Advances and Challenges in Conducting Clinical Trials with Proton Beam Therapy

Abstract

Advances in proton therapy have garnered much attention and speculation in recent years as the indications for proton therapy have grown beyond pediatric, prostate, spine, and ocular tumors. To achieve and maintain consistent access to this cancer treatment and to ensure the future viability and availability of proton centers in the United States, a call for evidence has been heard and answered by proton radiation oncologists. Answers provided in this review include the evolution of proton therapy research, rationale for proton clinical trial design, challenges in and barriers to the conduct of proton therapy research, and other unique considerations for the study of proton therapy.

Introduction

Numerous technological advances over the past several decades in radiation oncology have allowed a stepwise progression toward the delivery of increasingly conformal radiation treatments. These improvements have subsequently resulted in superior patient outcomes and widening of the therapeutic ratio. The rationale underlying radiotherapy delivery is based on the ‘as low as reasonably achievable’ (ALARA) principle, which dictates that, above all else, the goal of treatment is to deliver a meaningful and optimal dose to the target volume while concomitantly delivering as little dose as possible to normal surrounding tissues—in other words, to deliver the most conformal plan achievable to maximize tumor control while minimizing toxicity to normal tissues from excess radiation dose.

During the evolution from two-dimensional (2D) radiotherapy to 3D conformal radiotherapy (3D-CRT) to intensity-modulated radiation therapy (IMRT), the adoption of novel technologies in radiation oncology has involved the acquisition of new hardware, software, and clinical workflows, many of which have also involved increases in staff time, expenses to the treatment facility, and costs of treatment. Even so, these advancements in radiation therapy technology have been nearly universally adopted in the United States and are generally reimbursed by insurance carriers even though exceedingly few randomized trials or high-level data exist to demonstrate the superiority over older technologies. In the case of IMRT, only a handful of prospective randomized trials have ever shown benefits in toxicity or quality of life from use of this modality over 3D-CRT,^{(1/Yeung, 2/Gandhi)} and data on survival benefit from IMRT are still lacking. Instead, the wider incorporation of advanced technologies has been based on first principles of radiotherapy: striving to reduce the dose to non-target normal tissues to avoid toxicity while delivering more optimal dose to target areas to improve tumor control.

The Evolution of Proton Therapy Technology and Utilization

Proton therapy is an advanced form of external-beam radiation therapy that has arisen on a surge of technologic advancements over the past two decades. In clinical use since 1954, and approved by the United States Food and Drug Administration (FDA) since 1988, the early clinical uses of proton therapy were largely for pediatric tumors, prostate tumors, ocular tumors, and spinal tumors, with only recent expansion of its use for disease at other anatomic sites and other patient populations.^{(3/Slater, 4/Muren)} Part of the reason for the slow adoption of proton therapy has been the scarcity of proton centers in the United States, with only two proton centers in operation until 2001, three until 2006, and then a very gradual increase in centers in the ensuing years (www.ptcog.ch). Today, although geospatial disparities in access to proton therapy remain,^(5/Maillie) 42 proton centers are in operation in the United States, with several additional centers currently in different phases of development.

Proton technology has advanced over the same period from early passive and double-scattering technology to uniform scanning proton therapy, to modern pencil-beam scanning proton therapy, to intensity-modulated proton therapy (IMPT),^{(6//Frank, 7/Kaiser)} and, most recently, to image-guided proton therapy with volumetric imaging.^(8/Veiga) This progression has further widened both the therapeutic ratio and the relative benefit of proton therapy; indeed, the potential for reduced toxicity is such that proton therapy can be integrated with multimodality therapy to allow dose escalation and, for some patients, safe re-irradiation.^{(9/Simone, 10/Verma, 11//Phan)} The challenge in building new proton centers mostly reflects the higher upfront costs, and the ongoing facilities and maintenance costs, of proton therapy machinery and upkeep, which at present are substantially greater than the cost of even the most sophisticated photon technology. However, with the increasing recognition that normal tissues can be better spared by proton therapy, thereby leading to reduced toxicity and preservation of quality of life,^(12/Verma) new centers are being developed despite the high cost and concerns for financial viability.

Great scrutiny has also surrounded the appropriate use of proton therapy, despite its very low use to date (about 1.6% of all external-beam radiation treatment delivered in the United States).^{(13/Medicare)} Calls have been growing for high-level evidence to demonstrate the clinical benefit of proton therapy, to support its use given its higher cost. Although these calls have been recognized by and are being met by practitioners in the field, several barriers have limited the ability to conduct the types of studies and clinical trials needed to effect large-scale change to medical and insurance carrier policies. Herein, we describe the evolution of proton therapy research in the United States, past and current challenges in conducting clinical trials of proton therapy, and future directions for ongoing studies of the applications for and delivery of proton and other types of particle therapy.

Proton Therapy Availability in the United States

Clinical evidence supporting the use of proton therapy for indications other than pediatric, ocular, and spinal tumors has emerged only recently for a variety of reasons, primarily: (1) the dearth of proton centers capable of generating appreciable clinical experience and evidence; (2) technology limitations; and (3) insurance coverage and denials of treatment.

The existence of only five operational proton centers in the United States until 2009 has by necessity limited the use of proton therapy. Since that time, improvements such as uniform scanning, followed soon thereafter by pencil-beam scanning technology and the increased recognition and incorporation of more sophisticated on-board CT imaging for proton delivery, have brought burgeoning interest in using proton therapy for additional, increasingly complex disease sites and indications. Indeed, in the interval since 2009 the number of proton centers has greatly increased, with an additional 37 centers opening in the U.S. from 2009 through 2022. Much of this growth has been from the development of modern, single-room proton centers, the first of which became operational in 2013. From 1990 through 2013, all 10 proton centers in operation consisted of at least 3, but more commonly 4 or 5, treatment rooms. Most of the 18 centers developed and in operation since 2013 are single-room treatment centers, models that are more economical and efficient in development and maintenance, making the technology more accessible in appropriate geographic settings compared with the larger multi-room proton centers.

Proton Therapy Clinical Trial Development and Endpoint Selection

The numbers of published clinical reports of photon therapy over the past decade far exceeds those of proton therapy relative to the actual use of proton therapy in radiation oncology. Numerous comparative studies have shown that proton therapy led to improved toxicity,^{(14//Blanchard, 15//Zhang, 16//Holliday, 17//Baumann, 18/McDonald, 19/Xi, 20//Lin, 21/Hoppe, 22/Kahalley, 23/Boyce, 24/Romesser)} better preservation of quality of life,^{(25/Sio, 12/Verma)} higher work productivity,^(26/Smith) and fewer secondary malignancies^{(27/Xiang, 28/Chung)} relative to photon therapy; nevertheless, these reports have not been adequate to prompt significant recommendation changes and increased insurance coverage for proton therapy. Non-randomized comparative studies have also demonstrated survival benefits for proton therapy over photon therapy for several types of disease, including liver cancer,^{(29/Sanford, 30/Hasan)} lung cancer,^{(31/Higgins, 32/Chi)} esophageal cancer,^(19/Xi) and head and neck cancers.^{(33/Patel, 34/Li)} Similarly, these publications have also not been sufficient to effect widespread and consistent insurance coverage access to this type of therapy.

Thus, if we are to hold particle therapy to a different standard than that for previous adoption of new radiation modalities, and require higher-level data to support its use (possibly because of the larger absolute cost differential in delivering this treatment versus prior cost increases for delivering other new modalities), how do we determine—and who is the “we” who makes these determinations?—which endpoints are sufficiently meaningful to result in this treatment being recognized as a viable, and even favored, option, thus virtually necessitating its coverage by a patient’s insurance payor? What kinds of trial designs and level of evidence are necessary to make this determination?

Early proton investigations were limited by numerous logistical challenges owing to the scarcity of treatment centers, heterogeneity in proton technology, and low insurance coverage, all of which created an extremely limited pool of patients available for study. Reports of retrospective experiences have created a valuable foundation for understanding which disease presentations could be considered for treatment with proton therapy, and they have also demonstrated the safety and feasibility of proton therapy during this initial expansion of indications. However, it quickly became clear that studies supporting the hypothesis that proton therapy would result in outcomes at least equivalent to, if not superior to, outcomes from photon therapy because of protons’ superior conformality and normal tissue sparing would not constitute sufficient evidence to garner its acceptance as a modality of choice. Therefore, several early-phase, single-arm prospective trials were developed rapidly to provide additional evidence that would be gathered in a pre-planned, systematic manner. Substantial efforts have been made to gather these data, despite the aforementioned barriers to enrollment and completion of these trials that were still in place. Yet these single-arm, institutional studies, which again demonstrated favorable outcomes,^{(14/Blanchard, 16/Holliday, 35/Gunn)} still did not appease non-proton practitioners, policy makers, and insurance carriers that proton therapy is a necessary, important option to provide for appropriate patients.

Thus, the radiation oncology community has worked together to develop randomized clinical trials of proton versus photon therapy, and achieved rapid accrual to some of these trials, in recognition of the urgent need to demonstrate the clinical superiority of proton therapy for specific indications to make this resource more widely accepted and available to patients.

The very first randomized trials of proton therapy and photon therapy focused on the use of proton therapy to facilitate dose escalation.^{(36/Shipley, 37/Zietman)} Although benefits were identified from the dose escalation allowed by proton therapy, and these trials were considered to have ‘positive’ findings, they were not true comparisons between the different radiation modalities. To date, four true randomized trials have been reported that directly compare proton therapy with photon therapy.^{(38/Liao, 39/Nantavithya, 20/Lin, 40/Brown)} The focus in these trials, all of which are phase II (Table 1), was mostly toxicity. Specifically, one trial in locally advanced non-small cell lung cancer (NSCLC) assessed grade ≥3 treatment-related pneumonitis in parallel with local failure rate at 12 months; another trial of early-stage NSCLC assessed the rate of grade ≥3 toxicities at 2 years; a third trial of locally advanced esophageal cancer assessed total toxicity burden at 12 months and progression-free survival at 6 months; and the fourth trial of glioblastoma multiforme assessed grade ≥3 toxicity at 2 years.

Table 1.

United States Proton vs. Photon Randomized Trials with Completed Accrual and Reported Results

Trial Name and Reference	Study Design and Site(s)	No. Pts	Intervention and Trial Period	Inclusion Criteria	Primary Endpoint	Results
Completed Accrual, Resulted
Trial of Image-Guided Adaptive Conformal Photon vs Proton Therapy, With Concurrent Chemotherapy, for Locally Advanced Non-Small Cell Lung Carcinoma: Treatment-Related Pneumonitis and Locoregional Recurrence (NCT00915005)(38/Liao)	Bayesian adapted randomized MD Anderson and Mass General	272	PS-PBT or IMRT 74 Gy(RBE) / 37 fx with paclitaxel/carboplatin 2009–2014	Unresected, locoregionally advanced NSCLC	Grade ≥3 treatment-related RP Local failure	No difference in RP or local failure Improvements in both endpoints over course of trial
Phase IIB Randomized trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for the Treatment of Esophageal Cancer (NCT01512589)(20/Lin)	Phase IIB, randomized MD Anderson	145	PS-PBT (80%) or IMRT 50.4 Gy(RBE) / 28 fx 2012–2019	Locoregionally advanced esophageal cancer	Total toxicity burden at 12 months Progression-free survival (PFS)	2.3x increase in total toxicity burden for IMRT vs. PBT Similar 3-yr PFS (50.8% vs. 51.2%) and 3-yr OS (44.5% vs. 44.5%)
A Prospective Phase II Randomized Trial to Compare Intensity Modulated Proton Radiotherapy (IMPT) vs. Intensity Modulated Radiotherapy (IMRT) for Newly Diagnosed Glioblastoma (WHO Grade IV) (NCT01854554)(40/Brown)	Phase II, randomized MD Anderson	90	IMPT (73%) or IMRT 60 Gy(RBE) / 30 fx with concurrent and adjuvant temozolomide 2013–2016	Glioblastoma or gliosarcoma (WHO Grade IV), adapted RPA class III-V	Time to cognitive failure	No difference time to cognitive failure IMPT reduced grade ≥2 toxicity and patient-reported fatigue
Randomized Phase II Study Comparing Stereotactic Body Radiotherapy (SBRT) With Stereotactic Body Proton Therapy (SBPT) for Centrally Located Stage I, Selected Stage II and Recurrent Non-Small Cell Lung Cancer (NCT01511081)(39/Nanthakidthya)	Phase II, randomized MD Anderson	21	Stereotactic body proton therapy or stereotactic body radiotherapy to 50 Gy(RBE) / 4 fx daily	Medically inoperable NSCLC with high-risk features (centrally located or <5cm T3 or isolated lung parenchymal recurrences	Grade ≥3 toxicities at 2 years	Closed early for poor accrual Numerically improved 3-year OS with SBPT vs. SBRT 1 grade 2 toxicity with SBPT

Abbreviations: PS, passive scattering; PBT, proton therapy; fx, fractions; NSCLC, non-small cell lung cancer; yr, year; IMPT, intensity-modulated proton therapy; IMRT, intensity-modulated radiation therapy; RP, radiation pneumonitis; OS, overall survival; PFS, progression-free survival; RPA, recursive partitioning analysis

The total toxicity burden assessed in the esophageal cancer trial was a novel and logical, albeit widely criticized, endpoint. Total toxicity burden is a composite score of 13 possible instances of 11 different adverse events, assessed up to 12 months after randomization with the intent to quantify and assess global toxicity severity among patients.^(41/Hobbs) This endpoint is intuitive in the sense that, by reducing the integral dose and the dose delivered to numerous organs at risk (OARs), proton therapy can simultaneously reduce the toxicities associated with excessive irradiation to several organ systems relative to photon therapy. This point is particularly noteworthy because the phase II esophageal cancer trial was closed early when it met its predefined benefit and when a national phase III randomized trial of locally advanced esophageal cancer was activated (NRG Oncology GI006). The phase II esophageal cancer trial also had a high rate of unevaluable patients among those who did enroll, leaving little power to detect a significant difference in any single toxicity measure. In fact, although no significant difference would have been noted if only single forms of toxicity were assessed (e.g., atrial fibrillation [5 photon, 1 proton], pericardial effusion [6 photon, 2 proton], acute respiratory distress syndrome [4 photon, 0 proton], reintubation [4 photon, 0 proton], or postoperative pneumonia [7 photon, 1 proton]), combining these events into a total toxicity burden score revealed a statistically significant benefit from proton therapy over photon therapy, with the total toxicity burden being 2.3 times higher for IMRT than for proton therapy, and the postoperative complication score (for those patients who underwent surgery) being 7.6 times higher than for proton therapy.^(20/Lin)

However, even though experience with delivering proton therapy showed that pneumonitis could be reduced and local control improved (in the locally advanced NSCLC trial), that survival could be numerically increased (in the early-stage NSCLC trial), that toxicities, assessed by both physicians and patients, could be improved (in the glioblastoma trial), and that total toxicity burden could be reduced (in the esophageal cancer trial), each of these trials has been met with significant skepticism.^{(38/Liao, 39/Nantavithya, 20/Lin, 40/Brown)} Although skepticism may have been warranted for the early-stage NSCLC trial because it was closed early for poor accrual (largely because of insurance denials of proton therapy and physician concerns regarding the lack of volumetric imaging), had very few evaluable patients, and probably had imbalances between the treatment arms, such skepticism is not warranted for the esophageal cancer trial, which met its primary endpoint. In fact, that trial is the first-ever prospective randomized study of proton versus photon therapy to achieve a positive primary endpoint.^(42/Simone)

Recognizing that improvements in toxicity or quality of life would likely not be enough to prompt wide changes in opinion and insurance coverage for proton therapy, even though improvements such as these in retrospective studies were considered more than adequate to usher in the advent and widespread use of 3D-CRT and later IMRT, recent proton therapy trials have increasingly been phase III trials with a primary endpoint that includes overall survival.

NRG Oncology and the Proton Collaborative Group have led the charge to run large, multicenter trials to study the value of proton therapy. At present, three NRG Oncology phase III trials (Radiation Therapy Oncology Group [RTOG] 1308, GI003, GI006) and one phase II trial (BN005) designed to randomize and directly compare proton therapy to photon therapy across a broad variety of malignancies are currently accruing, and RTOG 1308 (for locally advanced NSCLC) is poised to complete accrual in 2023. BN001 was the first National Clinical Trial Network (NCTN) trial to allow proton therapy; that trial completed accrual in May 2022 and currently awaits data maturation. Another eight NRG Oncology clinical trials are currently active and enrolling that allow proton therapy as standard of care or that directly ask a proton therapy question (HN001, HN009, BN003, GU008, GU009, GU010, LU006, LU008). Some of these trials have achieved robust proton therapy enrollment, even from centers that historically have not appreciably participated in NCTN trials. In addition to the large, prospective worldwide registry of particle therapy (REG001, with nearly 27,000 patients enrolled as of April 2023), member institutions of the Proton Collaborative Group have accrued patients to randomized and single-arm trials assessing the benefits of proton therapy in breast cancer (BRE007, BRE008), prostate cancer (GU002, GU003), lung cancer (LUN005), and pancreatic cancer (PAN009), with encouraging results reported from the completed LUN005^{(43/Hoppe, 44/Hoppe)} and GU002^(45/Vargas) trials. Still more recently, several large investigator-initiated, multicenter trials being conducted outside of cooperative groups have accrued quite well, including the PARTIQoL and COMPPARE trials for prostate cancer, the RADCOMP trial for locally advanced breast cancer, and the MD Anderson Cancer Center–led oropharynx cancer trial, all of which recently completed accrual or have nearly complete enrollment.

However, despite the great excitement surrounding these randomized trials and other important cooperative and collaborative group trials in progress, one should bear in mind that some subsets of disease sites, and some disease types, are not sufficiently common for randomized comparison trials to be feasible. In these instances, a different standard in the level of data required to make proton therapy a viable treatment option for patients is needed. Otherwise, patients will consistently “lose out” on a modality that could be beneficial in terms of reduced toxicity and even improved survival.

Ultimately, endpoint selection should be determined by the disease type being studied and the appropriate question(s) to ask for that disease type. Proton therapy cannot improve survival in all types of disease, despite being able to achieve clinically meaningful reductions in toxicity or becoming cost-effective owing to those reductions in toxicity.^(46/Verma) Carrier coverage should be a secondary consideration in determining trial endpoints, if considered at all, and this should not drive the science behind resource-intensive clinical trials conducted in humans. Much more work is needed to reach consensus within the field and with policy-makers and health insurance carriers to identify which endpoints, and which level of evidence, should be considered to reach significance to the point at which patients will have rightful access to this radiation technology.

Enrollment Barriers to Trials of Particle Therapy

Once randomized clinical trials of proton versus photon therapy were finally opened, new challenges were recognized. First, the number of proton centers in operation was still limited, and thus the pool of potential candidates who could be enrolled on these trials, and the centers capable of such trials, were quite small. When the original iteration of the NRG Oncology Particle Therapy Work Group was launched by the RTOG in 2007 to begin the process of conceiving proton-related RTOG and NRG Oncology clinical trials (starting with RTOG 1308 for locally advanced NSCLC),^(47/Giaddui) only five proton centers were operational in the United States. Although considerably more proton centers are currently available to enroll patients on NRG Oncology and NCTN clinical trials, only 36 centers have completed baseline approval for participation in such trials, compared with many hundreds of centers and institutions that typically activate each phase III NCTN clinical trial of photon therapy. Nevertheless, as of April 1, 2023, an impressive 30 centers have enrolled patients on NCTN proton therapy clinical trials, and this number increases nearly every quarter as new proton centers become operational and are credentialed. The NRG Oncology Radiation Oncology Committee has a central role in credentialing and supporting clinical trial sites, and in standardizing proton therapy treatments, for innovative clinical trials.^(48/Lin)

A second challenge arises from a perceived lack of equipoise between treatment modalities among physicians, which has resulted in limited patient enrollment on clinical trials. Apprehension expressed by radiation oncologists hampered accrual to the completed trials comparing proton therapy with photon therapy for both early-stage and locally advanced NSCLC. If radiation oncologists are convinced that proton therapy can benefit certain patients—such as a patient with stage IIIC NSCLC with bilateral hilar disease and significant preexisting pulmonary compromise, an adolescent / young adult patient with breast cancer and gross internal mammary node disease, or a patient with multifocal, large-volume liver cancer with significant preexisting liver function compromise—they may not feel it is ethical to enroll those patients in randomized trials. As a result, however, trial accrual is hampered and trial outcomes can also be compromised, as patients who may experience more marginal benefit from proton therapy are preferentially enrolled.

Third, patients may not be willing to participate in trials in which they can be randomized to receive photon therapy, a treatment modality that is less new, less advanced, and may be perceived as less likely to provide optimal outcomes. Although discussions with physicians can influence patient willingness to undergo randomization, these discussions can be time-consuming and may still not convince patients of potential equipoise between treatment modalities. In one study, investigators at the University of Pennsylvania and Massachusetts General Hospital assessed patients’ willingness to participate in a randomized trial of IMRT versus proton therapy for prostate cancer, and identified several major themes: altruism/desire to compare treatments; randomization; deference to physician opinion; financial incentives; and time demands/scheduling that influenced the patients’ agreeing to enroll.^(49/Shah) Obtaining assessments such as these before trial activation may better ensure successful trial enrollment.^(50/Shah)

Finally, and importantly, insurance denial has been a primary and substantial barrier to clinical trial enrollment and advancing knowledge on proton therapy. Discussions among NRG Oncology Principal Investigators have led to estimates that 30%−40% of patients screened and eligible for proton versus photon randomized trials have been denied insurance approval for proton therapy and thus have not been able to enroll on these trials. This is a real “catch 22” for the proton therapy community. As stated above, the number of proton centers and the capacity of those centers are limited, and as such the pool of patients who can enroll in randomized trials is limited. At the same time, high-quality data comparing proton and photon therapy are scarce. However, a report from MD Anderson also showed that proton insurance approval rates have decreased over recent years.^(51/Ning) As difficulties in obtaining insurance approval for proton therapy at US centers have increased, so too have the number of patients who cannot be treated on randomized trials without insurance approval owing to concerns of study bias should patients need to cross treatment arms because they are denied coverage of proton therapy. Ironically, without these randomized trial enrollments to generate future data, insurance companies are increasingly not approving proton therapy because of “lack of evidence,” which many carriers believe consists only of completed, positive randomized data. As a result, trial enrollment is disproportionately skewed towards older patients with Medicare insurance, which may further skew ultimate trial outcomes.^(52/Verma)

Clearly, the policies used by insurance companies to determine coverage for advanced radiation modalities are not consistent with the clinical literature or with evidence-based model policies. In fact, proton therapy has the highest rate of discordance among all such advanced modalities.^{(53/Chhabra, 54/Verma)} Moreover, insurance carrier policies are highly variable and are rarely updated in a timely manner. Resulting delays in insurance approval driven by the need for appeals and prior authorizations can be life-threatening and can further dissuade patients and providers from considering or enrolling on clinical trials.^{(55/Yu, 51/Ning, 56/Gupta)}

Conclusions

Proton therapy is in a global renaissance due to remarkable technologic advancements such as IMPT, and as a treatment modality, proton therapy has expanded rapidly to many new centers across the country, thereby improving access for cancer patients. To continue to make this technology accessible and available for patients who could benefit from the conformality and normal tissue sparing it affords, change must occur at the health policy level to ensure insurance coverage of this treatment. To this end, past, current, and future clinical trials and other supporting research will continue to have pivotal roles in providing definitive evidence demonstrating reductions in toxicity, better preservation of quality of life, and even improvements in survival provided by this technology for well-selected patients. Notably, we need to better understand the barriers and challenges that stymie the conduct of these clinical trials, and to make efforts to maintain consistent and logical requirements for the level of evidence that will ultimately be needed to remove access barriers to proton therapy for cancer patients.

Table 2.

United States Proton vs. Photon Randomized Trials with Completed Accrual and Yet-To-Be Reported Results

Trial Name and ID no.	Study Design and Sites	No. Pts.	Intervention and Trial Period	Inclusion Criteria	Primary Endpoint
Prostate Advanced Radiation Technologies Investigating Quality of Like (PARTIQoL): A Phase III Randomized Clinical Trial of Proton Therapy vs IMRT for Low or Intermediate Risk Prostate Cancer (NCT01617161)	Phase III, randomized Multicenter	450	PBT or IMRT daily for up to 9 weeks 2012–2021	Low or intermediate risk prostate cancer	Reduction of mean EPIC bowel scores at 24 months
Randomized Phase II Trial of Hypofractionated Dose-Escalated Photon IMRT or Proton Beam Therapy Versus Conventional Photon Irradiation With Concomitant and Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma (BN001) (NCT02179086)	Phase II, randomized Multicenter	569	Proton center randomization: IMRT 60 Gy / 30 fx or PBT 75 Gy / 30 fx, with concurrent and adjuvant temozolomide 2014–2022	WHO grade IV glioblastoma	Overall survival
A Prospective Comparative Study of Outcomes With Proton and Photon Radiation in Prostate Cancer (COMPPARE) (NCT03561220)	Non-randomized, Parallel assignment	3000	Standard of care PBT or IMRT 2018–2022	Non-metastatic prostate cancer	Bowel urgency and bowel frequency EPIC score at 2 years
Phase II/III Randomized Trial of Intensity-Modulated Proton Beam Therapy (IMPT) Versus Intensity-Modulated Photon Therapy (IMRT) for the Treatment of Oropharyngeal Cancer of the Head and Neck (NCT01893307)	Phase II/III, randomized Multicenter	440	Chemoradiation with IMPT vs IMRT 70 CGE / 33 fx 2013–2022	Stage III-IVB (AJCC 7th Ed.) oropharyngeal squamous cell carcinoma	3-year Progression-free Survival

Abbreviations: PBT, proton therapy; XRT, photon radiotherapy; Gy(RBE) or CGE, units of dose in proton therapy; fx, fractions; IMPT, intensity-modulated proton therapy; IMRT, intensity-modulated radiation therapy

Table 3.

United States Phase III Randomized Proton vs. Photon Clinical Trials Currently Active or Recruiting Patients

Trial Name and ID no.	Study Design and Site	No. Pts	Intervention and Trial Period	Inclusion Criteria	Primary Endpoint
Pragmatic Randomized Trial of Proton vs. Photon Therapy for Patients With Non-Metastatic Breast Cancer: a Radiotherapy Comparative Effectiveness (RADCOMP) Consortium Trial (NCT02603341)	Phase III, randomized Multicenter	1278	PBT or XRT 45–50.4 Gy(RBE) / 25–28 fx 2016-present	Non-metastatic breast cancer with indication for including the internal mammary chain in regional-node irradiation	10-year rate of major cardiovascular events
Phase III Randomized Trial Comparing Overall Survival After Photon Versus Proton Chemoradiotherapy for Inoperable Stage II-IIIB NSCLC (RTOG1308) (NCT01993810)	Phase III, randomized Multicenter	330	PBT or XRT for 35 fx with concurrent chemotherapy 2014-present	Locally advanced non-small cell lung cancer	Overall survival Cardiac toxicity and lymphopenia
A Phase II Randomized Trial of Proton vs. Photon Therapy for Cognitive Preservation in patients With IDH Mutant, Low to Intermediate Grade Gliomas (NRG BN005) (NCT03180502)	Phase II, randomized Multicenter	120	PBT or IMRT for 30 fx 2017-present	IDH-mutant grade II or III glioma	Change in cognition per CTB COMP score
A Phase III Randomized Trial of Protons Versus Photons for Hepatocellular Carcinoma (NRG GI003) (NCT03186898)	Phase III, randomized Multicenter	186	PBT or XRT for 5 or 15 fx 2017-present	Unresectable or locally recurrent hepato-cellular cancer, Child-Turcotte-Pugh A or B7	Overall survival
Phase III Randomized Trial of Proton Beam Therapy Versus Intensity-Modulated Photon Radiotherapy for the Treatment of Esophageal Cancer (GI006) (NC03801876)	Phase III, randomized Multicenter	300	PBT or IMRT 50.4 Gy(RBE) / 28 fx with concurrent chemotherapy	Stage I-IVA esophageal cancer	Overall survival Incidence of grade ≥3 cardiopulmonary adverse events

Abbreviations: PBT, proton therapy; XRT, photon radiotherapy; Gy(RBE), unit of dose for proton therapy; fx, fractions; IMRT, intensity-modulated radiation therapy; CBT COMP, Clinical Trial Battery Composite