Proton Beam, Neutron Beam, and Carbon Ion Radiotherapy

Number: 0270

Policy

1. Aetna considers proton beam radiotherapy (PBRT) medically necessary for the curative treatment of any of the following tumors:

1. Primary CNS cancers that cannot be completely resected; or 
2. Head and neck cancers (excluding T1-T2N0M0 laryngeal cancer) that cannot be completely resected; or
3. Paranasal sinus or nasopharyngeal tumors; or
4. Skull-based tumors, (e.g., chordomas or chondrosarcomas); or
5. Malignancies in children (21 years of age and younger); or
6. Ocular tumors, including intraocular/uveal melanoma (includes the iris, ciliary body and choroid); or
7. Primary or metastatic tumors of the spine where the spinal cord tolerance would be exceeded with photon radiotherapy approaches; or
8. Localized unresectable hepatocellular carcinoma (HCC) in the curative setting when documentation is provided that sparing of the surrounding normal tissue cannot be achieved with standard radiation therapy techniques, including intensity-modulated radiation therapy (IMRT), stereotactic body radiation therapy (SBRT), selective internal radiation spheres, and transarterial therapy (for example, chemoembolization).

2. Aetna considers proton beam radiotherapy and IMRT clinically equivalent for localized cancer of an intact prostate. Medical necessity will be determined based on the terms of the member’s benefit plan. Please check benefit plan descriptions.

3. Aetna considers proton beam radiotherapy experimental and investigational for all other indications, including the following indications in adults (over age 21) (not an all-inclusive list) because its effectiveness for these indications has not been established:

   • Age-related macular degeneration
   • Angiosarcoma
   • Bladder cancer
   • Breast cancer
   • Cardiac intimal sarcoma
   • Carotid body tumor
   • Cavernous hemangioma
   • Cervical cancer
   • Cholangiocarcinoma
   • Choroidal hemangioma
   • Dermatofibrosarcoma protuberans
   • Desmoid fibromatosis
   • Desmoid tumor (aggressive fibromatosis)
   • Esophageal cancer
   • Ewing's sarcoma
   • Fibrosarcoma of the extremities
   • Hemangioblastoma
   • Hemangioendothelioma
   • Hodgkin's lymphoma
   • Intracranial arterio-venous malformations
   • Large cell lymphoma
   • Laryngeal cancer
   • Leiomyosarcoma of the extremities
   • Liposarcoma
   • Liver metastases (including liver metastases from carcinoid gastrinoma)
   • Lung cancer (including non-small-cell lung carcinoma)
   • Mediastinal lymphoma
   • Mesothelioma
   • Multiple myeloma
   • Non-Hodgkin lymphoma
   • Non-uveal melanoma
   • Palliative treatment
   • Pancreatic cancer
   • Prostate cancer, metastatic
   • Rectal cancer
   • Retroperitoneal/pelvic sarcoma
   • Rhabdomyoma
   • Seminoma
   • Small bowel adenocarcinoma
   • Soft tissue sarcoma
   • Thymic tumor
   • Thymoma
   • Uterine cancer
   • Yolk cell tumor.

4. Aetna considers neutron beam therapy medically necessary for the treatment of any of the following salivary gland tumors:

   • Inoperable tumor; or
   • Locally advanced tumor especially in persons with gross residual disease; or
   • Unresectable tumor.

5. Aetna considers neutron beam therapy experimental and investigational for all other indications including malignancies listed below (not an all inclusive list) because its effectiveness for these indications has not been established:

   • Colon cancer
   • Dermatofibrosarcoma protuberans
   • Ghost cell odontogenic carcinoma
   • Glioma
   • Kidney cancer
   • Laryngeal cancer
   • Lung cancer
   • Pancreatic cancer
   • Prostate cancer
   • Rectal cancer
   • Soft tissue sarcoma.

6. Aetna considers carbon ion therapy experimental and investigational for all indications because its effectiveness has not been established.

Background

Proton Beam Theapy

Proton beam radiation therapy (PBRT) is a type of external beam radiation therapy (EBRT) that utilizes protons (positively charged subatomic particles) that are precisely targeted to a specific tissue mass. Proton beams have the ability to penetrate deep into tissues to reach tumors, while delivering less radiation to superficial tissues such as the skin. This may make PBRT more effective for inoperable tumors or for those individuals in which damage to healthy tissue would pose an unacceptable risk.

Proton beams have less scatter than other sources of energy such as gamma rays, x-rays, or electrons.  Because of this feature, proton beam radiotherapy (PBRT) has been used to escalate radiation dose to diseased tissues while minimizing damage to adjacent normal tissues.  Proton beams have been used in stereotactic radiosurgery of intracranial lesions; the gamma knife and linear accelerator have also been used in stereotactic radiosurgery.  Proton beam radiotherapy has been shown to be particularly useful in treating radiosensitive tumors that are located next to vital structures, where complete surgical excision or administration of adequate doses of conventional radiation is difficult or impossible.  Examples include uveal melanomas, chordomas and chondrosarcomas at the base of the skull, and inoperable arterio-venous malformations.  There is inadequate data on the application of PBRT for the treatment of non-uveal melanoma.

Plastaras et al (2014) stated that the dose distributions that can be achieved with protons are usually superior to those of conventional photon external-beam radiation.  There are special cases where proton therapy may offer a substantial potential benefit compared to photon treatments where toxicity concerns dominate.  Re-irradiation may theoretically be made safer with proton therapy due to lower cumulative lifetime doses to sensitive tissues, such as the spinal cord.  Proton therapy has been used in a limited number of patients with rectal, pancreatic, esophageal, and lung cancers.  Chordomas and soft tissue sarcomas require particularly high radiation doses, posing additional challenges for re-irradiation.  Lymphoma is another special case where proton therapy may be advantageous.  Late toxicities from even relatively low radiation doses, including cardiac complications and second cancers, are of concern in lymphoma patients with high cure rates and long life expectancies.  Proton therapy has begun to be used for consolidation after chemotherapy in patients with Hodgkin and non-Hodgkin lymphoma.  Breast cancer is another emerging area of proton therapy development and use.  Proton therapy may offer advantages compared to other techniques in the setting of breast boosts, accelerated partial breast irradiation, and post-mastectomy radiotherapy.  In these settings, proton therapy may decrease toxicity associated with breast radiotherapy.  The authors concluded that as techniques are refined in proton therapy, one may be able to improve the therapeutic ratio by maintaining the benefits of radiotherapy while better minimizing the risks.

A comparative effectiveness review of proton beam therapy by the Veteran's Health Administration (2015) reached the following conclusions: "For the cancer sites and types reviewed by the ESP report, there are no reliable data from long-term randomized trials on survival, quality of life, or functional capacity of patients who underwent proton beam therapy (PBT) compared with any other modality. The authors could not fully assess the overall net health benefit of proton beam therapy versus its comparators because comparative observational studies did not consistently report many outcomes of greatest interest. Existing comparative studies have numerous methodological deficiencies that limited confidence in the findings, and the findings may have limited applicability across all US proton beam facilities. Although numerous randomized controlled trials are underway that carry the promise of improved toxicity measurement, the report noted it is unclear whether these will fully address gaps in evidence on such outcomes as recurrence, ability to deliver planned chemotherapy and radiation regimens, functional capacity, overall severe late toxicity, and secondary malignancies. Although the report found comparative studies in giant cell tumors, head and neck cancer, uveal hemangiomas, and meningiomas, they provided insufficient evidence for drawing conclusions. There is insufficient evidence to draw conclusions about the comparative effects of PBT versus other radiation modalities among patients with recurrent tumors or how the comparative effects of proton and photon beam therapies differ according to variation in tumor motion."

A report by the Canadian Agency for Drugs and Technologies in Health (CADTH, 2016) found: "Two systematic reviews of clinical evidence, two systematic reviews of economic evidence, and one primary economic evaluation were identified regarding the clinical and cost-effectiveness of proton beam therapy compared to photon radiotherapy for the treatment of cancer patients. There was limited comparative evidence, with insufficient evidence available for many indications, comparators, and outcomes. Comparable benefits and harms were demonstrated by most studies for the majority of outcomes in prostate, esophageal, lung, and breast cancer, as well as medulloblastoma, and pediatric brain tumours. An increased risk of patient harms was observed for some outcomes in breast, esophageal, prostate and lung cancer. As well, reduced survival was reported for spinal cord gliomas. Reduced harms were reported for some outcomes in patients with medulloblastoma, as well as lung, esophageal, and prostate cancer, and pediatric retinoblastoma. There was insufficient evidence to draw conclusions for recurrent liver and brain cancers, meningioma, head and neck cancers, uveal hemangioma, and for the outcome of secondary malignancies. The identified economic evidence is likely not generalizable to the Canadian context, and may not reflect accurate and up-to-date cost and benefit estimates. Most evaluations reported that PBT was not cost-effective; however, the technology was more likely to be cost-effective in pediatric populations, and under specific circumstances in younger adults, and patients with more advanced disease (e.g., high risk head and neck, lung cancer, and breast cancer patients). Overall, current comparative evidence does not suggest that PBT is superior to photon therapy from a clinical or cost perspective for the majority of indications. There are concerns regarding the quantity, quality and generalizability of the available evidence. Current ongoing studies and future investigation into differences in hard clinical endpoints and long-term outcomes may resolve some of this uncertainty."

A report by the Canadian Agency for Drugs and Technologies in Health (CADTH, 2017) found: "A review of the clinical evidence from nine systematic reviews found that PBT, alone or in combination with photon radiotherapy, is comparable to other types of radiotherapy for most types of cancer. Exceptions include meningioma and subgroups of malignant meningioma, and poorly differentiated tumours of prostate cancer in adults, for which greater benefits were found with PBT; some intramedullary spinal cord glioma in both children and adults, for which lower benefits were found with PBT; and eye cancer in adults, for which both greater benefits and lower benefits, depending on the specific type of eye cancer, were found with PBT. The clinical evidence also found that the safety of PBT, alone or in combination with photon radiotherapy, varies by the type of cancer it is used to treat, compared with other types of radiotherapy. It was found to be associated with greater harms in breast cancer and prostate cancer in adults; lower harms in retinoblastoma in children and medulloblastoma in adults; and both greater harms and lower harms in adults depending on the specific type of the following cancers: esophageal cancer, optic nerve sheath meningioma, and lung cancer."

Regarding cost-effectiveness analyses of PBRT, the VATAP assessment found that the availability of studies titled by their authors as "economic evaluations" is misleading (Flynn, 2010).  The assessment stated that such studies require cost and efficacy data about both the intervention and its alternatives (costs and consequences of alternative interventions), hence should be conducted only after efficacy data from randomized controlled trials are available.  The assessment noted that, in the case of proton therapy, the economic studies are premature, really should be labeled simple cost rather than cost-effectiveness analyses, and their conclusions based on unwarranted efficacy assumptions.  Cost data have been carefully collected and reported, but these are only one element of decision making about investment in proton therapy.  The VATAP assessment concluded that there are no indications for which proton therapy has been shown unequivocally to be effective, or more effective than its alternatives.  The VATAP assessment also concluded that no research published subsequent to the searches conducted for available systematic reviews has changed the conclusions of those reviews.

Regarding research implications, the VATAP assessment concluded that, in order to obtain the next generation of data, explicit decisions need to be made about which malignancies are amenable to/should require randomized trials (e.g., prostate cancer is sufficiently common) and which malignancies are sufficiently rare or difficult to treat with surgery or conventional radiotherapy (e.g., ocular tumors, tumors of the optical nerve, spinal cord, or central nervous system) that observational studies with larger cohorts than studies to date are the best approach (Flynn, 2010).  The VATAP assessment also concluded that future studies should strongly consider valid and reliable embedded collection of cost data in order to inform better quality economic evaluation than currently available.

An assessment prepared for the Agency for Healthcare Research and Quality (Trikalinos, et al., 2009) found that a large number of scientific papers on charged particle radiotherapy for the treatment of cancer currently exist. However, these studies do not document the circumstances in contemporary treatment strategies in which radiotherapy with charged particles is superior to other modalities. Comparative studies in general, and randomized trials in particular (when feasible), are needed to document the theoretical advantages of charged particle radiotherapy to specific clinical situations. The assessment noted that most eligible studies were noncomparative in nature and had small sample sizes. The report stated that it is likely that focused systematic reviews will not be able to provide a definitive answer on the effectiveness and safety of charged particle beam radiotherapies compared with alternative interventions. This is simply because of the relative lack of comparative studies in general, and randomized trials in particular. The report stated that comparative studies (preferably randomized) are likely necessary to provide meaningful answers on the relative safety and effectiveness of particle beam therapy versus other treatment options in the context of current clinical practice. This is especially true for the treatment of common cancers. The report stated that, especially for many common cancers, such as breast, prostate, lung, and pancreatic cancers, it is essential that the theorized advantages of particle beam therapy versus contemporary alternative interventions are proven in controlled clinical trials, along with concomitant economic evaluations.

An assessment of proton beam radiotherapy by the Veterans Health Administration Technology Assessment Program (VATAP) (Flynn, 2010) found that available English-language reviews for proton therapy generally concur on the state of the literature as consisting primarily of observational studies from which conclusions about the relative effectiveness of proton therapy versus alternatives cannot validly be made.  The assessment reported that available reviews reflect the state of the literature in that they attempt to cover so much territory (multiple poor-prognosis inoperable tumors in both children and adults) that the reviews themselves are cumbersome to read, not well organized, and provide only diffuse or equivocal conclusions by individual diagnoses.  "In other words, the literature reflects the early clinical investigation status of proton therapy, where observational studies are framed in terms of potential benefits, reasoning from pathophysiology, dose-finding, refinement of treatment protocols, and baseline safety of the entire approach" (Flynn, 2010).  The assessment noted that only prostate cancer is represented by randomized controlled clinical trials, and in that case two small ones primarily concerned with refinement of protocol/dose escalation.

The Alberta Health Services, Cancer Care’s clinical practice guideline on "Proton beam radiation therapy" (2013) noted that "Members of the working group do not currently recommend that patients with prostate cancer, non-small cell lung cancer, or most lymphomas be referred for proton beam radiotherapy, due to an insufficient evidence base".

An assessment by the Riete Italiana Health Technology Assessment (RIHTA, 2011) concluded: "The lack of comparative studies comparing HT [hadron therapy] with other currently available treatments (other RT techniques and/or chemotherapy) does not allow drawing firm conclusions about the effects of HT in cancer treatment. In specific circumstances, clinical studies suggested improvements in safety and effectiveness by using HT instead of traditional RT for some types of tumours (in particular uveal melanoma, skull and neck chordomas, and NSCLC). Nonetheless, there is uncertainty regarding these estimates, due to methodological and design flaws of available studies. Therefore presently available evidence is not sufficient to support routine clinical use of HT."

An assessment of proton therapy by the Ludwig Boltzmann Institute (Wild, et al., 2013) concluded: "The evidence basis for an added benefit is only very moderate. Since surrogate endpoints were primarily measured and no/hardly any prospectively comparative trial results with up-to-date photon therapy are available, there is no confirmed knowledge of whether the promise of theoretical advantages can be translated into patient-relevant advantages (longer survival, quality of life through fewer side effects)." A subsequent assessment by the Ludwig Boltzmann Institute (Wild & Selhc, 2020) concluded: "The identified reviews articulate in unison that the available - mostly retrospective - studies are of low quality and inadequate to make conclusive statements about the added value of proton or carbon ion therapy. The picture of the data situation remains unchanged compared to 2013. Only a few indications are recommended for proton or carbon ion therapy, more for reasons of plausibility than on the basis of convincing data. These are: chordomas and chondrosarcomas; Uveal melanoma (if required); Pediatric tumors (skull base, brain and head and neck tumors) to prevent secondary tumors. Further indications, with curative intent and non-metastatic, are only recommended under the conditions of prospective clinical studies: Tumors at the base of the skull and in the central nervous system, tumors in the head and neck area (exception oropharynx: G-BA), inoperable lung cancer (NSCLC) stages I to IIIb, lymphoma and sarcoma, some gastrointestinal tumors (esophagus, pancreas), inoperable liver cell carcinoma ( HCC), prostate cancer (with restrictions). Clearly excluded indications are operable HCC, operable NSCLC, NSCLC stage IV, rectal cancer (with exceptions), breast cancer (with the exception)." The assessment concluded (Wild & Selhc, 2020): "In summary, it can be said that numerous reviews come to the same conclusion, namely that only prospective high-quality primary studies can make statements about the superiority or equivalence of proton and carbon ion therapy for clinical endpoints of effectiveness and superiority for endpoints on acute and late toxicity."

An assessment by the INESSS (2017) of proton beam therapy for found: "Indeed, the evidence does not provide any proof in favour of PrT for the indications recognized by most organizations and experts worldwide, with the exception of ocular cancer, pediatric cancers and central nervous system cancers. Furthermore, the level of evidence is weak for the potential indications, which are presently not recognized in Québec. The recommendations in several countries differ with regard to hepatocellular carcinoma, non-small-cell lung cancer, prostate cancer and other clinical situations, such as re-irradiation. However, esophageal and breast cancers are not indications recognized in current practice. In conclusion, since the quality of the existing data is inadequate, it is presently not relevant to propose treatment with PrT for: non-small-cell lung cancer; hepatocellular carcinoma; prostate cancer; esophageal cancer; breast cancer; [and] re-irradiation cases."

The emerging technology committee of the American Society of Radiation Oncology (ASTRO) concluded that current evidence provides a limited indication for proton beam therapy (Allen, et al., 2012). The ASTRO report concluded that current data do not provide sufficient evidence to recommend proton beam therapy in lung cancer, head and neck cancer, gastrointestinal malignancies, and pediatric non-central nervous system (CNS) malignancies. The ASTRO report stated that, in hepatocellular carcinoma and prostate cancer, there is evidence for the efficacy of proton beam therapy but no suggestion that it is superior to photon based approaches. In pediatric central nervous system (CNS) malignancies, proton beam therapy appears superior to photon approaches but more data is needed. The report found that, in large ocular melanomas and chordomas, there is evidence for a benefit of proton beam therapy over photon approaches. The ASTRO report stated that more robust prospective clinical trials are needed to determine the appropriate clinical setting for proton beam therapy.

An ASTRO model policy (2017) lists indications for proton beam therapy. The ASTRO model policy states that it is not a clinical guideline and that it was created for insurance reimbursement purposes. Group 1 indications are "disease sites that frequently support" the use of proton beam therapy, and include: ocular tumors, including intraocular melanomas; tumors that approach or are located at the base of skull, including but not limited to chordoma and chondrosarcomas; primary or metastatic tumors of the spine where the spinal cord tolerance may be exceeded with conventional treatment or where the spinal cord has previously been irradiated; hepatocellular cancer; primary or benign solid tumors in children treated with curative intent and occasional palliative treatment of childhood tumors; patients with genetic syndromes making total volume ofradiation minimization crucial such as but not limited to NF-1 patients and retinoblastoma patients; malignant and benign primary CNS tumors; advanced (eg, T4) and/or unresectable head and neck cancers; cancers of the paranasal sinuses and other accessory sinuses; non-metastatic retroperitoneal sarcomas; and re-irradiation cases (where cumulative critical structure dose would exceed tolerance dose). Other indications are categorized as Group 2, which are "suitable for Coverage with Evidence Development (CED)": non-T4 and resectable head and neck cancers; thoracic malignancies, including non-metastatic primary lung and esophageal cancers, and mediastinal lymphomas; abdominal malignancies, including non-metastatic primary pancreatic, biliary and adrenal cancers; pelvic malignancies, including non-metastatic rectal, anal, bladder and cervical cancers; non-metastatic prostate cancer; and breast cancer.

The ASTRO model policy on intensity modulated radiation therapy (IMRT) (2017) indicates that these same indications are appropriate for IMRT: primary, metastatic or benign tumors of the central nervous system including the brain, brain stem and spinal cord; primary or metastatic tumors of the spine where the spinal cord tolerance may be exceeded with conventional treatment or where the spinal cord has previously been irradiated; primary, metastatic, benign or recurrent head and neck malignancies including, but not limited to those involving orbits, sinuses, skull base, aero-digestive tract, and salivary glands; thoracic malignancies; abdominal malignancies when dose constraints to small bowel or other normal tissue are exceeded and prevent administration of a therapeutic dose; pelvic malignancies, including prostatic, gynecologic and anal carcinomas; and other pelvic or retroperitoneal malignancies.

A systematic evidence review (Lodge et al, 2007) compared the efficacy and cost-effectiveness of PBRT and other types of hadron therapy (neutron and heavy and light ion therapy) with photon therapy.  The authors concluded that, overall, the introduction or extension of PBRT and other types of hadron therapy as a major treatment modality into standard clinical care is not supported by the current evidence base.  The authors stated, however, that the efficacy of PBRT appears superior to that of photon therapy for some ocular and skull base tumours.  The authors found that, for prostate cancer, the efficacy of PBRT seems comparable to photon therapy.  The authors stated that no definitive conclusions can be drawn for the other cancer types.  The authors also noted that they found little evidence on the relative cost-effectiveness of PBRT and other types of hadron therapy compared to photon therapy or with other cancer treatments.  Other systematic evidence reviews of PBRT have reached similar conclusions (Lance, 2010; Brada et al, 2009; Efstathiou et al, 2009; ICER, 2008; Wilt et al, 2008; Brada et al, 2007; Olsen et al, 2007).

An assessment of proton beam therapy prepared for the Washington State Health Care Authority (2019) found that the evidence for the net health benefit for proton beam therapy versus standard of care comparitors was "insufficient" for bladder cancer, bone cancer, gastrointestinal cancers, lymphomas, chondrosarcomas of the skull base, "mixed/various" cancers, ocular tumors (versus stereotactic radiosurgery), hemangiomas, pituitary adenomas, meningiomas and salvage therapy of brain/spinal tumors. They also found no studies meeting inclusion criteria comparing proton beam therapy versus standard of care photon therapy for gynecologic cancers, sarcomas, seminomas, thymomas, and arteriorvenous malformations. Based upon "low" quality evidence, they found "incremental" benefits of proton beam therapy over standard of care photon therapy for esophageal cancer, and for ocular tumors (comparing proton beam plus transscleral resection versus brachytherapy plus transscleral resection). Based on "low" quality evidence, they found "incremental" reduction in harms of proton therapy versus standard of care photon therapy for liver cancer (versus IMRT), Based on "moderate" quality evidence, they found "incremental" reduction in harms for proton beam therapy versus transarterial chemoembolization (TACE) for liver cancer. Based on "low" quality evidence, they found "comparable" outcomes of proton beam therapy versus standard of care photon therapy for lung cancer, prostate cancer, head and neck cancers (oropharyngeal, nasopharyngeal, paranasl sinus, and oral cancers), and curative treatment of brain and spinal tumors (comparing photons plus proton therapy boost versus photons alone). Based upon "low" quality evidence, the relative harms of proton beam therapy versus standard of care were "unclear" for breast cancer and for and for curative treatment of brain and spinal tumors (versus photon therapy) because the harms were not reported in the pivotal clinical studies. They found proton beam therapy alone to be "inferior", based upon "low" quality evidence, to brachytherapy alone for ocular tumors.

For pediatric cancers, the assessment prepared for the Washington State Health Care Authority (2019) found "insufficient" evidence for proton beam therapy versus standard of care photon therapy for bone cancers, head and neck cancers, ocular tumors, lymphomas, rhabdomyosarcomas, and "mixed/various" tumors. Based upon "low" quality evidence, they found an "incremental" reduction in harms from proton beam therapy versus standard of care for pediatric brain tumors.

The Washington State Health Care Authority Health Technology Clinical Committee (2019) determined that proton beam therapy is a covered benefit for children/adolescents less than 21 years old. The Health Technology Clinical Committee (2019) also determined that, for individuals 21 years old and older,  proton beam therapy is a covered benefit with conditions for the following primary cancers: esophageal, head/neck, skull-based, hepatocellular carcinoma, brain/spinal, ocular, and other primary cancers where all other treatment options are contraindicated after review by a multidisciplinary tumor board. The Health Technology Clinical Committee (2019) determined that proton beam therapy is not covered for all other conditions.

A technology assessment of proton beam therapy by the Belgian Health Care Knowledge Center (KCE, 2019) focused on the following indications: low grade glioma (LGG), primary sinonasal tumors and recurrences of head and neck tumors, breast cancer in women, pancreatic cancer, hepatocellular cancer (HCC), and locally recurrent rectal cancer. The technology assessment found that "[t]he available evidence on the effectiveness of proton treatment for the selected indications is limited to non-randomized comparative studies with methodological limitations and/or small sample sizes. The conclusions below therefore have a high degree of uncertainty." The assessment reached the following conclusions:

1. "There is evidence of very low level (1 study, 32 patients) that proton treatment is associated with a worse survival than photon radiotherapy in patients with primary intramedullary spinal cord gliomas. The data on recurrence are too imprecise to draw a firm conclusion";
2. "There is evidence of very low level (1 study, 98 patients) that proton treatment is associated with worse physician-rated cosmetic results at 5 years than photon radiotherapy in patients with stage I breast cancer. No significant difference was found for patient-rated cosmetic results. The data on local failure rate are too imprecise to draw a firm conclusion.";
3. "There is evidence of very low level (1 study, 25 patients) that proton treatment and hyperfractionated acceleration radiotherapy with concomitant S-1 do not differ significantly in their effect on survival and disease control in patients with locally advanced and unresectable pancreatic cancer although the estimates are imprecise. The data on local progression are too imprecise to draw a firm conclusion.";
4. "The data on the effect of proton treatment vs. photon radiotherapy on local recurrence rate in patients with recurrent hepatocellular cancer are too imprecise to draw afirm conclusion."

The assessment also found " In the absence of clinical studies comparing proton treatment with photon-based radiotherapy, no conclusions can be drawn on the effectiveness of proton treatment for primary sinonasal cancer, recurrent head and neck cancer, and locally recurrent rectal cancer."

The KCE (2019) determined that an assessment of proton beam therapy for lung cancer was considered premature given the fact that there are a number or ongoing studies in this indication, including three randomized controlled trials (RCTs) comparing proton versus photon radiation in non-small-cell lung cancer (NSCLC). The KCE report also did not assess proton beam therapy for prostate cancer; the KCE did not consider proton beam therapy appropriate for treatment of prostate cancer, following the negative recommendations by the American Society for Radiation Oncology (ASTRO) for the primary treatment of prostate cancer, outside of a prospective clinical trial or registry. These recommendations were based largely on the strength of evidence about effectiveness of proton beam therapy for treatment with PBT. The KCE report also did not assess indications for which proton beam therapy is reimbursed in Belgium, specifically: ocular melanoma, where brachytherapy is not possible; paraspinal or sacral, skull based chordoma paraspinal or sacral, skull base chondrosarcoma/sarcoma; meningioma, for which no other medical treatment (surgery, chemotherapy, photon therapy etc.) is possible; cerebral arteriovenous malformations (AVM), for which surgery, embolization and (stereotactic) photon radiotherapy are all impossible or have already been delivered without success; and medulloblastoma.

With respect to safety, the technology assessment (KCE, 2019) found: "The available evidence on the safety of proton treatment for the selected indications is limited to non-randomized comparative studies with methodological limitations and/or small sample size, and single-arm studies. The conclusions below therefore have a high degree of uncertainty." The report found:

1. "Toxicity is heterogeneously and often selectively reported. Furthermore, definitions of acute and late toxicity differ across studies, making comparison and conclusions difficult.";
2. "Toxicity data per indication reflect that the types of adverse events are highly dependent on the dose delivered to a certain volume of an organ at risk.";
3. "The incidence of fatal toxicity and treatment cessation because of toxicity seem to be comparable to that of conventional radiotherapy."

The report concluded that, "based on the comparative studies the following additional conclusions can be drawn:"

1. "The data on the effect of proton treatment vs. photon radiotherapy on radiation necrosis and pseudoprogression in patients with primary intramedullary spinal cord gliomas are too imprecise to draw a firm conclusion;"
2. "There is evidence of very low level (1 study, 98 patients) that proton treatment is associated with more dermatologic toxicity (skin colour changes, patchy atrophy, telangiectasia) than photon radiotherapy in patients with stage I breast cancer. The data on rib fractures and fat necrosis are too imprecise to draw a firm conclusion;"
3. "The data on the effect of proton treatment vs. hyperfractionated acceleration radiotherapy with concomitant S-1 on acute grade 3 leukopenia, thrombocytopenia and ulcer in patients with locally advanced and unresectable pancreatic cancer are too imprecise to draw a firm conclusion.";
4. "The data on the effect of proton treatment vs. photon radiotherapy on toxicity in patients with recurrent hepatocellular cancer are too scarce to draw a firm conclusion." 

The assessment concluded: "In conclusion, high-quality evidence on the effectiveness of proton treatment is lacking for the studied indications. With the available evidence, it is impossible to conclude that proton treatment is better or worse than photon-based radiotherapy. However, there are some concerns in patients with primary intramedullary spinal cord gliomas (survival) and stage I breast cancer (cosmesis)."

Ofuya, et al. (2019) conducted a systematic review of the methodology used in clinical studies evaluating the benefits of proton beam therapy. The objectives of the systematic review were to provide an overview of published clinical studies evaluating the benefits of PBT, and to examine the methodology used in clinical trials with respect to study design and outcomes. PubMed, EMBASE and Cochrane databases were systematically searched for published clinical studies where PBT was a cancer treatment intervention. All randomized and non-randomized studies, prospective or retrospective, were eligible for inclusion. In total, 219 studies were included. Prospective studies comprised 89/219 (41%), and of these, the number of randomized phase II and III trials were 5/89 (6%) and 3/89 (3%) respectively. Of all the phase II and III trials, 18/24 (75%) were conducted at a single PBT center. Over one-third of authors recommended an increase in length of follow up. Research design and/or findings were poorly reported in 74/89 (83%) of prospective studies. Patient reported outcomes were assessed in only 19/89 (21%) of prospective studies. The authors concluded that prospective randomized evidence for PBT is limited. The set-up of national PBT services in several countries provides an opportunity to guide the optimal design of prospective studies, including RCTs, to evaluate the benefits of PBT across various disease sites. The authors stated that collaboration between PBT centers, both nationally and internationally, would increase potential for the generation of practice changing evidence. The authors stated that there is a need to facilitate and guide the collection and analysis of meaningful outcome data, including late toxicities and patient reported QoL.

Jones, et al. (2019) conducted a systematic review of the literature to identify cost utiity analyses (CUAs) of proton beam therapy in adult disease using MEDLINE, EMBASE, EconLIT, NHS Economic Evaluation Database (NHS EED), Web of Science, and the Tufts Medical Center Cost-Effectiveness Analysis Registry from January1, 2010 to June 6, 2018. General characteristics, information relating to modelling approaches, and methodological quality were extracted and synthesized narratively. Seven PBT CUA studies in adult disease were identified. Without randomized controlled trials to inform the comparative effectiveness of PBT, studies used either results from one-armed studies, or dose-response models derived from radiobiological and epidemiological studies of PBT. Costing methods varied widely. The assessment of model quality highlighted a lack of transparency in the identification of model parameters, and absence of external validation of model outcomes. Furthermore, appropriate assessment of uncertainty was often deficient. The authors concluded that, in order to foster credibility, future CUA studies must be more systematic in their approach to evidence synthesis and expansive in their consideration of uncertainties in light of the lack of clinical evidence.

Hwang, et al. (2020) conducted a systematic review which aims to update the clinical evidence base for particle therapy (PT), both proton beam and carbon ion therapy. The purpose was to inform clinical decision-making for referral of patients to PT centers in Australia as they become operational overseas in the interim. Three major databases were searched by two independent researchers and evidence quality was classified according to the National Health and Medical Research Council evidence hierarchy. One hundred and thirty-six studies were included, two-thirds related to proton beam therapy alone. The authors found that PT at the very least provides equivalent tumor outcomes compared to photon controls with the possibility of improved control in the case of carbon ion therapy. The authors stated that there is suggestion of reduced morbidities in a range of tumor sites, supporting the predictions from dosimetric modelling and the wide international acceptance of PT for specific indications based on this. The authors stated that, though promising, this needs to be counterbalanced by the overall low quality of evidence found, with 90% of studies of level IV (case series) evidence. The authors concluded that prospective comparative clinical trials, supplemented by database-derived outcome information, preferably conducted within international and national networks, are strongly recommended as PT is introduced into Australasia.

In a review on "Promise and pitfalls of heavy-particle therapy", Mitin and Zietman (2014) stated that "Particle therapy [including proton beam], on a relatively thin evidence base, has established itself as the standard of care for these rare malignancies [chordoma and chondrosarcoma]". The authors stated that, "In others, the benefits are likely to be small or non-existent such as with skin cancer; and proton beam therapy should not be considered."

In a randomized, prospective, sham-controlled, double-masked study (n = 37), Ciulla et al (2002) examined the effect of PBRT on subfoveal choroidal neovascular membranes associated with age-related macular degeneration.  These investigators concluded that with the acceptance of photodynamic therapy, future studies will require more complex design and larger sample size to determine whether radiation can play either a primary or adjunctive role in treating these lesions.

In a phase II clinical study (n = 30), Kawashima and colleagues (2005) assessed the safety and effectiveness PBRT for patients with hepatocellular carcinoma (HCC).  Eligibility criteria for this study were: solitary HCC; no indication for surgery or local ablation therapy; no ascites; age of 20 years or older; Zubrod performance status of 0 to 2; no serious co-morbidities other than liver cirrhosis; written informed consent.  Proton beam radiotherapy was administered in doses of 76 cobalt gray equivalent in 20 fractions for 5 weeks.  No patients received transarterial chemoembolization or local ablation in combination with PBRT.  All patients had liver cirrhosis, the degree of which was Child-Pugh class A in 20, and class B in 10 patients.  Acute reactions of PBRT were well-tolerated, and PBRT was completed as planned in all patients.  Four patients died of hepatic insufficiency without tumor recurrence at 6 to 9 months; 3 of these 4 patients had pre-treatment indocyanine green retention rate at 15 minutes of more than 50 %.  After a median follow-up period of 31 months (range of 16 to 54 months), only 1 patient experienced recurrence of the primary tumor, and 2-year actuarial local progression-free rate was 96 %.  Actuarial overall survival rate at 2 years was 66 %.  These investigators concluded that PBRT showed excellent control of the primary tumor, with minimal acute toxicity.  They stated that further study is warranted to scrutinize adequate patient selection in order to maximize survival benefit of this promising modality.

In a phase II prospective trial, Bush et al (2011) evaluated the safety and effectiveness of PBRT for HCC.  Patients with cirrhosis who had radiological features or biopsy-proven HCC were included in the study.  Patients without cirrhosis and patients with extra-hepatic metastasis were excluded.  The mean age was 62.7 years.  The mean tumor size was 5.5 cm.  Eleven patients had multiple tumors, and 46 % were within the Milan criteria.  Patients received 63 Gy delivered over a 3-week period with PBRT.  A total of 76 patients were treated and followed prospectively.  Acute toxicity was minimal; all patients completed the full course of treatment.  Radiation-induced liver disease was evaluated using liver enzyme, bilirubin, and albumin levels; no significant change supervened 6 months post-treatment.  Median progression-free survival for the entire group was 36 months, with a 60 % 3-year progression-free survival rate for patients within the Milan criteria.  Eighteen patients subsequently underwent liver transplantation; 6 (33 %) explants showed pathological complete response and 7 (39 %) showed only microscopic residual.  The authors concluded that PBRT was found to be a safe and effective local-regional therapy for inoperable HCC.  They noted that a randomized controlled trial to compare its efficacy to a standard therapy has been initiated.

A systematic evidence review of proton beam therapy for hepatocellular carcinoma (Dionisi, et al., 2014) concluded: "The low quality of the retrieved studies reduces without eliminating the interest toward the impressive clinical results that have been registered in several stages of HCC. The cost-benefit of proton versus other treatment options is worth of study given the high cost of protons. A number of proton therapy centers are currently recruiting patients in various prospective trials and are testing proton therapy alone, comparing proton therapy vs TACE, or evaluating the role of proton therapy in advanced disease. A positive outcome of such trials would suggest the role of proton therapy as an effective option in the local treatment of unresectable HCC. Active-scanning based proton therapy treatment for HCC is under development, and it should be considered one of the 'modern approaches' to be tested in the next future."

A systematic review of proton beam for hepatocellular carcinoma (Qi, et al., 2015) found: "Survival rates for charged particle therapy are higher than those for conventional radiotherapy, but similar to stereotactic body radiotherapy in patients with hepatocellular carcinoma. Toxicity tends to be lower for charged particle therapy compared to photon radiotherapy."

An assessment of proton beam therapy for hepatocellular carcinoma prepared for the UK National Health Service (2019) reached the following conclusions: "The body of evidence regarding the effectiveness and safety of PBT in the treatment of HCC remains small. Two clinical papers were submitted to the Clinical Panel as part of the policy proposition; both were systematic reviews and not original research. A third paper submitted was a cost utility modelling, based on assumptions about effectiveness that were derived from phase II studies. Therefore, this did not add to the evidence on clinical effectiveness. The two systematic reviews demonstrated a low level of evidence of benefit of proton beam therapy. One paper concluded that there was a low level of evidence, suggesting a strong rationale to enrol patients into prospective studies. The other more recent paper found no randomized controlled trials or controlled studies that compared charged particle therapy with photon therapy directly. The Panel found no convincing evidence that demonstrated superiority of proton beam therapy over current standard treatment."

Olfactory neuroblastoma (ONB) is a rare disease, and a standard treatment strategy has not been established.  Radiation therapy for ONB is challenging because of the proximity of ONB to critical organs.  Nishimura et al (2007) analyzed the feasibility and effectiveness of PBRT for ONB.  A retrospective review was performed on 14 patients who underwent PBRT for ONB as definitive treatment.  The total dose of PBRT was 65 cobalt Gray equivalents (Gy(E)), with 2.5-Gy(E) once-daily fractionations.  The median follow-up period for surviving patients was 40 months.  One patient died from disseminated disease.  There were 2 persistent diseases, 1 of which was successfully salvaged with surgery.  The 5-year overall survival rate was 93 %, the 5-year local progression-free survival rate was 84 %, and the 5-year relapse-free survival rate was 71 %.  Liquorrhea was observed in 1 patient with Kadish's stage C disease (widely destroying the skull base).  Most patients experienced grade 1 to 2 dermatitis in the acute phase.  No other adverse events of grade 3 or greater were observed according to the RTOG/EORTC acute and late morbidity scoring system.  The authors concluded that these preliminary findings of PBRT for ONB achieved excellent local control and survival outcomes without serious adverse effects.  They stated that PBRT is considered a safe and effective modality that warrants further study.

Proton beam radiotherapy represents a special case for children for several reasons (Wilson et al, 2005; Hall, 2006; Merchant, 2009).  It has been shown in dosimetric planning studies to have a potential advantage over conventional photon therapy because of the ability to confine the high-dose treatment area to the tumor volume and minimize the radiation dose to the surrounding tissue.  This especially important in children, as children are more sensitive to radiation-induced cancer than adults.  An increased risk of second cancers in long-term survivors is more important in children than older adults. In addition to second malignant neoplasms, late effects of radiation to normal tissue can include developmental delay.  Also, radiation scattered from the treatment volume is more important in the small body of the child.  Finally, the question of genetic susceptibility arises because many childhood cancers involve a germline mutation.

A BCBS TEC assessment found insufficient evidence for PBRT in the treatment of non-small-cell lung cancer.  In addition, the American Society for Radiation Oncology (ASTRO) guidelines (Allen et al, 2012) found insufficient evidence for PBRT in lung cancer.

The Blue Cross and Blue Shield Association Medical Advisory Panel (BCBSA, 2010) concluded that proton beam radiation therapy for treatment of non-small-cell lung cancer at any stage or for recurrent non-small-cell lung cancer does not meet the Technology Evaluation Center criteria. The TEC assessment stated that, overall, evidence is insufficient to permit conclusions about the results of proton beam therapy for any stage of non-small-cell lung cancer. The report found that all proton beam therapy studies are case series; there are no studies directly comparing proton beam therapy and stereotactic body radiotherapy. Among study quality concerns, no study mentioned using an independent assessor of patient reported adverse events, adverse events were generally poorly reported, and details were lacking on several aspects of proton beam therapy treatment regimens. The proton beam therapy studies had similar patient ages, but there was great variability in percent within stage Ia, sex ratio, and percent medically inoperable. There is a high degree of treatment heterogeneity among the proton beam therapy studies, particularly with respect to planning volume, total dose, number of fractions, and number of beams. Survival results are highly variable. It is unclear if the heterogeneity of results can be explained by differences in patient and treatment characteristics. Indirect comparisons between proton beam therapy and stereotactic body radiotherapy, comparing separate sets of single-arm studies on proton beam therapy and stereotactic body radiotherapy, may be distorted by confounding. In the absence of randomized, controlled trials, the comparative effectiveness of proton beam therapy and stereotactic body radiotherapy is uncertain.

An ASTRO evidence-based guideline on radiotherapy for smal cell lung cancer (Simone, et al., 2020) found: "Proton therapy could potentially further decrease normal tissue toxicities, but there are limited prospective data on its role in SCLC treatment. Generation of evidence is encouraged through treatment of patients in prospective clinical trials or multiinstitutional registries." 

Bassim et al (2010) reviewed the literature on radiation therapy for the treatment of vestibular schwannoma (VS). PubMed searches for English language articles on radiation treatment of VS published from January 2002 to July 2007 were conducted. Studies presenting outcomes were selected, yielding 56 articles (58 studies) in journals of neurosurgery (30), oncology (18), otolaryngology (6), and other (2). Data included type of study, number of subjects, demographics, follow-up times, type of radiation, tumor size, tumor control definition, control rates, facial nerve function measure and outcome, type of hearing and vestibular testing and outcomes, and complications.  Descriptive statistics were performed.  Studies (72.9%) were retrospective reviews with stated sample sizes ranging from 5 to 829.  Gamma-knife (49.2%), linear accelerator (35.6%), and proton beam (6.8%) were used with various doses.  Average follow-up was less than 5 years in 79.6% of studies, and 67.4 % included patients at less than or equal to 1 year.  Tumor size was reported as diameter (23.7%), volume (49.2%), both (11.9%), other (3.4%), or not reported (11.9%).  Definition of tumor control varied: less than or equal to 2 mm growth (22.0%), no visible/measurable change (16.9%), required surgery (10.2%), other (17.0%), and not clearly specified (33.9%). Facial nerve outcome was reported as House-Brackmann (64.4%), normal/abnormal (11.9%), other (1.7%), or was not reported (22%). The authors concluded that the lack of uniform reporting criteria for tumor control, facial function and hearing preservation, and variability in follow-up times make it difficult to compare studies of radiation treatment for VS. They recommended consideration of reporting guidelines such as those used in otology for reporting VS resection results.

In a phase I clinical study, Hong et al (2011) evaluated the safety of 1 week of chemo-radiation with proton beam therapy and capecitabine followed by early surgery on 15 patients with localized resectable, pancreatic ductal adenocarcinoma of the head.  Patients received radiation with proton beam.  In dose level 1, patients received 3 GyE × 10 (week 1, Monday to Friday; week 2, Monday to Friday).  Patients in dose levels 2 to 4 received 5 GyE × 5 in progressively shortened schedules: level 2 (week 1, Monday, Wednesday, and Friday; week 2, Tuesday and Thursday), level 3 (week 1, Monday, Tuesday, Thursday, and Friday; week 2, Monday), level 4 (week 1, Monday through Friday).  Capecitabine was given as 825 mg/m(2) b.i.d.  Weeks 1 and 2 Monday through Friday for a total of 10 days in all dose levels.  Surgery was performed 4 to 6 weeks after completion of chemotherapy for dose levels 1 to 3 and then after 1 to 3 weeks for dose Level 4.  Three patients were treated at dose levels 1 to 3 and 6 patients at dose level 4, which was selected as the MTD.  No dose limiting toxicities were observed.  Grade 3 toxicity was noted in 4 patients (pain in 1; stent obstruction or infection in 3).  Eleven patients underwent resection.  Reasons for no resection were metastatic disease (3 patients) and unresectable tumor (1 patient).  Mean post-surgical length of stay was 6 days (range of 5 to 10 days).  No unexpected 30-day post-operative complications, including leak or obstruction, were found.  The authors concluded that pre-operative chemo-radiation with 1 week of PBRT and capecitabine followed by early surgery is feasible.  A phase II study is underway.

Furthermore, the NCCN's clinical practice guideline on "Pancreatic adenocarcinoma" (2020) does not mention the use of proton beam.

NCCN guidelines on head and neck cancer (NCCN, 2020) state that "[p]roton therapy may be considered when normal tissue constraints cannot be met by photon-based therapy."  A report from the American Society for Therapeutic and Radiation Oncology (ASTRO) (2012) concludes that there is insufficient evidence to support the use of proton beam therapy for head and neck cancers, and conclude that "current data do not provide sufficient evidence to recommend PBT in  ... head and neck cancer… ".  An AHRQ comparative effectiveness review (2010) on radiotherapy for head and neck cancer reached the following conclusions regarding proton beam therapy versus other radiotherapy treatments for head and neck cancer: "The strength of evidence is insufficient as there were no studies comparing proton beam therapy to any other radiotherapy modality. Therefore, no conclusions can be reached regarding the comparative effectiveness of proton beam therapy for any of the four key questions."  An updated AHRQ Comparative Effectiveness Review of radiotherapy treatments for head and neck cancer (Ratko, et al., 2014) concluded: "We did not identify any evidence for PBT." A review of proton beam therapy for head and neck cancer prepared by the UK National Health Service (2019) found a low level of evidence.

The American College of Radiology’s "Appropriateness Criteria retreatment of recurrent head and neck cancer after prior definitive radiation" (McDonald et al, 2014) stated that "Newer conformal radiation modalities, including stereotactic body radiation therapy and proton therapy, may be appropriate in select cases.  Additional data are needed to determine which patient subsets will most likely benefit from these modalities".

Romesser et al (2016) stated that re-irradiation therapy (re-RT) is the only potentially curative treatment option for patients with locally recurrent head and neck cancer (HNC).  Given the significant morbidity with head and neck re-RT, interest in proton beam radiation therapy (PBRT) has increased.  These investigators reported the first multi-institutional clinical experience using curative-intent PBRT for re-RT in recurrent HNC.  A retrospective analysis of ongoing prospective data registries from 2 hybrid community practice and academic proton centers was conducted.  Patients with recurrent HNC who underwent at least 1 prior course of definitive-intent external beam radiation therapy (RT) were included.  Acute and late toxicities were assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 and the Radiation Therapy Oncology Group late radiation morbidity scoring system, respectively.  The cumulative incidence of loco-regional failure was calculated with death as a competing risk.  The actuarial 12-month freedom-from-distant metastasis and overall survival (OS) rates were calculated with the Kaplan-Meier method.  A total of 92 consecutive patients were treated with curative-intent re-RT with PBRT between 2011 and 2014.  Median follow-up among surviving patients was 13.3 months and among all patients was 10.4 months.  The median time between last RT and PBRT was 34.4 months.  There were 76 patients with 1 prior RT course and 16 with 2 or more courses.  The median PBRT dose was 60.6 Gy (relative biological effectiveness, [RBE]); 85 % of patients underwent prior HNC RT for an oropharynx primary, and 39 % underwent salvage surgery before re-RT.  The cumulative incidence of loco-regional failure at 12 months, with death as a competing risk, was 25.1 %.  The actuarial 12-month freedom-from-distant metastasis and OS rates were 84.0 % and 65.2 %, respectively.  Acute toxicities of grade 3 or greater included mucositis (9.9 %), dysphagia (9.1 %), esophagitis (9.1 %), and dermatitis (3.3 %).  There was 1 death during PBRT due to disease progression.  Grade 3 or greater late skin and dysphagia toxicities were noted in 6 patients (8.7 %) and 4 patients (7.1 %), respectively; 2 patients had grade 5 toxicity due to treatment-related bleeding.  The authors concluded that proton beam re-RT of the head and neck can provide effective tumor control with acceptable acute and late toxicity profiles likely because of the decreased dose to the surrounding normal, albeit previously irradiated, tissue, although longer follow-up is needed to confirm these findings.

McDonald et al (2016) reported the clinical outcomes of head and neck re-RT  with proton therapy.  From 2004 to 2014, a total of 61 patients received curative-intent proton re-irradiation, primarily for disease involving skull base structures, at a median of 23 months from the most recent previous course of radiation.  Most had squamous cell (52.5 %) or adenoid cystic (16.4 %) carcinoma.  Salvage surgery before re-irradiation was undertaken in 47.5 %.  Gross residual disease was present in 70.5 %.  For patients with microscopic residual disease, the median dose of re-irradiation was 66 Gy (relative biological effectiveness), and for gross disease was 70.2 Gy (relative biological effectiveness).  Concurrent chemotherapy was given in 27.9 %.  The median follow-up time was 15.2 months and was 28.7 months for patients remaining alive.  The 2-year OS estimate was 32.7 %, and the median OS was 16.5 months.  The 2-year cumulative incidence of local failure with death as a competing risk was 19.7 %; regional nodal failure, 3.3 %; and distant metastases, 38.3 %.  On multi-variable analysis, Karnofsky performance status less than or equal to 70 %, the presence of a gastrostomy tube before re-irradiation, and an increasing number of previous courses of radiation therapy were associated with a greater hazard ratio for death.  A cutaneous primary tumor, gross residual disease, increasing gross tumor volume, and a lower radiation dose were associated with a greater hazard ratio for local failure.  Grade greater than or equal to 3 toxicities were seen in 14.7 % acutely and 24.6 % in the late setting, including 3 treatment-related deaths.  The authors concluded that re-irradiation with proton therapy, with or without chemotherapy, provided reasonable loco-regional disease control, toxicity profiles, and survival outcomes for an advanced-stage and heavily pre-treated population.  Moreover, they stated that additional data are needed to identify which patients are most likely to benefit from aggressive efforts to achieve local disease control and to evaluate the potential benefit of proton therapy relative to other modalities of re-irradiation.

A systematic review of proton beam therapy for paranasal sinus and nasal cavity cancers (Patel, et al., 2014) concluded: "Compared with photon therapy, charged particle therapy could be associated with better outcomes for patients with malignant diseases of the nasal cavity and paranasal sinuses. Prospective studies emphasising collection of patient-reported and functional outcomes are strongly encouraged."

An assessment by the Australian & New Zealand Horizon Scanning Network (2013) on "Proton beam therapy for the treatment of neoplams involving (or adjacent to) cranial structures" stated: "To date, treatment-planning studies have concluded that proton beam therapy results in substantial dose-sparing to adjacent critical structures which may translate to lower toxicity and thus increased survival. Unfortunately, clinical studies have not consistently proven that proton beam therapy is significantly better compared to conventional photon therapy. The prevalence of proton radiation-induced side effects in the studies included in this assessment appears to be within the range expected for conventional photon therapy, with some studies inferring that proton therapy is substantially safer. However the lack of consistency across studies and the lack of direct comparative studies severely limit the conclusiveness of these results. Meanwhile, most included studies reported local tumour control rates which are similar to conventional photon radiotherapy as well. . . . In conclusion, the evidence for proton beam therapy in neoplasms involving, or adjacent to, cranial structures remains inconclusive. Further studies are required to determine if proton therapy is indeed substantially better compared to conventional radiotherapy, as inferred by numerous treatment-planning studies."

Guidelines on soft tissue sarcoma from the National Comprehensive Cancer Network (2020) indicate a potential role for proton therapy in retroperitoneal soft tissue sarcomas. The guidelines state: "Newer techniques such as intensity-modulated radiation therapy (IMRT) and 3D conformal therapy with protons or photons may allow tumor target coverage and acceptable clinical outcomes within normal tissue dose constraints to adjacent organs at risk. . . . However, the safety and efficacy of adjuvant RT techniques have yet to be evaluated in multicenter randomized controlled studies."

Given concerns of excess malignancies following adjuvant radiation for seminoma, Efstathiou et al (2012) evaluated photon beam therapy and PBRT treatment plans to assess dose distributions to organs at risk and model rates of second cancers.  A total of 10 stage I seminoma patients who were treated with conventional para-aortic AP-PA photon radiation to 25.5 Gy at Massachusetts General Hospital had PBRT plans generated (AP-PA, PA alone).  Dose differences to critical organs were examined.  Risks of second primary malignancies were calculated.  Proton beam radiotherapy plans were superior to photons in limiting dose to organs at risk; PBRT decreased dose by 46 % (8.2 Gy) and 64 % (10.2 Gy) to the stomach and large bowel, respectively (p < 0.01).  Notably, PBRT was found to avert 300 excess second cancers among 10,000 men treated at a median age of 39 and surviving to 75 (p < 0.01).  The authors concluded that in this study, the use of protons provided a favorable dose distribution with an ability to limit unnecessary exposure to critical normal structures in the treatment of early-stage seminoma.  It is expected that this will translate into decreased acute toxicity and reduced risk of second cancers, for which prospective studies are warranted.  

Proton beam radiotherapy has been used as therapeutic option for choroidal hemangiomas.  However, available evidence on its effectiveness for this indication is mainly in the form of retrospective reviews with small sample size and a lack of comparison to standard therapies.  

In a retrospective study, Hocht et al (2006) compared the results of therapy in patients with uveal hemangioma treated with photon or proton irradiation at a single center.  From 1993 to 2002, a total of 44 patients were treated.  Until 1998 radiotherapy was given with 6 MV photons in standard fractionation of 2.0 Gy 5 times per week.  In 1998 PBRT became available and was used since then.  A dose of 20 to 22.5 Cobalt Gray Equivalent (CGE; CGE = proton Gy x relative biological effectiveness 1.1) 68 MeV protons was given on 4 consecutive days.  Progressive symptoms or deterioration of vision were the indications for therapy.  Of the 44 patients treated, 36 had circumscribed choroidal hemangiomas (CCH) and 8 had diffuse choroidal hemangiomas (DCH) and Sturge-Weber syndrome.  Of the patients, 19 were treated with photons with a total dose in the range of 16 to 30 Gy.  A total of 25 patients were treated with PBRT.  All patients with DCH but 1 were treated with photons.  Stabilization of visual acuity was achieved in 93.2 % of all patients.  Tumor thickness decreased in 95.4 % and retinal detachment resolved in 92.9 %.  Late effects, although generally mild or moderate, were frequently detected.  In all, 40.9 % showed radiation-induced optic neuropathy, maximum Grade I.  Retinopathy was found in 29.5 % of cases, but only 1 patient experienced more than Grade II severity.  Retinopathy and radiation-induced optic neuropathy were reversible in some of the patients and in some resolved completely.  No differences could be detected between patients with CCH treated with protons and photons; treatment was less effective in DCH patients (75 %).  The authors concluded that radiotherapy is effective in treating choroidal hemangiomas with respect to visual acuity and tumor thickness; but a benefit of PBRT could not be detected.

In a retrospective review, Levy-Gabriel et al (2009) evaluated the long-term effectiveness and outcome of low-dose PBRT in the treatment of symptomatic CCH.  A total of 71 patients with symptomatic CCH were treated by PBRT between September 1994 and October 2002 using a total dose of 20 CGE.  The median follow-up was 52 months (range of 8 to 133 months).  Retinal re-attachment was obtained in all cases.  Tumor thickness decreased in all cases and a completely flat scar was obtained in 65 patients (91.5 %).  Visual acuity was improved by 2 lines or more in 37 of the 71 patients (52 %), and in 30 of the 40 patients (75 %) treated within 6 months after onset of the first symptoms.  The main radiation complications detected during follow-up were cataract (28 %) and radiation-induced maculopathy (8 %).  None of the 71 patients developed eyelid sequelae or neovascular glaucoma.  The authors concluded that PBRT with a total dose of 20 CGE appeared to be a valid treatment for CCH, inducing definitive retinal re-attachment and decreasing tumor thickness.  However, delayed radiation-induced maculopathy may occur.  A successful functional outcome is dependent on a short interval between onset of the first symptoms and initiation of therapy.

In a retrospective chart review, Chan et al (2010) described the clinical outcomes of patients (n = 19) with CCH and DCH treated by PBRT using a non-surgical light-field technique.  Choroidal hemangiomas were treated with PBRT using a light-field technique and doses ranging from 15 to 30 CGE in 4 fractions.  Patients with at least 6 months' follow-up were included in the study.  Tumor regression, visual acuity, absorption of sub-retinal fluid, and treatment-associated complications were evaluated by clinical examination and ultrasonography.  Visual acuity improved or remained stable in 14 of 18 eyes (78 %).  Sub-retinal fluid was initially present in 16 of 19 eyes (84 %), and completely resolved in all 16 eyes.  Tumor height, as measured by B-scan ultrasonography, decreased in 18 of 19 eyes and remained stable in 1 of 19, as of the last examination.  Complications of radiation developed in 9 of 19 eyes (47 %) with the total applied dose ranging from 15 to 30 CGE for these 9 eyes.  The authors concluded that PBRT using a light-field technique without surgical tumor localization is an effective treatment option in managing both CCH and DCH associated with Sturge-Weber syndrome.  A total proton dose as low as 15 CGE applied in 4 fractions appeared to be sufficient to reduce tumor size, promote absorption of sub-retinal fluid, and improve or stabilize vision in most patients.

Published studies of proton beam therapy for Hodgkin lymphoma are limited to dosimetric planning studies; there is a lack of published clinical outcome studies of proton beam therapy demonstrating improvements over photon therapy modalities. Guidelines on Hodgkin Lymphoma from the National Comprehensive Cancer Network (NCCN, 2020) state, in under the section Principles of Radiation Therapy, "Treatment with protons, electrons or photons may all be appropriate depending upon the clinical circumstances." Guidelines on radiation therapy for Hodgkin lymphoma from the International Lymphoma Radiation Oncology Group (2014) state: "The role of proton therapy has not yet been defined, and it is not widely available." American College of Radiology Appropriateness Criteria (2010) for adult Hodgkin lymphoma have no recommendation for proton beam therapy in Hodgkin lymphoma. European Society for Medical Oncology guidelines on Hodgkin disease (Eichenauer, et al., 2014) have no recommendation for proton beam therapy. Other international Hodgkin disease guidelines (British Committee for Standards in Haematology, 2014; BC Cancer Agency, 2013; Alberta Health Services, 2013) have no recommendation for proton beam radiation therapy. Guidelines on proton beam therapy from Alberta Health Services (2013) do not recommend proton beam therapy for lymphomas in adults "due to an insufficient evidence base." 

A technology assessment of proton beam therapy for the Washington State Health Care Authority (2014) found no comparative studies of proton beam therapy for lymphomas that met inclusion criteria for the systematic evidence review. The assessment concluded that the evidence for proton beam therapy for lymphomas was "insufficient" based on no evidence, and reported that their review of guidelines and coverage policies on proton beam found lymphoma was not recommended or not covered.

Meyer et al (2012) noted that chemotherapy plus radiation treatment is effective in controlling stage IA or IIA non-bulky Hodgkin's lymphoma in 90 % of patients but is associated with late treatment-related deaths.  Chemotherapy alone may improve survival because it is associated with fewer late deaths.  These researchers randomly assigned 405 patients with previously untreated stage IA or IIA non-bulky Hodgkin's lymphoma to treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone or to treatment with subtotal nodal radiation therapy, with or without ABVD therapy.  Patients in the ABVD-only group, those with a favorable risk profile as well as those with an unfavorable risk-profile, received 4 to 6 cycles of ABVD.  Among patients assigned to subtotal nodal radiation therapy, those who had a favorable risk-profile received subtotal nodal radiation therapy alone and those with an unfavorable risk-profile received 2 cycles of ABVD plus subtotal nodal radiation therapy.  The primary end-point was 12-year OS.  The median length of follow-up was 11.3 years.  At 12 years, the rate of OS was 94 % among those receiving ABVD alone, as compared with 87 % among those receiving subtotal nodal radiation therapy (hazard ratio [HR] for death with ABVD alone, 0.50; 95 % CI: 0.25 to 0.99; p = 0.04); the rates of freedom from disease progression were 87 % and 92 % in the 2 groups, respectively (HR for disease progression, 1.91; 95 % CI: 0.99 to 3.69; p = 0.05); and the rates of event-free survival were 85 % and 80 %, respectively (HR for event, 0.88; 95 % CI: 0.54 to 1.43; p = 0.60).  Among the patients randomly assigned to ABVD alone, 6 patients died from Hodgkin's lymphoma or an early treatment complication and 6 died from another cause; among those receiving radiation therapy, 4 deaths were related to Hodgkin's lymphoma or early toxic effects from the treatment and 20 were related to another cause.  The authors concluded that among patients with Hodgkin's lymphoma, ABVD therapy alone, as compared with treatment that included subtotal nodal radiation therapy, was associated with a higher rate of OS owing to a lower rate of death from other causes.  This study did not address the use of PBT for the treatment of Hodgkin lymphoma; in fact it argued against the combination use of chemo- and radiation-therapy.

An evidence review of proton beam therapy for adult lymphoma prepared for the UK National Health Service (2019) reached the following conclusions: "Three papers were submitted to the Clinical Panel as part of the policy proposition. One contained the findings from an observational trial, another reported long terms risks based on theoretical modelling of the outcome of different treatment scenarios and a third was a nonsystematic review of the use of proton therapy in lymphoma. Therefore, we were only able to consider findings from the observational trial in informing the policy decision. The Panel found no convincing evidence that demonstrated superiority of proton beam therapy over current standard treatment."

The European Society for Medical Oncology’s guidelines on biliary cancers (Eckel et al, 2011) made no recommendation regarding the use of PBT in the treatment of cholangiocarcinoma.  Furthermore, NCCN guidelines on "Hepatobiliary cancers" (Version 5.2020) made no recommendation for use PBT in cholangiocarcinoma.

Dermatofibrosarcoma protuberans is an uncommon tumor that arises in the skin.  The tumor is firm and often flesh-colored although it can be reddish, bluish, or purplish.  The tumor is often found on the chest or shoulders, but it can be found on other parts of the body.  Dermatofibrosarcoma protuberans may cause no symptoms, and the initial size of the tumor tends to be around 1 to 5 centimeters.  This tumor has a low potential to spread to other tissues (metastasize).  Treatment often involves surgery to remove the tumor, such as by Mohs’ micrographic surgery. Moreover, NCCN’s clinical practice guideline on "Dermatofibrosarcoma protuberans" (Version 1.2020) does not mention proton or neutron beam therapy as a therapeutic option.

Amsbaugh (2012) reported acute toxicities and preliminary outcomes for pediatric patients with ependymomas of the spine treated with proton beam therapy at the MD Anderson Cancer Center.  A total of 8 pediatric patients received proton beam irradiation between October 2006 and September 2010 for spinal ependymomas.  Toxicity data were collected weekly during radiation therapy and all follow-up visits.  Toxicities were graded according to the Common Terminology Criteria for Adverse Events version 3.0.  All patients had surgical resection of the tumor before irradiation (7 subtotal resection and 1 gross total resection).  Six patients had World Health Organization Grade I ependymomas, and 2 had World Health Organization Grade II ependymomas.  Patients had up to 3 surgical interventions before radiation therapy (range of 1 to 3; median, 1).  Three patients received proton therapy after recurrence and 5 as part of their primary management.  The entire vertebral body was treated in all but 2 patients.  The mean radiation dose was 51.1 cobalt gray equivalents (range of 45 to 54 cobalt gray equivalents).  With a mean follow-up of 26 months from the radiation therapy start date (range of 7 to 51 months), local control, event-free survival, and overall survival rates were all 100 %.  The most common toxicities during treatment were Grade 1 or 2 erythema (75 %) and Grade 1 fatigue (38 %).  No patients had a Grade 3 or higher adverse event.  Proton therapy dramatically reduced dose to all normal tissues anterior to the vertebral bodies in comparison to photon therapy.  The authors concluded that preliminary outcomes showed the expected control rates with favorable acute toxicity profiles.  They noted that proton beam therapy offers a powerful treatment option in the pediatric population, where adverse events related to radiation exposure are of concern.  Moreover, they stated that extended follow-up will be required to assess for late recurrences and long-term adverse effects.

Greenberger et al (2014) reported their experience with pediatric patients treated with PBT.  A total of 32 pediatric patients with low-grade gliomas of the brain or spinal cord were treated with PBT from 1995 to 2007; 16 patients received at least 1 regimen of chemotherapy before definitive radiotherapy (RT).  The median radiation dose was 52.2 Gy relative biological effectiveness (RBE) (48.6 to 54 GyRBE).  The median age at treatment was 11.0 years (range of 2.7 to 21.5 years), with a median follow-up time of 7.6 years (range of 3.2 to 18.2 years).  The 6-year and 8-year rates of progression-free survival were 89.7 % and 82.8 %, respectively, with an 8-year overall survival of 100 %.  For the subset of patients who received serial neurocognitive testing, there were no significant declines in Full-Scale Intelligence Quotient (p = 0.80), with a median neurocognitive testing interval of 4.5 years (range of 1.2 to 8.1 years) from baseline to follow-up, but subgroup analysis indicated some significant decline in neurocognitive outcomes for young children (less than 7 years) and those with significant dose to the left temporal lobe/hippocampus.  The incidence of endocrinopathy correlated with a mean dose of greater than or equal to 40 GyRBE to the hypothalamus, pituitary, or optic chiasm.  Stabilization or improvement of visual acuity was achieved in 83.3 % of patients at risk for radiation-induced injury to the optic pathways.  The authors concluded that this report of late effects in children with low-grade gliomas after PBT is encouraging.  Proton beam therapy appears to be associated with good clinical outcome, especially when the tumor location allows for increased sparing of the left temporal lobe, hippocampus, and hypothalamic-pituitary axis.  The authors also stated that larger cohorts are likely needed to enable accurate assessment of the incidence of moyamoya disease after PBT.

Li et al (2011) stated that the papillary tumor of the pineal region (PTPR) is a distinct entity that is particularly rare in the pediatric population.  The authors documented the youngest reported patient with this clinicopathological entity to date.  These researchers described the case of PTPR in a 15-month old boy.  Initially thought to be a tectal glioma, the tumor was later identified as a pineal region tumor after demonstrating growth on routine imaging.  Diagnosis of PTPR was established by histopathological evaluation of biopsy samples, which revealed papillary, cystic, and solid tumor components.  The patient's post-operative course was complicated by tumor growth despite several debulking procedures and chemotherapy, as well as persistent hydrocephalus requiring 2 endoscopic third ventriculostomies and eventual ventriculo-peritoneal shunt placement.  After a 15-month follow-up period, the patient has received proton-beam therapy (PBT) and has a stable tumor size.  The PTPR is a recently described tumor of the CNS that must be included in the differential diagnosis of pineal region masses.  The biological behavior, prognosis, and appropriate treatment of PTPR have yet to be fully defined.

Clivio et al (2013) evaluated intensity modulated proton therapy (IMPT) in patients with cervical cancer in terms of coverage, conformity, and DVH parameters correlated with recommendations from magnetic resonance imaging (MRI)-guided brachytherapy.  A total of 11 patients with histologically proven cervical cancer underwent primary chemo-radiation for the pelvic lymph nodes, the uterus, the cervix, and the parametric region, with a symmetric margin of 1 cm.  The prescription was for 50.4 Gy, with 1.8 Gy per fraction.  The prescribed dose to the parametria was 2.12 Gy up to 59.36 Gy in 28 fractions as a simultaneous boost.  For several reasons, the patients were unable to undergo brachytherapy.  As an alternative, IMPT was planned with 5 fractions of 6 Gy to the cervix, including the macroscopic tumor with an MRI-guided target definition, with an isotropic margin of 5 mm for PTV definition.  Groupe-Europeen de Curietherapie and European society for Radiotherapy and Oncology (GEC-ESTRO) criteria were used for DVH evaluation.  Reference comparison plans were optimized for volumetric modulated rapid arc (VMAT) therapy with the RapidArc (RA).  The dose to the high-risk volume was calculated with α/β = 10 with 89.6 Gy.  For IMPT, the clinical target volume showed a mean dose of 38.2 ± 5.0 Gy (35.0 ± 1.8 Gy for RA).  The D98% was 31.9 ± 2.6 Gy (RA: 30.8 ± 1.0 Gy).  With regard to the organs at risk, the 2Gy Equivalent Dose (EQD2) (α/β = 3) to 2 cm(3) of the rectal wall, sigmoid wall, and bladder wall was 62.2 ± 6.4 Gy, 57.8 ± 6.1 Gy, and 80.6 ± 8.7 Gy (for RA: 75.3 ± 6.1 Gy, 66.9 ± 6.9 Gy, and 89.0 ± 7.2 Gy, respectively).  For the IMPT boost plans in combination with external beam radiation therapy, all DVH parameters correlated with less than 5 % risk for grades 2 to 4 late gastro-intestinal and genitourinary toxicity.  The authors concluded that in patients who are not eligible for brachytherapy, IMPT as a boost technique additionally to external beam radiation therapy provides good target coverage and conformity and superior DVH parameters, compared with recommendations to MRI-guided brachytherapy.  They stated that for selected patients, IMPT might be a valid alternative to brachytherapy and also superior to reference VMAT plans.  (These preliminary findings from a small study [n = 11] need to be validated by well-designed studies).

Moreover, the National Comprehensive Cancer Network’s clinical practice guideline on "Uterine neoplasms" (Version 2.2020) does not list proton beam therapy as a therapeutic option.

Hemangioendothelioma

Hemangioendothelioma refers to a group of vascular neoplasms that may be considered benign as well as malignant, depending on the specific group member's activity.  The primary treatment of intra-cranial hemangioendothelioma is surgical excision.  Although some have advocated adjuvant radiotherapy or chemotherapy, there is insufficient evidence on the use of PBT for hemangioendotheliomas.  The "Consensus-derived practice standards plan for complicated Kaposiform hemangioendothelioma" (Drolet et al, 2013) had no recommendation for PBT.

Mesothelioma

Cao and colleagues (2014) noted that IMPT is commonly delivered via the spot-scanning technique.  To "scan" the target volume, the proton beam is controlled by varying its energy to penetrate the patient's body at different depths.  Although scanning the proton beamlets or spots with the same energy can be as fast as 10 to 20 m s(-1), changing from one proton energy to another requires approximately 2 additional seconds.  The total IMPT delivery time thus depends mainly on the number of proton energies used in a treatment.  Current treatment planning systems typically use all proton energies that are required for the proton beam to penetrate in a range from the distal edge to the proximal edge of the target.  The optimal selection of proton energies has not been well-studied.  In this study, these researchers sought to determine the feasibility of optimizing and reducing the number of proton energies in IMPT planning.  They proposed an iterative mixed-integer programming optimization method to select a subset of all available proton energies while satisfying dosimetric criteria.  They applied their proposed method to 6 patient datasets: 4 cases of prostate cancer, 1 case of lung cancer, and 1 case of mesothelioma.  The numbers of energies were reduced by 14.3 % to 18.9% for the prostate cancer cases, 11.0 % for the lung cancer cases and 26.5 % for the mesothelioma case.  The results indicated that the number of proton energies used in conventionally designed IMPT plans can be reduced without degrading dosimetric performance.  The IMPT delivery efficiency could be improved by energy layer optimization leading to increased throughput for a busy proton center in which a delivery system with slow energy switch is employed.  This was a small (n = 6; 1 case of mesothelioma) feasibility study; it did not provide any data regarding the effectiveness of PBRT for the treatment of mesothelioma.

In a case-series study, Pan et al (2015) described their experience implementing IMPT for lung-intact malignant pleural mesothelioma (MPM), including patient selection, treatment planning, dose verification, and process optimization.  A total of 7 patients with epithelioid MPM were reviewed; 6 underwent pleurectomy, whereas 1 had biopsy alone.  Four patients received IMPT and 3 received intensity modulated radiation therapy.  Treatment plans for the other modality were created for dosimetric comparisons.  Quality assurance processes included dose verification and robustness analysis.  Image-guided set-up was performed with the first isocenter, and couch shifts were applied to reposition to the second isocenter.  Treatment with IMPT was well-tolerated and completed without breaks.  IMPT plans were designed with 2 isocenters, 4 beams, and ≤64 energy layers per beam.  Dose verification processes were completed in 3 hours.  Total daily treatment time was approximately 45 minutes (20 minutes for set-up and 25 minutes for delivery).  IMPT produced lower mean doses to the contralateral lung, heart, esophagus, liver, and ipsilateral kidney, with increased contralateral lung sparing when mediastinal boost was required for nodal disease.  The authors concluded that their initial experience showed that IMPT was feasible for routine care of patients with lung-intact MPM.  This was a small (n = 4) feasibility study; it did not provide any data regarding the effectiveness of PBRT for the treatment of mesothelioma.

Retroperitoneal/Pelvic Sarcoma

Kelly et al (2015) compared outcomes of patients with retroperitoneal or pelvic sarcoma treated with peri-operative (RT versus those treated without peri-operative RT.  Prospectively maintained databases were reviewed to retrospectively compare patients with primary retroperitoneal or pelvic sarcoma treated during 2003 to 2011.  Multivariate Cox regression models were used to assess associations with the primary end-points: local recurrence-free survival (LRFS) and disease-specific survival.  At 1 institution, 172 patients were treated with surgery alone, whereas at another institution 32 patients were treated with surgery and peri-operative PBRT or IMRT with or without intra-operative RT.  The groups were similar in age, tumor size, grade, and margin status (all p > 0.08).  The RT group had a higher percentage of pelvic tumors (p = 0.03) and a different distribution of histologies (p = 0.04).  Peri-operative morbidity was higher in the RT group (44 % versus 16 % of patients; p = 0.004).  After a median follow-up of 39 months, 5-year LRFS was 91 % (95 % CI: 79 % to 100 %) in the RT group and 65 % (57 % to 74 %) in the surgery-only group (p = 0.02).  On multivariate analysis, RT was associated with better LRFS (HR, 0.26; p = 0.03); 5-year disease-specific survival was 93 % (95 % CI: 82 % to 100 %) in the RT group and 85 % (78 % to 92 %) in the surgery-only group (p = 0.3).  The authors concluded that the addition of advanced-modality RT to surgery for primary retroperitoneal or pelvic sarcoma was associated with improved LRFS, although this did not translate into significantly better disease-specific survival.  They stated that this treatment strategy warrants further investigation in a randomized trial.

Choroidal Melanoma

In a retrospective review, Patel and colleagues (2016) reported visual outcomes in patients undergoing PBRT of tumors located within 1 disc diameter of the fovea.  Patients with choroidal melanoma involving the fovea treated with proton beam therapy between 1975 and 2009 were included in this analysis.  A total of 351 patients with choroidal melanomas located 1 disc diameter (DD) or less from the fovea and more than 1 DD away from the optic nerve were included in this study.  In a subgroup of 203 of the patients with small and medium choroidal melanomas, the effect of a reduced dose of radiation, 50 Gy (relative biological effectiveness [RBE]) versus 70 Gy (RBE), on visual outcomes was analyzed.  The Kaplan-Meier method and Cox regression analysis were performed to calculate cumulative rates of vision loss and to assess risk factors for vision loss, respectively.  Visual acuity (VA) and radiation complications, which included radiation maculopathy, papillopathy, retinal detachment, and rubeosis, were assessed.  This study had a mean follow-up time of 68.7 months.  More than 1/3 of patients (35.5 %) retained 20/200 or better vision 5 years after PBRT.  For those patients with a baseline VA of 20/40 or better, 16.2 % of patients retained this level of vision 5 years after PBRT.  Tumor height less than 5 mm and baseline VA 20/40 or better were associated significantly with a better visual outcome (p < 0.001).  More than 2/3 (70.4 %) of patients receiving 50 Gy (RBE) and nearly half (45.1 %) of patients receiving 70 Gy (RBE) retained 20/200 or better vision 5 years after treatment, but this difference was not significant.  Approximately 20 % of patients with these smaller macular tumors retained 20/40 vision or better 5 years after irradiation.  The authors concluded that the results of this retrospective analysis demonstrated that despite receiving a full dose of radiation to the fovea, many patients with choroidal melanoma with foveal involvement maintain useful vision.  A radiation dose reduction from 70 to 50 Gy (RBE) did not appear to increase the proportion of patients who retain usable vision.  The major drawbacks of this study were:

1. its retrospective design, and
2. despite decreasing the risk of coincidental maculopathy and papillopathy by choosing tumors more than 1 DD away from the optic nerve, there is still a definite overlap in the incidence of maculopathy and papillopathy  occurring in these patients. 

These researchers were unable to distinguish whether the cause of vision loss in individual patient  was the result of radiation effects on the macula or the optic nerve.  The authors stated that further elucidation of factors that distinguish the small minority of patients able to retain excellent vision is needed for future improvement of visual outcomes.

Multiple Myeloma

National Comprehensive Cancer Network’s clinical practice guideline on "Multiple myeloma" (Version 2.2021) does not mention proton beam therapy as a therapeutic option.

Thymic Tumor

Vogel et al (2016) stated that radiation is an important modality in treatment of thymic tumors.  However, toxicity may reduce its overall benefit.  These researchers hypothesized that double-scattering proton beam therapy (DS-PT) can achieve excellent local control with limited toxicity in patients with thymic malignancies.  Patients with thymoma or thymic carcinoma treated with DS-PT between 2011 and 2015 were prospectively analyzed for toxicity and patterns of failure on an institutional review board (IRB)-approved study.  A total of 27 consecutive patients were evaluated.  Patients were a median of 56 years and had thymoma (85 %).  They were treated with definitive (22 %), salvage (15 %) or adjuvant (63 %) DS-PT to a median of 61.2/1.8 Gy [CGE].  No patient experienced grade greater than or equal to 3 toxicity.  Acute grade 2 toxicities included dermatitis (37 %), fatigue (11 %), esophagitis (7 %), and pneumonitis (4 %).  Late grade 2 toxicity was limited to 1 patient with chronic dyspnea.  At a median follow-up of 2 years, 100 % local control was achieved; 3-year regional control, distant control, and overall survival (OS) rates were 96 % (95 % confidence interval [CI]: 76 to 99 %), 74 % (95 % CI: 41 to 90 %), and 94 % (95 % CI: 63 to 99 %), respectively.  The authors concluded that this was the first cohort and prospective series of proton therapy to treat thymic tumors, demonstrating low rates of early toxicity and excellent initial outcomes.

Parikh et al (2016) evaluated the dosimetric differences between proton beam therapy (PBT) and intensity modulated radiation therapy (IMRT) for resected thymoma.  These investigators simultaneously reported their early clinical experience with PBT in this cohort.  These researchers identified 4 patients with thymoma or thymic carcinoma treated at their center from 2012 to 2014 who completed adjuvant PBT to a median dose of 57.0 cobalt Gy equivalents (CGE; range of 50.4 to 66.6 CGE) after definitive resection.  Adjuvant radiation was indicated for positive (n = 3) or close margin (n = 1).  Median age was 45 (range of 32 to 70) years.  Stages included II (n = 2), III (n = 1), and IVA (n = 1).  Analogous IMRT plans were generated for each patient for comparison, and pre-set dosimetric end-points were evaluated.  Early toxicities were assessed according to retrospective chart review.  Compared with IMRT, PBT was associated with lower mean doses to the lung (4.6 versus 8.1 Gy; p = 0.02), esophagus (5.4 versus 20.6 Gy; p = 0.003), and heart (6.0 versus 10.4 Gy; p = 0.007).  Percentages of lung, esophagus, and heart receiving radiation were consistently lower in the PBT plans over a wide range of radiation doses.  There was no difference in mean breast dose (2.68 versus 3.01 Gy; p = 0.37).  Of the 4 patients treated with PBT, 3 patients experienced grade 1 radiation dermatitis, and 1 patient experienced grade 2 dermatitis, which resolved after treatment.  With a median follow-up of 5.5 months, there were no additional grade greater than or equal to 2 acute or sub-acute toxicities, including radiation pneumonitis.  The authors concluded that PBT is clinically well-tolerated after surgical resection of thymoma, and was associated with a significant reduction in dose to critical structures without compromising coverage of the target volume.  Moreover, they stated that prospective evaluation and longer follow-up is needed to assess clinical outcomes and late toxicities.

National Comprehensive Cancer Network’s clinical practice guideline on "Thymomas and thymic carcinomas" (Version 1.2020) states that proton beam therapy may be considered in certain circumstances.

Yolk Cell Tumor

Park et al (2015) performed dosimetric comparisons between proton beam therapy and intensity modulated radiotherapy (IMRT) of intra-cranial germ cell tumors (ICGCTs) arising in various locations of the brain.  IMRT, passively scattered proton therapy (PSPT), and spot scanning proton therapy (SSPT) plans were performed for 4 different target volumes:

1. the whole ventricle (WV),
2. pineal gland (PG),
3. supra-sellar (SS), and
4. basal ganglia (BG);

5 consecutive clinical cases were selected from the patients treated between 2011 and 2014 for each target volume.  A total 20 cases from the 17 patients were included in the analyses with 3 overlap cases which were used in plan comparison both for the whole ventricle and boost targets.  The conformity index, homogeneity index, gradient index, plan quality index (PQI), and doses applied to the normal substructures of the brain were calculated for each treatment plan.  The PQI was significantly superior for PSPT and SSPT than IMRT for ICGCTs in all locations (median; WV: 2.89 and 2.37 versus 4.06, PG: 3.38 and 2.70 versus 4.39, SS: 3.92 and 2.49 versus 4.46, BG: 3.01 and 2.49 versus 4.45).  PSPT and SSPT significantly reduced the mean dose, and the 10 and 15 Gy dose volumes applied to the normal brain compared with IMRT (p ≤ 0.05).  PSPT and SSPT saved significantly greater volumes of the temporal lobes and hippocampi (p < 0.05) in the SS and PG targets than IMRT.  For tumors arising in the BG, PSPT and SSPT also saved greater volumes of the contralateral temporal lobes.  The authors concluded that PSPT and SSPT provided superior target volume coverage and saved more normal tissue compared with IMRT for ICGCTs in various locations.  Moreover, they stated that future studies should examine if the extent of normal tissue saved has clinical benefits in children with ICGCTs.

Atypical Meningioma

An UpToDate review on "Management of atypical and malignant (World Health Organization [WHO] grade II and III) meningioma" (Shih and Park. 2018) states that "Complete surgical resection is generally difficult to achieve for malignant and atypical meningiomas, and partially resected tumors have a high rate of local recurrence as well as increased disease-specific mortality.  Adjuvant radiation therapy (RT) is a standard component of initial therapy in patients with malignant meningiomas and subtotally resected atypical meningiomas in an effort to improve local control.  For patients with atypical meningioma who undergo apparent gross total resection, the role of adjuvant radiation is less clear … Newer RT techniques that have been used in small series include stereotactic radiosurgery, hypofractionated stereotactic RT, and heavy particle irradiation (proton beam, carbon ion).  No single approach has been shown to be superior to others, but they all reflect advances in conformal techniques".

Sacral Chordoma

Takahashi et al (2010) noted that sacral chordomas constitute more than 50 % of all chordomas and have a slower local growth than other bone malignant tumors.  Although complete radical resection produces a longer local control and disease-free survival (DFS) at the initial visit, chordomas are already often too large for complete resection to be possible.  Particle radiotherapy consisting of proton and carbon-ion is a promising new modality that has an inherent anti-tumor effect against many types of malignancies.  However, the application of particle radiotherapy for tumors adjacent to the gastro-intestinal tract like sacral chordoma is restricted because the tolerance dose of the intestine is extremely low.  A novel 2-step treatment was developed with surgical spacer placement and subsequent proton radiotherapy to administer particle radiotherapy with curative intent.  This report presented a case of a patient with a huge sacral chordoma treated by this method.  The authors concluded that this new strategy may potentially be an innovative and standard therapy for unresectable sacral chordoma in the near future.

Mima et al (2014) retrospectively evaluated the effectiveness and toxicity of particle therapy using carbon ions or protons for primary sacral chordomas.  These investigators evaluated 23 patients with primary sacral chordoma treated with carbon ion therapy (CIT) or proton therapy (PT) between July 2005 and June 2011 at the Hyogo Ion Beam Medical Center, Hyogo, Japan.  The median patient age was 72 years. 14 patients were treated with 70.4 Gy equivalents (GyE) in 16 fractions and 9 were treated with 70.4 GyE in 32 fractions.  CIT was used for 16 patients, and PT was used for 7 patients.  The median follow-up period was 38 months.  At 3 years, local control (LC), overall survival (OS) and progression-free survival (PFS) for all patients were 94 %, 83 % and 68 %, respectively.  The log-rank test revealed that male sex was significantly related to better PFS (p = 0.029).  No other factors, including dose fractionation and ion type, were significant for LC, OS or PFS.  In 9 patients, greater than or equal to Grade 3 acute dermatitis was observed, and greater than or equal to Grade 3 late toxicities were observed in 9 patients.  The 32-fraction protocol reduced severe toxicities in both the acute and late phases compared with the 16-fraction protocol.  The authors concluded that particle therapy for patients with sacral chordoma showed favorable LC and OS.  Severe toxicities were successfully reduced by modifying the dose fractionation and treatment planning in the later treatment era.  They stated that this therapeutic modality should be considered useful and safe.  This study had several drawbacks.  This study was retrospective, and the statistical power was low.  The number of patients was small (23 patients; and only 7 patients received proton beam therapy).  The follow-up period was relatively short (median of 38 months).  The authors noted that they continued recruiting and observing patients and reported these follow-up data.  They stated that no conclusions about the clinical merit of PT or CIT can be drawn from this study; dosimetric comparisons with IMRT would be needed; the recruitment of greater numbers of patients with a longer follow-up period is needed.

Yu and colleagues (2016) noted that sacral chordomas represent 50 % of all chordomas, a rare neoplasm of notochordal remnants.  Current NCCN guidelines recommend surgical resection with or without adjuvant radiotherapy or definitive radiation for unresectable cases.  Recent advances in radiation for chordomas include conformal photon and proton beam radiation.  These investigators examined the incidence, treatment, and survival outcomes to observe any trends in response to improvements in surgical and radiation techniques over a near 40-year time period.  A total of 345 microscopically confirmed cases of sacral chordoma were identified between 1974 and 2011 from the surveillance, epidemiology, and end results program of the National Cancer Institute.  Cases were divided into three cohorts by calendar year, 1974 to 1989, 1990 to 1999, and 2000 to 2011, as well as into 2 groups by age less than or equal to 65 versus greater than 65 to investigate trends over time and age via Chi-square analysis.  Kaplan-Meier analyses were performed to determine effects of treatment on survival.  Multi-variate Cox regression analysis was performed to determine predictors of OS.  Five-year OS for the entire cohort was 60.0 %; OS correlated significantly with treatment modality, with 44 % surviving at 5 years with no treatment, 52 % with radiation alone, 82 % surgery alone, and 78 % surgery and radiation (p < 0.001).  Age greater than 65 was significantly associated with non-surgical management with radiation alone or no treatment (p < 0.001).  Relatively, fewer patients received radiation between 2000 and 2011 compared to prior time periods (p = 0.03) versus surgery, for which rates which did not vary significantly over time (p = 0.55).  However, 5-year OS was not significantly different by time period.  Age group and treatment modality were predictive for OS on multivariate analysis (p < 0.001).  The authors concluded that surgery remains an important component in the treatment of sacral chordomas in current practice.  Fewer patients were treated with radiation more recently despite advances in photon and proton beam radiation; OS remains unchanged.  They stated that additional analyses of margin status, radiation modality, and local control in current practice are needed.

Demizu and associates (2017) conducted a retrospective, nationwide multi-center study to evaluate the clinical outcomes of PBT for bone sarcomas of the skull base and spine in Japan.  Eligibility criteria included histologically proven bone sarcomas of the skull base or spine; (no metastases; greater than or equal to 20 years of age; and no prior treatment with radiotherapy.  Of the 103 patients treated between January 2004 and January 2012, these researchers retrospectively analyzed data from 96 patients who were followed-up for greater than 6 months or had died within 6 months.  A total of 72 patients (75.0 %) had chordoma, 20 patients (20.8 %) had chondrosarcoma, and 4 patients (7.2 %) had osteosarcoma.  The most frequent tumor locations included the skull base in 68 patients (70.8 %) and the sacral spine in 13 patients (13.5 %).  Patients received a median total dose of 70.0 Gy (relative biological effectiveness).  The median follow-up was 52.6 (range of 6.3 to 131.9) months.  The 5-year OS, progression-free survival (PFS), and local control rates were 75.3 %, 49.6 %, and 71.1 %, respectively.  Performance status was a significant factor for OS and PFS, while sex was a significant factor for local control.  Acute grade-3 and late toxicities of greater than or equal to grade-3 were observed in 9 patients (9.4 %) each (late grade-4 toxicities [n = 3 patients; 3.1 %]).  No treatment-related deaths occurred.  The authors concluded that PBT was safe and effective for the treatment of bone sarcomas of the skull base and spine in Japan; however, larger prospective studies with a longer follow-up are needed to validate these findings.  This study had several drawbacks.  The foremost were its retrospective design and the relatively low impact of the statistical analyses.  The follow‐up period was relatively short (median of 52.6 months) and the major histological subtypes (chordoma and CS) in this study were slow growing with the potential for recurrence 5 years post‐PBT.

Furthermore, an UpToDate review on "Spinal cord tumors" (Welch et al, 2018) states that "Newer radiation therapy techniques, including stereotactic radiosurgery and charged particle irradiation (e.g., protons, carbon ions), have been used to target the bone lesion while reducing the radiation exposure to the surrounding nerve roots and the cauda equina.  Even for patients with unresectable spine and sacral chordomas, high-dose definitive radiation therapy using advanced techniques may achieve durable local control and disease-free survival in a subset of patients".

Central Nervous System Tumors

Shih and colleagues (2015) evaluated potential treatment toxicity and PFS in patients with low-grade glioma who received treatment with PBRT.  A total of 20 patients with WHO grade-2 glioma who were eligible for radiation therapy were enrolled in a prospective, single-arm trial of proton therapy.  Subjects received PBRT at a dose of 54 Gy (RBE) in 30 fractions.  Comprehensive baseline and regular post-treatment evaluations of neurocognitive function, neuroendocrine function, and quality of life (QOL) were performed.  All 20 patients (median age of 37.5 years) tolerated treatment without difficulty.  The median follow-up after PBRT was 5.1 years.  At baseline, intellectual functioning was within the normal range for the group and remained stable over time.  Visuospatial ability, attention/working memory, and executive functioning also were within normal limits; however, baseline neurocognitive impairments were observed in language, memory, and processing speed in 8 patients.  There was no overall decline in cognitive functioning over time.  New endocrine dysfunction was detected in 6 patients, and all but 1 had received direct irradiation of the hypothalamic-pituitary axis; QOL assessment revealed no changes over time.  The PFS rate at 3 years was 85 %, but it dropped to 40 % at 5 years.  The authors concluded that patients with low-grade glioma tolerated PBRT well, and a subset developed neuroendocrine deficiencies.  There was no evidence for overall decline in cognitive function or QOL.  The authors noted that "An obvious limitation in their study is the lack of randomization of patients between proton versus photon therapy.  The utility of this study relies on the ability to place our data in context with other investigations.  We used commonly accepted indications for radiation therapy and radiation dose schedules to minimize potential sources of differences in our outcomes.  Our study includes a relatively small number of patients.  Further investigation would benefit from a multicenter approach to achieve increased patient numbers.  Our results with proton therapy demonstrate feasibility of delivery, preservation of cognitive function, and maintenance of QOL.  Larger studies that include the integration of standardized, contemporary chemotherapy regimens with randomization of proton versus photon therapy would be useful to further characterize potential differences in radiation late effects, such as effects on neuroendocrine function".

Yock et al (2016) stated that compared with traditional photon radiotherapy, PRT irradiates less normal tissue and might improve health outcomes associated with photon radiotherapy by reducing toxic effects to normal tissue.  In a non-randomized, open-label, single-center, phase-II clinical trial, these researchers evaluated late complications, acute side-effects, and survival associated with PRT in children with medulloblastoma.  They enrolled patients aged 3 to 21 years who had medulloblastoma.  Patients had cranio-spinal irradiation of 18 to 36 Gy radiobiological equivalents (GyRBE) delivered at 1.8 GyRBE per fraction followed by a boost dose.  The primary outcome was cumulative incidence of ototoxicity at 3 years, graded with the Pediatric Oncology Group ototoxicity scale (0 to 4), in the intention-to-treat (ITT) population.  Secondary outcomes were neuroendocrine toxic effects and neurocognitive toxic effects, assessed by ITT.  These investigators enrolled 59 patients from May 20, 2003, to December 10, 2009: 39 with standard-risk disease, 6 with intermediate-risk disease, and 14 with high-risk disease; 59 patients received chemotherapy.  Median follow-up of survivors was 7.0 years (inter-quartile range [IQR] 5.2 to 8.6).  All patients received the intended doses of PRT.  The median cranio-spinal irradiation dose was 23.4 GyRBE (IQR 23.4 to 27.0) and median boost dose was 54.0 GyRBE (IQR 54.0 to 54·0); 4 (9 %) of 45 evaluable patients had grade 3 to 4 ototoxicity according to Pediatric Oncology Group ototoxicity scale in both ears at follow-up, and 3 (7 %) of 45 patients developed grade 3 to 4 ototoxicity in 1 ear, although 1 later reverted to grade 2.  The cumulative incidence of grade 3 to 4 hearing loss at 3 years was 12 % (95 % CI: 4 to 25).  At 5 years, it was 16 % (95 % CI: 6 to 29).  Pediatric Oncology Group hearing ototoxicity score at a follow-up of 5.0 years (IQR 2.9 to 6.4) was the same as at baseline or improved by 1 point in 34 (35 %) of 98 ears, worsened by 1 point in 21 (21 %), worsened by 2 points in 35 (36 %), worsened by 3 points in 6 (6 %), and worsened by 4 points in 2 (2 %).  Full Scale Intelligence Quotient decreased by 1.5 points (95 % CI: 0.9 to 2.1) per year after median follow-up up of 5.2 years (IQR 2.6 to 6·4), driven by decrements in processing speed and verbal comprehension index.  Perceptual reasoning index and working memory did not change significantly.  Cumulative incidence of any neuroendocrine deficit at 5 years was 55 % (95 % CI: 41 to 67), with growth hormone deficit being most common.  These researchers recorded no cardiac, pulmonary, or gastro-intestinal (GI) late toxic effects; 3-year progression-free survival (PFS) was 83 % (95 % CI: 71 to 90) for all patients.  In post-hoc analyses, 5-year PFS was 80 % (95 % CI: 67 to 88) and 5-year overall survival (OS) was 83 % (95 % CI: 70 to 90).  The authors concluded that PRT resulted in acceptable toxicity and had similar survival outcomes to those noted with conventional radiotherapy, suggesting that the use of the treatment may be an alternative to photon-based treatments.

English and colleagues (2016) congratulated Yock et al (2016) on their publication describing the outcomes of patients following proton radiotherapy (PRT) for medulloblastoma.  These investigators agreed that toxic effects were acceptable, and survival outcomes were similar to published results for conventional radiotherapy.  Indeed, the reported survival outcomes were identical to the recent larger European trial, PNET 4.  The gold standard treatment for standard risk medulloblastoma in Europe is the standard arm from the PNET 4 trial, with post-surgical radiotherapy and chemotherapy.  Results of PNET 4 showed a significant reduction in survival if time to radiotherapy was delayed, with a 5 year event-free survival (EFS) of 0.67 % (SD 0·009) for patients with a treatment delay of more than 49 days, and 0.81 (SD 0.02) for those treated more promptly.  The target for all patients is to begin therapy within 28 days.  It is crucial to take this into account when planning the adjuvant treatment of any child with medulloblastoma, balancing the potential benefits of PRT with the known risks of treatment delay.  Given the availability of proton therapy in many countries, the reported median delay of 30 days could be challenging for many to achieve.  The authors' statement, "other late effects common in photon-treated patients, such as cardiac, pulmonary and gastrointestinal toxic effects were absent", is somewhat premature, as it will take 20 years to confirm or refute the authors' conclusions in this respect.  English et al (2016) stated that "We must also be explicit that omission or reduction of chemotherapy after administration of proton beam radiotherapy is likely to substantially reduce the likelihood of cure in this group of patients, as there is no expectation that proton beam radiotherapy increases the chance of cure compared with conventional treatment with photons.  Ideally, a randomized clinical trial between conventional and proton beam radiotherapy would be done, but it has not, and it is now neither realistic nor appropriate for such a trial to take place.  Therefore, case-control and historical comparison studies must be performed.  Key challenges in the care of children with medulloblastoma are: to avoid delayed diagnosis, to avoid morbidity from prolonged hydrocephalus and neurological damage developing before surgery; to minimize surgical morbidity and complications such as posterior fossa syndrome; to coordinate care so that radiotherapy treatment is started within 4 weeks of surgery, unless a neoadjuvant chemotherapy approach is used; to provide active neuro-rehabilitation from the time of diagnosis, specifically targeted to needs identified after neuropsychological evaluation; and to collect data and monitor late effects systematically.  In the UK, patients with medulloblastoma will be offered proton beam therapy when it is available in the NHS centers in Manchester and London.  The UK is ideally positioned to extend the single center work reported by Yock and colleagues to a national cohort of patients with medulloblastoma treated with proton beam radiotherapy 2018-9.  Work should begin to collect morbidity and mortality data on all UK patients with medulloblastoma to optimize future management of the most common childhood malignant brain tumor.  Looking to the future, we need to continue this quest for more effective and less damaging treatments, to improve survival and the quality of that survival. 

Eaton et al (2016) noted that endocrine dysfunction is a common sequela of cranio-spinal irradiation (CSI).  Dosimetric data suggested that PRT may reduce radiation-associated endocrine dysfunction but clinical data are limited.  In this study, a total of 77 children were treated with chemotherapy and proton (n = 40) or photon (n = 37) radiation between 2000 and 2009 with greater than or equal to 3 years of endocrine screening.  The incidence of multiple endocrinopathies among the proton and photon cohorts was compared.  Multi-variable analysis and propensity score adjusted analysis were performed to estimate the effect of radiotherapy type while adjusting for other variables.  The median age at diagnosis was 6.2 and 8.3 years for the proton and photon cohorts, respectively (p = 0.010).  Cohorts were similar with respect to gender, histology, CSI dose, and total radiotherapy dose and whether the radiotherapy boost was delivered to the posterior fossa or tumor bed.  The median follow-up time was 5.8 years for proton patients and 7.0 years for photon patients (p = 0.010).  PRT was associated with a reduced risk of hypothyroidism (23 % versus 69 %, p < 0.001), sex hormone deficiency (3 % versus 19 %, p = 0.025), requirement for any endocrine replacement therapy (55 % versus 78 %, p = 0.030), and a greater height standard deviation score (mean (± SD) -1.19 (± 1.22) versus -2 (± 1.35), p = 0.020) on both uni-variate and multi-variate and propensity score adjusted analysis.  There was no significant difference in the incidence of growth hormone deficiency (53 % versus 57 %), adrenal insufficiency (5 % versus 8%), or precocious puberty (18 % versus 16 %).  The authors concluded that PRT may reduce the risk of some, but not all, radiation-associated late endocrine abnormalities.  Moreover, these researchers stated that further analysis of growth hormone deficiency and non-hormonally mediated alterations of growth among proton- and photon-treated patients is needed.

Combs (2017) stated that PBRT is characterized by certain physical properties leading to a reduction in integral dose.  As PBRT becomes more widely available, the ongoing discussion on the real indications for PBRT becomes more important.  This investigator summarized data on PBRT for tumors of the CNS and discussed in view of modern photon treatments.  Still today, no randomized controlled trials (RCTs) are available confirming any clinical benefit of protons in CNS tumors.  For certain skull base lesions, such as chordomas and chondrosarcomas, dose escalation is possible with protons thus patients should be referred to a proton center if readily available.  For vestibular schwannoma, at present, proton data are inferior to advanced photons.  For glioma patients, early data is present for low-grade gliomas, presenting comparable results to photons; dose escalation studies for high-grade gliomas have led to significant side effects, thus strategies of dose-escalation need to re-thought.  For skull base meningiomas (SBM), data from stereotactic series and IMRT present excellent local control with minimal side effects, thus any improvement with protons might only be marginal.  The largest benefit is considered in pediatric CNS tumors, due to the intricate radiation sensitivity of children's normal tissue, as well as the potential of long-term survivorship.  Long-term data is still lacking, and even recent analyses did not all lead to a clear reduction in side effects with improvement of outcome; furthermore, clinical data appeared to be comparable.  However, based on the pre-clinical evidence, PBRT should be evaluated in every pediatric patient.  Protons most likely have a benefit in terms of reduction of long-term side effects, such as neurocognitive sequelae or secondary malignancies; moreover, dose escalation could be performed in radio-resistant histologies.  The authors concluded that clinical data with long-term follow-up is still needed to prove any superiority to advanced photons in CNS tumors.  If available, protons should be evaluated for chordoma or chondrosarcoma of the skull base and pediatric tumors.  However, many factors are important for excellent oncology care, and no time delay or inferior oncological care should be accepted for the sake of protons only.

Moraes and Chung (2017) noted that SBM pose unique challenges for radiotherapy as these tumors are often in close proximity to a number of critical structures and may not be surgically addressed in many cases, leaving the question about the tumor grade and expected biological behavior.   External beam radiotherapy and radiosurgery are longstanding treatments for meningioma that are typically used as upfront primary therapy, for recurrent tumors and as adjuvant therapy following surgical resection.  There is controversy regarding the optimal timing and approach for radiation therapy in various clinical settings such as the role of adjuvant radiotherapy for completely resected grade 2 tumors.  Despite the use of radiotherapy for many decades, the evidence to guide optimal radiation treatment is limited largely to single institution series of EBRT, SRS and particle therapy.  These investigators reviewed the published data to clarify the role of EBRT, PBRT and single- and multi-fraction radiosurgery for SBM.  The authors also highlighted the areas of potential research and need for clinical improvement, including the growing awareness and effort to improve cognitive function in this patient population, who typically have long life expectancy following their meningioma diagnosis.  These researchers stated that particle therapy showed promising results in patients with SBM in terms of local tumor control and treatment-related toxicities.  In addition, it has been proposed that data supported that protons are associated with a lower risk of secondary malignancies.

El Shafie and co-workers (2018) evaluated the outcome of 110 patients with SBM treated with particle therapy.  It was performed within the framework of the "clinical research group heavy ion therapy" and supported by the German Research Council (DFG, KFO 214).  Between May 2010 and November 2014, a total of 110 patients with SBM were treated with particle radiotherapy at the Heidelberg Ion Therapy Center (HIT).  Primary localizations included the sphenoid wing (n = 42), petroclival region (n = 23), cavernous sinus (n = 4), sella (n = 10) and olfactory nerve (n = 4); 60 meningiomas were benign (WHO °I); whereas 8 were high-risk (WHO °II (n = 7) and °III (n = 1)).  In 42 cases histology was not examined, since no surgery was performed.  Proton (n = 104) or carbon ion (n = 6) radiotherapy was applied at HIT using raster-scanning technique for active beam delivery; 51 patients (46.4 %) received radiotherapy due to tumor progression, 17 (15.5 %) after surgical resection and 42 (38.2 %) as primary treatment.  Median follow-up in this analysis was 46.8 months (95 % CI: 39.9 to 53.7; Q1-Q3 34.3 to 61.7).  Particle radiotherapy could be performed safely without toxicity-related interruptions.  No grade IV or V toxicities according to CTCAE v4.0 were observed.  Particle RT offered excellent overall local control rates with 100 % PFS after 36 months and 96.6 % after 60 months.  Median PFS was not reached due to the small number of events.  Histology significantly impacted PFS with superior PFS after 5 years for low-risk tumors (96.6 % versus 75.0 %, p = 0,02); OS was 96.2 % after 60 months and 92.0 % after 72 months from therapy.  Of 6 documented deaths, 5 were definitely not and the 6th probably not meningioma-related.  The authors concluded that particle radiotherapy was an excellent therapeutic option for patients with SBM and can lead to long-term tumor control with minimal side effects.  Moreover, they stated that further prospective studies with longer follow-up are needed to further confirm the role of particle radiotherapy in SBM.

An UpToDate review on "Management of known or presumed benign (WHO grade I) meningioma" (Park and Shih, 2018) states that "Newer conformal RT techniques, including SRS, fractionated stereotactic radiotherapy (SRT), intensity-modulated radiation therapy (IMRT), volumetric modulated arc radiotherapy (VMAT), and proton radiotherapy, help to minimize radiation to the normal brain at large and are particularly important for the delivery of radiation to meningiomas that are in close proximity to critical structures such as the pituitary gland and the optic nerves … The rationale of proton therapy in treating patients with meningioma is to avoid acute and long term potential adverse effects in a patient population with projected long term survival.  Protons achieve greater avoidance of normal tissue radiation dose than photon-based techniques.  In turn, protons may help to prevent side effects such as radiation-associated secondary tumors and hypopituitarism, if the irradiated target is in proximity to the pituitary.  As with photon radiation, technological advancements have made intensity modulation feasible with protons, a technique called intensity modulated proton therapy (IMPT).  Additional experience is required to determine whether or not these approaches offer any benefit compared with other contemporary conformal techniques".

A systematic evidence review of proton beam therapy prepared for the Washington State Healthcare Authority (2014) reviewed studies comparing proton beam therapy to photon therapies. The investigators identified two poor-quality retrospective comparative cohort studies of primary PBT for brain, spinal, and paraspinal tumors. One was an evaluation of proton beam therapy versus photon therapy in 40 adults who received surgical and radiation treatment of medulloblastoma at MD Anderson Cancer Center (citing Brown, et al., 2013). No statistical differences between radiation modalities were seen in Kaplan-Meier assessment of either overall or progression-free survival at two years. A numeric difference was seen in the rate of local or regional failure (5% for PBT vs. 14% for photon), but this was not assessed statistically. The second study involved 32 patients treated for intramedullary gliomas at Massachusetts General Hospital (citing Kahn, et al, 2011) with either proton beam therapy (n=10) or IMRT (n=22). While explicit comparisons were made between groups, the proton beam therapy population was primarily pediatric (mean age 14 years), while the IMRT population was adult (mean age 44 years). Patients in both groups were followed for a median of 24 months. While the crude mortality rate was lower in the proton beam therapy group (20% vs. 32% for IMRT), in multivariate analyses controlling for age, tumor pathology, and treatment modality, proton beam therapy was associated with significantly increased mortality risk (Hazard Ratio 40.0, p = 0.02). The rate of brain metastasis was numerically higher in the proton beam therapy group (10% vs. 5% for IMRT), but this was not statistically tested. Rates of local or regional recurrence did not differ between groups.

NCCN guidelines on central nervous system cancers (version 3.2020) state that, "[t]o reduce toxicity from craniospinal radiation in adults, consider the use of intensity-modulated radiation therapy or protons if available." International guidelines on CNS malignancies (ESMO, 2010; Alberta Cancer Care, 2012; Cancer Council Australia, 2009) have no recommendation for proton beam therapy. An ASTRO Technology Review of proton beam therapy (2012) stated that, for CNS malignancies other than skull base and cervical spine chordomas and chondrosarcomas, "the potential benefit of proton beam therapy remains theoretical and deserving of further study."

Conjunctival Squamous Cell Carcinoma

The conventional treatment for squamous cell carcinoma (SCC) of the conjunctiva is topical agents and surgical excision.  Radiation can be used in refractory cases.  However, there are only a handful of cases reported in the literature on the use of PBT for conjunctival SSC or for ocular surface squamous neoplasia (OSSN) generally.

Ramonas et al (2006) stated that the therapeutic options available to the clinician for the treatment of superficial conjunctival and corneal SCC have expanded.  Promising reports in the literature described the use of photodynamic therapy and topical mitomycin C for the treatment of more extensive and recurrent lesions.  However, previous to this article, the options that were suggested for the treatment of intra-ocular invasive SCC were limited to enucleation.  This article suggested proton beam therapy PBT as a potential alternative to enucleation.  The authors stated that their knowledge of the efficacy of PBT was limited by the fact that they had only treated 1 patient and that had relatively short-term (approximately 9 months) follow-up data.  However, these researchers stated that the regression of tumor and lack of recurrence in this patient suggested that PBT should be considered as a possible alternative to enucleation for the treatment of invasive conjunctival SCC.

Caujolle and associates (2009) noted that invasive SCCs are uncommon neoplasia with high recurrence and mortality rates.  The improvement of tumoral control requires additional treatments such as cryotherapy, topical chemotherapy, and radiotherapy.  These researchers presented the technique and preliminary results of associating treatment with surgery and PBT for recurrent and invasive SCCs.  From June 2001 to September 2008, a total of 15 patients were treated in the authors’ ocular oncologic center for SCCs either with recurrences or with invaded resection margins.  The treatment combined new surgical resection with PBT.  Specific improvements in PBT have been made at the Nice Cyclotron to adapt the treatment to conjunctival tumors.  Proton beam carving consisted of using a specific device to treat the thickness of the whole lesion site and the adjacent conjunctiva and to spare the surrounding healthy structures.  Patients were staged according to the TNM classification of malignant tumors in T2: 3; T3: 5; T4: 7.  Mean follow-up was 39.1 months (range of 6 to 90 months).  The 15 participants included 12 men and 3 women.  Left eyes were involved in 8 cases.  The mean age at first consultation was 63.7 years (range of 46 to 80 years).  In 13 cases (86.8 %), the bulbar and limbic conjunctiva was involved, in 5 of these cases the cornea was invaded, and the anterior chamber was involved in 1 case.  In 1 case, the tumor was located on bulbar conjunctiva near the caruncle (6.6 %) and in 1 case in the fornix (6.6 %); 1 patient died of another cancer after 48 months of follow-up.  These investigators obtained local tumor control for 13 patients (86.8 %) and recurrences for 2 patients (13.2 %).  One of them has presented with cervical node metastases.  These 2 patients who presented recurring and extensive tumors had had previous repeated surgeries in other centers.  Moreover, PBT was performed more than 6 months after the initial treatment.  Exenteration and enucleation had to be performed to treat these recurrences 6 and 24 months after PBT.  The exentered patient was lost to follow-up.  No patients developed recurrences with additional PBT performed within 6 months after initial surgical resection.  As for side effects, 7 patients suffered from sicca syndrome, 6 needed cataract surgeries, 3 unesthetic dilatations of episclera vessels, 2 conjunctival post-radiation dysplasia, 2 experienced eyelash loss, 1 stenosis of the lacrimal duct, and 1 glaucoma controlled by monotherapy.  Conjunctiva and amniotic grafts had to be performed on 1 of the patients presenting with dysplasia.  Due to the rarity and diversity of these cases, it is nearly impossible to carry out prospective and comparative studies.  The authors concluded that traditional adjuvant treatments often failed to control recurring and invasive SCCs.  These investigators often ended up performing exenteration to control local recurrences.  They stated that the preliminary findings of this study suggested that PBT may be considered as a good alternative to traditional treatments with acceptable side effects.

El-Assal and colleagues (2013) stated that OSSN has the potential for causing significant ocular and systemic morbidity and mortality.  The standard treatment for OSSN is surgical excision with safety margin and cryotherapy to the edges.  Topical mitomycin C, 5-fluorouracil, interferon, and radiotherapy (including external beam radiotherapy and brachytherapy) have been used as adjuvant treatment with variable success rates.  PBT, a type of external beam radiotherapy, delivers a high dose of ionizing radiation to the tumor with minimal damage to surrounding tissues.  Only 1 case has been reported in the literature for which PBT was successfully used as primary treatment for invasive OSSN and these researchers reported the first 2 successful cases in United Kingdom.  A case series in which PBT was used for recurrent OSSN or where the surgical margins were involved after excision was published with encouraging results.  In both presented cases, PBT has regressed the tumor without recurrence.  Both patients received a 6-week course of topical steroids post-treatment.  No immediate side effects were noted, however 1 developed a cataract 2 years later, and 2nd subject developed a patch of scleral thinning that was stable on follow-up.  These investigators suspected it was an area of deeper tumor invasion that melted away with treatment.  The authors believed that PBT should be considered for OSSN when surgical excision is not possible.  These preliminary findings need to be validated by well-designed studies.

Liver Metastases from Carcinoid Gastrinoma

Available evidence on PBRT for liver metastases has been limited to dosimetric planning studies, case reports, and uncontrolled series.

Hong and colleagues (2014) examined the feasibility of a respiratory-gated PBRT for liver tumors.  A total of 15 patients were enrolled in a prospective IRB-approved protocol.  Eligibility criteria included Childs-Pugh A/B cirrhosis, unresectable biopsy-proven HCC, intrahepatic cholangiocarcinoma (ICC), or metastatic disease (solid tumors only), 1 to 3 lesions, and tumor size of less than or equal to 6 cm.  Patients received 15 fractions to a total dose of 45 to 75 Gy [gray equivalent] using respiratory-gated PBRT.  Gating was performed with an external respiratory position monitoring based system.  Of the 15 patients enrolled in this clinical trial, 11 had HCC, 3 had ICC, and 1 had metastasis from another primary; 10 patients had a single lesion, 3 patients had 2 lesions, and 2 patients had 3 lesions.  Toxicities were grade 3 bilirubinemia (n = 2), grade 3 gastro-intestinal (GI) bleed (n = 1), and grade 5 stomach perforation (n = 1); 1 patient had a marginal recurrence, 3 had hepatic recurrences elsewhere in the liver, and 2 had extra-hepatic recurrence.  With a median follow-up for survivors of 69 months, 1-, 2-, and 3-year overall OS were 53 %, 40 %, and 33 %, respectively; PFS were 40 %, 33 %, and 27 % at 1, 2, and 3 years, respectively.  The authors concluded that respiratory-gated PBRT for liver tumors was feasible; phase-II clinical trials for primary liver tumors and metastatic tumors are underway.

Verma and co-workers (2016) stated that PBT is frequently shown to be dosimetrically superior to photon RT, though supporting data for clinical benefit are severely limited.  Because of the potential for toxicity reduction in GI malignancies, these investigators reviewed the literature on clinical outcomes (survival/toxicity) of PBT.  They performed a systematic search of PubMed, Embase, abstracts from meetings of the American Society for Radiation Oncology (ASRT), Particle Therapy Co-Operative Group (PTCOG), and American Society of Clinical Oncology (ASCO) was conducted for publications from 2000 to 2015. A total of 38 original investigations were analyzed.  Although results of PBT were not directly comparable to historical data, outcomes roughly mirror previous data, generally with reduced toxicities for PBT in some neoplasms.  For esophageal cancer, PBT was associated with reduced toxicities, post-operative complications, and hospital stay as compared to photon RT, while achieving comparable local control (LC) and OS.  In pancreatic cancer, numerical survival for resected/un-resected cases was also similar to existing photon data, whereas grade greater than or equal to 3 nausea/emesis and post-operative complications were numerically lower than those reported with photon RT.  The strongest data in support of PBT for HCC came from phase-II clinical trials demonstrating very low toxicities, and a phase-III clinical trial of PBT versus trans-arterial chemoembolization (TACE) demonstrating trends towards improved LC and PFS with PBT, along with fewer post-treatment hospitalizations.  Survival and toxicity data for cholangiocarcinoma, liver metastases, and retroperitoneal sarcoma were also roughly equivalent to historical photon controls.  There were 2 small reports for gastric cancer and 3 for anorectal cancer; these were not addressed further.  The authors concluded that limited quality (and quantity) of data hampered direct comparisons and conclusions.  However, the available data, despite the inherent caveats and limitations, suggested that PBT offered the potential to achieve significant reduction in treatment-related toxicities without compromising survival or LC for multiple GI malignancies.  Several randomized comparative trials are underway that will provide more definitive answers.

Colbert and colleagues (2017) noted that bi-lobar colorectal liver metastases (CRLM), are now aggressively managed in a multi-disciplinary fashion with a 2-stage hepatectomy; however, up to 30 % of patients are not candidates for 2nd stage hepatectomy.  These researchers described a novel technique of delivering ablative radiation to the entire right hemi-liver by using PBRT in a series of patients.  A data base of patients undergoing entire right hemi-liver ablative radiation was maintained prospectively.  Clinical, pathologic and treatment characteristics were collected for these patients.  Survival duration was calculated from end of radiation.  Radiation was delivered with PBRT using deep inspiratory breath hold (DIBH) and a phase contrast simulation CT scan.  All 5 patients tolerated radiation treatment well.  All 4 patients treated with biologic equivalent dose (BED) of greater than 89.6 Gy achieved partial or complete radiographic response and in-field local control at last follow up; 2 patients were alive and without evidence of disease; 2 patients experienced disease progression outside of the liver.  The authors concluded that these findings suggested that the use of stereotactic PBRT as a salvage therapy for patients with CRLM not amenable to 2nd stage hepatectomy may achieve good local control and allow an opportunity for long-term survival.

Fukumitsu and associates (2017) stated that liver metastases from gastric cancer (LMGC) is a non-curable, fatal disease with a 5-year survival rate of less than 10 %.  Although various local treatments have been applied, their clinical utility has not been established.  These investigators examined the safety and effectiveness of PBT for the treatment of patients with LMGC.  A total of 9 patients (7 men, 2 women; aged 56 to 78 years) with LMGC who received PBT between 2002 and 2012 were retrospectively reviewed.  Patients who had tumors confined to the liver were included in this study, and patients who had extra-hepatic tumors were excluded; 6 of the patients had solitary tumors, and 3 had multiple tumors.  The total irradiation dose was 64 to 77 Gy (RBE), and 3 patients received concurrent chemotherapy.  The OS and PFS rates, local control (LC) rate, and AEs were investigated.  All patients completed treatment without interruption, and late AEs of higher than Grade 3 were not observed.  The OS rates at 1, 3 and 5 years were 100 %, 78 % and 56 %, respectively (median of 5.5 years); the PFS rates were 67 %, 40 % and 40 % (median of 2.6 years); and the LC rates were 89 %, 71 % and 71 %.  The authors concluded that PBT was demonstrated to be a safe treatment, and the OS and PFS rates were not inferior to those for other types of local treatment; thus, PBT should be considered as an effective local therapeutic option for patients with LMGC.  Moreover, these researchers noted that they only had the data for 9 patients; they were considering further investigation with a great number of patients to provide more detailed information on PBT for patients with LMGC.

Mediastinal Lymphoma

Zeng and colleagues (2016) stated that modern radiotherapy (RT) for lymphoma is highly personalized.  While advanced imaging is largely employed to define limited treatment volumes, the use of proton pencil beam scanning (PBS) for highly conformal lymphoma RT is still in its infancy.  These researchers examined the dosimetric benefits and feasibility of PBS for mediastinal lymphoma (ML).  A total of 10 patients were planned using PBS for involved-site RT.  The initial plans were calculated on the average four-dimensional computed tomography (4D-CT); PBS plans were compared with 3D conformal radiotherapy (3D-CRT), IMRT, and proton double scattering (DS).  In order to evaluate the feasibility of PBS and the plan robustness against inter- and intra-fractional uncertainties, the 4D dose was calculated on initial and verification CTs.  The deviation of planned dose from delivered dose was measured.  The same proton beamline was used for all patients, while another beamline with larger spots was employed for patients with large motion perpendicular to the beam.  PBS provided the lowest mean lung dose (MLD) and mean heart dose (MHD) for all patients in comparison with 3D-CRT, IMRT, and DS.  For 8 patients, internal target volume (ITV) D98% was degraded by less than 3 %; and the MLD and MHD deviated by less than 10 % of prescription over the course of treatment when the PBS field was painted twice in each session.  For 1 patient with target motion perpendicular to the beam (greater than 5 mm), the degradation of ITV D98% was 9 %, which was effectively mitigated by employing large spots; 1 patient exhibited large dose degradation due to peri-cardial effusion, which required re-planning across all modalities.  The authors concluded that this study demonstrated that PBS plans significantly reduced MLD and MHD relative to 3D-CRT, IMRT, and DS and identified requirements for robust free-breathing ML PBS treatments, showing that PBS plan robustness could be maintained with repainting and/or large spots.

Hoppe and associates (2017) examined early outcomes for patients receiving chemotherapy followed by consolidative proton therapy (PT) for the treatment of Hodgkin lymphoma (HL).  From June 2008 to August 2015, a total of 138 patients with HL enrolled on either IRB-approved outcomes tracking protocols or registry studies received consolidative PT.  Patients were excluded due to relapsed or refractory disease.  Involved-site radiotherapy field designs were used for all patients.  Pediatric patients received a median dose of 21 Gy (RBE) [range of 15 to 36 Gy (RBE)]; adult patients received a median dose of 30.6 Gy (RBE) [range of 20 to 45 Gy (RBE)].  Patients receiving PT were young (median age of 20 years; range of 6 to 57).  Overall, 42 % were pediatric (less than or equal to 18 years) and 93 % were under the age of 40 years; 38 % of patients were male and 62 % female.  Stage distribution included 73 % with I/II and 27 % with III/IV disease.  Patients predominantly had mediastinal involvement (96 %) and bulky disease (57 %), whereas 37 % had B symptoms.  The median follow-up was 32 months (range of 5 to 92 months).  The 3-year RFS rate was 92 % for all patients; it was 96 % for adults and 87 % for pediatric patients (p = 0.18).  When evaluated by positron emission tomography/computed tomography (PET/CT) scan response at the end of chemotherapy, patients with a partial response had worse 3-year PFS compared with other patients (78 % versus 94 %; p = 0.0034).  No grade 3 radiation-related toxicities have occurred to-date.  The authors stated that although these results were preliminary, they represent excellent 3-year outcomes, especially considering most patients (70 %) had unfavorable early-stage or advanced-stage disease.  They concluded that consolidative PT following standard chemotherapy in HL was primarily used in young patients with mediastinal and bulky disease.  Early RFS rates were similar to those reported with photon radiation treatment, and no early grade 3 toxicities have been observed; continued follow-up to evaluate late effects is critical.  Moreover, these researchers stated that these results were encouraging and supported continued treatment of patients with HL with PT in a registry setting, which allowed long-term follow-up and potential confirmation of decreased late toxicity.

The authors stated that this study was subject to the weaknesses of any observational study.  Treatment techniques, including chemotherapy regimen, PT technique, and motion management strategies were not standardized across the cohort; nevertheless, such heterogeneity could also be considered a strength as it made the study more pragmatic and demonstrated the feasibility of delivering PT safely and effectively across different institutions, including community and academic hospitals. 

In an editorial on the afore-mentioned study by Hoppe et al (2017), Ricardi and colleagues (2017) stated that "Proton therapy is another evolving technology that potentially allows significant reduction in radiotherapy related toxicity by decreasing normal tissues exposure.  Unlike photons, which penetrate beyond the target and expose normal tissues to the ‘exit dose’, protons will stop after they deposit all their energy near the end of their range, a phenomenon known as the Bragg peak.  Multiple studies have shown that this physical advantage of protons could lead to reduction in estimated normal tissue dose compared to photon RT in a variety of clinical scenarios.  However, given the relative novelty of proton therapy, clinical evidence of equivalent disease control, particularly in lymphoma, has been scarce.  Clinical confirmation of effectiveness is particularly critical since the deposition of dose from protons is more sensitive to changes in tissue density than photons, and the planning software algorithms that estimate proton dose are less well developed.  Consequently, for a patient receiving mediastinal RT, changes in the volume of lung tissue during respiration are more likely to affect the accuracy of a proton plan than a photon plan, and managing daily set up, particularly internal organ motion, is even more critical to insure dose accuracy.  Further, there is some uncertainty regarding the radiobiological equivalence of proton doses, with greater cellular damage occurring at the tail of the Bragg-peak.  This can create planning constraints in order to avoid beam arrangements that produce dose uncertainty within critical normal tissues.  The study from Hoppe et al is an important contribution to demonstrate the clinical effectiveness of proton therapy for HL.  It is the first proton outcomes study on HL to merge data from 3 separate institutional review board-approved registry studies (138 patients; 42 % pediatric and 93 % under the age of 40 years; 62 % female; 73 % with stage I/II and 27 % with stage III/IV disease; 96 % with mediastinal involvement and 57 % with bulky disease).  Proton therapy was delivered using modern treatment planning concepts of ISRT and INRT, with a mean dose of 21 Gy (RBE) and 30.6 Gy (RBE) for pediatric and adult patients, respectively.  The results show excellent 3-year relapse-free survival (92 %) for all patients, absolutely similar to those reported with modern photon radiotherapy in HL.  There were no marginal relapses attributed to the dramatic dose fall-off observed with proton therapy nor end-of-range uncertainty, which is an important finding considering the potential for increased relapse when treating limited volumes (ISRT/INRT) with steeper dose gradients … Detailed evaluation of dose-risk studies is also critical as we move toward understanding which patients may benefit from proton therapy, and to what degree.  For example, while it is true that Cutter et al (2015) found a significant trend of increasing risk of valvular heart disease with increasing dose to a given valve, there was little or no increased risk among survivors who received valve doses ≤ 30 Gy – i.e., doses that would be received by the large majority of patients receiving contemporary mediastinal photon RT.  It would likely be incorrect, then, to conclude that a transition to proton therapy would produce a significant reduction in valvular heart disease, despite the cited dose-risk relationship.  Similarly, Maraldo et al (2013) applied dose-risk data to a series of 27 HL patients planned with photons or protons and reported that the modeled estimates predicted lower risks of second cancers and cardiovascular with the latter.  Looking at the results in detail, however, the estimated reductions in the lifetime absolute risk of cardiac mortality, radiation-induced lung or breast cancer were arguably small: 0.1 %, 1.1 % and 2.3 %, respectively, with significant variation among patients.  It is apparent then that a critical issue that needs to be addressed is not whether proton therapy can reduce normal tissue dose – we know it can –  but whether the magnitude of these reductions are clinically significant for individual patients, and what defines ‘reasonable’ in a ‘reasonably achievable’ dose reduction.  Therefore, as with all new technologies, patient selection plays a major role in determining who might benefit mostly from proton therapy, especially when comparing protons with modern photons radiotherapy in lymphoma.  It may be that a subset of risk-stratified patients can be identified as the most appropriate candidates to get a clinical benefit, considering factors such as tumor location, inability to achieve important normal tissue dose constraints (and we still need specific constraints in lymphoma), as well as patient’s age, sex, and comorbidities, and specific risk of second cancers.  As with decisions to use chemotherapy alone or combined modality therapy, we recommend a multidisciplinary approach involving a radiation oncologist expert in lymphoma when choosing wisely the most appropriate RT modality; there is no a single technical option when treating HL patients: the decision has to be made at an individual level by experts".

The published literature on proton beam therapy for mediastinal lymphomas is limited to case reports, dosimetric planning comparisons, and small retrospective and prospective series.  The NCCN clinical practice guideline on "B-cell lymphomas" (Version 4.2020) provides no recommendation for protons over photon techniques in any particular circumstance: "Treatment with photons, electrons, or protons, electrons is appropriate, selection depends upon the clinical scenario.".

Esophageal Cancer

Mizumoto et al (2010) evaluated the efficacy and safety of PBRT for locoregionally advanced esophageal cancer.  The subjects were 51 patients with esophageal cancer who were treated between 1985 and 2005 using proton beams with or without X-rays.  All but 1 had squamous cell carcinoma.  Of the 51 patients, 33 received combinations of X-rays (median of 46 Gy) and protons (median of 36 GyE) as a boost.  The median total dose of combined X-rays and proton radiation for these 33 patients was 80 GyE (range of 70 to 90 GyE).  The other 18 patients received PBRT alone (median of 79 GyE, range of 62 to 98 GyE).  Treatment interruption due to radiation-induced esophagitis or hematologic toxicity was not required for any patient.  The overall 5-year actuarial survival rate for the 51 patients was 21.1 % and the median survival time was 20.5 months (95 % confidence interval [CI]: 10.9 to 30.2).  Of the 51 patients, 40 (78 %) showed a complete response within 4 months after completing treatment and 7 (14 %) showed a partial response, giving a response rate of 92 % (47/51).  The 5-year local control rate for all 51 patients was 38.0 % and the median local control time was 25.5 months (95 % CI: 14.6 to 36.3).  The authors concluded that these findings suggested that PBRT is an effective treatment for patients with locally advanced esophageal cancer.  Moreover, they stated that further studies are needed to determine the optimal total dose, fractionation schedules, and best combination of PBRT with chemotherapy.  Furthermore, the National Comprehensive Cancer Network (NCCN) guideline on esophageal cancer (2011) does not mention the use of PBRT as a therapeutic option for this condition.

Mizumoto et al (2011) evaluated the safety and effectiveness of hyper-fractionated concomitant boost proton beam therapy (PBT) for patients with esophageal cancer.  The study participants were 19 patients with esophageal cancer who were treated with hyperfractionated photon therapy and PBT between 1990 and 2007.  The median total dose was 78 GyE (range of 70 to 83 GyE) over a median treatment period of 48 days (range of 38 to 53 days).  Ten of the 19 patients were at clinical T Stage 3 or 4.  There were no cases in which treatment interruption was required because of radiation-induced esophagitis or hematologic toxicity.  The overall 1- and 5-year actuarial survival rates for all 19 patients were 79.0 % and 42.8 %, respectively, and the median survival time was 31.5 months (95 % limits: 16.7 to  46.3 months).  Of the 19 patients, 17 (89 %) showed a complete response within 4 months after completing treatment and 2 (11 %) showed a partial response, giving a response rate of 100 % (19/19).  The 1- and 5-year local control rates for all 19 patients were 93.8 % and 84.4 %, respectively.  Only 1 patient had late esophageal toxicity of Grade 3 at 6 months after hyperfractionated PBT.  There were no other non-hematologic toxicities, including no cases of radiation pneumonia or cardiac failure of Grade 3 or higher.  The authors concluded that these findings suggested that hyperfractionated PBT is safe and effective for patients with esophageal cancer.  They stated that further studies are needed to establish the appropriate role and treatment schedule for use of PBT for esophageal cancer.

Lin et al (2017) stated that relative radiation dose exposure to vital organs in the thorax could influence clinical outcomes in esophageal cancer (EC).  These researchers examined if the type of radiation therapy (RT) modality used was associated with post-operative outcomes after neoadjuvant chemoradiation (nCRT).  Contemporary data from 580 EC patients treated with nCRT at 3 academic institutions from 2007 to 2013 were reviewed.  3D conformal RT (3D), intensity modulated RT (IMRT) and proton beam therapy (PBT) were used for 214 (37 %), 255 (44 %), and 111 (19 %) patients, respectively.  Post-operative outcomes included pulmonary, GI, cardiac, wound healing complications, length of in-hospital stay (LOS), and 90-day post-operative mortality.  Cox model fits, and log-rank tests both with and without Inverse Probability of treatment Weighting (IPW) were used to correct for bias due to non-randomization.  RT modality was significantly associated with the incidence of pulmonary, cardiac and wound complications, which also bore out on multi-variate analysis.  Mean LOS was also significantly associated with treatment modality (13.2 days for 3D (95 % confidence interval [CI]: 11.7 to 14.7), 11.6 days for IMRT (95 % CI: 10.9 to 12.7), and 9.3 days for PBT (95 % CI: 8.2 to 10.3) (p < 0.0001)).  The 90-day post-operative mortality rates were 4.2 %, 4.3 %, and 0.9 %, respectively, for 3D, IMRT and PBT (p = 0.264).  The authors concluded that advanced RT technologies (IMRT and PBT) were associated with significantly reduced rate of post-operative complications and LOS compared to 3D, with PBT displaying the greatest benefit in a number of clinical endpoints.  These researchers stated that ongoing prospective randomized trial will be needed to validate these results.

Xi et al (2017) compared clinical outcomes between PBT and IMRT in patients with EC treated with definitive CRT.  From 2007 through 2014, a total of 343 EC patients who received definitive CRT with either PBT (n = 132) or IMRT (n = 211) were retrospectively analyzed.  Survival, recurrence, and treatment toxicity were compared between groups.  A Cox proportional hazards regression model was performed to test the association between patient/treatment variables and survival.  Patient/treatment variables were overall well balanced, except for age and race.  Compared with IMRT, PBT had significantly better overall survival (OS; p = 0.011), progression-free survival (PFS; p = 0.001), distant metastasis-free survival (DMFS; p = 0.031), as well as marginally better loco-regional failure-free survival (LRFFS; p = 0.075).  No significant differences in rates of treatment-related toxicities were observed between groups.  On multi-variate analysis, IMRT had worse OS (hazard ratio [HR] 1.454; p = 0.01), PFS (HR 1.562; p = 0.001), and LRFFS (HR 1.461; p = 0.041) than PBT.  Subgroup analysis by clinical stage revealed considerably higher 5-year OS (34.6 % versus 25.0 %, p = 0.038) and PFS rates (33.5 % versus 13.2 %, p = 0.005) in the PBT group for patients with stage III disease.  However, no significant inter-group differences in survival were identified for stage I/II patients.  The authors concluded that compared with IMRT, PBT might be associated with improved OS, PFS, and LRFFS, especially in EC patients with locally advanced disease.  Moreover, these  researchers stated that these results need confirmation by prospective studies.

An evidence review of proton beam therapy for esophageal cancer prepared for the UK National Health Service (2019) reached the following conclusions: "There is no high level published clinical trial evidence investigating the superiority of proton beam therapy over current treatment modalities for effectiveness or reduced toxicity in oesophageal cancer. Three papers were submitted to the Clinical Panel as part of the policy proposition. Two contained the findings from retrospective reviews of patients treated with PBT as well as other modalities of radiotherapy. The third was a meta-analysis which did not explicitly have PBT as a treatment modality and therefore does not add to the evidence on the clinical effectiveness of PBT in treating oesophageal cancer. However, it does add information about the magnitude of benefit of using chemoradiation prior to surgery and highlights the toxicity of the combined modality treatment. The Panel found insufficient evidence to demonstrate the superiority of proton beam therapy over current standard treatment to justify routine commissioning for this indication."

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on "Esophageal and esophagogastric junction cancers" (Version 4.2020) states that "Data regarding proton beam therapy are early and evolving.  Ideally, patients should be treated with proton beam therapy in a clinical trial".

Prostate Cancer

Available evidence indicates that proton beam therapy achieves similar outcomes to intensity modulated radiation therapy for localized prostate cancer.

The American Society of Radiation Oncology (ASTRO, 2013) has stated: "At the present time, ASTRO believes the comparative efficacy evidence of proton beam therapy with other prostate cancer treatments is still being developed, and thus the role of proton beam therapy for localized prostate cancer within the current availability of treatment options remains unclear."

The only randomized controlled clinical trial comparing PBRT to conventional radiotherapy for prostate cancer published to date found no advantage of PBRT in overall survival (OS), disease-specific survival, or total recurrence-free survival (Shipley, 1995).  A total of 202 patients with stage T3-T4 prostate cancer were randomly assigned to a standard dose of conventional radiotherapy plus a 25.2 Gy equivalent PBRT boost or to a standard dose of conventional radiotherapy with a 16.8 Gy boost of conventional radiotherapy.  After a median follow-up of 61 months, there were no significant differences between the 2 groups in OS, disease-specific survival, total recurrence-free survival, or local control.  Local control was better with the proton beam boost only among the subgroup of patients with poorly differentiated carcinoma.  Patients receiving the proton beam boost had increased rates of late radiation sequelae.

Loma Linda University’s experience with PBRT of prostate cancer was reported in an article published in 1999 by Rossi et al.  These investigators reported the results of an uncontrolled study of PBRT treatment of 319 patients with biopsy-proven early-stage prostate cancer, with no patient having an initial PSA of greater than 15.  Because the study was uncontrolled, one is unable to determine whether the results of PBRT are superior to conventional forms of radiation therapy.  In addition, the definitions of success and failure used in this study are not comparable to those used in other recent studies of prostate cancer treatments.  In the study by Rossi et al, patients were considered to have an adequate response if their PSA level fell below 1.0; most other recent studies define an adequate response as PSA level below 0.5.  In the study by Rossi et al, patients were considered treatment failures if they had 3 consecutive rises of PSA of 10 % or more, measured at 6-month intervals.  In other words, for a patient to be considered a treatment failure, it would take at least 18 months, and patients would have to have 3 consecutive rises in PSA, each greater than 10 %.  By contrast, other reported studies of prostate cancer radiotherapy have defined failure as any PSA elevation over a target PSA nadir.  Finally, Rossi et al defined clinical disease free survival as having "no symptoms and no evidence of disease upon physical examination or radionuclide scans".  These are very gross tests to determine success, and one would expect these tests to be negative in a high number of patients who harbored occult disease.

Of the 319 patients included in the study by Rossi et al, only 288 patients (91 %) who had achieved a nadir (any nadir) or who had been followed for at least 24 months were included in the analysis.  This would indicate that 31 (9 %) of the patients originally included in the study either had persistently rising PSA levels without a nadir despite treatment, had dropped out of the study, or had not been followed for a sufficient length of time for some unspecified reason.  Only 187 patients (59 % of the original 319 patients) achieved a PSA nadir of 0.5 or less, 66 (21 %) achieved a PSA nadir of 0.51 to 1.0, and 35 (11 %) achieved a PSA nadir of 1.0 and above.  Thus, only 59 % of patients would be considered to have had an adequate response by the measure most commonly used in other recent prostate cancer treatment studies.  In addition, because of the peculiar way the results are reported, there is no way of knowing how many patients' PSA nadirs were maintained.

An assessment of the comparative effectiveness and value of management options in low-risk prostate cancer by the Institute for Clinical and Economic Review (ICER) (Ollendorf et al, 2008) found that the evidence on the comparative effectiveness and harms of proton beam therapy is limited to relatively small, highly selective case series of short duration, making any judgments about its relative benefit or inferiority to other options premature.  The uncertainty regarding PBRT is accentuated because this technology involves delivery of a novel form of radiation, and there remain important questions about the full spectrum of possible effects.  ICER rated PBRT's comparative clinical effectiveness as "insufficient", indicating that there is not enough evidence to allow a reasonable judgment of the likely balance of harms and benefits of PBRT in comparison to radical prostatectomy or other management options.  ICER judged the comparative value of PBRT to be low compared to other options.  The ICER reported explained, that, while ICER does not always provide a comparative value rating for technologies with insufficient evidence on comparative clinical effectiveness, the decision was made to rate the comparative value of PBRT as "low" relative to radical prostatectomy, based on current levels of reimbursement that are more than 3-fold higher for PBRT.

Mendenhall et al (2014) reported 5-year clinical outcomes of 3 prospective trials of image-guided proton therapy for prostate cancer.  A total of 211 prostate cancer patients (89 low-risk, 82 intermediate-risk, and 40 high-risk) were treated in institutional review board-approved trials of 78 cobalt gray equivalent (CGE) in 39 fractions for low-risk disease, 78 to 82 CGE for intermediate-risk disease, and 78 CGE with concomitant docetaxel therapy followed by androgen deprivation therapy for high-risk disease.  Toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Median follow-up was 5.2 years.  Five-year rates of biochemical and clinical freedom from disease progression were 99 %, 99 %, and 76 % in low-, intermediate-, and high-risk patients, respectively.  Actuarial 5-year rates of late CTCAE, version 3.0 (or version 4.0) grade 3 gastrointestinal and urologic toxicity were 1.0 % (0.5 %) and 5.4 % (1.0 %), respectively.  Median pre-treatment scores and International Prostate Symptom Scores at greater than 4 years post-treatment were 8 and 7, 6 and 6, and 9 and 8, respectively, among the low-, intermediate-, and high-risk patients.  There were no significant changes between median pre-treatment summary scores and Expanded Prostate Cancer Index Composite scores at greater than 4 years for bowel, urinary irritation and/or obstructive, and urinary continence.  The authors concluded that 5-year clinical outcomes with image-guided proton therapy included extremely high efficacy, minimal physician-assessed toxicity, and excellent patient-reported outcomes.  Moreover, they stated that further follow-up and a larger patient experience are needed to confirm these favorable outcomes.

Furthermore, NCCN’s clinical practice guideline on "Prostate cancer" (Version 2.2020) states that "An ongoing prospective randomized trial is accruing patients to compare prostate proton therapy to prostate IMRT.  The NCCN panel believes no clear evidence supports a benefit or decrement to proton therapy over IMRT for either treatment efficacy or long-term toxicity".

Guidelines on prostate cancer from the European Association of Urology (Mottet, et al., 2020) concluded that "A RCT comparing equivalent doses of proton-beam therapy with IMRT is underway. Meanwhile, proton therapy must be regarded as a promising, but experimental, alternative to photon-beam therapy."

An assessment by the Ludwig Boltzmann Institute for Health Technology Assessment (2018) concluded that "The conclusion is accordingly that there is at present inadequate and insufficient evidence to show that . . . PT [proton therapy] have either a positive impact on survival and quality of life or the ability to prevent or delay prostatectomy".

Atypical / Anaplastic Meningioma

Coggins and colleagues (2019) noted that atypical and anaplastic meningiomas, unlike their benign counterparts, are highly aggressive, locally destructive, and likely to recur after treatment.  These diseases are difficult to definitively treat with traditional RT without injuring adjacent brain parenchyma.  The physical properties of ion RT allows for treatment plans that avoid damaging critical neural structures.  In a systematic review, these researchers examined the use and efficacy of ion RT in the treatment of atypical and anaplastic meningiomas.  They performed a systematic review of the literature by querying the PubMed and Ovid databases to identify and examine literature addressing the efficacy of ion RT in maintaining long-term local tumor control for patients with atypical or anaplastic meningiomas.  The outcome of interest was rate of local tumor control at 5 years following ion RT.  Across the included studies, PBRT delivered a mean local control rate of 59.62 % after 5 years.  Carbon ion RT studies showed local control rates of 95 % and 63 % at 2 years for grade II and III meningiomas, respectively.  In contrast, carbon ion RT studies that failed to differentiate between atypical and anaplastic meningiomas produced a local control rate of 33 % at 2 years.  The authors concluded that PBRT and carbon ion RT maintained comparable rates of local control to conventional photon therapy and allowed for more targeted treatment plans that may limit excess radiation damage.  These researchers stated that although additional, prospective trials are needed, ion therapy represents a burgeoning field in the treatment of atypical and anaplastic meningiomas.

Wu and associates (2019) stated that adjuvant RT has become a common addition to the management of high-grade meningiomas, as immediate treatment with radiation following resection has been associated with significantly improved outcomes.  Recent investigations into particle therapy have expanded into the management of high-risk meningiomas.  These investigators systematically reviewed studies on the efficacy and utility of particle-based RT in the management of high-grade meningioma.  A literature search was developed by first defining the population, intervention, comparison, outcomes, and study design (PICOS).  A search strategy was designed for each of 3 electronic databases: PubMed, Embase, and Scopus.  Data extraction was conducted in accordance with the PRISMA guidelines.  Outcomes of interest included local disease control, OS, and toxicity, which were compared with historical data on photon-based therapies.  A total of 11 retrospective studies including 240 patients with atypical (WHO grade II) and anaplastic (WHO grade III) meningioma undergoing particle RT were identified; 5 of the 11 studies included in this systematic review focused specifically on WHO grade II and III meningiomas; the others also included WHO grade I meningioma.  Across all of the studies, the median follow-up ranged from 6 to 145 months.  Local control rates for high-grade meningiomas ranged from 46.7 % to 86 % by the last follow-up or at 5 years; OS rates ranged from 0 % to 100 % with better prognoses for atypical than for malignant meningiomas.  Radiation necrosis was the most common adverse effect of treatment, occurring in 3.9 % of specified cases.  The authors concluded that despite the lack of randomized prospective trials, this review of existing retrospective studies suggested that particle therapy, whether an adjuvant or a stand-alone treatment, conferred survival benefit with a relatively low risk for severe treatment-derived toxicity compared to standard photon-based therapy; however, additional controlled studies are needed.

Leiomyosarcoma Encasing the Aorta

Yoon et al (2010) sought to reduce local recurrence for retroperitoneal sarcomas (RPS) by using a coordinated strategy of advanced radiation techniques and aggressive en-bloc surgical resection.  Proton-beam radiation therapy (PBRT) and/or intensity-modulated radiation therapy (IMRT) were delivered to improve tumor target coverage and spare selected adjacent organs.  Surgical resection of tumor and adjacent organs was performed to obtain a disease-free anterior margin.  Intra-operative electron radiation therapy (IOERT) was delivered to any close posterior margin.  A total of 20 patients had primary tumors and 8 had recurrent tumors.  Tumors were large (median size of 9.75 cm), primarily liposarcomas and leiomyosarcomas (71 %), and were mostly of intermediate or high grade (81 %).  PBRT and/or IMRT were delivered to all patients, preferably pre-operatively (75 %), to a median dose of 50 Gy.  Surgical resection included up to 5 adjacent organs, most commonly the colon (n = 7) and kidney (n = 7).  Margins were positive for disease, usually posteriorly, in 15 patients (54 %).  IOERT was delivered to the posterior margin in 12 patients (43 %) to a median dose of 11 Gy.  Surgical complications occurred in 8 patients (28.6 %), and radiation-related complications occurred in 4 patients (14 %).  After a median follow-up of 33 months, only 2 patients (10 %) with primary disease experienced local recurrence, while 3 patients (37.5 %) with recurrent disease experienced local recurrence.  The authors concluded that aggressive resection of retroperitoneal sarcomas could achieve a disease-negative anterior margin.  PBRT and/or IMRT with IOERT may possibly deliver sufficient radiation dose to the posterior margin to control microscopic residual disease.  This strategy may minimize radiation-related morbidity and reduce local recurrence, especially in patients with primary disease.

The authors stated that this study had several drawbacks including a heterogeneous patient population, heterogeneity in the administration of radiation, and small sample size (n = 28).  This report described a somewhat favorable group of patients compared to other series of RPS; given that 43 % of patients were asymptomatic, most patients were able to tolerate pre-operative therapy, and median tumor size was 9.75 cm.  In addition, PBRT was not widely available, making broad application of this strategy difficult. 

Neutron Beam Therapy

Most radiation therapies utilize photons – lightweight particles that damage cancerous cells.  Neutron beam therapy (NBT) uses neutrons, which are much heavier than photons and appear to be more effective in destroying very dense tumors.  Compared to roentgen ray (X-ray), neutrons are characterized by several properties:

1. reduced oxygen enhancement factor,
2. less or no repair of sub-lethal or potentially lethal cell damage, and
3. less variation of sensitivity through cell cycle. 

Neutron beam radiation therapy (NBRT) is a specialized type of EBRT that uses high energy neutrons (neutral charged subatomic particles). The neutrons are targeted toward tissue masses that are characterized by lower tumor oxygen levels and a slower cell cycle, since neutrons require less oxygen and are less dependent on the cell’s position in the cell division cycle. Neutrons impact with approximately 20 to 100 times more energy than conventional photon radiation and may be more damaging to surrounding tissues. For that reason, the radiation is delivered utilizing a sophisticated planning and delivery system. 

Neutron beam therapy entails the use of a particle accelerator; protons from the accelerator are deflected by a magnet to a target which creates the neutron beam.  Neutron bean therapy has been employed mainly for the treatment of the salivary gland cancers.  It has also been used to treat other malignancies such as soft tissue sarcoma (STS) as well as lung, pancreatic, colon, kidney and prostate cancers.  Nevertheless, NBT has not gained wide acceptance because of the clinical difficulty in generating neutron particles.  It should be noted that NBT is different from boron neutron capture therapy (BNCT), which is a radiotherapy based on the preferential targeting of tumor cells with non-radioactive isotope (10)B and subsequent activation with thermal neutrons to produce a highly localized radiation, and is often used to treat brain tumors.  In BNCT, the patient is given a drink containing boron, which is taken up by tumor cells.  The tumor is then irradiated with a neutron beam, causing the boron to split into two highly energetic particles (helium and lithium) that destroy the cancerous cells while largely sparing adjacent healthy cells.

Salivary Gland Cancer

In the treatment of patients with salivary gland cancer, primary radiation including NBT may play a role in certain histological types or non-operative patients (Day, 2004).  Neutron beam therapy has been most extensively used either for an incompletely excised primary tumor or for recurrent disease.

In a randomized clinical study, Laramore and associates (1993) compared the effectiveness of fast neutron radiotherapy versus conventional photon and/or electron radiotherapy for unresectable, malignant salivary gland tumors.  Eligibility criteria included either inoperable primary or recurrent major or minor salivary gland tumors.  Patients were stratified by surgical status (primary versus recurrent), tumor size (less than or greater than 5 cm), and histology (squamous or malignant mixed versus other).  After a total of 32 patients were entered into this study, it appeared that the group receiving fast neutron radiotherapy had a significantly improved local/regional control rate and also a borderline improvement in survival and the study was stopped earlier than planned for ethical reasons.  Twenty-five patients were study-eligible and analyzable.  Ten-year follow-up data for this study was presented.  On an actuarial basis, there was a statistically-significant improvement in local/regional control for the neutron radiotherapy group (56 % versus 25 %, p = 0.009), but there was no statistically significant improvement in OS (15 % versus 25 %).  Patterns of failure were analyzed and it was demonstrated that distant metastases account for the majority of failures on the neutron radiotherapy arm and local/regional failures account for the majority of failures on the photon/electron radiotherapy arm.  Long-term, treatment-related morbidity was analyzed and while the incidence of morbidity graded "severe" was greater on the neutron arm, there was no significant difference in "life-threatening" complications.  These investigators concluded that fast neutron radiotherapy appeared to be the treatment-of-choice for patients with inoperable primary or recurrent malignant salivary gland tumors.

Prott et al (2000) reported their findings of fast neutron therapy in 72 patients with adenoid cystic carcinoma (ACC) of the salivary glands.  The median age was 54 years; and the median follow-up was 50 months.  This study showed that 39.1 % of the patients achieved a complete remission and 48.6 % achieved partial remission.  The survival probability was 86 % after 1 year, 73 % after 2 years and 53 % after 5 years.  The recurrence-free survival was 83 % after 1 year, 71 % after 2 years and 45 % after 5 years.  These investigators concluded that NBT appeared to have been an effective treatment in these selected patients.

Huber and colleagues (2001) compared retrospectively radiotherapy with neutrons, photons, and a photon/neutron mixed beam in patients (n = 75) with advanced ACC of the head and neck.  Local control, survival, distant failure, and complications were analyzed.  Follow-up ranged from 1 to 160 months (median 51 months), and the surviving patients had a minimum follow-up of 3 years at the time of analysis.  The actuarial 5-year local control was 75 % for neutrons, and 32 % for both mixed beam and photons (p = 0.015, log-rank).  This advantage for neutrons in local control was not transferred to significant differences in survival (p > 0.1).  In multi-variate analysis post-operative radiotherapy (p = 0.003) and small tumor size (p = 0.01) were associated with high local control, while primary therapy (p = 0.006) and negative lymph nodes (p = 0.01) were associated with longer survival.  While acute toxicity was similar in all 3 radiotherapy groups, severe late grade 3 and 4 toxicity tended to be more prevalent (p > 0.1) with neutrons (19 %) than with mixed beam (10 %) and photons (4 %).  These researchers concluded that fast neutron radiotherapy provides higher local control rates than a mixed beam and photons in advanced, recurrent or not completely resected ACC of the major and minor salivary glands.  Neutron radiotherapy can be recommended in patients with bad prognosis with gross/macroscopic residual disease (R2 resection), with unresectable tumors, or inoperable tumors.

Douglas et al (2003) evaluated the effectiveness of fast neutron radiotherapy for the treatment of salivary gland neoplasms.  Of the 279 patients, 263 had evidence of gross residual disease at the time of treatment, while16 had no evidence of gross residual disease; 141 had tumors of a major salivary gland, and 138 had tumors of minor salivary glands.  The median follow-up period was 36 months (range of 1 to 142 months).  The main outcome measures were local-regional control, cause-specific survival, and freedom from metastasis.  The 6-year actuarial cause-specific survival rate was 67 %.  Multi-variate analysis revealed that low group stage (I - II) disease, minor salivary sites, lack of skull base invasion, and primary disease were associated with a statistically significant improvement in cause-specific survival.  The 6-year actuarial local-regional control rate was 59 %.  Multi-variate analysis revealed size 4 cm or smaller, lack of base of skull invasion, prior surgical resection, and no previous radiotherapy to have a statistically significant improved local-regional control.  Patients without evidence of gross residual disease had a 100 % 6-year actuarial local-regional control.  The 6-year actuarial freedom from metastasis rate was 64 %.  Factors associated with decreased development of systemic metastases included negative lymph nodes at the time of treatment and lack of base of skull involvement.  The 6-year actuarial rate of development of grade 3 or 4 long-term toxicity (using the Radiation Therapy Oncology Group and European Organization for Research on the Treatment of Cancer criteria) was 10 %.  No patient experienced grade 5 toxic effects.  The authors concluded that NBT is an effective treatment for patients with salivary gland neoplasms who have gross residual disease and achieves excellent local-regional control in patients without evidence of gross disease.

Other Types of Cancer

Russell et al (1994) evaluated the effectiveness of fast neutron radiation therapy in treatment of locally advanced carcinomas of the prostate (n = 178).  Median follow-up was 68 months (range of 40 to 86 months).  The 5-year actuarial clinical local-regional failure rate was significantly better for neutron-treated patients than photon-treated patients (11 % versus 32 %).  When findings of routine post-treatment prostate biopsies were incorporated, the resulting "histological" local-regional tumor failure rates were 13 % for the neutron-treated group versus 32 % for the photon-treated group (p = 0.01).  Moreover, actuarial survival and cause-specific survival rates were statistically indistinguishable for the 2 patient cohorts, with 32 % of the neutron-treated patient deaths and 41 % of the photon-treated patient deaths caused by prostate cancer.  Prostate specific antigen values were elevated in 17 % of neutron-treated patients and 45 % of photon-treated patients at 5 years (p < 0.001).  Severe late complications of treatment were higher for the neutron-treated patients (11 % versus 3 %), and were inversely correlated with the degree of neutron beam shaping available at the participating institutions.  The authors concluded that high energy fast neutron radiotherapy is safe and effective when adequate beam delivery systems and collimation are available, and it is significantly superior to external beam photon radiotherapy in the local-regional treatment of large prostate tumors.

In a review on the use of fast neutron radiation for the treatment of prostatic adenocarcinomas, Lindsley et al (1998) stated that the Radiation Therapy Oncology Group performed a multi-institutional randomized trial comparing mixed beam (neutron plus photon) irradiation to conventional photon irradiation for the treatment of locally advanced prostate cancer.  A subsequent randomized trial by the Neutron Therapy Collaborative Working Group compared pure neutron irradiation to standard photon irradiation.  Both studies reported significant improvement in loco-regional control with neutron irradiation compared to conventional photon irradiation in the treatment of locally advanced prostate carcinoma.  To date, only the mixed beam study has demonstrated a significant survival benefit.  Future analysis of the larger Neutron Therapy Collaborative Working Group trial at the 10-year follow-up should confirm whether or not improved loco-regional control translates into a survival advantage.

Lindsley et al (1996) noted that a phase III clinical study comparing NBT to photon radiotherapy for inoperable regional non-small cell lung cancer showed no overall improvement in survival.  However, a statistically significant improvement in survival was observed in the subset of patients with squamous cell histology.  Engenhart-Cabillic and colleagues (1998) discussed the use of NBT in the management of locally advanced non-resectable primary or recurrent rectal cancer.  They noted that the value of radiation therapy in managing such patients is being appreciated, although up to 40 % of the treated patients have no symptomatic response.  The authors also stated that over 350 patients were entered in studies comparing NBT alone and mixed-beam treatments.  At present, no therapeutic gain for long-lasting survival has been achieved.  However, local control and pain improvement seems to be better with NBT than with photon therapy.  There is insufficient evidence regarding the effectiveness of NBT for rectal and lung cancers.

Strander et al (2003) stated that there is some evidence that adjuvant radiation therapy in combination with conservative surgery improves the local control rate in the treatment of STS of extremities and trunk in patients with negative, marginal or minimal microscopic positive surgical margins.  A local control rate of 90 % has been achieved.  Improvement is obtained with radiation therapy added in the case of intralesional surgery, but the local control rate is somewhat lower.  More studies are needed on this issue.  For STS in other anatomical sites, retroperitoneum, head and neck, breast and uterus, there is only weak indication of a benefit for the local control rate, with the use of adjuvant radiation therapy.  There is still insufficient data to establish that pre-operative radiotherapy is favorable compared to post-operative radiotherapy for local control in patients presenting primarily with large tumors.  One small study has shown a possible survival benefit for pre-operative radiotherapy.  There is fairly good evidence to suggest that the pre-operative setting results in more wound complications.  There is no randomized study comparing external beam radiotherapy and brachytherapy.  The data suggested that external beam radiotherapy and low-dose rate brachytherapy result in comparable local control for high-grade tumors.  Some patients with low-grade STS benefit from external beam radiotherapy in terms of local control.  Brachytherapy with low-dose rate for low-grade tumors seems to be of no benefit, but data are sparse.  The available data are inconclusive concerning the effect of intra-operative high-dose rate radiotherapy for retroperitoneal STS.  Further studies are needed.  Neutron radiotherapy might be beneficial for patients with low-grade and intermediate-grade tumors considered inoperable and for those operated with intralesional margins.  More severe adverse effects for NBT have been reported.

Murray (2004) noted that the commonest STS of the upper extremity are the epithelioid sarcoma, synovial cell sarcoma, and malignant fibrous histiocytoma.  Limb salvage surgery is the treatment of choice for STS to preserve upper extremity function.  Following wide tumor resection, adjuvant therapies such as chemotherapy, external beam radiation therapy, and brachytherapy may lessen local recurrence rates, but their effect on overall survival remains unclear.

A review by Hassen-Khodja and Lance (2003) stated that the efficacy of NBT is well-established only for the treatment of inoperable or unresectable salivary gland tumors, regardless of their degree of malignancy or stage of progression, and for the treatment of large residual tumors after surgical resection.  The authors also examined the data on the effectiveness of for NBT in the treatment of malignant prostate tumors, STS and central nervous system tumors.  However, these data are insufficient to rule on its therapeutic efficacy.

An assessment of the evidence for neutron beam radiotherapy prepared by the Australia and New Zealand Horizon Scanning Network (Purins et al, 2007) found that NBT is a promising technology.  The assessment cautioned, however, that "[t]he studies identified in this prioritising summary were not of high quality and, as such, the conclusions must be taken as preliminary in nature."

In a phase I study, Kankaanranta and colleagues (2011) examined the safety of BNCT in the treatment of malignant gliomas that progress after surgery and conventional external beam radiation therapy.  Adult patients who had histologically confirmed malignant glioma that had progressed after surgery and external beam radiotherapy were included in this study, provided that greater than 6 months had elapsed from the last date of radiation therapy.  The first 10 patients received a fixed dose, 290 mg/kg, of l-boronophenylalanine-fructose (l-BPA-F) as a 2-hour infusion before neutron irradiation, and the remaining patients were treated with escalating doses of l-BPA-F, either 350 mg/kg, 400 mg/kg, or 450 mg/kg, using 3 patients on each dose level.  Adverse effects were assessed using National Cancer Institute Common Toxicity Criteria version 2.0.  A total of 22 patients entered the study.  Twenty subjects had glioblastoma, and 2 patients had anaplastic astrocytoma, and the median cumulative dose of prior external beam radiotherapy was 59.4 Gy.  The maximally tolerated l-BPA-F dose was reached at the 450 mg/kg level, where 4 of 6 patients treated had a grade 3 adverse event.  Patients who were given more than 290 mg/kg of l-BPA-F received a higher estimated average planning target volume dose than those who received 290 mg/kg (median of 36 versus 31 Gy [W, i.e., a weighted dose]; p = 0.018).  The median survival time following BNCT was 7 months.  The authors concluded that BNCT administered with an l-BPA-F dose of up to 400 mg/kg as a 2-hour infusion is feasible in the treatment of malignant gliomas that recur after conventional radiation therapy. 

Ghost Cell Odontogenic Carcinoma

Martos-Fernandez et al (2014) noted that ghost cell odontogenic carcinoma is a rare condition characterized by ameloblastic-like islands of epithelial cells with aberrant keratinitation in the form of ghost cell with varying amounts of dysplastic dentina.  These investigators reported a case of a 70-year old woman with a rapid onset of painful swelling right maxillary tumor.  Magnetic resonance showed a huge tumor dependent on the right half of the right hard palate with invasion of the pterygoid process and focally to the second branch of the trigeminal.  Radiological stage was T4N0.  The patient underwent a right subtotal maxillectomy with clear margins.  Adjuvant radiotherapy was given.  The patient was free of residual or recurrent disease 12 months after surgery.  The tumor was 3.9 cm in diameter.  It was spongy and whitish gray.  Microscopically the tumor was arranged in nets and trabeculae, occasionally forming palisade.  Tumoral cells had clear cytoplasm with vesicular nuclei.  There was atipia and mitosi with vascular and peri-neural invasion.  The excised tumor was diagnosed as a GCOC.  The authors concluded that ghost cell carcinoma is a rare odontogenic carcinoma.  Its course is unpredictable, ranging from locally invasive tumors of slow growth to highly aggressive and infiltrative ones.  Wide surgical excision with clean margins is the treatment of choice although its combination with post-operative radiation therapy, with or without chemotherapy, remains controversial.  This was a single-case study, and it’s unclear whether NBT was used as adjuvant radiotherapy.  Moreover the authors stated that post-operative radiation therapy, with or without chemotherapy, remains controversial.

Li et al (2014) stated that the diagnosis of ameloblastic carcinoma is often difficult and the optimal treatment methods remain controversial.  The current study retrospectively investigated the optimal diagnosis and treatment methods of 12 ameloblastic carcinoma patients at the West China Hospital of Stomatology, Sichuan University (Chengdu, China), and 20 patients selected from the PubMed database, were reviewed.  The clinical features, diagnosis and outcome of the different treatments were evaluated.  Ameloblastic carcinoma occurred in 12 out of a total of 538 ameloblastoma patients; the majority were of the primary type.  Of the 538 ameloblastoma patients, 294 were males, 244 were females with a male to female ratio of 1.2:1.  The predilection age is 20 to 30 years, which accounts for 40 % of the total.  In total, 461 cases were in the mandible and 77 were located in the maxilla.  The cure rate of the primary type and the recurrence rate of the secondary type tumors were higher in the patients from the West China Hospital of Stomatology compared with those reported in the literature.  In particular, a case with a long-term survival of 30 years was presented, which was considered to be relatively rare.  The evolution of the clinical course has experienced 3 stages: Ameloblastoma (1978) followed by metastatic ameloblastoma (2000) and finally ameloblastic carcinoma (2008).  To avoid recurrence, wide local excision with post-operative radiation therapy was required.  While novel therapeutic regimens should also be considered as appropriate, including carbon ion therapy and Gamma Knife stereotactic radiosurgery.  However, controlled studies with larger groups of patients are required to increase the accuracy of results.  This study did not mention ghost cell odontogenic carcinoma and NBT.

Furthermore, reviews on "Ghost cell odontogenic carcinoma" (Martos-Fernandez et al, 2014; Ahmed et al, 2015) do not mention NBT as a therapeutic option.

Carbon Ion Radiotherapy

An assessment of carbon ion radiotherapy for cancer treatment, conducted by the Ludwig Boltzmann Institut (2018) found that carbon ion therapy should be considered unproven for all of the indications examined in the assessment. Noting that it is unclear for which tumor indications carbon ion radiotherapy (CIRT) should be used and if CIRT is more effective and safe than conventional photon radiotherapy, the investigators conducted a systematic review on the effectiveness (mortality, morbidity) and safety of CIRT for 54 oncologic indications in 12 parts of the body (i.e., skull base, eyes, brain, ear-nose-throat, lung, gastrointestinal tract, bone and soft tissue, prostate, breast, kidney, nervous system, hematologic cancer). A systematic search was conducted for data on the safety and efficacy of CIRT in the following databases: Cochrane (CENTRAL), CRD (HTA, NHS-EED, DARE), Embase and Ovid MEDLINE. Additionally, a hand search was conducted on the websites of those cancer therapy centers currently offering CIRT, and the Particle Therapy Co-Operative Group (PTCOG) to identify further relevant published and ongoing studies. Overall, 56 published studies elaborating on the efficacy and/or safety of CIRT were identified: The majority of the studies chose samples with CIRT patients suffering from tumors in the brain and skull base, prostate and lung region, with 14, 11 and 9 identified studies in those regions respectively. Ear-nose-throat cancer was another significant cluster, consisting of 7 clinical studies. Less frequent clusters were in the bone and soft tissue and gastrointestinal (GI) regions, with 2 and 4 clinical studies respectively assessing the efficacy and safety of CIRT in those regions of the body. In addition, 1 study was identified including patients with choroidal melanomas (of the eye) in their sample. Of those 56 studies, 27 clinical studies were eligible for qualitative synthesis of the efficacy and safety of CIRT when compared to standard irradiation: 1 randomized controlled trial focusing on toxicity and feasibility of CIRT/PRT with a high risk of bias using a historical control, but no other controlled study, was found. The other 26 included studies were either prospective case series (n=20) or, less frequently, case control studies (n=3) or single arm before-after studies (n=3), focusing on health-related quality of life (HRQoL). When assessing the superiority/inferiority of CIRT regarding efficacy and safety on the basis of the selected oncologic endpoints, in comparison to standard irradiation, no scientific evidence was found for 41 indications while insufficient scientific evidence was found for 13 indications in 7 regions: skull base: chordomas, chondrosarcomas; brain: glioma grade II, glioma grade III; glioblastoma; ear-nose-throat: sarcomas in the head and neck, tumors in the nasal cavity and paranasal sinus, adenoid cystic salivary gland carcinoma; bone and soft tissue: soft tissue sarcoma; lung: non-small cell lung carcinoma; prostate: prostate carcinoma; gastrointestinal tract: esophageal carcinoma, rectum carcinoma. The assessment concluded: "Currently, neither superiority nor inferiority on the basis of the selected endpoints regarding efficacy (OS, CSS, DFS, RFS, PFS, LCR, HRQoL) or safety (acute radiation morbidity, late radiation morbidity) can be concluded from the currently (un)available evidence for 54 oncologic indications. CIRT must, at present, therefore be considered an experimental treatment."

Appendix

Note: The benefit plan definition of medical necessity typically includes consideration of the comparative costs of alternative treatments that are at least as likely to produce equivalent therapeutic results. Please check benefit plan descriptions.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Proton Beam Radiotherapy (PBRT):
CPT codes covered if selection criteria are met:
77520	Proton treatment delivery; simple, without compensation
77522	simple, with compensation
77523	intermediate
77525	complex
Other CPT codes related to the CPB:
61796	Stereotactic radiosurgery (particle beam, gamma ray or linear accelerator); 1 simple cranial lesion
+61797	each additional cranial lesion, simple (List separately in addition to code for primary procedure)
61798	1 complex cranial lesion
+61799	each additional cranial lesion, complex (List separately in addition to code for primary procedure)
63620	Stereotactic radiosurgery (particle beam, gamma ray, or linear accelerator); 1 spinal lesion
+63621	each additional spinal lesion, complex (List separately in addition to code for primary procedure)
77432	Stereotactic radiation treatment management of cranial lesion(s) (complete course of treatment consisting of 1 session)
Other HCPCS codes related to the CPB:
C9728	Placement of interstitial device(s) for radiation therapy/surgery guidance (e.g., fiducial markers, dosimeter), for other than the following sites (any approach): abdomen, pelvis, prostate, retroperitoneum, thorax, single or multiple
S8030	Scleral application of tantalum ring(s) for localization of lesions for proton beam therapy
ICD-10 codes covered if selection criteria are met for adults:
C00.0 – C00.9	Malignant neoplasm of lip
C01 - C02.9	Malignant neoplasm of tongue
C03.0 – C10.9	Malignant neoplasm of gum, floor of mouth, palate, other and unspecified parts of mouth, parotid gland, other and unspecified major salivary glands, tonsil, oropharynx
C11.0 – C11.9	Malignant neoplasm of nasopharynx
C12	Malignant neoplasm of pyriform sinus
C13.0 – C13.9	Malignant neoplasm of hypopharynx
C14.0 – C14.8	Malignant neoplasm of other and ill-defined sites in the lip, oral cavity and pharynx
C22.0	Liver cell carcinoma
C30.0 – C31.9	Malignant neoplasm of nasal cavity, middle ear, and accessory sinuses
C32.0 – C32.9	Malignant neoplasm of larynx
C41.0	Malignant neoplasm of bones of skull and face [Skull base tumors]
C41.2	Malignant neoplasm of vertebral column
C44.00 – C44.49	Other and unspecified malignant neoplasm of head and neck
C69.00 – C69.02	Malignant neoplasm of conjunctiva
C69.10 – C69.12	Malignant neoplasm of cornea
C69.20 – C69.22	Malignant neoplasm of retina
C69.30 - C69.32	Malignant neoplasm of choroid
C69.40 - C69.42	Malignant neoplasm of ciliary body
C69.50 – C69.52	Malignant neoplasm of lacrimal gland and duct
C69.60 – C69.62	Malignant neoplasm of orbit
C69.80 – C69.82	Malignant neoplasm of overlapping sites of eye and adnexa
C69.90 – C69.92	Malignant neoplasm of unspecified site of eye
C70.0 – C70.9	Malignant neoplasm of meninges
C71.0 – C71.9	Malignant neoplasm of brain
C72.0 – C72.9	Malignant neoplasm of spinal cord, cranial nerves and other parts of central nervous system
C76.0	Malignant neoplasm of head, face and neck
D35.5	Benign neoplasm of carotid body
D43.0 – D43.9	Neoplasm of uncertain behavior of brain and central nervous system
ICD-10 codes not covered for indications listed in the CPB for adults (not all-inclusive):
C15.3 - C15.9	Malignant neoplasm of esophagus
C17.0 - C17.9	Malignant neoplasm of small intestine
C19 - C21.8	Malignant neoplasm of rectum, rectosigmoid, rectosigmoid junction, and anus
C22.1 - C22.9	Malignant neoplasm of liver and intrahepatic bile ducts [hepatocellular] [cholangiocarcinoma]
C25.0 - C25.9	Malignant neoplasm of pancreas
C34.00 - C34.92	Malignant neoplasm of bronchus and lung [including non-small-cell lung carcinoma]
C37	Malignant neoplasm of thymus
C40.0 - C40.92, C31.1, C41.3 - C41.9	Malignant neoplasm of bone and articular cartilage of limbs [Ewing's sarcoma] [hemangioendothelioma]
C43.0 - C43.9	Malignant melanoma of skin
C44.90	Unspecified malignant neoplasm of skin, unspecified [Dermatofibrosarcoma protuberans]
C45.0 - C45.9	Mesothelioma
C48.0	Malignant neoplasm of retroperitoneum [retroperitoneal sarcoma]
C49.0 - C49.9	Malignant neoplasm of connective and soft tissue [soft tissue sarcoma] [desmoid fibrosarcoma] [fibrosarcoma of extremities] [squamous cell carcinoma of the head and neck][leiomyosarcoma of extremities] [angiosarcoma] [hemangioendothelioma] [cardiac intimal sarcoma]
C50.01 - C50.929	Malignant neoplasm of breast [male and female]
C53.0 - C53.9	Malignant neoplasm of cervix uteri
C55	Malignant neoplasm of uterus, part unspecified
C56.1 - C56.9	Malignant neoplasm of ovary [yolk cell tumor]
C57.4	Malignant neoplasm of uterine adnexa, unspecified
C61	Malignant neoplasm of prostate
C62.00 - C62.92	Malignant neoplasm of testis [yolk cell tumor]
C62.10 - C62.92	Malignant neoplasm of testis
C67.0 - C67.9	Malignant neoplasm of bladder
C75.0	Malignant neoplasm of parathyroid gland
C75.1	Malignant neoplasm of pituitary gland
C75.2	Malignant neoplasm of craniopharyngeal duct
C75.3	Malignant neoplasm of pineal gland [pineal tumor]
C75.4	Malignant neoplasm of carotid body
C78.00 - C78.02	Secondary malignant neoplasm of lung
C78.7	Secondary malignant neoplasm of liver and intrahepatic bile duct
C79.31 - C79.49	Secondary malignant neoplasm of brain, cerebral meninges, and other and unspecified parts of nervous system
C79.82	Secondary malignant neoplasm of genital organs
C79.89	Secondary malignant neoplasm of other specified sites [carotid body] [submandibular gland]
C81.00 - C81.99	Hodgkin's lymphoma
C82.00 - C91.92	Malignant neoplasms of lymphoid, hematopoietic and related tissue [non-Hodgkin lymphoma]
D00.00 - D00.08	Carcinoma in situ of lip, oral cavity, and pharynx
D02.3	Carcinoma in situ of other parts of respiratory system [maxillary sinus tumor]
D10.39	Benign neoplasm of other parts of mouth [Benign neoplasm of minor salivary gland NOS]
D10.6	Benign neoplasm of nasopharynx
D11.0 - D11.9	Benign neoplasm of major salivary glands
D14.0	Benign neoplasm of middle ear, nasal cavity and accessory sinuses [maxillary sinus tumor]
D15.0	Benign neoplasm of thymus
D18.00 - D18.01, D18.03	Hemangioma [hemangioendothelioma]
D18.02	Hemangioma of intracranial structures [cavernous hemangioma]
D18.09	Hemangioma of other sites
D19.0 - D19.9	Benign neoplasm of mesothelial tissue [benign mesothelioma NOS]
D21.0 - D21.9	Other benign neoplasms of connective and other soft tissue [rhabdomyoma]
D32.0 – D32.9	Benign neoplasm of meninges
D33.0 - D33.2	Benign neoplasm of brain
D35.2 - D35.3	Benign neoplasm of pituitary gland or craniopharyngeal duct (pouch)
D35.4	Benign neoplasm of pineal gland [pineal tumor]
D35.5	Benign neoplasm of carotid body
D37.030 - D37.039	Neoplasm of uncertain behavior of major salivary glands
D38.5	Neoplasm of uncertain behavior of other and unspecified respiratory organs [maxillary sinus tumor]
D44.6 - D44.7	Neoplasm of uncertain behavior of paraganglia [carotid body]
D48.1	Neoplasm of uncertain behavior of connective and other soft tissue [desmoid tumor (aggressive fibromatosis)]
D49.0	Neoplasm of unspecified behavior of digestive system
D49.1	Neoplasm of unspecified behavior of respiratory system
D49.6	Neoplasm of unspecified behavior of brain
H35.051 - H35.059	Retinal neovascularization, unspecified
H35.30 - H35.3293	Macular degeneration (age-related)
Q27.9	Congenital malformation of peripheral vascular system, unspecified [cerebrovascular system] [arterio-venous malformations]
Q28.2	Arteriovenous malformation of cerebral vessels [Spinal vessel anomaly] [arterio-venous malformations]
ICD-10 codes covered if selection criteria are met for children:
C00.0 - C7a.8 D00.00 - D09.9	Malignant neoplasm [radiosensitive]
Neutron Beam Therapy (NBT):
CPT codes covered if selection criteria are met:
61796	Stereotactic radiosurgery (particle beam, gamma ray or linear accelerator); 1 simple cranial lesion
+ 61797	each additional cranial lesion, simple (List separately in addition to code for primary procedure)
61798	1 complex cranial lesion
+ 61799	each additional cranial lesion, complex (List separately in addition to code for primary procedure)
77423	High energy neutron radiation treatment delivery, 1 or more isocenter(s) with coplanar or non-coplanar geometry with blocking and/or wedge, and/or compensator(s)
ICD-10 codes covered if selection criteria are met:
C07 - C08.9	Malignant neoplasm of major salivary glands [locally advanced, unresectable, or inoperable]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C00.0 - C06.9 C09.0 - C80.2	Malignant neoplasms [other than salivary gland] [includes ghost cell odontogenic carcinoma]
Carbon Ion Radiotherapy (CIRT):
CPT codes not covered for indications listed in the CPB:
Carbon Ion Radiotherapy - no specific code:

The above policy is based on the following references: