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Originally published as JCO Early Release 10.1200/JCO.2008.17.1843 on April 28 2008 © 2008 American Society of Clinical Oncology.
Should Randomized Clinical Trials Be Required for Proton Radiotherapy? An Alternative View
Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA
Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA The great tragedy of Science—the slaying of a beautiful hypothesis by an ugly fact. —T.H. Huxley Recently, an editorial in the Journal of Clinical Oncology (JCO)1 offered reasons why there have been no randomized prospective clinical trials that compare proton beam radiation therapy to conventional photon x-ray therapy. Herein we offer an alternative view on the need for randomized clinical trials. The facts offered by Goitein and Cox are incontrovertible in that the dose distribution of proton therapy is superior that of to x-rays. The question really has to do with whether or not these facts translate into measurable benefits for patients, and how significant those gains may be. The editorial in question alluded to a prior article in JCO by Brada et al,2 in which data were reviewed for a number of treatment sites and a conclusion was made that there was no evidence to demonstrate an obvious superiority of protons over photons, despite the confidence that Drs Goitein and Cox express for the superiority of proton treatment. Although the analysis performed by Brada et al does not lead one to make definitive conclusions regarding the clinical benefit of proton therapy, it does raise important questions that our field must answer. Most important is the necessity of performing randomized clinical trials of proton therapy versus conventional x-rays. Given the fact that the analysis by Brada et al does not show clear evidence of a clinical superiority for protons, then it is difficult, in our opinion, to see why it would be "unethical" to perform such randomized trials. Goitein and Cox believe that the superiority of protons rests largely on an improvement of the dose distribution that will almost certainly make for less morbidity. Exploiting that improvement in treatment-related toxicity suggests that dose escalation is feasible and that an improvement of local control should follow. Though local control is important, it is not clear that this will affect overall survival at all, which is, in our opinion, still the most important end point. Nonetheless, there is a potential for clinical benefit to be derived from proton therapy compared with conventional x-rays, either from dose escalation and improved local control and/or survival, or from reduced treatment-related morbidity, especially in children. Another important consideration is the potential for increased secondary cancers from proton therapy that has been postulated on a theoretical basis by Hall3 in a recent article. Of course, Hall makes such predictions on the basis of a scattered proton beam, which is not the most modern technology available. The scattered beam is almost certainly going to have a higher rate of induced cancer than a scanning beam, which is now in use in Switzerland and is considered state-of-the-art treatment. All of these conflicting concerns highlight the importance of determining the benefit from protons in well-designed, randomized clinical trials. In our opinion, some of the largest gains for protons are likely to be found in conjunction with other modalities, such as surgery and chemotherapy. The fact that the dose is confined and that normal tissue will see a considerably lower dose suggests strongly that combined-modality treatments will be much easier to carry out with protons than with photons. We think it is essential for the radiation oncology community to think more in terms of combined-modality treatment rather than radiation therapy alone. Indeed, at the moment, significant improvements in survival have taken place over the last several years in randomized controlled studies for breast,4,5 lung,6,7 head and neck,8,9 cervix,10 and rectum11; all of these studies exploited combined-modality treatment rather than single-modality treatment. We believe this trend toward multimodality treatment ultimately yielding improvements in survival will continue, and we think that proton treatments will facilitate that to a major degree. Enhanced effects on the tumors but without overlapping toxicities should make for such improved outcomes. The only conclusive way to demonstrate this, however, is with carefully constructed randomized prospective clinical trials. Goitein and Cox argue that it is difficult to present this option to the patient. The fact that it is difficult does not mean that it is impossible; no one ever said it was supposed to be easy. There is no doubt that conducting a randomized clinical trial is difficult, as many patients come with a preconceived idea about the treatment they are seeking. This, in particular, has been the case in trials in which patients are randomly assigned to a surgical procedure or nonsurgical treatment in situations where the benefit of operation is unclear. Despite the contention by Goitein and Cox that protons are superior to photons, it is fair to say that there remains enough uncertainty in the medical community that randomized clinical trials can be justified. In fact, such trials are on strong ethical ground based on the principle of clinical equipoise, a situation that exists when there is collective professional uncertainty about treatment. The secret in doing a randomized clinical trial that is controversial is that the investigators really have to want to do it. They have to spend time explaining it to patients. They have to explain the other options and go into details about the potential differences in morbidities. Not every patient will agree, but we think it will be possible to carry out perhaps two or maybe three randomized studies that look at protons versus photons. These studies will have to be well designed, and, where appropriate clinically, they will need to be multimodal. Why is it important to do such studies? Most importantly, we want to deliver treatments to our patients that have measurable benefits. Patients depend on us to recommend therapies based on evidence, typically derived from well-designed clinical trials. In addition, the new treatments are expensive. We cannot and should not make light of this fact. In some instances governments want to know whether there really is an advantage to protons because, without demonstrating such an advantage, they would be unwilling to invest in the new technology. Third-party payers want to know if they really need to support such a treatment or not. A randomized study is one way to get the answer that they need. This not only has implications for third-party payers, but also for their subscribers: the patients and those who are ultimately going to be patients. It can be argued that intensity-modulated radiation therapy did not go through such a clinical trial. The reason for that is that the proliferation of intensity-modulated radiation therapy technology was so rapid that it was available to virtually every radiation oncologist overnight (and thus every patient) before a randomized study could be done. In our opinion, that was unfortunate. This inability to perform the randomized trials has hurt our field within the broader medical community, whether we admit it or not. The enormous expenditures to build a proton center at the moment mean that during the next 5 to 10 years, there will be a relatively small number of facilities that have proton beam therapy.12 The rest of the radiotherapeutic community will be interested in the outcomes to see if they really need to obtain such technology. It is likely that well-designed clinical trials that randomly assign proton beam therapy to patients would be supported by the National Cancer Institute and possibly even third-party payers themselves. To accrue the required numbers for such studies would probably require a concerted effort from virtually all the major centers where proton beam therapy is available. We believe this would be a good thing. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Collection and assembly of data: Eli Glatstein Data analysis and interpretation: Eli Glatstein Manuscript writing: Eli Glatstein, John H. Glick, Larry R. Kaiser, Stephen M. Hahn Final approval of manuscript: Eli Glatstein, John H. Glick, Larry R. Kaiser, Stephen M. Hahn 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. Brada M, Pils-Johannesma M and DeRuys-Scher D: Proton therapy in clinical practice: Current clinical evidence. J Clin Oncol 25:965-970, 2007 3. 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] 4. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337:949-955, 1997 5. Ragaz J, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337:956-962, 1997 6. Dillman RO, Seagren SL, Propert KJ, et al: A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 323:940-945, 1990[Abstract] 7. Schaake-Koning C, van den Bogaert W, Dalesio O, et al: Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med 326:524-530, 1992[Abstract] 8. Brizel DM, Albers ME, Fisher SR, et al: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338:1798-1804, 1998 9. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006 10. Tattersall MH, Lorvidhaya V, Vootiprux V, et al: Randomized trial of epirubicin and cisplatin chemotherapy followed by pelvic radiation in locally advance cervical cancer: Cervical Cancer Study Group of the Asian Oceanian Clinical Oncology Association. J Clin Oncol 13:444-451, 1995 11. Wolmark N, Wieand HS, Hyanes DM, et al: Randomized trial of postoperative adjuvant chemotherapy with or without radiotherapy for carcinoma of the rectum: National Surgical Adjuvant Breast and Bowel Project Protocol R-0. J Natl Cancer Inst 92:388-396, 2000 12. Jagsi R, DeLaney TF, Donelan K, et al: Real-time rationing of scarce resources: The Northeast Proton Therapy Center experience. J Clin Oncol 22:2246-2250, 2004 Related Editorial
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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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