Proton therapy is the best radiation treatment modality for prostate cancer

Arguing against the Proposition is Jean Pouliot. Dr. Pouliot received an M.Sc. in Experimental Physics and a Ph.D. in Nuclear Physics from Université Laval, Québec, Canada. From 1993 to 1999 he was a Medical Physicist in the Department of Radiation Oncology at Hotel-Dieu de Québec and Associate Professor at Université Laval, Québec. He is currently Professor, Department of Radiation Oncology, at the University of California, San Francisco. Dr. Pouliot's main research interests are the development and clinical integration of dose-guided radiation therapy with megavoltage cone-beam computed tomography (CT) for patient verification, organ motion and tumor evaluation studies during cancer irradiation, and inverse planning for dose distribution optimization and relative biological effectiveness of image-guided high dose-rate and permanent prostate implant brachytherapy. The goals of cancer therapy are to maximize the tumor control probability (TCP) and minimize the normal tissue complication probability (NTCP). The TCP can be increased by escalating the tumor dose. The NTCP can be reduced by de-escalating the normal tissue dose and using noninvasive procedures and, because treatments are provided on an outpatient basis, potential complications due to hospitalization are eliminated. In the past, intensity modulated radiation therapy (IMRT) with x rays has been used in an attempt to escalate the tumor dose and reduce the normal tissue dose compared with traditional three dimensional (3D) megavoltage x-ray beam therapy. Unfortunately, megavoltage beams deposit dose maximally near the patient's surface and then continue to deposit dose as they traverse through to the opposite side. There is little that can be done to affect the total energy deposited within the patient, i.e., the integral dose. The most that can be achieved using IMRT is to move dose from one sensitive part of the body to a less sensitive part. In contrast, proton beams deposit dose maximally at the depth of the tumor and deliver no dose distal to the target. If each x-ray beam in an optimized IMRT plan is replaced by a proton beam which has been range modulated to give the same depth-dose distribution over the target volume as the x-ray beam, then it is obvious that much less dose will be delivered outside of the target volume.1 Although this type of plan does not take full advantage of a proton beam's characteristics, the exercise does demonstrate that proton therapy (PT) can always deliver a better dose distribution than IMRT. For typical PT treatments, the integral dose given to nontarget tissues is only a factor of 0.5–0.6 of that delivered by IMRT. Brachytherapy (BT) is another modality that has been used in an effort to escalate the tumor dose and reduce the normal tissue dose. BT is an invasive procedure that has associated risks of compromising blood vessels, nerves, and other critical tissues. BT also has the risks associated with anesthesia, infection, and edema. None of these risks is encountered during PT. In addition, not all patients are candidates for the BT procedure because of preexisting medical conditions and/or gland size. Another disadvantage of BT is that there is a large range of doses and dose rates delivered to the tumor cells because of the large inverse square gradients around each source. This makes the biology of BT difficult to understand and optimize.2,3 In contrast, delivering a uniform dose throughout the target with PT is accomplished simply by modulating the depth of the Bragg peak. Yet another disadvantage of BT is the difficulty in treating the seminal vesicles and/or lymph nodes if involved. Most often, PT can encompass all three targets within one field. As of 2006, over 8000 patients have been successfully treated worldwide for prostate cancer using PT. The demand for PT is increasing rapidly in part because highly motivated and informed patients find this modality attractive due to its equivalent cure rate and small risk of morbidity compared with other treatment modalities. The use of intensity modulated proton therapy, which is just now becoming available, will further reduce the dose to normal tissues and may allow further escalations of tumor dose. Proton therapy is a good example of the level of technology the fight against cancer may require. Add that prostate cancer is the most prevalent type of cancer among men, and one may be tempted to infer that PT is best for prostate cancer. There are, however, two main reasons that preclude reaching this conclusion. First, prostate cancer patients can count on an armada of well-proven and long-term validated treatment approaches. And second, there are several significant unanswered questions related to the technical implementation of PT for prostate cancer. Very good long-term local control of early-stage disease is obtained with permanent prostate implant (PPI) brachytherapy. For external beam radiation therapy (EBRT), recent randomized studies have shown that men with localized prostate cancer have a lower risk of failure if they receive high- rather than conventional-dose conformal radiation.4,5 When the same high dose is used, published proton results are nearly identical to EBRT.6 Thus, the key point is that men with prostate cancer, in particular those with advanced local disease, benefit from dose escalation. A UCSF7 study shows that the response of the tumor to PPI is more rapid than for EBRT, not a surprise since the BT dose is substantially higher than the EBRT dose. High dose rate (HDR) BT, as a boost to EBRT, can also provide significant dose escalation with very good sparing of organs at risk (OARs).8 Furthermore, the finding that treatment failures of EBRT patients were located in the proximity of known macroscopic disease,9 suggests that dose escalation to these regions would be beneficial. This has been performed with EBRT, PPI and HDR,10 where increasing the dose to the (MR spectroscopy defined) dominant intraprostatic lesion (DIL) was achieved without increasing dose to OARs. Can PT safely boost a DIL within the prostate? Does PT produce the most conformal dose distribution? The physics can indicate the theoretical potential of each technique: Bragg peak vs inverse square law (and short distances) vs IMRT. But in the end, it depends on the specific clinical implementation. For instance, the prostate moves from day to day, sometimes from minute to minute. Anatomical changes such as rectal filling may have a large impact on local control when using EBRT.11 Therefore, where the dose is delivered is of equal importance to dose escalation itself. Prostate motion and setup uncertainties are not an issue for BT, and for EBRT are accounted for by precise daily alignment of the prostate using markers or other forms of image guided radiation therapy (IGRT). Does PT resolve the organ motion problem? There are technical problems of using high- markers in proton beams, especially with a small number of beam angles. Daily rectal balloons can be tolerated by patients during PT, but they may push the rectum into high dose regions, and residual prostate motions are observed. What are the consequences of a sudden Bragg peak displacement due to bowel or rectum fillings being replaced with gas? Because of the sharp dose falloff, it is even more important to integrate the lessons learned with IGRT in PT before its benefit for prostate may be realized. There are other questions: economics, neutron dose, biology, etc. PT may be equivalent in some prostate cases to other radiation therapy modalities, but the answer today to the Point/Counterpoint Proposition is clearly NO. Perhaps PT might offer a unique approach for a subset of prostate patients, or even be the best approach in the future. It is only by performing more research and pursuing more developments that future prostate patients will have their hope of being cured increased while enjoying a high quality of life. Dr. Pouliot's first argument against PT is that there are many well-proven and long-term validated treatment approaches for prostate cancer. While this is true, there is still room for improvement in TCP and NTPC. IMRT and BT have already been highly optimized and further technical improvements in these delivery approaches are not obvious. Indeed, Dr. Pouliot's reference showing the benefits of dose escalation was performed with proton beams.5 The low rate of complications in this study indicates that even further dose escalation is possible with PT. The basic technique for PT is two uniform lateral beams.12 If advanced imaging techniques could demonstrate a localized region of the prostate with a high concentration of tumor cells, then a boost dose could easily be provided by strategically placing proton Bragg peaks at the site of those tumor cells using narrow beams from only one or a few directions that bypass critical normal tissues. Dr. Pouliot's second argument concerns a number of perceived technical issues, most of which have been answered over the last . All prostate patients that have received PT were localized daily with orthogonal kilovoltage x rays. In fact, IGRT has always been an integral component of PT. Most patients had the prostate immobilized between a urine-filled bladder and a constant-volume water-filled balloon inserted into the rectum. This technique, which was well tolerated, displaced gas cavities from the path of the protons, and pushed most of the rectum and bladder out of the irradiated volume.13,14 A study that compared a set of four implanted marker seeds with skeletal landmarks demonstrated that both intra-fraction and inter-fraction motion were minimal using this immobilization technique.15 With regard to neutron dose, a recent study has shown that, in the plane of the isocenter, the neutron dose equivalent from an entire course of treatment is roughly equivalent to that received from a single CT exam.16 In conclusion, there appear to be no impediments to dose escalation using PT while maintaining a low risk of complications. I agree with Dr. Moyers that some of the inherent theoretical physics characteristics of proton beams are of prime significance for prostate cancer treatment. However, in an era of evidence-based medicine, the best modality provides the best disease control with the least complication rate at the lowest cost, along with the best global quality of life. Studies show that what is most invasive for one patient may be least for another. For the same treatment outcome, completing a treatment in one or two days, even with needle insertion, may sound appealing compared with several weeks of daily commuting in order to receive a fractionated course of treatment. Years of improvements on the practical issues have led to sophisticated treatments using either IMRT or BT, which can address the practical issues for each specific cohort of patients. PT is in its infancy compared to IMRT or BT, and if you can afford the price tag, it can offer an equivalent treatment outcome. IMRT and BT are also evolving. In many ways, we are faced with a moving target. A fair evaluation should compare the best of all three modalities. If there is one thing that I remember of my transition from nuclear to medical physics, it is that a solid fundamental concept is only the beginning of a long uphill road leading to an improvement in care. Radiation Oncology is a multidisciplinary field with, at its core, a unique human being in need of treatment. One should devote all efforts to perfect the treatment today to make it better than the one of a few years ago, while still realizing that new knowledge may eventually make today's treatment obsolete, and the sooner the better.

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