Prostate Cancer Image-Guided IMRT Trial Shows Low Toxicity, Good Outcomes

Figure: Intra-fractional variations of anatomy in a prostate cancer patient in the span of 20 minutes: CT images immediately prior to and after an IMRT treatment fraction. The contours of pelvic anatomy before treatment (left) are overlaid on the CT image of the patient acquired immediately after the treatment (right). Prostate target (red) was displaced anteriorly for more than 5 mm.Despite reservations among many oncologists about recommending less intensive radiation therapy for patients after a prostatectomy, a five-year prospective trial of outcomes following postoperative image-guided intensity-modulated radiation therapy (IG-IMRT) found low toxicity for the technique and very good patient-reported outcomes for urinary, bowel, and sexual function, as well as overall quality of life. The researchers note that while most radiation oncologists are already familiar with the benefits of image-guided IMRT in their practices, many oncologists overall remain unaware of the positive effects and make decisions based on earlier studies—some dating back to the 1990s when the reported toxicity and other complications were a much larger concern than they are now. The Phase II study, published in the September-October issue of Practical Radiation Oncology (2015;5:e473-e482), involved 68 men between the ages of 43 and 74, with a median age of about 60. Approximately 78 percent received postoperative salvage radiation therapy and 22 percent received adjuvant radiation therapy. The investigators—co-led by Alejandro Berlin, MD, MS, Assistant Professor of Radiation Oncology at the University of Toronto Radiation Medicine Program, Princess Margaret Cancer Centre (and now at the University of Montreal), and Cynthia Ménard, MD, Associate Professor there—used published consensus guidelines for clinical target volumes of the prostate bed and radiation levels. The team then evaluated treatment-related toxicities, health-related quality of life (HRQOL), and biochemical outcomes. Patients received a dose of 66 Gy in 33 fractions with treatment-prioritized rectal dose constraints over recommended target volumes and daily cone beam computed tomographic guidance. Follow-up evaluation was conducted every three to six months during the first five years. The primary objectives were met in 97 and 98.5 percent of cases (the dose received by 99 percent of the planning target volume and rectal wall maximum dose, respectively). The secondary planned target volume of at least 95 percent of the prescribed dose was also achieved in two-thirds of the patients. At five years, the biochemical relapse-free rate was about 73 percent. “The findings lend support to other recent studies that have demonstrated the effectiveness and low toxicity profile of image-guided IMRT,” Berlin said in an interview. “Notably, a 2014 study found that only about 10 percent of eligible patients undergo the technique in the United States. Modern radiotherapy and the continuous improvements in treatment techniques have changed significantly over the last few years. “Our prospective study, although it was in a relatively small group of patients, illustrates this progress. I believe the results demonstrate that radiation treatment after prostatectomy no longer has to negatively impact patients' quality of life, especially regarding sexual, urinary, or bowel function. These and other recent findings show that such concerns should not impact the recommendation of radiation therapy treatment following prostatectomy.” The results also showed that treatment does not increase toxicity or affect cancer outcomes for at least five years, he added. “Unfortunately, most patients are still receiving inaccurate information about this approach and believe or are told that such treatment has the potential for bad outcomes. We hope this study will be used to reassure patients that this will not hurt them.” Study Details The study included prostate cancer patients considered candidates for post-prostatectomy, recruited between August 2007 and October 2008. Median follow-up after treatment was 5.9 years (range of 0.1 to 6.7 years). Toxicity was based on the National Cancer Institute's Common Terminology Criteria for Adverse Events. Health-related quality of life (HRQOL) was evaluated using the Expanded Prostate Cancer Index Composite (EPIC) questionnaire, which was collected prospectively at baseline, at week five (during radiation therapy), three months after the completion of radiation, and at one-, two-, three-, and five-year follow-up visits. The cumulative five-year incidence of late gastrointestinal Grade 2 symptoms was 12.3 percent, while the incidence of Grade 2 genitourinary toxicities was 10.6 percent There were no Grade 3 or Grade 4 late toxicities. The team reported transient declines in EPIC gastrointestinal domain summary scores and genitourinary irritation. Complete recovery occurred between three and 12 months after therapy, and remained stable compared with baseline at five-year follow-up. Sexual HRQOL also was stable at five years, with an improving trend, with the five-year mean score at about 58 versus about 45 at baseline. Berlin said this might have been due to the patients becoming accustomed to erectile dysfunction over time. Limitations Among the limitations the researchers noted were the small number of patients in the trial. Still, Berlin said, having patients answer the EPIC questionnaire was effective in getting the results that were directly affected by treatment, especially in an area lacking much patient-reported data. Another concern was that the rate of patients completing EPIC questionnaires declined over time, and that the volume definition of organs at risk could be different at other institutions. “Caution should be used in determining the equivalence of other normal tissue dosimetric parameters to be applied for plan evaluation when different contouring techniques are used,” the authors said. “The low toxicity rates we observed, particularly rectal toxicity, were surprising,” Berlin noted. “Despite the limitations, I think our study provides clinical validation and evidence to support the use of current guidelines for post-prostatectomy radiotherapy.” Greater Awareness Asked for his perspective, Eric Horwitz, MD, Professor of Medicine and the Gerald E. Hanks, MD Chair in Radiation Oncology at Fox Chase Cancer Center, said that most radiation oncologists are already aware of the benefits of image-guided IMRT, but word is now beginning to reach clinical oncologists and surgeons. “Over the past five years radiation oncologists have come to understand how far this approach has progressed, but the rest of oncology has been slow to catch up. Like any new treatment it takes a long time for word to get out, and older post-op radiation therapy is the poster child for treatment. It took forever to complete randomized prospective clinical trials of that approach and for the results to be replicated.” IG-IMRT, on the other hand, is still in the early stages of this process. Nonetheless, what data is available is convincing, he said. “Twenty years ago, there were terrible side effects reported in studies of IG-MRT, but a lot has changed in two decades. “This was not a big study, but it was very well done, and the results make a lot of sense,” he continued. “They address many of the issues and concerns that patients and oncologists talk about. But what they have heard and said about postoperative radiotherapy does not match what we as radiation oncologists see with modern treatment in 2015. Patients tell us: ‘I've heard about terrible side effects,’ but this is information that related to treatment 20 years ago, not today.”

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