Back to the Future: a Proton Pro/Con

Fifteen years from now, graduate business school students seeking a PhD in medical economics will write dissertations on the topic of proton therapy and its place in the health care reform efforts of the 2010s. Perhaps by then the proper role of protons in the spectrum of anti-cancer therapies will have been identified, and maybe the challenges associated with the high costs of proton therapy will have been solved by technological advances. At the moment, though, the topic remains controversial, sparking lively if not downright fractious discourse between proton “haves” and “have-nots” about whether protons do or do not represent a legitimate advance in radiation therapy delivery technology for various clinical indications.

Dr. Hoppe and the University of Florida group have offered their thoughts on the use of proton therapy for prostate cancer. Their concise and easily readable review covers issues related to proton therapy physics, the use of protons as a boost therapy, protons as sole therapy, dose escalation, and matters related to the cost-effectiveness of this particular modality.

To comment on their review while maintaining a certain lightness (in the spirit of collegiality), let's pretend that we can reach through a wormhole for a sneak peak at those Class of '26 dissertations. We are, after all, discussing applied quantum physics, so why not add time travel just for fun? The only caveat-and what good science fiction story doesn't require a leap of faith?-is that a prankster on the other end is handing us a mix of serious papers and satirical ones. To help us sift through which parts might be truthful and which are fantasies, we'll summarize the possible theses and intersperse some data and commentary.

The GOP (Grand Old Particle) Manifesto, by Newt O'Reilly

This treatise details the randomized controlled trials (RCTs) conducted between the years 2014 and 2022 comparing proton therapy with other forms of radiation therapy. There has proven to be no meaningful difference in the overall efficacy of these treatments. However, despite this outcome, in a stunning reversal of traditional policy, Republicans introduce legislation in 2023 that calls for increased Medicare support of high-cost therapy, with a preference for the MCA (most costly alternative) where possible.

The first part of this thesis- ie, the negative trial results-would not be surprising. Consider, for example, the recently reported case-matched comparison between low- and intermediate-risk patients treated in the high-dose arm of the Proton Radiation Oncology Group (PROG) randomized study[1,2] with patients treated using low–dose rate brachytherapy at Massachusetts General Hospital.[3] No significant difference in biochemical failure rates was observed between the PROG study group and the brachytherapy group.

In fairness to proton therapy, the competition is a formidable opponent. Zelefsky et al recently reported clinical outcomes of a series of 729 patients treated with either intensity-modulated radiotherapy (IMRT) or brachytherapy for low-risk prostate cancer. The biochemical relapse-free survival at 7 years was 95% in the brachytherapy group, and the rate of grade 3 or higher rectal toxicity was approximately 1%.[4] Using those outcomes as what would be expected in the control population, an RCT with a 90% power to detect improvement to a 97.5% relapse-free survival would require about 2,500 patients. An RCT with a 90% power to detect a reduction in the rate of grade 3 or higher rectal toxicity from 1% to 0.5% would require more than 12,500 patients.

The second part, in which Republicans shift gears on health care financing, might not actually be as far-fetched as it seems at first glance. The American Medical Association's 2011 report, “The State-Level Economic Impact of Office-Based Physicians,” suggests that the dollars re-circulated within the United States through health care delivery likely stimulate local economic activity,[5] or at the very least can provide a sturdy trellis on which the vines of prosperity might grow to provide a shady pergola that protects against the harsh sun of an economic dry spell. (Full disclosure about that last metaphor: one of us is married to an avid gardener.)

The Chargeyard Solution, by Barack Colbert

Prospective large-scale observational studies are completed, and the results show that protons are a very effective form of radiation therapy in a variety of settings. However, by 2023 the United States government has gone bankrupt, and all federal programs come to a screeching halt. In a stunning reversal of traditional policy, the Democrats introduces legislation requiring all agencies to balance their budgets by finding non-tax revenue to make ends meet. Luckily, a chemical reaction discovered by a Duke University undergrad in 2014 proves useful. Known as Water-Infused Neo-Esterification (WINE), the process involves mixing H₂O, plant products (tulips provide nice color), and a stream of protons to create hydroxylated carbon-based adult beverages. On weekend days in 2026, cyclotrons from coast to coast are re-purposed to produce popular drinks with names like Sauv-ion Blanc and Proton Noir. Profits from sales allow the government to pay for cancer care and, as a bonus, detox centers.

The first part of this one, the idea of performing large observational studies, is certainly a realistic scenario. Comparative effectiveness research (CER) is probably at this moment the buzziest of all buzzwords in the field of clinical investigation. Bekelman et al recently provided a timely review of CER basics with reference to the field of radiation oncology,[6] and in an accompanying editorial, Steinberg added additional insights into the differences between CER for pharmaceuticals and CER for new technology.[7] The bottom line: while the RCT remains the gold standard of evidence gathering, it is not the only way to evaluate medical therapies, and its “gold-standard status” does not remove our obligation to apply good judgment and common sense to the interpretation of other legitimate forms of evidence.

While its history involves unique circumstances,[8] in the end proton therapy is just another example of a costly medical technology that has emerged and been developed to a point where turning back completely is probably not an option, given the resources already invested.[9] In retrospect, it might have been better for federal and other payers to offer coverage during early evidence development at one or two selected centers, with the understanding that broader dissemination of the technology would be supported only if warranted by demonstrated benefits-and maybe that is a lesson for the future. Regardless, it is extremely likely that eventually we will have an accumulation of phase II studies of proton therapy available whose outcomes can be compared and contrasted with those reported for other types of radiation therapy-and stakeholders (patients, physicians, payers) will have to make decisions about what to do based on that information rather than on the basis of RCT data.

As for whether the US government, or the Medicare program in particular, will go bankrupt in the next decade, we defer to other prognosticators to make that call. (Hey, we're physicians, not economists!) Having said that, we hereby officially join the chorus of many who have pointed out that in a real world of finite resources, even in wealthy countries like the United States, we physicians do have a responsibility to society to weigh the value of expensive interventions helpful to a few against the potential benefits of broadening access to lower-cost interventions that could benefit many. We would not be the first to question the cost-effectiveness of proton therapy for prostate cancer according to current expense estimates.[10] And there is also the larger question of just which patients need any treatment for low-risk prostate cancer[11]-but that's a topic for another day.

Finally, on that matter of the WINE business…OK, that part is probably fantasy. As everyone knows, microwave irradiation is the preferred form of electromagnetic energy when it comes to aging wine and improving its flavor,[12] and both Cobalt-60 and electron beam irradiation effectively reduce the risk of cork taint from 2,4,6-trichloroanisole.[13,14] Protons will have trouble muscling into that turf.

Toward the Middle Path, by Sid Hartha

By 2020, clinical trials have demonstrated that proton therapy is appropriate for certain groups of patients and not for others. Notably, for many prostate cancer patients, protons offer a cost-effective treatment via 5-fraction schedules modeled on the photon-based stereotactic body radiation therapy protocols initiated in the early 2000s. Additionally, in 2025 an Indian inventor develops a solar-powered cyclotron that costs less than the average flat screen television. Astonishingly, he rejects lucrative offers to sell out to large corporations who want to maximize profits and instead partners with a national retail chain to create Caf Beam franchises, where patients receive affordable treatment and anyone can receive half-priced latte.

There is published level I evidence from the Regina Elena National Cancer Institute in Rome that for patients with high-risk prostate cancer, the combination of androgen suppression and hypofractionated external beam radiotherapy (62 Gy given in 20 treatments) offers a superior 3-year freedom from biochemical recurrence rate compared with that of the same androgen suppression combined with a longer course of radiotherapy (80 Gy given in 40 fractions), with no difference in late toxicity.[15] The scientific rationale for this study relates to certain radiobiologic properties of prostate cancer whereby it might be advantageous to deliver higher individual daily doses in fewer treatments rather than extend the course of treatment over a longer duration. This hypothesis is being tested independently in a very similar large (>2000 patients) ongoing study in the United Kingdom sponsored by the Institute of Cancer Research,[16] and in North America the Radiation Therapy Oncology Group (RTOG) has completed accrual for a similar study for low-risk patients (comparison of a 28-treatment regimen and a 43-treatment regimen).[17]

Even more compressed and efficient are the 5-fraction stereotactic body radiation therapy (SBRT) photon-beam trials currently maturing at a number of US cancer centers. Already there has been a report documenting excellent biochemical control (93%) at 5 years in a cohort of low-risk patients followed for a minimum of 5 years, with negligible late grade 3 rectal or genitourinary toxicity.[18] All of which begs the question: if proton beam dosimetry is as good as or better than photon beam dosimetry, and if we are concerned about the costs of therapy, shouldn't there be more urgency to evaluate protons in the context of these types of more efficient and less resource-intensive treatment schedules?

Regarding the notion of less expensive proton therapy, there is reason to believe that help is on the way. Several companies are working feverishly to develop lower-cost delivery technology, and sooner or later one of them will break through. When the cost of protons eventually shrinks down close to the level of the cost of photons, all of the controversy will fade away.

But what about the discount gourmet coffee? Unlikely. We suspect that last part is a fragment of a screenplay for a Bollywood movie starring Shah Rukh Khan as the sweet, awkward genius trying to win the heart of a beautiful girl whose parents were killed in an automobile accident in which the other driver had fallen asleep at the wheel due to hypocaffeinemia. Nice ending, though: the guy gets the girl, the patients are well cared for, and the rest of us get some vicious espresso.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References:

1. Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA. 2005;294:1233-9.

2. Zietman AL. Correction: Inaccurate analysis and results in a study of radiation therapy in adenocarcinoma of the prostate. JAMA. 2008;299:898-9.

3. Coen JJ, Zietman AL, Rossi CJ, et al. Comparison of high-dose proton radiotherapy and brachytherapy in localized prostate cancer: a case-matched analysis [corrected proof]. Int J Radiat Oncol Biol Phys. In Press. Available online 4 April 2011.

4. Zelefsky MJ, Yamada Y, Pei X, et al. Comparison of tumor control and toxicity outcomes of high-dose intensity-modulated radiotherapy and brachytherapy for patients with favorable risk prostate cancer. Urology. 2011;77:986-90.

5. The state-level economic impact of office-based physicians. Prepared for the American Medical Association by SNR Denton & The Lewin Group, Inc. February, 2011. Available from: www.ama-assn.org/resources/doc/arc/economic-impact/economic-impact-report.pdf. Accessed May 4, 2011.

6. Bekelman JE, Shah A, Hahn SM. Implications of comparative effectivenes research for radiation oncology. Pract Radiat Oncol. 2011;1:72-80.

7. Steinberg M. The overthrow of the (evidence) hierarchy. Pract Radiat Oncol. 2011;1:81-2.

8. Steinberg ML, Konski A. Proton beam therapy and the convoluted pathway to incorporating emerging technology into routine medical care in the United States. Cancer J. 2009;15:333-8.

9. Raben D, Kavanagh BD, Crawford ED. Proton/photon therapies: clinical trials unlikely. The Wall Street Journal. 2005 Feb 24;Sect. A:15.

10. Konski A, Speier W, Hanlon A, et al. Is proton beam therapy cost effective in the treatment of adenocarcinoma of the prostate? J Clin Oncol. 2007;25:3603-8.

11. Hayes JH, Ollendorf DA, Pearson SD, et al. Active surveillance compared with initial treatment for men with low-risk prostate cancer: a decision analysis. JAMA. 2010;304:2373-80. Erratum in: JAMA. 2011;305:1862.

12. Zheng X, Liu C, Huo J, Li C. Effect of the microwave irradiated treatment on the wine sensory properties. Int J Food Eng. 2011;7:Article 10. Available from: http://www.bepress.com/ijfe/vol7/iss2/art10. Accessed May 20, 2011.

13. Pereira C, Gil L, Carrico L. Reduction of the 2,4,6-trichloroanisole content in cork stoppers using gamma radiation. Radiat Phys Chem. 2007;76:729-32.

14. Careri M, Mazzoleni V, Musci M, Molteni R. Study of electron beam irradiation effects on 2,4,6-trichloroanisole as a contaminant of cork by gas chromatography-mass spectrometry. Chromatographia. 2001;53:553-7.

15. Arcangeli G, Saracino B, Gomellini S, et al. A prospective phase III randomized trial of hypofractionation versus conventional fractionation in patients with high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2010;78:11-18.

16. Conventional or hypofractionated high-dose intensity modulated radiotherapy for prostate cancer (CHCHiP). Chief Investigator, D Dearnaley. Available from: www.icr.ac.uk/research/research_sections/clinical_trials/clinical_trials_list/7558.shtml. Accessed May 20, 2011.

17. A phase III randomized study of hypofractionated 3DCRT/IMRT versus conventionally fractionated 3DCRT/IMRT in patients treated for favorable-risk prostate cancer. Principal Investigator, WR Lee. Available from: www.rtog.org/ClinicalTrials/ProtocolTable.aspx. Accessed May 20, 2011.

18. Freeman DE, King CR. Stereotactic body radiotherapy for low-risk prostate cancer: five-year outcomes. Radiat Oncol. 2011;6:3.