning they were all out of date. In addition one had missing studies [ 11 ], one included both adults and children with brain tumours [ 12 ] and one included all paediatric cancers, not just brain tumours [ 13 ]. With the recent opening of two UK NHS proton facilities in Manchester at The Christie Hospital and in London at the University College London Hospital (UCLH) [ 14 ] [ 15 ], it is timely for an up-to-date assessment of the evidence base.

The aim of this systematic review was to evaluate the effectiveness of PBT in children and young adults with CNS tumours to assess the potential benefits and harms and identify any research gaps.

Standard systematic review methodology aimed at minimising bias as recommended by the Cochrane Collaboration was employed and reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [ 16 ]. For more details see the published protocol (PROSPERO CRD42016036802) [ 17 ].

Eligibility criteria

Studies were included in the review if they met the following criteria:

Children and young adults (age up to 25 years) with any type of CNS tumour. Studies had to have a minimum sample size of nine patients [ 18 , 19 ]. Studies with a mix of older adults and children/young adults were included provided that patient baseline data and outcomes were reported separately for children/young adults. Studies reporting a mix of tumour types were initially included, however, it was felt that disease-specific data within these was at risk of reporting bias, therefore a decision to exclude them was made at data extraction where this was suspected.

Intervention

PBT, used alone or as part of a multimodality treatment regimen.

For comparative studies, we accepted conventional photon external beam radiation including three-dimensional (3D) conformal techniques or intensity-modulated radiation therapy (IMRT) including arc therapy, stereotactic radiosurgery, or brachytherapy used alone or as part of a multimodality treatment programme.

Study designs/publication type

Published full text studies that were either randomised controlled trials (RCTs), non-randomised controlled studies, phase II single arm trials and case series studies were included.

Search strategy

Searches were undertaken from database inception to May 2021 in twelve bibliographic databases including MEDLINE, EMBASE and the Cochrane Library (search strategy provided in Supplementary Information (SI 1 and SI 2)). No language, publication or study design filters were applied. Reference lists of relevant studies were reference checked and clinical experts in the field consulted.

Study selection

Study selection was undertaken independently by multiple reviewers in the author group and disagreements resolved by discussion, with JSW and BP making the final decisions.

Data items and extraction process

Data extraction and risk of bias assessment were undertaken by one reviewer and checked by a second. Data was collected on specially designed pro-forma in Word and included data on patient characteristics, treatment regimens, and outcome measures. Proton radiation dose was measured in SI units of Gray Relative Biological Effectiveness (Gy RBE ). Missing data was not imputed (SI 3). Risk of bias was assessed using a checklist designed to assess the validity of case series [ 17 , 20 ], covering the domains of selection, detection and attrition bias. Additional criteria to assess the adequacy of the sample size, methods of analysis, outcome reporting and external validity of the study were also added and reported as a global assessment of the data set—see questions 13–17 of the data extraction sheet (SI 3).

Effect measures

Effect measures were categorised as tumour related or toxicity related. Tumour related included: overall survival (OS), progression-free survival (PFS), event-free survival (EFS), recurrence-free survival (RFS), local and distant failure rates (LFR/DFR), response rates (RR), nodular failure-free survival (NFFS), and cystic failure-free survival (CFFS). Toxicity-related included: short- and long-term adverse events, such as necrosis, endocrine insufficiencies, ototoxicity and health related quality of life (HRQoL).

Synthesis methods

Results were grouped according tumour type, and reported in a standard format across the tumour types, allowing for consistent reporting and missing data to be identified. The format was as follows: study characteristics, including number of patients, study design, patient characteristics and interventions received. Outcomes were grouped as tumour related outcomes and toxicity related outcomes.

Quantity of the research

Thirty-one full-text studies met the inclusion criteria, consisting of one phase II study, 24 retrospective and six prospective case studies. Twenty-three studies were single arm, the remaining were non-randomised comparisons of PBT with photon RT. There were no RCTs (Fig.  1 ).

PRISMA diagram showing search process and number of included studies

Conducted in 10 institutions, 27 studies were based in the USA, one in France and two in Switzerland. One study was multinational with data from the USA and Canada [ 21 ]. In total, 1731 children participated in the studies, with 1465 children (85%) receiving PBT and 266 (15%) receiving photon RT. The studies were conducted between 1991 and 2018, with the majority of studies conducted between the years 2000 and 2015. The mean sample size was 51 and ranged from 10 to 179. Average follow-up ranged from 0.9 to 7.6 years (Table  1 ).

Eleven studies included children with medulloblastoma/primitive neuroectodermal tumours (PNET) (n = 712) [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ], five ependymoma (n = 398) [ 32 , 33 , 34 , 35 , 36 ], four atypical teratoid/rhabdoid tumour (AT/RT) (n = 72) [ 37 , 38 , 39 , 40 ], six craniopharyngioma (n = 272) [ 41 , 42 , 43 , 44 , 45 , 46 ], three low-grade glioma (LGG) (n = 233) [ 47 , 48 , 49 ], one germ cell tumours (GCT) (n = 22)[ 50 ], and one pineoblastoma (n = 22) [ 51 ]. Ninety percent of patients were receiving first-line therapy and 57% were male (Table  1 ).

Quality of the research

Selection bias and reporting bias were the major methodological limitations, due to studies involving opportunity/convenience samples and the retrospective nature of the data collection. Poor reporting compounded selection bias with few studies reporting eligibility criteria making it difficult to assess representativeness and generalisability. Where studies included patients at different stages in disease progression, most did not report results separately by disease status. Poor reporting also hampered assessments of outcomes, for example, timing of outcome assessments was generally not reported and long-term adverse events were frequently reported in a seemingly arbitrary sub-group of patients. Length of follow-up was long enough for some outcomes to occur (e.g. PFS in AT/RT), but not others (e.g. long-term adverse events, particularly neuro-cognitive outcomes) (SI Fig. 1).

Medulloblastoma

Eleven studies assessed the effects of PBT, reporting data on 712 patients with medulloblastoma/PNET, with 515 receiving PBT and 197 receiving photon RT. In seven studies children were treated with PBT at the Massachusetts General Hospital (MGH). All MGH studies have slightly different study designs and focus, but it should be noted that double counting for common outcomes may have occurred as there is substantial overlap in study dates/periods suggesting a shared cohort of patients particularly between 2002 and 2009 and for OS outcomes.

The 11 studies comprised of one single-arm phase II trial [ 31 ] and 10 case series studies (three prospective [ 26 , 27 , 30 ] and seven retrospective [ 21 , 22 , 23 , 24 , 25 , 28 , 29 ]. Five studies compared PBT (n = 179) with photon RT (n = 197) [ 21 , 22 , 23 , 28 , 30 ]. The mean sample size was 65. Median follow-up ranged from 0.9 to 7 years. One study had 11 (14%) recurrent patients [ 21 ].

Eight studies defined patients according to risk, with 78% (429/551) defined as standard-risk and 21% (115/551) defined as high-risk. One study defined six patients as intermediate-risk—see paper for definitions—accounting for 1% of the total, however, these patients outcomes are reported as if they were high-risk [ 31 ]. Across the studies the youngest patient was 1.9 years [ 25 ], the oldest 21.9 years [ 22 ] but the median age within the studies ranged from 2.9 to 10 years. Two studies focused solely on very young children [ 24 , 25 ] (Table  1 ).

PBT was given as part of a multimodal treatment regimen consisting of surgical resection prior to radiotherapy and chemotherapy (various protocols). Gross total resection (GTR) was achieved in 86% of PBT patients. The median craniospinal irradiation (CSI) dose for standard-risk patients was 23.4 Gy RBE (36.0 Gy RBE for high-risk patients) with a median boost dose to the tumour bed of 54 Gy RBE both delivered in fractions of 1.8 Gy RBE . (Table  1 and SI Table 1).

Tumour related outcomes

Survival was reported in five studies (n = 285) [ 23 , 24 , 25 , 29 , 31 ]. OS for all PBT patients ranged from 68 to 89% in newly diagnosed patients, depending on patient and tumour characteristics and follow-up. For example, Yock (2016) reported 7-year OS rates of 81% for 39 standard-risk PBT patients compared with 68% for 20 high-risk PBT patients [ 31 ]. Eaton (2016) reported a 6-year OS of 82% for 45 PBT patients compared with 88% for 43 photon RT patients but the comparison was non-significant [ 23 ]. In very young children, Grewal reported an OS of 84% at 5 years in 14 PBT patients [ 24 ] (Table  2 ).

Failure rates were given in three studies for PBT patients [ 24 , 25 , 29 ]. At 3.2 years, LFR was 5% and DFR 10% (n = 109), with the spine the most common site for isolated local failure (Table  2 ).

Toxicity related outcomes

Early to medium term toxicities were reported in two studies [ 24 , 31 ]. Serious adverse events experienced 90-days post PBT included stroke (grade IV) in one patient and brainstem injury consistent with necrosis (grade III) in another, with no toxicity-related deaths reported [ 24 , 31 ]. One patient died from viable tumour and necrosis in the brainstem, but it was unclear if the necrosis was related to PBT [ 24 ] (Table  3 ).

A variety of late effects were reported. Endocrinopathies were reported in four studies (165 patients) [ 22 , 24 , 25 , 31 ]. Yock reported at 3, 5 and 7 years post PBT, observing that deficiencies increased over time. By year 7, 61% (36/59) of patients had at least one endocrine deficiency, the most common being growth hormone deficiency (GHD) occurring in 31 patients [ 31 ]. Comparing PBT with photon RT, Eaton (2016) found a statistically significant reduction in the incidence of central hypothyroidism (p < 0.001) and sex hormone deficiency (p = 0.013) in PBT patients at 5.8 and 7-years follow-up [ 22 ] (Table  4 ).

Conducted in three institutions, five case series studies (two prospective [ 32 , 34 ] and three retrospective [ 33 , 35 , 36 ]) assessed the effects of PBT in 398 children with predominantly intracranial ependymoma. One study was comparative and compared PBT with patients who had received photon RT (non-randomised) [ 36 ]. The mean sample size was 80 and the median study follow-up was 3.6 years (Table  1 ).

Eighty-eight percent of patients were receiving first-line chemotherapy while 12% had recurrent local or metastatic disease [ 33 , 34 , 35 , 36 ]. Patients ranged from infants to young adults with median age within the studies ranging from 2.5 to 5.3 years. Patients received PBT as part of a multi-modal treatment regimen with patients undergoing surgical resection (78% achieving GTR) and chemotherapy (38%) prior to PBT/photon RT. The median dose of PBT was 55.8 Gy RBE delivered in fractions of 1.8 Gy RBE (Table  1 and SI Tale 1).

Survival was reported in all five studies. In patients treated with PBT, three-year OS ranged from 90% [ 34 ] to 97% [ 36 ] in patients receiving first-line therapy, with 3-year PFS ranging from 76% [ 34 , 35 ] to 82% [ 36 ]. In Eaton’s study of 20 patients with recurrent disease, 3-year OS was 79% and PFS was 28% [ 33 ]. Comparing PBT with photon RT, Sato found statistically significant differences in favour of PBT for both 3-year PFS (82% versus 60%; p = 0.031) and local RFS (88% versus 65%; p = 0.01), but no statistical difference for OS [ 36 ]. Ares reported a 5-year OS of 84% in respect of 50 patients treated with pencil beam scanning PBT [ 32 ] (Table  2 ).

Failure rates were reported in all five studies. LFR at 3-years was 15% [ 34 ] and 17% [ 35 ] with 5-year LFR at 22% [ 32 ] and 23% [ 35 ]. DFR at 3-years was 15% [ 34 ] and 23% [ 35 ] and at 5-years 17% [ 35 ]. Median time to LFR and DFR was 1.4-years and 1-year, respectively [ 34 ]. In a univariate analysis LFR was related to extent of surgery (GTR: 21.6%, subtotal resection (STR): 35.5% (p = 0.003)) [ 34 ]. Comparing PBT with photon RT, Sato reported a LFR of 15% and DFR of 2% for PBT assessed at 2.6 years follow-up and LFR of 47% and DFR of 8% for photon RT assessed at 4.9 years follow-up, but this difference is likely to be due to the differences in follow-up times [ 36 ]. In recurrent patients 3-year LFR and DFR was 45% and 67%, respectively with second failure following first failure patterns [ 33 ] (Table  2 ).

Short-term serious adverse events were reported in all five studies (398 patients) [ 32 , 33 , 34 , 35 , 36 ]. There were 14 cases of RT-associated vasculopathy presenting as stroke [ 34 , 36 ] and radio-necrosis [ 36 ], 11 cases of brainstem toxicity including one fatality reported [ 32 , 34 , 36 ] as well as three cavernoma and two cervical subluxations [ 35 ] (Table  3 ).

Various medium-term and late endocrine toxicities were reported. Central hypothyroidism and GHD were the only endocrinopathies reported over three studies, with GHD being the most common [ 32 , 34 , 35 ] (Table  4 .)

Ototoxicity was reported in three studies [ 32 , 34 , 35 ], but occurred at low levels and appeared to be related to prior cisplatin chemotherapy or in patients with the tumour close to the cochlea [ 32 , 35 ] (Table  5 ).

Neuro-cognitive outcomes were only assessed by MacDonald (2013) who reported small and non-statistically significant increases in both mean Full Scale Intelligence Quotient test (FSIQ) (n = 14) and adaptive skills/functional independence (n = 28) at 2.2 years follow-up compared to baseline [ 35 ] (Table  6 ).

No studies reported quality of life measures.

Atypical teratoid/rhabdoid tumours (AT/RT)

Conducted in separate institutions, four single-arm, retrospective case series studies assessed PBT in 72 children with AT/RT [ 37 , 38 , 39 , 40 ]. The mean sample size was 18 and study follow-up ranged from 2.0 to 3.2 years.

All patients were receiving first-line therapy and 28% had confirmed metastatic disease at presentation. Mean age across the studies was 1.7 years. Prior to PBT, 97% of patients underwent surgical resection (47% achieved GTR) followed by induction chemotherapy (92%). The average PBT dose was 50.4 Gy RBE in two studies [ 37 , 39 ] and 54 Gy RBE in two studies [ 38 , 40 ] delivered in fractions of 1.8 Gy RBE . Chemotherapy was delivered either concurrently (25%) or post-PBT (67%) (Table  1 and SI Table).

All four studies reported comprehensive lists of adverse events. Radiation necrosis was reported in six patients all of whom survived [ 38 , 40 ] (Table  3 ).

Endocrinopathies and ototoxicity were assessed by De Amorim Bernstein in seven (70%) and ten patients, respectively (100%). Two patients (28%) developed hypothyroidism and three (43%) GHD at 2.5 years. One patient developed high-frequency sensorineural hearing loss (SNHL) at 2.3 years follow-up [ 37 ] (Tables  4 and 5 ).

HRQoL was assessed by Weber in 15 children, predominantly less than 2 years of age. Based on parental proxy reports, there was little variation between mean scores for physical, social, emotional and psycho-social functioning at two-months follow-up compared with baseline [ 40 ] (SI Table 2).

Survival was reported in all four studies with variable follow-up schedules possibly impacting estimates. OS ranged from 53% at 2 years [ 39 ] to 90% at 2.3 years [ 37 ]. PFS ranged from 46% at 2 years [ 39 ] to 75% at 1.4 years [ 38 ] (Table  2 ).

Failure rates were reported in three studies (n = 41). LFR ranged from 0 to 20%, and DFR 20% to 27% [ 37 , 38 , 40 ] (Table  2 ).

Craniopharyngioma

Six studies assessed the effects of PBT in 272 children with craniopharyngioma. Of these, five were single arm retrospective case series [ 41 , 43 , 44 , 45 , 46 ] and one was an historical control study, comparing PBT with photon RT [ 42 ]. The average sample size was 45 and study follow-up ranged from 2.0 to 6.2 years (Table  1 ).

Fifty-one percent of patients were receiving first-line therapy and 49% had recurrent disease [ 42 , 43 , 44 , 45 , 46 ]. Patient age ranged from 1.3 to 20 years [ 43 , 44 , 45 , 46 ]. Prior to radiotherapy, 97% of patients underwent surgical resection (69% STR, 11% GTR) and 20% either had a cyst drainage, fenestration or shunt inserted [ 41 , 42 , 43 , 44 , 46 ]. The median dose of PBT ranged from 50.4 to 59.4 Gy RBE delivered in fractions of 1.8 Gy RBE (Table  1 and SI Table 1).

OS was reported in three studies (n = 149) [ 42 , 43 , 45 ]. Comparing PBT and photon RT, Bishop reported a non-statistically significant difference in 3-year OS between 21 patients who received PBT (OS 94%) and 31 patients who received photon RT (OS 97%) [ 42 ]. In 77 patients treated with PBT, 5-year OS was 97.7% [ 43 ]. Luu (n = 16) also reported a 5-year OS of 100% for patients who had undergone one surgical resection compared to 60% for those with more than one resection [ 45 ]. PFS was not reported (Table  2 ).

Specific to craniopharyngioma, Bishop reported NFFS and CFFS. No statistically significant differences were found in 3-year NFFS (92% versus 96%; p = 0.54) or 3-year CFFS (67% versus 77%; p = 0.99) between the PBT and photon RT groups [ 42 ].

LFR was reported in three studies. Winkfield (n = 24) reported LFR at 0% at 3.4 years [ 46 ]. In Luu (n = 16) and Jiminez (n = 77) the 5-year LFR was 6% and 10%, respectively [ 43 , 45 ]. Median time to failure from PBT completion was 3.6 years (range 1.8–8.4) (Table  2 ).

Bishop reported no significant differences in the incidence of post-RT vasculopathy, visual dysfunction and obesity between PBT and photon RT [ 42 ] (Table  4 and 5 ). In the Jiminez report one patient had vasculopathy symptoms (1.3%), one patient had a stroke (1.3%) and one Moyamoya syndrome (1.3%). Jiminez also reported visual outcomes including pre and post PBT, with 68% experiencing stable vision, 10% worsening, 10% improving and 12% unknown [ 43 ] (Table  3 ).

Endocrinopathies were reported in four studies [ 42 , 43 , 44 , 45 ]. Bishop reported no statistically significant difference between PBT and photon RT patients in the incidence of endocrinopathies newly acquired from the start of RT. The most common endocrinopathy was panhypopituitarism occurring in seven (13%) PBT and 17 (33%) photon RT patients (p = 0.162) [ 42 ]. Luu reported just one patient (6%) with panhypopituitarism [ 45 ], while Laffond reported pituitary dysfunction in 28 patients (96%) and hypothalamic syndrome in 18 PBT patients (62%) between 1.7 and 14 years follow-up [ 44 ]. Jiminez measured endocrinopathies pre- and post-PBT and found 49% were stable, 47% worsened and 4% improved [ 43 ] (Table  4 ).

Ototoxicity was comprehensively reported by Bass. Rates were low for clinically significant SNHL in the extended high frequency (EHF) range at 3% [ 41 ] (Table  5 ).

Neurocognitive outcomes were reported by Jiminez [ 43 ]. FSIQ, verbal and visual memory scores were stable, with adaptive skills (Scales of Independent Behaviour Revised (SIB-R)) had a statistically significant decrease in mean follow-up score compared with baseline, however this was not considered clinically important (Table  6 ).

HRQoL and executive functioning outcomes were reported by Lafford [ 44 ]. HRQoL was assessed via patient and parental proxy reported scores in 22 PBT patients (nine of which also received photon RT). At 3.4 year follow-up, overall HRQoL was deemed satisfactory, although between 25 and 50% of scores were indicative of low HRQoL for seven of the ten sub-domains. Fifty percent of patients had mild-moderate mood disorders, but no patients experienced severe depression. With respect to executive function, 24–38% of patients experienced problems with flexible thinking (‘shift’), emotional control and working memory (SI Table 2).

Low grade glioma (LGG)

Three non-comparative single centre case series studies (one prospective [ 49 ] and two retrospective [ 47 , 48 ]) assessed the effects of PBT in 233 children with LGG. The two retrospective studies had small sample sizes and both started recruitment in the 1990s, however, the prospective study by Indelicato involved 174 patients and was conducted between 2007 and 2017. Study follow-up ranged from 3.3 to 7.6 years.

Reported in two studies (n = 59), 75% were newly diagnosed while 25% had recurrent disease [ 47 , 48 ]. No patients had metastatic disease. Mean patient age at time of PBT ranged from 8.7 to 11 years, although most included children from 2 to 21 years. Prior to PBT, a selection of patients underwent surgery (87%) followed by chemotherapy (44%) [ 47 , 49 ]. One-hundred and seventy patients in the Indelicato series had > 0.5 cm gross disease at time of irradiation, the remaining four patients received RT due to multiple prior recurrences [ 49 ]. The average dose of PBT was 54 Gy RBE (Table  1 and SI Table 1).

Survival was reported in all three studies. OS rates of 85%, 92% and 100% were reported at 3.3, 5.0 and 8.0 years follow-up, respectively [ 47 , 48 , 49 ]. PFS, reported in two studies (n = 206) was 84% and 90% at 5.0- and 6.0 years, respectively [ 47 , 49 ] (Table  2 ).

LFR, reported in two studies, was 22% and 15% at 3.3 and 5.0 years, respectively [ 48 , 49 ]. DFR reported in one study was 0% at 3.3 years [ 48 ] (Table  2 ).

Indelicato reported serious PBT-attributable late toxicities in seven patients (4%), most notably brainstem necrosis (treated with steroids), vasculopathy and second malignancy [ 49 ] (Table  3 ).

Across the studies, endocrine abnormalities were reported in 23% of patients assessed, including hypopituitarism [ 48 ], growth hormone deficiency [ 49 ] and cortisol insufficiency [ 47 ] (Table  4 ).

Reported in one study, there was no significant decline in neuro-cognitive outcomes (FSIQ, verbal comprehension or perceptual reasoning) at 5-years relative to baseline in 12 patients (38%) assessed [ 47 ]. Visual acuity, assessed in 18 patients, was stable/improved relative to baseline in the 15 non-high-risk patients [ 47 ]. Ototoxicity was assessed in 174 patients, at 4.4 years, 4 patients (2%) had grade II partial hearing loss in one ear and one patient had grade III hearing loss with need for amplification [ 49 ] (Table  5 and 6 ).

For HRQoL, Hug reported that of 27 patients, no patient experienced a drop of more than 10% in the Lanksky performance scale [ 48 ] (SI Table 2).

Germ cell tumours (GCT)

One single-arm retrospective case series by MacDonald, reported the effects of PBT in 22 children (mean age 11 years) with newly diagnosed GCT [ 50 ]. Fifty-nine percent had germinoma and 41% non-germinomatous germ-cell tumours (NGGCT) (Table  1 and 2 ). OS and PFS were 100% and 95%, respectively at 2.3 years follow-up. No patients experienced a local failure whilst DFR rates were 0% and 11% for germinoma and NGGCT patients, respectively (Table  2 ). Two patients (9%) experienced hypothyroidism and two (9%) required growth hormone replacement at 2.3 years. No patients developed RT-related diabetes insipidus (Table  4 ).

Pineoblastoma

One study by Farnia reported the effects of PBT in children with pineoblastoma [ 51 ]. Undertaken in a single institution between 1982 and 2012, this historical control study included 22 patients under 25 years, of which 11 received PBT and 11 received photon RT and one gamma knife treatment. Median age was 7.7 years and 14.5 years for PBT and photon RT, respectively (Table  1 ). Survival and recurrence rates between PBT and photon RT were not statistically different (Table  2 ). Long-term toxicities—which all occurred in patients treated with photon RT—included grade 3 cognitive decline (n = 3), grade 3 seizures (n = 1), grade 3 hearing impairment (n = 1) and grade 3 avascular necrosis of the femoral head (n = 1) (Table  3 , 5 and 6 ).

The aim of this systematic review was to investigate if the published clinical evidence supports the assumptions derived from dosimetry studies of PBT compared with photon RT in terms of equivalent survival, improved quality of life and/or reduced long-term treatment sequelae. Furthermore, recommendations for improving the quality and consistency of output data are presented.

In order to minimise bias we have undertaken this systematic review according to Cochrane methodology, which is designed to produce a systematic review that is as free as possible from methodological flaws, is reproducible and transparent. Our scoping search identified three previous systematic reviews, however, all are out of date with searches up to 2014 [ 11 , 12 , 13 ]. The review by Laprie 2015 [ 11 ] was the most closely aligned to our review, with aims to examine PBT and photon RT in children with brain tumours. However, some of the methodology that they have used may have introduced bias, for example they only utilised the database Medline, only sought English language publications, did not have an a priori protocol, did not quality assess the included studies and their searches were up to 2014. Systematic review is a powerful tool, but is by nature a retrospective exercise and governed by the available evidence. In rapidly evolving fields such as PBT it is important that reviews are regularly updated to ensure that they include all of the evidence and are as up-to-date as possible.

Thirty-one full-text published studies involving 1,730 children met our inclusion criteria. All but five studies [ 21 , 32 , 40 , 41 , 44 ] were conducted in the USA. Publication dates ranged from 2002 [ 48 ] to 2021 [ 43 ]. Studies were undertaken from 1982 [ 51 ] to 2018 [ 21 ]. Most of the patients were treated between the years 2000 and 2015, so the studies in this review are fairly similar regarding the dates, therefore any era differences may be small within this data set. There was one phase II single-arm study, six prospective case series studies, with one of these being comparative and 24 retrospective studies with seven of these being comparative. No RCTs were identified. Largely because of referral patterns in the USA, all the case series used opportunity sampling, i.e. data was based on patients referred to the proton centre routinely, not part of a specific PBT clinical trial, and in terms of the retrospective studies this was derived mainly from patient records. Tumour types included: medulloblastoma (11 studies); ependymoma (5 studies); ATRT (4 studies); craniopharyngioma (6 studies); LGG (3 studies); GCT (1 study) and pineoblastoma (1 study).

The studies were heterogeneous regarding aims and objectives, patient diagnoses, patient populations (some assessed younger patients) and outcomes. For this review we identified nine outcomes of interest. Five measured disease control (OS, PFS/RFS, LFR DFR), four measured treatment related short- to long-term side effects (adverse events, endocrinopathy, ototoxicity, neurotoxicity), and one measured treatment related HRQoL. Across the studies OS was the most frequently reported outcome, followed by LFR, and endocrinopathy. Adverse event reporting was inconsistent across the tumour types making it impossible to assess the incidence across the dataset. However, there were some serious adverse events reported—albeit in very small numbers—such as radio-necrosis, stroke and brainstem toxicity [ 24 , 31 , 32 , 33 , 34 , 35 , 36 , 38 , 40 , 45 , 49 ]. Outcomes least reported were HRQoL, neurocognitive and ototoxicity. HRQoL was reported in just three tumour types (medulloblastoma, AT/RT, craniopharyngioma) and neurotoxicity in four tumour types (medulloblastoma, ependymoma, craniopharyngioma, LGG). Given that a reduction of late effects is the proposed key advantage of using PBT, it is disappointing that few studies reported these outcomes. Some study authors commented on the difficulty in obtaining long-term follow-up data as many patients had travelled from other hospital facilities to receive PBT and long-term outcomes were either not evaluated at or not reported to the proton centres. The difficulty in acquiring long-term late effects and HRQoL data has been an issue for many paediatric cancer trials including those which have included RT delay or avoidance. Prospective initiatives such as the USA Pediatric Proton Consortium Registry may yield more useful data in the future [ 52 , 53 ] but may not be able to solve all these problems [ 54 ].

Ependymoma provided the most comprehensive dataset, both in terms of the number of outcomes measured and the proportion of patients in each study evaluated per outcome. The remaining tumour types were either inconsistent in terms of outcomes reported, only included a small percentage of the available patients across the outcomes or as in the case of GCT, pineoblastoma and AT/RT, were extremely limited in the number of patients available, therefore caution must be used in interpreting the results due to lack of power of the dataset.

OS was the most common outcome measure. Generally, for standard paediatric CNS indications, the rates of tumour control and hence cure are expected to be the same for protons as for photons. Most of the patients included in this review were newly diagnosed. OS was reported to be 100% to 68% depending on patient characteristics, follow-up times, etc. however without a randomised comparator it is not possible to “prove” whether PBT offers better, worse or equivalent disease control compared to photon RT. On the other hand, conducting survival equivalence randomised trials in a variety of different histological types with small patient numbers is probably not achievable. Taking into account the totality of radiobiological data and clinical experience it is universally accepted that considering the RBE of PBT tumour control and hence OS are equivalent.

Our systematic review included eight comparative studies, but these utilised either historical [ 28 , 30 , 36 , 42 , 51 ] or opportunity controls [ 21 , 22 , 23 ]. The main problem with the use of historical controls is confounding due to temporal shifts in care [ 55 ], particularly in older historical controls [ 28 , 42 , 51 ]. This is particularly pertinent to radiotherapy practices which has seen a shift from whole brain radiotherapy to more localised treatments, which may have impacted long-term adverse events and HRQoL. In addition, the multimodality of brain tumour treatment and improvements in delivering photon RT may also have had a substantial impact on disease control in historical comparisons. Temporal shifts may also have improved the accuracy of outcome assessment measures, for example, improvements in imaging may make adverse events such as radio-necrosis easier to identify and appear more common in newer studies, a consideration when comparing PBT radio-necrosis event rates with those from historical controls treated with photon RT. In studies using opportunity controls, the main problem is selection bias where patients not receiving PBT may not have been eligible to receive it and are therefore fundamentally different in terms of prognosis. This is exemplified by Sato, where 93% of patients receiving PBT had had a GTR at surgery compared to 76% of photon RT patients, indicating patients given photon RT were in the higher risk group, potentially biasing survival outcomes in favour of PBT [ 36 ].

Retrospective opportunity sampling also limits the type and methods of data collection. Across the studies, measurement and reporting of outcomes (particularly in patients with the same tumour type) were inconsistent, making between study comparisons difficult. One study which reported outcomes measured from diagnosis and completion of PBT demonstrated a marked difference between the two time points, with 2-year OS at 68% when measured from diagnosis and 48% when measured from PBT—a difference of 20% [ 39 ]. By using prospective data collection researchers can control what data are collected and the methods of collection. Utilising data from clinical trials investigating non-radiotherapy questions, such as the ongoing SIOP (International Society of Paediatric Oncology) Ependymoma II study [ 56 ] and the PNET5 study [ 57 ] which include patients treated with both PBT and photon RT can allow better prospective control on data collection. Although non-randomised, data derived from prospective trials also provides data with associated radiation therapy quality assurance and more robust evidence on the relative outcomes, and may help to demonstrate equivalence or otherwise for tumour control and toxicities.

Description of patient populations was also inconsistent within the studies. Seven studies included patient populations comprising both newly diagnosed children receiving first-line therapy as well as those with recurrent disease, but failed to report patient baseline status or outcomes separately [ 28 , 35 , 42 , 44 , 45 , 46 , 48 ]. We originally planned to include studies with mixed tumour types provided data for individual tumours were reported. Three were identified [ 58 , 59 , 60 ] however, after examining these studies we felt that an element of reporting bias could be a factor, as not all the results were consistently reported across the tumour types with the possibility that only exceptional results had been reported, therefore we excluded these studies.

For PBT centres publishing work on expanding cohorts, it is important that it is clear which data has been previously reported, so that the data is not double counted in systematic reviews. Unique cohort identifiers could help this problem [ 61 ] such as the system employed for Randomised Controlled Trials [ 62 ]. However, this may cause issues with getting studies published as many journals follow the Inglefinger rule, which stipulates that only new previously unpublished data is published [ 63 , 64 ]. Journals could help by allowing expanding cohorts and encouraging authors to be transparent. This is particularly pertinent to rare disease research where there are fewer patients available to study and where there is a tendency for specific specialist treatment centres to be research active and likely to report on expanding cohorts.

The medical literature has seen a great deal of debate on the necessity or ethical justification of conducting RCTs to evaluate PBT in children. Some commentators contend that equipoise does not apply as the superior dose distributions associated with PBT, must translate into improved patient outcomes and therefore an RCT would not only be unnecessary but unethical [ 7 ]. Others argue that it is unethical to use a technology that has had insufficient controlled evaluation of clinically relevant benefit [ 7 , 65 ]. As well as ethical considerations, differences in the development of radiotherapy treatment compared to drug development also provide challenges in evaluating clinical effectiveness [ 66 , 67 ]. This may explain why previous paradigm shifts in RT delivery technology, such as IMRT which have been widely implemented, were supported by relatively few RCTs in adults and none in children. The rarity of paediatric CNS tumours, the severity and delayed nature of many of the late effects and willingness of patients and families to undergo randomisation may also render RCTs with late effect endpoints impractical [ 7 , 68 ] It is, however, recognised that RCTs between PBT and photon therapy are being conducted or planned in adults with cancer including the forthcoming APPROACH trial in adult patients with grade 2 and 3 oligodendroglioma with neurocognitive function as an end point.

This review did not identify any published RCTs, therefore we are unable to answer our primary review questions regarding effectiveness of PBT compared to other radiotherapy treatments in particular photon RT and its role in ameliorating long-term adverse events. Given the increasing use of PBT as standard of care for paediatric brain tumours, perhaps it is too late to ask this question. Indeed, in the UK the large majority of children with primary brain tumours receive radiotherapy with PBT as opposed to photon therapy although this does not apply to many other countries worldwide. We may need to ask how we can maximise the use of PBT both in patients traditionally treated with radiotherapy and patients thus far prohibited such as younger children. If this were the question, again the current body of evidence would have limitations, particularly given the haphazard nature of the research, with few proton centres reporting their activity. Problems with long-term follow-up of patients and little standardisation of the data collected and reported compound the literature. These factors highlighted in this review, stress the need for consistent and systematically collected data on all patients receiving PBT (both trial and non-trial patients) to monitor the effects of treatment including short-term side effects such as radio-necrosis and long term sequelae such as neuro-psychological dysfunction. This is necessary to fully inform clinicians and thus patients and their families of the likely treatment outcome. Indeed such arguments should ideally apply to children receiving photon radiotherapy, and thus may potentially offer a comparison of outcomes between the two techniques albeit in a non-randomised setting. Such comparisons could be subject to future systematic reviews.

Registry data may be one model that could collect data and is a growing area especially with the development of ‘big data’ techniques employed to analyse the data [ 69 ]. The success of these ventures is reliant upon the accuracy and consistency of the data input, as well as the continued engagement of stakeholders especially patients, parents, referring teams and of course sufficient long-term funding. Alongside comprehensive prospective databases, there also needs to be a well thought out publications strategy to avoid data duplication/double counting, if separate research teams access one single data source. Although, as discussed above, it is unlikely to see RCTS in children with CNS tumours that will directly compare PBT with photon therapy, RCTs are potentially more feasible with respect to important PBT questions such as delivery techniques (e.g. proton arc therapy), dose and volume, and these are to be encouraged.

In conclusion this review provides a summary of the available data of PBT delivered for a range of CNS tumours arising in children. PBT has been widely implemented in many high-income countries for the treatment of children with cancer including many with CNS tumours. However, in order for the implementation of PBT to continue to evolve, areas where the quality of data could be improved have been highlighted. This may be useful in the context of health systems where cost or geographic access to PBT are issues. Furthermore, improved outcome data, particularly with respect to late effects could inform the continued evolution of the standard indications for PBT.

Data availability

Completed data extraction forms are available from the corresponding author on reasonable request. All data included is available in the public domain.

Code availability

Not applicable.

Change history

05 march 2024.

A Correction to this paper has been published: https://doi.org/10.1007/s11060-024-04612-7

Abbreviations

Three-dimensional

Atypical teratoid/rhabdoid

Cystic failure-free survival

Central nervous system

Craniospinal irradiation

Distant failure rate

Event-free survival

Extended high-frequency

Full scale Intelligence Quotient

Growth hormone deficiency

Gross total resection

SI unit Gray Relative biological effectiveness

Health-related quality of life

Intensity-Modulated Radiation therapy

Intelligence Quotient;

International Standard Randomised Controlled Trial Number

Local failure rate

Low-grade glioma

Massachusetts General Hospital

Nodular failure-free survival

Non-germinomatous germ-cell tumours

National Health Service

Overall survival

• Proton beam radiotherapy

Progression-free survival

Primitive neuroectodermal tumours

Preferred Reporting Items for Systematic Reviews and Meta-analyses

International prospective register of systematic reviews

Randomised controlled trials

Relapse-free survival

Response rates

Radiotherapy

Scales of independent behaviour revised

International Society of Pediatric Oncology

Sensorineural hearing loss

Subtotal resection

University College London Hospital

United Kingdom

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Acknowledgements

The authors acknowledge Dr Mark Pritchard (Royal Stoke University Hospital, Stroke-on-Trent, UK) for screening studies for inclusion in the review, Dr Matthew Morrall (Leeds General Infirmary, Leeds, UK) for his comments on the protocol, and Ms Rachel Dodds (Department of Psychology, University of Leeds, UK) for her comments on the protocol and undertaking study data extraction and checking. We would also like to acknowledge the input of the Patient and Public Involvement (PPI) group and the wider clinical team who helped to frame the review question and contributed to the direction of the paper.

This paper presents independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-1112–29122). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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Jayne S. Wilson, Caroline Main, Saimma Majothi, Pamela R. Kearns & Keith Wheatley

The Clatterbridge Cancer Centre, Liverpool, UK

Nicky Thorp

The Christie Hospital Foundation Trust Proton Beam Therapy Centre, Manchester, UK

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Roger E. Taylor

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Pamela R. Kearns & Martin English

National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

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Children’s Brain Tumour Research Centre, University of Nottingham, Nottingham, UK

Madhumita Dandapani

Queen’s Medical Centre, Nottingham University Hospitals’ NHS Trust, Nottingham, UK

Centre for Reviews and Dissemination (CRD), University of York, York, UK

Robert Phillips

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All: Conceived and designed the study; CM, JW/all remaining authors: Wrote protocol/commented on protocol; JSW, CM, SM, RP, KW: Provided methodology input; CM/JW: Wrote first draft/revised first draft; All/all: Critically revised subsequent drafts/approved final draft; NT, RET: Provided radiotherapy clinical input; PRK, ME, RP, MD, BP: Provided CNS tumour input; BP, NT, RET, PRK, ME: Provided overall clinical input; JSW: Guarantor for methodology; BP: Guarantor for clinical input.

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Wilson, J.S., Main, C., Thorp, N. et al. The effectiveness and safety of proton beam radiation therapy in children and young adults with Central Nervous System (CNS) tumours: a systematic review. J Neurooncol 167 , 1–34 (2024). https://doi.org/10.1007/s11060-023-04510-4

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Updated Standard of Care Cements Ruling in Health Benefits Dispute

by Mark Debofsky | May 31, 2023 | Cancer Treatments , ERISA , Health Benefits | 0 comments

Proton beam radiation therapy is used to treat various forms of cancer. Rather than using X-rays, proton therapy directs focused energy from protons at tumors.

Although the proven benefits of proton therapy have expanded its usage to different types of cancers, health insurers have balked at expanding coverage for such treatment, resulting in multiple lawsuits around the country.

A recent decision issued by the 5th U.S. Circuit Court of Appeals,  Salim v. Louisiana Health Service and Indemnity Company , 2023 WL 3222804 (5th Cir. May 3, 2023) (unpublished), upheld a lower court ruling directing a health insurer to cover proton therapy.

The case was brought by Robert Salim, who sought coverage for proton beam therapy to treat throat cancer. The insurer denied his claim, maintaining the treatment was not medically necessary according to its claim guidelines. Salim challenged the denial but was unsuccessful. Salim then brought suit and won both in the district court and in the appeals court.

Because Salim’s insurance coverage was provided through a group policy he purchased for himself and his employees, his claim was subject to the Employee Retirement Income Security Act and was decided based on an arbitrary and capricious standard of judicial review. Nonetheless, both the trial court and the reviewing court found the denial unreasonable.

After the initial claim denial, Salim’s treating doctor pointed out to the insurer that the guideline relied upon as the basis of the denial had been updated by the American Society for Radiation Oncology (ASTRO) to specifically encompass head and neck cancers. Proton beam therapy for treatment of head and neck cancers was also recommended by the National Comprehensive Cancer Network Head and Neck Guidelines. In addition, Salim’s doctor cited more than a dozen peer-reviewed studies that supported the use of proton therapy for treatment of his cancer.

However, a consultant hired by the insurance company disagreed, claiming that Salim did not meet medical criteria to receive treatment.

The court framed the issue as raising the question of whether proton beam therapy was medically necessary to treat Salim’s cancer. It answered that question in the affirmative, finding the denial was unsupported by substantial evidence. The court defined substantial evidence as meaning that so long as “there is more than a scintilla of evidence supporting denial, then Blue Cross prevails.” (Citations and internal quotations omitted.) The court explained that under ERISA’s deferential review standard, its job was not to weigh the evidence, but that it could overturn the denial if the denial was unreasonable.

The court pointed out that the initial denial was based on the insurer’s reliance on an outdated guideline. Because the guideline was based on evidence-based treatment standards developed by ASTRO, the guideline in use became invalid when ASTRO updated its treatment recommendations to deem proton beam therapy the standard of care for head and neck cancers. Hence, the court explained:

“The updated ASTRO Policy is not competing evidence that requires a court to weigh one policy against another. Rather, the updated Policy is superseding evidence showing that ASTRO — a source which [the defendant] treated as reliable — in fact classifies proton therapy as medically necessary for Salim’s condition.”

The court added that while the insurer had discretion to make a benefit determination, it did “not have discretion to deny Salim’s claim by attributing to ASTRO a view that ASTRO does not hold.”

The court was also troubled by the independent review, which generically stated without providing specific citations that “most investigators recommend additional study … before adopting [proton therapy] as a standard treatment option for patients with head and neck cancer.” The court viewed that conclusory statement as unreliable since it conflicted with the ASTRO guidelines and the peer-reviewed studies cited by Salim’s physician.

The court further pointed out that the independent reviewer misstated the medical criteria developed by both ASTRO and the National Comprehensive Cancer Network for treatment since the updated policies recommended proton beam therapy to treat “advanced head and neck cancers,” which was precisely the diagnosis Salim had received.

Finally, although the defendant argued that Salim failed to establish that he fully met the policy’s medical necessity criteria, his physician had asserted that proton beam therapy was less costly and otherwise superior to other treatment options. Absent any rebuttal to that opinion, the treatment was found medically necessary.

There are many lessons to be drawn from this ruling. First and foremost, while a deferential standard of judicial review poses a difficult hurdle for benefit claimants to overcome, it is not impossible, although had there been differing views on the efficacy of proton beam therapy by the experts in the field, the defendant would have easily won. Instead, the insurer’s reliance on an outdated and superseded medical guideline failed to pass muster with the court, and the defendant’s doubling down when the plaintiff proved the guideline was outdated was an even poorer choice.

This ruling also illustrates the value of claim appeals and the importance of the treating physician’s involvement in the appeal process. The 5th Circuit’s opinion also mapped out a best practice that is not only advisable for medical claims, but also applies to any type of benefit claim involving medical evidence. Because medicine is rapidly changing, as new and better treatments become available, the place to start when challenging a benefit denial is to determine whether the criteria used as the basis for a denial remains up to date. Yesterday’s experimental or investigational treatment is today’s recognized standard of care.

The treating doctor won this case by doing much more than merely offering his opinion. By providing the insurance company with the most recent treatment guidelines and with peer-reviewed studies supporting his treatment recommendation, he established that proton beam therapy was medically necessary. That lesson cannot be overstated and should be used as a blueprint in future cases.

Mark DeBofsky is a shareholder at DeBofsky Law Ltd. ). He handles civil and appellate litigation involving employee benefits, disability insurance and other insurance claims and coverage issues.

This article was first published by the Chicago Daily Law Bulletin on May 30, 2023 .

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Re-Irradiation With Proton Beam Therapy for Localized Perineural Spread Following Presacral Recurrence in Sigmoid Colon Cancer: A Case Report

Affiliation.

• 1 Department of Radiation Oncology, University of Tsukuba, Tsukuba, JPN.
• PMID: 38650764
• PMCID: PMC11034400
• DOI: 10.7759/cureus.56765

This report describes the effective management of localized perineural spread (PNS) to the sacral peripheral nerves following a presacral recurrence of colon cancer using proton beam therapy (PBT). The patient, a male in his 60s with a history of sigmoid colon cancer treated with laparoscopic Hartmann's procedure, presented with presacral recurrence two years post-surgery. Radical resection was deemed infeasible, leading to a combined treatment of PBT (75 Gy relative biological effectiveness (RBE) in 25 fractions) and capecitabine. However, three years post-PBT, magnetic resonance imaging revealed swelling of the left S2 nerve with abnormal fluorodeoxyglucose uptake, indicating localized PNS. Re-irradiation with PBT (75 Gy RBE in 25 fractions) was conducted, carefully considering the overlap with the previous PBT field and aiming to minimize dosage to adjacent organs. At 1.5 years post-reirradiation, the patient remained free of recurrence. This case underscores the potential efficacy of PBT and emphasizes the need for further research to assess its broader applicability in comparable situations.

Keywords: colorectal cancer; perineural spread; presacral recurrence; proton beam therapy; re-irradiation.

Copyright © 2024, Harada et al.

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