Proton therapy in the palliative setting^※

Introduction

Proton beam therapy (PBT) is a unique form of external beam radiotherapy (EBRT) that offers several key physical advantages relative to conventional electron or photon-based techniques. First, protons have significantly more mass than electrons or photons, which can result in less scatter and a sharper lateral beam distribution. Second, PBT allows for energy to be deposited at a specific depth within tissues, with considerable energy fall-off beyond this point—exploiting a phenomenon known as the Bragg Peak (1). As such, with its superior lateral and distal dose conformality, in well-selected patient populations, PBT can offer: (I) safer delivery of therapeutic dose radiation to tumors in challenging anatomic locations that can reduce acute toxicities and/or better optimize tumor control; and (II) decreased integral dose (or exposure to low dose radiation) to adjacent normal tissues, potentially reducing the risks of subacute and late toxicities (1). Additionally, recent improvements in the delivery of PBT, such as pencil beam scanning, allow for an even higher degree of conformality, further amplifying its potential clinical benefit in reducing toxicities and improving clinical outcomes (2-4).

While the dosimetric advantages of PBT are clear, important considerations including high capital costs and limited randomized clinical data have historically limited widespread use and distribution of proton centers (5). However, the recent emergence of single-room proton units has made this technology more logistically and economically viable, thereby improving access and utilization rates across the United States (6,7). Additionally, the indications for PBT have only continued to grow in the past decade: 2022 National Comprehensive Cancer Network guidelines support PBT use across 43 different cancer types, and numerous ongoing phase III randomized trials are directly comparing proton versus photon therapy for the treatment of breast, lung, esophageal, head and neck, liver, brain, and prostate cancers in the upfront or definitive setting (8). While the true clinical benefit of PBT remains an active area of investigation, ongoing studies measuring potential reductions in treatment-related adverse effects will help to elucidate these controversies.

Importantly, rising use of PBT nationally has coincided with the rapid development of novel targeted agents and immunotherapies for a variety of cancer diagnoses. Consequently, patients with locally advanced, recurrent, and metastatic disease are living longer, deriving benefit from advances in systemic therapy. As such, radiation oncologists have also begun to explore the use of PBT in the palliative setting. By definition, palliative radiation therapy is any course of radiation in which a disease is treated with non-curative intent. This includes management of diffusely metastatic, oligometastatic, or even locally advanced disease (9). There have been several studies demonstrating a benefit to PBT for the palliation of tumor-related symptoms, particularly in cases where low dose radiation from photon-based radiation to surrounding normal tissues could cause considerable toxicity, particularly mucosal structures and bone marrow, thereby posing a significant threat to quality-of-life, even if expected prognosis is 6 months to a year. As such, proton therapy can be particularly beneficial in preserving quality of life in patients with advanced malignancies (10). However, it is important to evaluate the appropriateness of PBT on a case-by-case basis, as PBT may not always offer distinct advantages over photon-based approaches. Moreover, as with any decision to deliver treatment in the palliative setting, the decision to deliver PBT must always carefully balance risk with benefit, ensuring that the use of PBT is in alignment with the patient’s goals of care.

Herein, we discuss the use of PBT in the palliative setting across an array of disease sites. We review available data on its overall safety and efficacy, and we explore potential applications for its use, highlighting important limitations as well as considerations for appropriate patient selection when treating with palliative intent.

Lung cancer

Lung cancer is the leading cause of cancer-related mortality, with a 5-year survival rate of only approximately 7% for patients diagnosed with metastatic non-small cell lung cancer (NSCLC). Despite considerable advances in the definitive treatment of localized disease, lung cancer patients have a high recurrence rate of approximately 30–55% (11). Therefore, given that radiation therapy is a primary modality used in the definitive treatment of both early-stage and locally advanced disease, patients with recurrent lung cancer can often benefit from reirradiation (12). Due to its proximity to critical structures such as the heart and spinal cord, reirradiation of the lung can result in significant cardiotoxicity, as well as bone marrow suppression (13). Additionally, the risks of acute and late pulmonary and esophageal toxicities are higher in the reirradiation setting, as the lungs and esophagus have often received high irradiation doses during the initial radiotherapy course. In this setting, the ability of PBT to deliver a conformal reirradiation dose that limits overall radiation to surrounding tissue, may help significantly mitigate these risks (14,15).

In 2017, Chao et al. published the current largest multi-center prospective study to date focusing reirradiation for locally recurrent NSCLC cases treated at the University of Pennsylvania, Procure Oklahoma City, and the Northwestern Medicine Chicago Proton Center. Of the 52 patients who completed their full course of PBT reirradiation, locoregional control was 75% and median overall survival (OS) was 14.9 months. One-year OS and progression free survival (PFS) were 59% and 58%, respectively. This intervention, however, resulted in 6 grade 5 toxicities and 24 total grade 3 or greater acute or late toxicities. Grade 5 toxicities were noted to be bronchopulmonary fistula, severe sepsis secondary to neutropenia and radiation-induced bone marrow suppression, as well as hypoxic respiratory failure secondary to pulmonary effusion (Table 1). Centrally located tumors that abutted critical structures, such as the mainstem bronchus, were noted at higher risk for developing more significant toxicity (16).

Other studies have reported lower toxicity rates in the thoracic reirradiation setting. In a retrospective study from investigators from MD Anderson Cancer Center, 102 patients with locally recurrent NSCLC were treated with reirradiation using either proton or photon therapy. Despite high reirradiation doses [median dose of 60.5 EQD2 (equivalent total dose in 2-Gy fractions) Gy], grade ≥3 toxicities were limited primarily to esophageal (7%) and pulmonary (10%), and higher reirradiation doses were associated on multivariate analysis with improved survival (17). This is notable given that PBT can often allow for safer escalation of radiation dose in the reirradiation setting (18,19). In a prospective registry Proton Collaborative Group multi-center report, proton reirradiation among a cohort of 79 lung cancer patients was generally well tolerated, with only 6% acute grade 3 toxicities and 1% late grade 3 toxicities, although three deaths were determined to be possible related to reirradiation toxicity (20).

Discrepancies in toxicities noted between these studies may be due to a variety of factors. For instance, in one multi-institutional prospective study, participants were stratified into two groups: high-volume [clinical target volume (CTV) ≥250 cm³] and low-volume (CTV <250 cm³). Two of the six patients who developed grade 5 toxicities had high-volume disease, with all but one high-volume patients experiencing a grade ≥3 toxicity as a result of their treatment (21). Additionally, more participants in the multi-institutional prospective study received concurrent chemotherapy which may have augmented treatment toxicity, which was associated with higher toxicities rates in both that trial and the MD Anderson report (16,20). Notably, the incidence of grade 5 toxicities waned over time, thus suggesting that refining delivery of radiation can reduce risks of adverse events. To that end, an intensity-modulated approach to proton reirradiation may help prevent high grade toxicities, while still providing a durable response to treatment as was recently demonstrated in an esophageal cancer proton reirradiation report (22).

Head and neck cancers

Head and neck cancer is the sixth most common cancer worldwide, resulting in more than 350,000 deaths every year (23). Most head and neck cancers are squamous cell carcinomas (HNSCC) arising from the mucosal surfaces of the oral cavity. Patients diagnosed with recurrent or secondary head and neck cancers often have poor prognoses, usually surviving less than a year (24). Unfortunately, up to half of patients with locally advanced head and neck cancers develop locoregional recurrences (24), and for most patients, recurrence is associated with significant morbidity, including pain, bleeding, respiratory distress, dysphagia, speech impairment, and negative self-image (25). While salvage reirradiation has the potential to slow further disease progression, in many cases, retreatment may further diminish a patient’s quality-of-life, especially among those who already received significant treatment in areas of recurrence.

While there is no consensus regarding the optimal management of patients with recurrent or secondary HNSCC, a Quad Shot (QS) regimen has used to palliate patients who have failed or are unable to tolerate standard-of-care therapies. This treatment paradigm, which requires that radiation be delivered twice daily and at least 6 h apart for 2 consecutive days (for a total of 4 fractions), can be repeated with multiple cycles depending on treatment response (26) As with SRS, QS can be delivered with either photon or proton beams, with emerging data supporting the use of proton QS (pQS) in the palliative setting.

A 2020 study assessed palliative responses of recurrent head and neck cancer patients who received photon QS versus proton QS reirradiation between 2011–2018. Out of 166 patients, 68% achieved palliative benefit, with the most common response being relief from tumor-related pain. On multivariate analysis, patients who had a documented palliative response to pQS therapy had improved OS and PFS (27).

Similarly, a 2018 article analyzed 26 patients with recurrent or metastatic HNSCC who received palliative pQS to 3.7 Gy [radiobiological effectiveness (RBE)] twice daily across 2 days. Of note, 88% of patients in this study had prior head and neck radiation. Overall, 73% of patients reported relief from pain interfering with overall quality of life. Pain relief was measured subjectively using a 1 to 10 severity scale and reported at various follow-up intervals after completion of radiation treatment. While 58% of participants experienced a grade 1 toxicity from pQS, none of the participants experienced grade 3 or 4 Common Terminology Criteria for Adverse Events (CTCAE)-designated adverse events or grade 5 toxicity (28).

Collectively, these data support the use of pQS as effective palliative radiation for HNSCC, even among those who received prior photon radiation. Furthermore, the subjective benefit of the proton therapy in this population and the relief from symptoms that these patients achieve generally outweighs the risks of undesired toxicity (27,28).

Proton craniospinal irradiation for leptomeningeal disease (LMD)

LMD is a late-stage sequela of various solid and hematologic malignancies that involves development of multifocal metastases to the leptomeninges. LMD is most common in breast cancer, lung cancer, and malignant melanoma, and it also develops in patients with multiple myeloma, leukemia (most commonly acute lymphoblastic leukemia), lymphoma (most commonly non-Hodgkin’s lymphoma), and primary central nervous system (CNS) malignancies. Estimates suggest that between 1–8% of cancer patients develop LMD. Unfortunately, the prognosis for these patients is grim, with an average median OS of 3–6 months with standard treatments and only 4–6 weeks without intervention (29). In this setting, EBRT can be an effective form of palliation, slowing inevitable disease progression and ultimate neurologic demise (30). However, the use of palliative radiotherapy has historically been avoided in patients, as it can cause significant marrow toxicity, thereby precluding patients from receiving further systemic therapies for treatment of their disease (31). As such, there has been growing interest in using proton craniospinal irradiation (pCSI) to deliver biologically effective radiation dose to diseased tissues, while minimizing potential marrow-related toxicity.

In a 2021 systematic review of 13 retrospective studies investigating the use of CSI for LMD in adult patients greater than 18 years of age, 18% of the total aggregate study cohort (N=275) received pCSI. Notably, while the median OS for the entire cohort was 5.3 months, patients treated with proton pCSI had a slightly higher median OS of 8 months. Additionally, the incidence of bone marrow suppression resulting in leukopenia and neutropenia was significantly reduced among patients who received pCSI relative to photon-based techniques/bone marrow suppression can lead to increased risk of bleeding and life-threatening infections, thus deleteriously impacting patient quality of life (32). In addition to minimizing the incidence of dose-limiting cytopenias, studies suggest that pCSI may also reduce the risk of cardiotoxicity, a documented late effect of photon CSI. Owing to its exit dose through anterior structures, photon-based CSI delivers a small, yet often significant, amount of radiation to the heart. In contrast, pCSI offers virtually zero exit dose, and thus normal cardiac tissue is spared (33). This may provide benefit to younger patients with limited sites of intracranial disease and more favorable performance statuses and prognoses.

A 2021 prospective phase I study by Yang et al. examined the role of hypofractionated pCSI in the management of patients with solid tumors who developed LMD. The study’s primary endpoint was to characterize treatment-related toxicity, while secondary endpoints included CNS PFS and OS. Of the 24 patients enrolled, only 2 patients experienced dose-limiting toxicities (DLTs), notably grade 4 lymphopenia, grade 4 thrombocytopenia, and/or grade 3 fatigue; all DLTs were self-limiting, resolving without further medical intervention. While the median CNS PFS was 7 months, 4 patients had extended periods of freedom from CNS progression for 12 months or longer. The study concluded that hypofractionated pCSI is a safe option for patients with LMD, with some patients experiencing durable disease control (34).

In a recently published subsequent Phase II trial by investigators at Memorial Sloan Kettering Cancer Center exploring pCSI versus photon involved-field radiotherapy (IFRT) for patients with solid tumor LMD, 63 patients were randomized to either IFRT or pCSI. The study’s primary endpoint was CNS PFS, and secondary endpoints included OS and treatment-related adverse events. The study found a significant improvement in PFS in patient’s receiving pCSI vs. IFRT (7.5 vs. 2.3 months). Interestingly, the study also concluded that there was a significant OS benefit to pCSI (9.9 vs. 6.6 months) with no significant increased toxicity (35).

While further investigation with phase III trials are warranted, collectively, these data suggest that pCSI may not only be safe and effective but may also confer a potential survival benefit to patients with this difficult to manage condition. Thus, pCSI should be considered in patients with LMD who have good performance statuses and thus stand to gain a reasonable benefit from this technology.

Brain metastasis and primary CNS malignancies

It is estimated that 10–20% of patients with cancer will develop brain metastasis over the course of their disease (36). Similar to LMD, cancers of the lung, breast, colon, kidney and skin (melanoma) generally tend to have the greatest propensity to metastasize to the brain (37). The treatment intent for patients with brain metastases is largely palliative. In the last decade, there have been a number of immunotherapy options and targeted therapies approved by the FDA that have significant blood-brain barrier activity and. As such, these drugs have been incorporated into the treatment paradigm for brain metastases. Additionally, rising use of highly focused forms of radiation, namely, stereotactic radiosurgery (SRS), have proven effective in the management of brain metastases, improving intracranial disease control and, in many instances, survival (38). In contrast to whole brain radiotherapy (WBRT), which indiscriminately delivers conventional doses of radiation to all brain tissue, SRS is a newer and more advanced modality that allows for the delivery of highly conformal, high-dose radiation to much smaller targets at discrete points throughout the brain (39). Technologic advances in its delivery (e.g., improved image guidance and immobilization), increasing familiarity and comfort among U.S. practitioners, as well as purported neurocognitive advantages over WBRT have led to its widespread use in the treatment of multiple brain metastases, with some centers having the capacity to treat far more than the standard 1–5 lesions (40). In the setting of reirradiation, SRS is particularly useful, even in patients who have previously received WBRT (41). However, as the brain is an inherently radiosensitive organ (42), reirradiation with SRS is associated with the potential risk of radionecrosis (43). Historically, the risk of symptomatic radionecrosis is approximately 20% in patients who have already received radiation to the brain, especially in patients with high-risk features such as large gross tumor burden (44). Although the vast majority of SRS is performed using photon beams, it has been postulated that proton SRS could reduce the risk of radionecrosis in patients with brain metastases or primary CNS malignancies requiring reirradiation (45). Radionecrosis can significantly impact a patient’s overall quality of life and can often be difficult to manage. Treatment of radionecrosis may involve initiation of long-term steroids, bevacizumab, surgery, or a combination of these therapies (46). However, steroids have unfavorable side effects when used long-term, including weight gain, hyperglycemia, mood issues, adrenal insufficiency and increased risk of bone fracture, and bevacizumab has a myriad of contraindications including anticoagulant use or recent bleed (47,48). Additionally, surgery for radiation necrosis has potential morbidity, with some patient developing new or worsening neurologic deficits following surgery (49).

Studies have been conducted comparing overall the quality of plans between proton and photon therapy using the conformity index (CI), the ratio between a fraction of the tumor volume and the volume covered within a certain isodose line. A lower CI generally means that there is less dose administered to normal tissue. In a study published in 2018 evaluated the CI of proton based and photon-based plans across multiple disease sites in both adult and pediatric malignancies, PBT displayed better conformity with a reduction in the integral non-target dose (50).

In a large retrospective 2018 study, Atkins and colleagues from Massachusetts General Hospital reviewed a large single-institution cohort of 370 patients treated with proton SRS between April 1991 and November 2016 for recurrent brain metastasis or primary gliomas or glioblastomas (N=815 brain lesions) who were previously treated with WBRT or photon-based SRS. Median OS was 12.4 months, and estimates of 6-month and 12-month local failure, distant brain failure, and OS were 4.3% and 8.5%, 39.1% and 48.2%, and 76.0% and 51.5%, respectively. Approximately 40.5% of patients experienced treatment-related toxicities, most of which were grade 1 (N=109, 72.7%), and none of which were grade 4 or 5. The common mild to moderate adverse events included fatigue, weakness, and dizziness. Significant symptomatic radionecrosis, confirmed through neuroimaging, was only reported in 3.6% of patients at one year following their initial surgery. The 3.6% rate of radionecrosis reported in this study is notably lower than the historical average of approximately 20%. Overall, this study demonstrates that proton SRS is well-tolerated and provides similar local control when compared to traditional photon SRS. Moreover, proton SRS may prolong OS in patients with aggressive, advanced tumors of the brain not amenable to curative surgery (51).

Similarly, a 2015 study examined the role of proton reirradiation in patients diagnosed with recurrent gliomas or glioblastomas. Between 2005–2012, 20 patients with recurrent gliomas were irradiated with PBT at the Indiana University Health Proton Therapy Center. Median survival from completion of reirradiation was 24.9 months for grade 3 gliomas and 7.8 months for glioblastomas. While most patients tolerated treatment well, 2 patients experienced radiation necrosis following radiation requiring further treatment with hyperbaric oxygen and steroids. Given the high doses of radiation received by these patients previously, the 10% rate of radiation necrosis was deemed modest by the study authors and, once again, was noted to be half that of the reported historic average of approximately 20%. Thus, it was concluded that proton reirradiation for primary CNS tumors is relatively safe and associated with favorable long-term survival outcomes (52).

Informed by positive findings from earlier studies, there are ongoing trials to further evaluate the safety of efficacy of PBT in patients with high grade gliomas or brain metastases, as compared to standard photon-based approaches. An ongoing phase III randomized study conducted by the University Hospital Heidelberg in Germany (NCT04752280) is seeking to evaluate the safety of PBT versus photon beam therapy as standard of care palliative therapy. The primary endpoint of the study is to evaluate overall toxicity, defined as CTCAE grade 2 or higher, within 4 months of treatment. Secondary endpoints include overall and PFS, as well overall quality of life (QoL) scores and neurocognitive ability following treatment (53).

As in LMD, proton therapy for brain metastases and primary high-grade gliomas could prove to minimize toxicity, better preserve quality of life, and potentially even confer an overall PFS benefit (51,52). Additional studies are necessary, however, to better support this postulation (54).

Liver cancer

Primary liver cancers are notoriously difficult to manage. As many patients with liver cancer also have some degree of liver damage or cirrhosis, curative options are often limited. Liver transplantation remains the gold standard in the treatment of localized, unresectable disease (55). However, there are finite livers available for transplantation, and many patients may be on transplant lists for extended periods of time oftentimes exceeding 1 year (56). Additionally, a patient’s Model for End-Stage Liver Disease (MELD) score, which is reflective of underlying liver dysfunction, may preclude them from liver transplantation candidacy (57). Given these treatment challenges, there is a clear need for palliative approaches that could both help prolong a patient’s life expectancy while preserving overall quality-of-life. For patients with unresectable, locally advanced, or metastatic disease, chemotherapy has been a mainstay in the palliative management of liver cancer (58). In contrast, in decades prior, radiation therapy historically was not used in overall management of this disease due to concern for unacceptable toxicities (59).

Like the brain, the liver is considered a highly radiosensitive organ (60). As such, patients who receive radiation to the liver are at risk for developing radiation-induced liver disease (RILD)—a clinically diagnosed radiation-induced hepatitis associated with right upper quadrant pain, ascites and significant transaminitis (61). Researchers have postulated that using protons as opposed to photons can help mitigate the risk of developing RILD, while offering a safe and effective modality with which to palliate symptoms and prevent further disease progression.

In a 2020 prospective study of 63 patients with unresectable primary liver cancers diagnosed with either intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC), participants received a median prescribed PBT dose of 58.05 Gy (RBE) in a median of 15 fractions. Overall, treatment was well-tolerated, with 17 patients (39.5%) experiencing grade 2 toxicities, most commonly fatigue, anorexia, nausea, or vomiting. No patients experienced a grade ≥3 toxicity. Additionally, none of the patients who received proton therapy developed RILD. This approach offered excellent local control at 1 year, with rates of 91.2% and 90.9% for HCC and ICC, respectively. OS estimates at 1-year were 65.6% for HCC and 81.8% for ICC. Although further assessment of late toxicities is pending longer follow-up, study authors concluded that hypofractionated PBT offers excellent local control, with significant organ sparing and a favorable acute toxicity profile relative to what can be achieved with photon therapy (62).

Similarly, a 2016 phase II, multi-institutional study by Hong et al. evaluated 92 patients with biopsy-confirmed HCC or ICC determined to be unresectable by multidisciplinary review with a Child-Turcotte-Pugh score (CTP) of A or B, ECOG performance status of 0 to 2, no extrahepatic disease, and no prior radiation. These patients received 15 fractions of PBT to a maximum total dose of 67.5 Gy (RBE). The study determined that the LC rate was 94.8% for HCC and 94.1% for ICC. In terms of OS, 63.2% of HCC patients were alive at 2 years, as were 45% of ICC patients (63).

A 2014 study published by Makita and his colleagues examined 28 patients with various forms of cholangiocarcinoma treated with PBT. Six patients had ICC or peripheral cholangiocarcinoma (CC), 6 had hilar cholangiocarcinoma, 3 had distal extrahepatic CC, 3 had gallbladder carcinoma, and 10 patients had local or lymph node recurrent tumors. Eight patients had a palliative stent placed prior to PBT initiation, while 3 patients received concurrent platinum-based therapy (either cisplatin or carboplatin). The study found that OS at 1 year was 50%, while LC and PFS rates were 68% and 30%, respectively. In regards to toxicity, gastrointestinal toxicities of grade 2 or higher were observed in 7 patients within 12 months after PBT; these toxicities included development of a duodenal or gastric ulcer and duodenal stenosis. Additionally, 11 patients enrolled in this study developed cholangitis, treated with intravenous antibiotics, and three developed biliary stent strictures. No patient, however, experienced Grade 3 or higher toxicities, thus suggesting this regimen to be relatively safe (64).

Comparative data between proton and photon therapy have emerged for advanced hepatocellular carcinoma. In a single institution retrospective study from Massachusetts General Hospital, 133 patients with unresectable HCC were treated with ablative protons (n=49) or photons (n=84). Proton therapy was associated with an improved OS (HR =0.47, P=0.008) and more than doubling of median OS (31 vs. 14 months), driven by a reduction in risk of radiation-induced liver disease (OR =0.26, P=0.03) (65). Similarly, among inoperable HCC cases in the National Cancer Database, PBT was an independent predictor for longer survival (HR =0.48) despite being delivered to HCC patients with multiple poor prognostic factors relative to photon stereotactic body radiation therapy (SBRT) (66).

Overall, these studies suggest that PBT is safe and provides durable local control for patients with liver cancer who are not candidates for resection or liver transplantation. Additionally, PBT has a reduced overall incidence of RILD, allowing providers the ability to palliate symptoms and prevent further tumor proliferation while minimizing overall toxicity. Although these results are promising, further additional prospective studies are needed to further explore the safety and efficacy of PBT, especially in larger cohorts, with studies ongoing in the management of both primary liver cancer and metastatic disease to the liver. An enrolling NRG Oncology phase III trial (NCT03186898) for patients with unresectable or locally recurrent HCC seeks to directly compare OS of patients with HCC treated with protons versus those treated with traditional photon therapy (67).

Sarcoma

Sarcomas are an uncommon, heterogeneous group of cancers that develop in the bones, cartilage and soft tissues, accounting for only approximately 1% of cancer diagnosed annually (68). While localized sarcoma is often treatable with surgery and adjuvant radiation, the 1-year survival rate for patients diagnosed with metastatic sarcoma is only 15% (69). Common sites of metastatic disease include the thorax and abdomen, often with direct abutment of critical structures. Moreover, most sarcomas are high-grade and highly radioresistant, often resulting in a poor clinical response to traditional photon-based cEBRT (70). To that end, PBT not only offers many potential physical and anatomic advantages, but also potential radiobiological advantages as well owing to the energy and charge properties of protons, with an estimated RBE of at least 1.1 (71). Although this remains an active area of research, available data suggest that PBT is at least as biologically effective as photon therapy, if not greater, thus adding to its appeal in the treatment of metastatic sarcoma.

In the first study of its kind, Lee et al. examined the use of proton QS in the palliative management of 28 patients with 40 sites of metastatic or recurrent sarcoma. The most common histologies were gastrointestinal stromal tumor and leiomyosarcoma, and 67.5% of disease sites were in the abdomen or pelvis. Seventeen (42.5%) treatments involved concurrent systemic therapy and 13 (32.5%) patients received further systemic therapy following proton therapy. Overall, 70% of patients reported a subjective palliative response to treatment. The most common distressing symptom was pain at the tumor site for patients in this cohort, which significantly improved in 67.7% of patients following PBT. While seven grade 3 toxicities were observed, notably intraabdominal infection and colonic obstruction, there were no grade 4 or grade 5 toxicities noted. Also, as this regimen proved effective in palliating symptoms and thus improving overall performance status, 33% of patients were subsequently able to pursue additional systemic therapy for disease management, which was associated with improved OS (72).

A prospective study assessed proton reirradiation as an alternative to systemic therapy or amputation in 23 patients with soft tissue sarcoma who had recurred following prior surgical resection and radiation therapy. Only one grade 3 toxicity (acute dysphagia) was seen, and no grade 4–5 acute or late toxicities were reported. The 3-year cumulative incidence of local failure was 41%, median OS was 44 months, and median PFS was 29 months. Quality of life was also well preserved, with 7/10 (70%) extremity patients being spared an amputation (73).

Limitations to PBT in the palliative setting

Overall, PBT can be a safe and effective palliative treatment modality for advanced solid tumors of varied histologies. However, there are certain limitations to PBT in the palliative setting that must also be considered, along with potential scenarios in which the ultimate risk of PBT outweighs its benefits.

It is important to be cognizant of a patient’s performance status as well as their medical comorbidities prior to initiating palliative PBT. While protons may confer more favorable dosimetric properties compared to photons, these advantages cannot completely mitigate all treatment toxicity, as evidenced by the studies above. Therefore, providers considering PBT for patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater should exhibit caution. In patients who are chronically deconditioned, any palliative radiotherapy—including PBT—may confer greater harm than benefit. For instance, patients with recurrent lung cancer who have significant chronic obstructive pulmonary disease may benefit more from medical analgesic therapy and bronchodilators than they would radiation therapy, as PBT can result in radiation pneumonitis (RP) rates approaching or comparable to rates seen with photon therapy (74,75).

It is also imperative to note that most clinical trials evaluating the safety and efficacy of PBT have stringent inclusion and exclusion criteria, with most excluding patients with poor performance status (i.e., ECOG ≥2). This proves to be a limitation of many oncologic trials (76). Pragmatic studies are still needed to assess the safety of PBT in a frail, older adult population. Additionally, while many patients with advanced cancer are able to tolerate PBT, for some, the process of planning for and undergoing additional therapy may be daunting. Like photon-based radiation, initiating PBT involves a consultation with a radiation oncologist and treatment consent, along with a simulation CT scan to plan treatment, followed by the treatment itself. While each treatment is only a few minutes in length, patients are expected to present to their radiation oncology facility on a daily basis for the duration of their treatment. Treatment length may be a few days to a few weeks depending on tumor type and extent of disease, as well as the radiation technique employed (77). Patients who are deconditioned, have highly symptomatic disease burden, and/or have high pain levels may have difficulty tolerating lying flat on a hard surface while radiation is administered. This is also true for patients with serious comorbidities, including severe congestive heart failure or degenerative joint disease. Intrafractional patient motion in such cases may be more challenging to mitigate with proton therapy than photon therapy. Similarly, many patients such as those with significant ambulatory dysfunction or those with extreme fatigue as a result of either their disease or prior cancer-directed treatments may be less able to come to a radiation oncology facility on a daily basis for treatment. For these patients, either single-fraction photon-based treatment (78) or hospice services, either in-home or facility-based, may be the best option. Additionally, it is important to note that although not widely employed, patients under hospice care may still elect to pursue palliative radiation therapy, whether proton or photon based, to help alleviate their symptoms (79).

Ultimately, these decisions are personal and multifactorial, and they are unique to each patient. Therefore, it is important for providers to appropriately assess their patient’s performance status, and tailor their treatment recommendations accordingly. Additionally, and perhaps most importantly, prior to the initiation of any palliative treatment, it is of the utmost importance to fully understand a patient’s expectations and directives regarding their cancer treatment. Fully understanding and respecting a patient’s desires regarding end-of-life care can help practitioners make informed, shared decisions with their patients in order to implement the most appropriate treatment course (80).

Future directions

Although patients with locally advanced and metastatic cancer historically had limited treatment options and relatively short life expectancies, the advent and continued development of targeted therapies allow patients to live longer with their disease (81). Therefore, new and advanced treatment modalities are needed to help preserve overall quality of life in these patients and better manage symptoms that may arise due to progression of their disease.

While PBT typically has been thought to be more expensive than traditional photon-based plans, new solutions are helping make PBT more affordable for patients. First, since its nascence in the 1990s, the infrastructure required to administer PBT has drastically shrunk. The weight of proton linear accelerators has been effectively reduced from hundreds of tons to less than twenty tons. Furthermore, superconducting magnets have the ability to confine protons to a smaller space. This has led to the advent of single-room proton centers which have significantly fewer overhead costs when compared to large proton centers, thus reducing the overall cost of care for the patient (5,6).

Similarly, in the past, PBT has been denied by insurers given its greater costs when compared to photon-based therapy. However, as health policy continues to evolve and governing bodies continue to affirm the utility and benefit of PBT, insurance coverage for PBT will likely continue to improve. In 2014, the American Society for Radiation Oncology (ASTRO) composed a list of diagnoses that its leaders recommended insurers should cover. Based on the interval data reported supporting this modality, the 2023 update to the ASTRO Model Policy on Proton Beam Therapy has significantly expanded the recommended indications for proton therapy, including for many of the advanced, incurable, and recurrent tumors discussed above. Additionally, for patients on Medicare, PBT is already considered medically appropriate and necessary for a number of cases, including unresectable malignant CNS tumors, advanced stage and unresectable malignant lesions of the head and neck and unresectable peritoneal sarcomas (82).

As demonstrated by the results of the studies outlined above, PBT has been demonstrated to have a favorable toxicity profile in the palliative management across a wide variety of tumor types. Owing to its various physical and biologic advantages, PBT allows radiation oncologists the ability to deliver radiation safely and effectively to tumors in the palliative setting. In the setting of reirradiation, PBT is particularly beneficial in reducing toxicities, providing durable tumor control, and palliating tumor-related symptoms (83), with generally more favorable outcomes and toxicities relative to photon reirradiation (84) (Table 2). Ultimately, the decision to treat with PBT proves dependent on appropriate patient selection and stratification. Capital costs should ultimately not hinder providers from offering less toxic therapies, such as PBT, that can help preserve patients’ overall quality of life while adequately managing their cancer.

Lastly, proton therapy has recently had a prominent role in the experimental palliative treatment of patients with metastatic disease when delivered as ultra-high-dose-rate FLASH therapy. Increasing preclinical data over the past few years (85) has demonstrated that radiation therapy, when delivered at an ultra-high dose rate, better spares normal tissues without impairing anti-tumor activity (86). The first in human clinical trial of ultra-high-dose-rate FLASH was delivered with proton therapy in patients with symptomatic bone metastases (87). That recently published trial demonstrated that proton FLASH was clinically feasible with high levels of treatment efficacy and few adverse events (88). Currently, proton therapy is the optimal radiotherapy modality for delivering FLASH (89), as existing proton accelerators can more readily deliver ultra-high-dose-rate deliveries and as proton FLASH can allow for the treatment of deeper and larger tumors than FLASH delivered with other modalities (90). Should such ultra-high-dose-rate radiotherapy delivered with protons prove to reduce toxicities in future clinical trials, this would allow for the safer delivery of radiotherapy in patients with advanced and metastatic disease, and thus would result in an event larger role for proton therapy in the palliative setting.

Conclusions

Despite these encouraging results, more research on PBT in the palliative setting is needed. Most available studies are limited by their retrospective study design and small sample size. This may be due, in part, to limitations in access to PBT: currently, there are only 41 proton centers operational in the United States, and most are located in large metropolitan cities (91). Additionally, PBT is generally more expensive, with photon therapy generally considered to be the more economical option (92). However, as more proton centers (and especially single-room proton therapy centers) open, and as the cost of PBT continues to decline, prospective studies will prove more logistically feasible and thus, will help generate further robust data on PBT for patients who have exhausted all other treatment options. In the interim, the studies that have been conducted to date demonstrate that proton therapy may be a safe, well-tolerated option for patients with unresectable or metastatic cancer across various disease sites and histologies.

Acknowledgments

Funding: This research was funded, in part, through the NIH/NCI Cancer Center Support Grant P30 CA008748.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Edward L. W. Chow and Candice Johnstone) for the series “Palliative Radiotherapy Column” published in Annals of Palliative Medicine. The article has undergone external peer review.

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-23-230/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-23-230/coif). The series “Palliative Radiotherapy Column” was commissioned by the editorial office without any funding or sponsorship. C.B.S serves as the co-Editor-in-Chief of Annals of Palliative Medicine. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

^※Special series on Palliative Radiotherapy Column.

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