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Originally published as JCO Early Release 10.1200/JCO.2008.16.5670 on April 28 2008 © 2008 American Society of Clinical Oncology.
In Reply
The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom
Department of Radiation Oncology Maastricht Radiation Oncology, Research Institute of Growth & Development, University Hospital Maastricht, Maastricht, the Netherlands Morgan1 enters the debate about proton therapy from the consumer perspective and raise a number of important points about the introduction of new technology into clinical practice. It is worth noting that neither Morgan nor other authors2 challenge the principal message of our3 and other systematic reviews4,5: that despite the potential technical advantage, no evidence even at a basic level shows improved outcome after protons compared with photons in any of the tumor types so far treated. The current wisdom embodied in the principles of evidence-based medicine, to which most clinical and academic practice as well as pharmaceutical industry adhere, is that apart from exceptional circumstances where magnitude of benefit demonstrated in a level 2/3 clinical study is overwhelming, a randomized controlled trial is mandatory as proof of benefit of one treatment over another. A randomized trial is based on the premise of equipoise, yet the statistical design assumes benefit of one treatment over another, and this is generally expected from preceding phase II studies. The ethical dilemma, pointed out by Morgan, is that if one treatment is shown to be superior, those randomly assigned to the ultimately inferior arm will have received less effective treatment. This is a valid debate not specific to proton therapy. The author, after personal research, "felt proton therapy was the best option." While we indeed "do not contest the various arguments that favor the use of protons over x-rays,"1 we did point out that the evidence is only shown in selected cases. It is worth examining the magnitude of such improvement, for example, in relation to the prostate. A recent planning study of 10 patients with early-stage prostate cancer6 shows that "In the range higher than 60 Gy/CGE, IMRT achieved significantly better sparing of the bladder (than protons), whereas rectal sparing was similar with 3D-CPT (protons) and IMRT. Dose to healthy tissues in the range lower than 50% of the target prescription was substantially lower with proton therapy," and this was without substantial difference in the distribution of dose to the target.6 In practical terms this means that there is unlikely to be any difference in the important adverse effects due to high-dose radiation to the rectum and the bladder after protons. The remaining debate centers on the risk of low-dose irradiation, which is principally in the form of carcinogenesis. The 10-year risk in adults is in the region of 1.4% (one in 70).7,8 Although a reduction in low-dose normal tissue volume may be postulated to decrease the risk further, the neutron contribution from protons may increase it. Such low-risk events are difficult to measure unless thousands of patients are observed for decades.7 Even if demonstrated, these events are of questionable importance in an aging population affected by prostate cancer. Before embarking on costly clinical studies, it may be of value to assess the potential clinical benefit with more objective modeling studies (so-called in silico trials) examining end points of clinical relevance. The authors argue that a technical benefit of new therapy demonstrated in a model situation should be considered sufficient as proof of subsequent clinical benefit. Would the authors chose to fly in a new rocket-propelled plane (rocket engines will clearly make the plane faster) purported by the manufacturers to cut a significant time off a transatlantic flight, without demonstrating the new design actually achieves what it claims and does so without unexpected hitches. The belief that an improvement in a single parameter of a complex system will be of clear overall benefit is disarming. In a highly complex clinical situation of cancer radiotherapy, for which the exact dose distribution is only one of many parameters determining outcome, this attitude is more troubling. The consumer representatives have been influenced by information that mostly originates from proponents of protons with frequent commercial interest in the new equipment. Such reports are subject to understandable bias and conflict of interest with few qualms about overstating the available evidence. The current spate of systematic reviews tries to redress the balance. In the light of the overall agreement of lack of existing clinical evidence for benefit of protons, to demand that at least some of the claims are substantiated does not seem too much to ask. Randomized controlled trials in the absence of level 2 evidence at this stage may be excessive, and outcome from well designed prospective phase II studies, away from commercial influence and focusing principally on toxicity end points, would be a good start. Even the Institute of Medicine, part of the US National Academic of Science, is in favor of knowing what works (www.iom.edu). Finally, regarding cost—yes, Morgan can travel across the oceans in a new rocket-propelled plane, and yes, do not ask us to pay for it. If the plane actually gets him to the land destination faster, we may pay. 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. Morgan JP: A patient's perspective on randomized clinical trials for proton radiotherapy. J Clin Oncol 26:2592, 2008 2. Goitein M, Cox JD: Should randomized clinical trials be required for proton radiotherapy? J Clin Oncol 26:175-176, 2008 3. Brada M, Pijls-Johannesma M, De Ruysscher D: Proton therapy in clinical practice: Current clinical evidence. J Clin Oncol 25:965-970, 2007 4. Olsen DR, Bruland OS, Frykholm G, et al: Proton therapy: A systematic review of clinical effectiveness. Radiother Oncol 83:123-132, 2007[CrossRef][Medline] 5. 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] 6. Trofimov A, Nguyen PL, Coen JJ, et al: Radiotherapy treatment of early-stage prostate cancer with IMRT and protons: A treatment planning comparison. Int J Radiat Oncol Biol Phys 69:444-453, 2007[Medline] 7. Brenner DJ, Curtis RE, Hall EJ, et al: Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer 88:398-406, 2000[CrossRef][Medline] 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] Related Editorial
Related Comments and Controversies
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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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