POINT/COUNTERPOINT

Suggestions for topics suitable for these Point/Counterpoint debates should be addressed to Colin G. Orton, Professor Emeritus, Wayne State University, Detroit: ortonc@comcast.net. Persons participating in Point/Counterpoint discussions are selected for their knowledge and communicative skill. Their positions for or against a proposition may or may not reect their personal opinions or the positions of their employers.

We do not need randomized clinical trials to demonstrate the superiority of proton therapy
Hideyuki Sakurai, M.D., Ph.D.
Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba, Ibaraki 305-0042, Japan (Tel: 81-29-853-7100; E-mail: hsakurai@pmrc.tsukuba.ac.jp)

W. Robert Lee, M.D.

Department of Radiation Oncology, Duke University, School of Medicine, Durham, North Carolina 27710 (Tel: 919-668-5640; E-mail: w.robert.lee@duke.edu)

Colin G. Orton, Ph.D., Moderator (Received 8 November 2011; accepted for publication 10 November 2011; published 8 March 2012) [DOI: 10.1118/1.3681013]

OVERVIEW Despite the very signicant costs involved, proton therapy centers are opening up all over the world. Yet no clinical trials have been conducted to demonstrate that proton therapy is superior to much less expensive photon treatment. It is claimed that such trials are not necessary because it is obvious that protons are better and this is the premise debated in this months Point/ Counterpoint. Arguing for the Proposition is Hideyuki Sakurai, MD, PhD. Dr. Sakurai obtained his M.D. and Ph.D. (Radiation Oncology) degrees from Gunma University, Gunma, Japan, where he worked in the Radiation Oncology Department until 2008. He then moved to his current position as Professor and Chairman in the Department of Radiation Oncology and Director of the Proton Medical Research Center, University of Tsukuba, Ibaraki, Japan. He has published extensively in radiation oncology with his major research interests being gynecological, gastrointestinal and pediatric therapy, proton beam and carbon ion therapy, brachytherapy, and hyperthermia.
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Arguing against the Proposition is W. Robert Lee, M.D. Dr. Lee completed his M.D. degree at the University of Virginia, Charlottesville, and his residency in radiation oncology at the University of Florida, Gainesville. He subsequently held faculty positions at Fox Chase Cancer Center and Wake Forest School of Medicine, Winston Salem, North Carolina. During this period, Dr. Lee completed two masters degrees, one in Clinical Epidemiology and another in Adult Education. In 2006, he was recruited to Duke University, where he is currently Professor of Radiation Oncology, Associate Professor of Urology, and Director of the Radiation Oncology residency program. His major research interests are development of novel fractionation schedules in the treatment of prostate cancer and measures of quality in prostate brachytherapy. He is currently working on development of a curriculum devoted to improving medical decision making for patients and healthcare professionals. FOR THE PROPOSITION: Hideyuki Sakurai, M.D., Ph.D.
Opening Statement

Before this discussion, it is important to compare the interactions of photons and protons. First, there is very little
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difference in the biological effects of photons and protons. The relevant differences are only physics. Second, due to these physical differences, protons generally deliver a lower dose to surrounding normal tissues in almost all cases.1 To consider randomized clinical trials (RCTs), an important factor should be ethics. The ethical point of randomization is whether or not the patient can accept the result of a ip of a coin.1,2 In other words, the two arms must appear to be substantially equivalent from the patients point of view,3 with one arm not clearly inferior to the other from the professionals viewpoint. In the eld of radiation oncology, for instance, RCTs are appropriate to compare fractionation schedules or to determine which chemotherapy agent is the best in combination with radiation for the treatment of specic tumors. Additionally, we can also accept RCTs that compare treatment techniques with different mechanisms, for example, surgery vs radiation for early stage cancer or carbon beams vs protons for radioresistant tumors.4 However, for RCTs comparing protons and photons, both treatments have similar mechanisms, so we would be comparing only different dose distributions. There is no medical rationale for such RCTs because it is known that protons deliver lower doses to nontarget tissues than do photons for the same specied dose and dose distribution to the target.5 RCTs to provide answers to questions that can be readily answered by simple planning comparisons are not necessary.6 I think this is the rst reason for not conducting RCTs to compare photon and proton radiotherapies. The second problem with such RCTs is treatment cost. In Japan at present, for instance, national public insurance covers all radiation therapy except particle therapy. Patient payment for early stage lung cancer in surgery, xray stereotactic therapy, and proton therapy are (in U.S. $ equivalents) $5400, $2400, and $33 000, respectively. Who pays the treatment fees for the patients randomized to receive protons? RCTs often give important results, but they rarely produce radical changes in treatment, and there is the ethical problem in randomization described previously.3 Hence, from the patients point of view, it is difcult to recommend RCTs that are likely to demonstrate no major differences in cure rates with big differences in cost. The design of such RCTs could involve considerable difculty, both ethically and socially. Other problems of RCTs are the small number of proton centers available, and hence the small number of patients that can be treated, which makes it impossible to complete these RCTs in a timely manner. For rapid progression of radiation therapy techniques, especially proton therapy, the current approaches are substantial nonrandomized phase II trials,7 case control studies,1 prospective cohort studies, and physics and dosimetry studies. Ongoing studies with more patients and longer follow-up will demonstrate the true benets of proton therapy. Lack of evidence from RCTs is no reason to deny the superiority of protons.

AGAINST THE PROPOSITION: W. Robert Lee, M.D.

Opening Statement

I am arguing against the proposition because it is antithetical to science and it subtly attempts to shift the burden of proof. I will begin my argument by describing the burden of proof. The burden of proof is the obligation on a party in an epistemic dispute to provide sufcient warrant for their position.8 The burden of proof is used in legal, political, and scientic disputes. In most epistemic disputes, the burden of proof lies with the claimant. Although not apparent in the proposition, the claim put forward is that proton therapy is superior to photon therapy. The proposition is worded in such a way that it subtly shifts the responsibility or burden of proof to the critic and is, therefore, an example of the fallacy of argument from ignorance (argumentum ad ignorantiam). Perhaps the best example of the fallacy of argument from ignorance is Bertrand Russells teapot.9 Russell wrote that if he claimed that a teapot were orbiting the sun, it would be nonsense for him to expect others not to doubt him just because they could not prove him wrong. Russells analogy illustrates the idea that the burden of proof lies upon a person making claims rather than shifting the burden of proof to others. Russells example, of course, was used to argue against the existence of God. If you grant that the present conversation is scientic, then the appropriate motion or claim should be framed as a hypothesis. Simply put Proton therapy is superior to photon therapy. This is a hypothesis that can be tested and the burden of proof lies with the claimants. More than 2000 years ago, Hippocrates began the long process of dissociating medicine from magic. His lasting contribution remains that he established medicine as a discipline dependent on the laws of nature and, therefore, capable of being studied scientically. In medicine, by convention and community standards, this burden is met by accumulating evidence. For the better part of 60 years, it has been accepted that randomized controlled trials provide the least biased estimates of treatment effects.10 To date, there are no randomized controlled trials comparing proton therapy to photon therapy in any clinical scenario. To aver that proton therapy does not require this level of evidence when claims of superiority are made implicitly suggests that proton therapy is supernatural, beyond the limits of the natural world; in short, magic. This complete absence of level I evidence has not kept proton enthusiasts from claiming that proton therapy is superior. There is a long list of new treatments that were widely adopted on weak evidence but, following rigorous comparison, were found to be inferior to standard therapy.11 Statements of superiority in any realm of clinical medicine in the absence of randomized trials should be viewed with suspicion. To assert that proton therapy is superior to photon therapy in the absence of rigorous evidence is to engage in faith-based medicine.

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Rebuttal: Hideyuki Sakurai, M.D., Ph.D. Dr. Lee is clearly an RCT enthusiast and his comments are too abstract to be persuasive. He apparently considers the normal process of development of radiation therapy to be antithetical to science. I disagree. Consider, for example, the dearth of RCTs comparing conventional radiation therapy with high-tech x-ray therapies such as stereotactic radiosurgery and intensity-modulated radiation therapy. Although numerous phase I and II trials were conducted, there are almost no reports of phase III RCTs with two radiation therapy arms to compare conventional techniques with the new highly encouraging ones. Additionally, I also regret that Dr. Lee did not propose a practical way to appropriately design an RTC to compare x-rays and protons. To my knowledge, for example, only one phase II RCT to compare x-ray vs proton therapy is ongoing for advanced lung cancer (at the MD Anderson Cancer Center). For this trial, rst 20 patients who are suitable for high dose radiation are randomly assigned to either of the two arms. After 20 cases, with a method of Bayesian adaptive randomization, subsequent patients will be more likely to be assigned to receive the type of therapy that the radiation oncologist considers to be better based on the results for earlier patients in the study. This type of randomization has been accepted recently in order to take into consideration any slight inequality of the treatments that may be developing during the study. I think this is an appropriate approach because it considers patient benet. It illustrates the difculties involved in the design of such clinical trials. Hippocrates established medicine (not magic) based on practice and experience. RCTs do not always give a true answer to all medical questions, and conducting RCTs is sometimes inappropriate. We need to recognize that not only RCTs but also non-RCT studies must be science. Rebuttal: W. Robert Lee, M.D. I disagree with several elements of the argument put forth. First, it is not true that there are no biologic differences between protons and photons. More than 30 years ago, Robertson et al. published a paper that indicated the RBE of the proton beam increases beyond the peak.12 A recent paper from Paganetti et al. describes the phenomenon and states that there is a local hot region over the terminal few millimeters of the SOBP and extension of the biologically effective range.13 It is an oversimplication to believe that biology does not matter in proton beam therapy and state that the only relevant differences are physics. Second, it is not prudent to state that RCTs are unnecessary because questions can be readily answered by simple planning comparisons. Two recent examples of planning comparison are not consistent with one another.14,15 How

can one use studies like this to readily answer the question of whether protons are superior to photons? Given our limited understanding of dose-volume relationships in most contexts, it is unwise to use DVH comparisons as a surrogate; clinical results in patients are what should be important. I agree with Dr. Sakurai that proton beam therapy is more expensive than photons, and I was surprised by the fact that Japans public insurance does not pay for particle therapy. It is intriguing that Dr. Sakurai imagines that some RCTs of protons are likely to demonstrate no major differences in cure rates with big differences in cost. It would be wonderful if Dr. Sakurai could list some examples and share them with our American proton enthusiasts! At the end of the day, the question remains. Are we willing to accept the claim that proton beam therapy is superior in the absence of high-level evidence? I am of the opinion that medicine is a discipline that should be rooted in science. Randomized trials are the best method to test hypotheses, and the proton beam lends itself to many hypotheses that can be tested.
M. Goitein, Trials and tribulations in charged particle radiotherapy, Radiother. Oncol. 95, 2331 (2010). 2 M. Goitein and J. D. Cox, A patients perspective on randomized clinical trials for proton therapy: In reply, J. Clin. Oncol. 26, 25932596 (2008). 3 S. Hellman and D. S. Hellman, Of mice but not men. Problem of the randomized clinical trial, N. Engl. J. Med. 324, 15851589 (1991). 4 H. Suit, T. DeLaney, S. Goldberg, H. Paganetti, B. Clasie, L. Gerweck, A. Niemierko, E. Hall, J. Flanz, J. Hallman, and A. Tromov, Proton vs carbon ion beams in the denitive radiation treatment of cancer patients, Radiother. Oncol. 95, 322 (2010). 5 H. Suit, H. Kooy, A. Tromov, J. Farr, J. Munzenrider, T. DeLaney, J. Loefer, B. Clasie, S. Safai, and H. Paganetti, Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No, Radiother. Oncol. 86, 148153 (2008). 6 H. Suit and H. Kooy, In response to Schulz and Kagan, Int. J. Radiat. Oncol., Biol., Phys. 72, 13091310 (2008). 7 J. E. Tepper, Protons and parachutes, J. Clin. Oncol. 26, 24362437 (2008). 8 A. Michalos, Principles of Logic (Prentice-Hall, Englewood Cliffs, 1969). 9 B. Russell, Is There a God?. (Commissioned but not published by Illustrated Magazine in 1952). Available at http://www.cfpf.org.uk/ articles/religion/br/br_god.html. 10 A. B. Hill, The clinical trial, New Engl. J. Med. 247, 113119 (1952). 11 E. J. Emanuel, What cannot be said on television about health care, J. Am. Med. Assoc. 297, 21312133 (2007). 12 J. B. Robertson, J. R. Williams, R. A. Schmidt, J. B. Little, D. F. Flynn, and H. D. Suit, Radiobiological studies of a high-energy modulated proton beam utilizing cultured mammalian cells, Cancer 35, 16641677 (1975). 13 H. Paganetti et al., Relative biological effectiveness (RBE) values for proton beam therapy, Int. J. Radiat. Oncol., Biol., Phys. 53, 407421 (2002). 14 X. Zhang et al., Effect of anatomic motion on proton therapy dose distributions in prostate cancer treatment, Int. J. Radiat. Oncol., Biol., Phys. 67, 620629 (2007). 15 A. Tromov et al., Radiotherapy treatment of early-stage prostate cancer with IMRT and protons: a treatment planning comparison, Int. J. Radiat. Oncol., Biol., Phys. 69, 444453 (2007).
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