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Journal of Clinical Oncology, Vol 24, No 13 (May 1), 2006: pp. 1975-1977 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.7612
Exploring Dose-Intensity: Carefully Comparing High-Dose With Low-Dose External-Beam Radiotherapy for Prostate CancerUniversity of Michigan Medical Center, Ann Arbor, MI It is nearly axiomatic that higher doses of radiotherapy will result in fewer surviving cancer clonogens within the radiotherapy target, and this strongly held hypothesis has guided radiotherapy investigations over the last two decades.1 Radiation oncologists have been mindful of the two-edged nature of dose intensification and have carefully monitored patients for late toxicity in the context of clinical trials that have tested the dose-intensification hypothesis. Unfortunately, the results of more intense radiotherapy have been mixed, with many situations showing no long-term benefit with higher doses of radiotherapy. The absence of benefit may be explained by subclinical metastatic disease and a lack of highly effective treatment for this component of cancer, but even in conditions with a highly localized neoplasm (primary glial tumors), substantial dose escalation has sometimes been ineffective and perhaps resulted in increased toxicity.2,3 Thus, despite the self-evident nature of our axiom and years of investigation, careful clinical studies are still warranted before higher doses can be routinely used. More optimistically, however, the clinical experience of radiation oncologists using more intense radiotherapy techniques for prostate cancer has been quite encouraging. As radiotherapy techniques evolved to allow more conformal dose delivery and to restrict doses to uninvolved surrounding tissues, many centers began to intensify radiotherapy treatment in prostate cancer. The technical innovations occurred at an opportune time in the prostate cancer field, just as prostate-specific antigen (PSA) became widely available for monitoring patients after local treatment, and it became recognized that radiotherapy treatments to traditional doses of less than 70 Gy were less effective than previously believed.4 Early adopters of more intense therapy discovered, in phase I and phase II trials using three-dimensional conformal radiotherapy and more recently using intensity-modulated radiotherapy, that higher doses of radiotherapy resulted in fewer failures when using PSA-defined end points, along with reasonable toxicity.5-9 Two PSA-era phase III trials exploring radiotherapy dose level have shown a benefit by reducing biochemical failure rates with higher radiotherapy doses. Pollack et al10 compared 70 Gy with conventional radiotherapy versus 78 Gy using three-dimensional conformal radiotherapy in 305 patients. A significant improvement in biochemical control rates, from 64% to 70% at 6 years, was observed, and there was an intriguing decrease in distant metastases seen with the higher doses, although there was an increase in chronic rectal toxicity with the higher dose.10 In addition, Zietman et al11 recently reported a randomized comparison of 70.2 Gy versus 79.2 Gy in 393 patients, using a mixture of photons and proton beam treatment in both of the arms. They also noted a significant improvement in biochemical control, from 61% to 80% at 5 years, also with an increase in low-grade chronic rectal toxicity, despite the use of highly conformal proton beam treatment for the dose-escalation component of therapy. Along the lines of careful clinical investigations of higher doses, this issue of the Journal of Clinical Oncology contains the initial outcome results of the largest randomized study examining the role of radiotherapy dose-intensity for prostate cancer. Peeters et al12 compared 68 Gy with 78 Gy in a trial that enrolled 669 patients from four Dutch centers and had freedom from biochemical failure as the primary end point. They observed an improvement in freedom from failure (64% v 54% at 5 years for 78 v 68 Gy, respectively), with a hazard ratio of 0.74 (P = .02). Hormonal therapy was used in 21% of the participants at the investigator's discretion. We now have three PSA-era randomized studies that demonstrate a freedom from PSA failure benefit with higher doses of external-beam radiation. So, are we done? Can we conclude that 78 Gy is the standard dose for localized prostate cancer? Unfortunately, despite these encouraging reports, we still have a few more concerns to cover and more work to do. First, regarding end points, the Peeters et al12 study is not alone in examining the role of PSA as the primary end point for clinical trials. The use of PSA as a surrogate for more important clinical end points, such as cause-specific or overall survival, is complex and is still unresolved, especially in the setting of hormone-refractory prostate cancer,13 but one might make an argument that PSA-determined failure is an acceptable end point in certain types of localized prostate cancer clinical trials. That is, in a hypothetical phase III trial, when the only difference between the two arms is the radiation therapy technique under investigation (eg, radiation type A v radiation type B) and the use of hormone therapy, which complicates the PSA end point, is the same between the two arms, a PSA end point will allow investigators to determine which of the two treatments is more effective at reducing prostate cancer recurrence. Whether this translates into a survival benefit is a separate issue and is complicated by the long natural history of prostate cancer. However, if one is attempting to improve radiotherapy techniques (or other local treatment modalities such as radical prostatectomy), as Peeters et al12 and the other phase III trials have attempted, PSA-driven end points seem perfectly reasonable. The article by Peeters et al12 raises some interesting technical issues for the radiotherapy cognoscenti. For example, the planning target volume (PTV) that the study employed used a 0-mm margin posteriorly for the 10-Gy boost from 68 to 78 Gy. That is, there was no margin for either dose build up or set up uncertainty over the peripheral zone. Additionally, the dose was prescribed to the isocenter, with an allowance for up to 5% cold zones in the PTV. For those less familiar with radiotherapy techniques, the implication of the description of the Peeters et al12 technique is that the peripheral zone (where most cancers are located) was notably underdosed during the experimental part of the treatment. Significantly, the experimental arm was superior to the standard dose arm, but this benefit may have been attenuated by their prescription and delivery instructions. Regarding the additional work that still needs to be completed, the Radiation Therapy Oncology Group (RTOG) is conducting a phase III trial of dose escalation for prostate cancer that is similar to the Dutch trial, but it differs in some important respects and remains worthy of active support. Briefly, RTOG 0126 compares 70.2 Gy with 79.2 Gy, and hormone therapy is not allowed. Of note, the dose is prescribed to the margin of the PTV, and the edge of the PTV is not truncated at the prostate-rectal interface, as in the Peeters et al12 study. Thus, given the prescription methodology differences, the lower dose arm in the RTOG study delivers a higher dose to portions of the peripheral zone than the higher dose arm of the Peeters et al12 study. This should allay fears that the low-dose cohort of the RTOG study is receiving a dose that is too low. Also, most patients in the RTOG trial are receiving intensity-modulated radiotherapy, which was used sparingly in the Dutch study and which will likely have an influence on the morbidity of treatment. Perhaps the most important difference is the size of the trial and the primary end point. The RTOG 0126 study is designed to test for an overall survival end point and will accrue 1,520 patients, of whom more than 800 have been accrued to date. As has been recently shown, local treatment for prostate cancer can influence survival.14 Whether the same effect can be demonstrated by intensifying the radiotherapy dose is the objective of the ambitious RTOG study, which will be the largest ever, phase III, radiation therapy dose study. Naturally, increased dose-intensity can be accompanied by more acute and chronic treatment-related complications. The phase III prostate dose studies to date have relied mostly on physician-determined traditional Common Toxicity Criteria toxicity scales to report morbidity. Assuming that higher doses truly reduce biochemical failure somewhere around 6% (Pollack et al10), 10% (Peeters et al12), and 19% (Zietman et al11), is this reduction in failure rate, in the absence of any yet to be proven survival benefit, worth a potential increase, albeit mild, in chronic rectal toxicity, as noted in all three studies? Here is where further work is clearly needed. The RTOG trial is gathering prospective validated-instrument data in bowel, urinary, and sexual domains and will allow for the sophisticated adjusted quality-of-life analyses that may inform dose prescription decision making. As noted, important clinical work has been performed to optimize the radiation therapy of prostate cancer. Technologic improvements in radiation therapy treatment planning and dose delivery, most recently intensity-modulated radiotherapy, are allowing new frontiers to be explored. The radiotherapy communities in North America and the Netherlands are to be congratulated for their efforts in carefully testing the dose-benefit hypothesis in prostate cancer. Yet, to break new ground, further investigations into the risks and benefits of high-dose radiotherapy are required; in addition, comparative clinical trials of competing radiation treatment modalities, such as permanent prostate brachytherapy and high–dose-rate temporary brachytherapy, are essential. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. Author Contributions
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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