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Originally published as JCO Early Release 10.1200/JCO.2008.16.5514 on April 28 2008 © 2008 American Society of Clinical Oncology.
Proton Therapy Should Be Tested in Randomized Trials
National Collaborating Centre for Cancer, Cardiff, United Kingdom
Addenbrooke's Hospital, Cambridge, United Kingdom To the Editor: We suspect that the article by Goitein and Cox1 is deliberately provocative and it clearly deserves rebuttal. As leading providers of proton therapy in the US, they are not objective and their vested interests (intellectual, professional, and reputational, rather than financial) are not fully declared. First, they claim that because of the demonstrable physical and radiobiologic properties of proton therapy, "an objective person" should conclude that is highly probable that it provides "superior therapy" to x-ray therapy "in almost all circumstances." Others have taken the view that, "It is not intuitively obvious that a marginally better radiation dose distribution with protons, elaborately designed photons, or brachytherapy will achieve increased tumor control or clinically measurable decreased toxicity—these are testable hypotheses."2 Secondly they misuse the term "equipoise." They claim that there is no "equipoise" because proton therapy is obviously so much better. However the "equipoise" required for a randomized controlled trial is not between the treatment arms, but in the opinion of clinicians who manage the patients. In this case, there may well be equipoise in the wider clinical community. They believe that randomized trials are "ethically inappropriate"—but that is their personal opinion, not that of an independent medical ethics committee. How ethical would it be for the gatekeepers of a new therapy to prevent a randomized trial if the wider clinical community, with independent ethical advice, felt it was appropriate and necessary? There is no reliable, objective evidence that proton therapy improves clinical outcomes, either survival or quality of life. Recent reviews identify 40,000 patients who have been treated worldwide.3-6 Four randomized controlled trials have been performed, but all are proton-proton comparisons of different dose levels in the treatment of ocular melanoma, prostate cancer, and base-of-skull tumors.3 They shed no light on whether protons are better than photons. There have been five comparative studies and 44 case series. The only tumors for which there is any evidence for the superiority of protons on the basis of clinical results is in the treatment of base of skull cordomas and ocular tumors. The cordoma literature consists of five photon studies including 100 cases and three proton studies including 302 cases.3,4 Local control and 5-year survival were better in the proton series (25% v 63% and 44% v 81%). However, these are not randomized comparisons, and there is a surgical series reporting 65% local control in patients, only 20% of whom had any radiotherapy at all. The proton protagonists contend that they have treated the worst cases, but these results cannot be accepted as proof of benefit on the basis of classical health technology assessment criteria. For years, similar arguments were used to justify the postoperative radiotherapy of low-grade glioma in children; the practice is now discredited. For ocular tumors, there are similar problems.3,4 There are 11 proton series reporting on 7,700 patients and five photon series reporting on 350 patients. The results are indistinguishable in terms of local control (97%), 5-year overall survival (85%), eye retention (90%), and useful vision after 5 years (50%). The difficulty is that there is extensive case selection for the different modalities including radical surgery, plaque brachytherapy, external beam radiotherapy, and proton therapy. This is not to say that protons are not an excellent treatment for some cases of ocular melanoma; rather, they have not been shown to be better than photons. Again we must fall back on the Scottish verdict of "not proven." The proponents of evidence-based medicine do not insist that randomized controlled trials are the only evidence on which to base decisions. Glasziou et al7 recently discussed the circumstances under which observational evidence alone could be accepted as reliable evidence of effectiveness. They suggested that there needed to be a clear temporal relationship between the treatment and the effect, that the time to the effect was short relative to the duration of the preexisting condition, and that the magnitude of the observed effect was great (perhaps 10-fold) compared with the result of doing nothing (or a comparator). Neither of the last two conditions apply to proton therapy relative to photon therapy, and the risk of bias in observational studies remains significant. There is also the risk of adverse effects. One of the most attractive arguments put forward for the use of protons is to reduce the risk of second cancers in children. They are at least 10 times more sensitive to radiation-induced cancer,8 and it might be supposed that reducing the volume of normal tissue exposed would reduce the incidence of second cancers. However, passive modulation of a proton beam results in a significant total-body dose of neutrons, a potent carcinogen. There are ongoing arguments about the magnitude of this risk, but it can be avoided only by using a scanning pencil beam.8 Goitein and Cox argue that it would be inappropriate to carry out a randomized trial just to demonstrate cost effectiveness. Even if proton therapy really is more effective than photon therapy, it would still be important to know how much more effective it is and for which groups of patients. With an increase in cost variably estimated at between 70% and 150%,1,9,10 anyone paying for the treatment, whether an individual patient, an insurance company, a health maintenance organization, or taxpayers, deserves to know how much better the outcomes are that they are buying. Otherwise, they are buying the proverbial "pig in a poke." Although significant technical advances have taken place in radiotherapy during the last 20 years, it is surprising how few have been subjected to proper evaluation. Widespread introduction of proton therapy for an ever increasing range of indications would be folly without better evidence of effectiveness. If Goitein, Cox, and their proton colleagues throughout the world are adamant in their refusal to allow randomized controlled trials, they should at least encourage and take part in other large-scale comparative studies. A hadron therapy registry4 would form the basis for careful case-control studies, and provide some information despite the problems of establishing randomized trials.5 Or are they anxious that the emperor may in fact be naked? AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on April 28, 2008 REFERENCES
1. Goitein M, Cox JD: Should randomized clinical trials be required for proton radiotherapy? J Clin Oncol 26:175-176, 2008 2. Halperin EC: Overpriced technology in radiation oncology. Int J Radiat Oncol Biol Phys 48:917-918, 2000[CrossRef][Medline] 3. Olsen DR, Bruland OS, Frykholm G, et al: Proton therapy: A systematic review of clinical effectiveness. Radiother Oncol 83:123-132, 2007[CrossRef][Medline] 4. Lodge M, Pijls-Johannesma M, Stirk L, et al: A systematic literature review of the clinical and cost-effectiveness of hadron therapy in cancer. Radiother Oncol 83:110-122, 2007[CrossRef][Medline] 5. Glimelius B, Montelius A: Proton beam therapy: Do we need the randomised trials and can we do them? Radiother Oncol 83:105-109, 2007[CrossRef][Medline] 6. Brada M, Pijls-Johannesma M, De Ruysscher D: Proton therapy in clinical practice: Current clinical evidence. J Clin Oncol 25:965-970, 2007 7. Glasziou P, Chalmers I, Rawlins M, et al: When are randomised trials unnecessary? Picking signal from noise. BMJ 334:349-351, 2007 8. Hall EJ: Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol Phys 65:1-7, 2006[CrossRef][Medline] 9. Lievens Y, Van den Bogaert W: Proton beam therapy: Too expensive to become true? Radiother Oncol 75:131-133, 2005[CrossRef][Medline] 10. Goitein M, Jermann M: The relative costs of proton and X-ray radiation therapy. Clin Oncol 15:S37-S50, 2003[CrossRef]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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