In other news ...
To discuss the controversial topic of protons versus photons in prostate cancer, let us establish some truths:
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Approximately 70% (and growing) of all level 1 evidence in localized prostate cancer involves the use of photon-based radiation therapy. Surgery is a distant second with ∼20%, and brachytherapy and conservative management round out 99% of all randomized trials in localized prostate cancer. The last 1% is from a combination of typically small or under-accrued trials of treatments such as cryotherapy.
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Two published dose-escalation randomized trials have used protons as a boost for prostate cancer. One demonstrated high rates of gastrointestinal (GI) toxicity (32% had rectal bleeding), and the other showed a modest increase in toxicity (12% increase in grade 2+ GI toxicity).
1,
2 In both trials, the majority of the treatment was delivered with photons and used outdated proton and photon technologies.
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No randomized phase 3 trials of protons versus photons in prostate cancer have been reported to date. Thus, the entirety of comparative effectiveness research to support or reject the use of protons for prostate cancer is retrospective and/or nonrandomized research.
Given these data, what are we able to conclude about protons for prostate cancer? Not much definitively, good or bad, as there remains only level 3 evidence to support their use. Thus, a better question is, what are the
potentialbenefits of proton therapy for prostate cancer?
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Cost. Cost is a complex amalgamation of dollars spent by an institution or investor, payer, and patient. In the context of prostate cancer, the net upfront costs to the health care system for protons is currently higher than that for other options. Demonstration of an improvement in patient outcomes is needed for protons to provide long-term cost savings.
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Survival. Given that there remains no level 1 evidence that any local therapy, even dose escalation, improves survival, proton users generally have not claimed it will improve tumor control over other modalities.
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Secondary malignancies. An advantage of protons for secondary malignancies is theoretical, limited to modeling studies, and unproven clinically for adult patients with cancer. In ProtecT, there were similar rates of death from cancers other than prostate cancer (23 for radiation therapy and 25 for surgery).
3 If secondary malignancies are the primary concern, one would argue that surgery or brachytherapy may be preferred given no or lower integral dose compared with protons.
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Convenience. Proton facilities, although increasingly common, require the furthest travel distance of any radiation facility.
4Ultrahypofractionation remains less common with protons, although this may be changing.
5
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Toxicity/quality of life (QOL). Thus, we are left to conclude that the primary theoretical advantage of protons for prostate cancer is on toxicity or QOL. This is supported by the fact that the only open randomized trial of protons versus photons in prostate cancer has a primary endpoint of QOL.
To this point, in the current issue of the Red Journal, Vapiwala et al conducted a retrospective study on physician-reported toxicity for patients treated with moderately hypofractionated protons or photons across 7 institutions.
6 Protons were delivered to all patients via uniform scanning or pencil beam scanning. Patients who received protons were younger and treated more recently; they had lower rates of diabetes, anticoagulant use, and androgen deprivation therapy use, lower prostate-specific antigen levels, and lower (better) baseline urinary symptom scores; they were less likely to be black and less likely to be a current or former smoker; and they had a greater use of rectal spacers and rectal balloons. These differences highlight the incredibly strong selection biases at play for patients who receive proton beam therapy.
Most of the baseline differences would
a priori be expected to favor the proton group to have lower toxicity. They reported an increase in acute GU grade 3+ toxicity with photons (2.7% vs 0% for photons vs protons), but data on acute toxicity were available in less than half of patients. In contrast, there was an increase in late GI grade 2+ toxicity with protons (11.1% vs 4.8%) on unadjusted analyses; this increase widened after adjustments (14.6% vs 4.7%) but was biased toward the null due to multiple covariable adjustments and did not reach conventional statistical significance. Notably, their multivariable analysis included only a select number of the reported baseline differences and did not include multiple covariables that could confound the results (eg, depression status, measures of socioeconomic status, other concurrent medications, baseline symptom scores across domains). Thus, their multivariable analysis is likely still comparing imbalanced groups for numerous variables.
Regardless, what should we conclude from these data? Given that the expected bias would favor patients being treated with protons to have better outcomes, this does give pause: The proton patients had higher grade 2+ rectal toxicity, which has been shown in other studies.
7However, it has been repeatedly shown that retrospective comparative effectiveness research is no more likely than chance to accurately identify independent causal treatment effects from randomized trials.
8 Thus, although it is tempting to use retrospective data to affirm our own biases, we would caution against this, especially because other retrospective studies show similar or improved outcomes with protons—which equally may be spurious results.
The most important lesson from the paper is that comparative effectiveness research done through observational study designs will not yield reliable answers to the question of the role of protons versus photons, owing to the incredibly high selection of biases present. Although there are ongoing observational comparative effectiveness studies with protons in prostate cancer (NCT03561220, NCT04083937), we owe it to patients to not simply report the results of potential self-fulfilling prophecies and conduct and report the results of randomized trials.
The Prostate Advanced Radiation Technologies Investigating Quality of Life (PARTIQoL, NCT01617161) trial is the first multicenter phase 3 randomized trial of protons versus photons and the only one in prostate cancer, to our knowledge. The trial has been open for 8 years, with 423 of 450 patients accrued as of March 1, 2021. The study is well positioned to rigorously address the question of protons versus photons for prostate cancer in regard to QOL. It also contains a companion registry for patients unwilling to undergo randomization, to further quantify the impact of selection bias on outcomes. Although the difficulty in conducting such a trial should not be underestimated, we must acknowledge that over 15,000 men have received proton therapy not on a randomized trial for prostate cancer during the past decade in the United States. Even if just a proportion of the patients on the study by Vapiwala et al were put on the PARTIQoL trial, it would already be fully accrued.
We congratulate Vapiwala et al for having the academic integrity to report what some will consider negative results for protons, and it will be interesting to observe how these data affect practice patterns at proton centers. This study should motivate the field now more than ever to support randomized trials to define the optimal utility of protons in oncology. If we can randomize patients to watchful waiting versus surgery (including men with high-risk prostate cancer), external beam radiation therapy versus combination brachytherapy, or external beam radiation therapy versus surgery, we can and should have equipoise to complete randomized trials of protons versus photons and not simply conduct retrospective and/or observational studies. Otherwise, this debate will continue ad infinitum.
