Despite evidence from clinical trials and recommendations from professional organizations for the use of adjuvant radiotherapy after radical prostatectomy in men with localized prostate cancer with high-risk features, a new study finds little use of radiation in this setting.
The study, published online April 20 in European Urology, reports that fewer than than 20% of men with prostate cancer at risk for recurrence received postoperative radiotherapy within 6 months of surgery.
"Despite category 1 evidence, the trend for providing adjuvant radiotherapy to men with localized prostate cancer with adverse pathological features is not as one would expect," corresponding author Helmneh M. Sineshaw, MD, MPH, senior epidemiologist at the American Cancer Society, Atlanta, Georgia, told Medscape Medical News.
Senior author Jason A. Efstathiou, MD, DPhil, who is associate professor at Harvard Medical School and is with the Department of Radiation Oncology at Massachusetts General Hospital, in Boston, told Medscape Medical News: "The broad adoption of adjuvant radiotherapy has been low. Indeed, usage is decreasing since the availability of high-level evidence."
The evidence comes from three randomized clinical trials, two in Europe and one in the United States, which have shown significant progression-free survival benefits and decreased risk for recurrence when men with prostate cancer with adverse pathologic features are provided adjuvant radiation therapy (RT) following radical prostatectomy (RP).
The American Society for Radiation Oncology (ASTRO) and the American Urological Association (AUA) endorsed these studies with a guideline in 2013.
Variable Expert Opinion
Medscape Medical News reached out to several radiation oncologists not associated with the study. The opinions received were conflicting, varying from disappointment with current practice to lack of wholehearted support that advances adjuvant radiotherapy for all men with prostate cancer post surgery.
"It is extremely disappointing to see that the urologic oncology community has not embraced the consistent results of three prospective randomized trials that have provided class 1 evidence of benefit from adjuvant radiation therapy for men with adverse pathologic features following radical prostatectomy," Jeffrey M. Michalski, MD, vice chairman of radiation oncology and chief of the genitourinary service at the Washington University School of Medicine in St. Louis, told Medscape Medical News.
"Despite data demonstrating the low rate of toxicity from adjuvant radiation therapy, men are being denied the opportunity to receive this important and highly effective treatment," he added.
Anthony V. D'Amico, MD, PhD, FASTRO, professor in the Department of Radiation Oncology and chief of genitourinary radiation oncology at the Dana-Farber and the Brigham and Women's Hospital, Boston, Massachusetts, indicated that "some clinicians are not entirely convinced about the three randomized trials that support adjuvant RT for men undergoing RP because while all three show a benefit in progression-free survival, only one showed a decrease in metastasis-free survival and prolongation in overall survival."
"Some have interpreted this to suggest that only men with multiple indications [high-risk features] for adjuvant radiotherapy after surgery, and not a single indication, may be best treated," Dr D'Amico told Medscape Medical News.
Michael J. Zelefsky, MD, professor of radiation oncology in the Department of Radiation Oncology at Memorial Sloan Kettering Cancer Center, New York City, told Medscape Medical News: "These findings are not surprising and reflect current practice patterns and trends."
"While one study has demonstrated a survival benefit for the use of adjuvant radiotherapy in high-risk patients, it remains unclear that the outcomes are compromised if one waits until the PSA begins to become detectable," he added.
Data From the National Cancer Data Base
For the newly published study, Dr Sineshaw and colleagues garnered data from the National Cancer Data Base — a national hospital-based cancer registry database that captures approximately 70% of newly diagnosed cancer patients.
They found that 97,270 men aged 18 to 79 years with newly diagnosed invasive prostate cancer had been treated with RP between 2005 and 2011 but that only 7766 (8%) of these patients received RT with or without androgen deprivation therapy (ADT) following RP.
The following trends were reported:
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Reasons Advanced for Decline in Use of Adjuvant RT
According to Dr Sineshaw and colleagues, "The pattern of declining use [of RT] could be due to multiple factors, including patient preference, physician and referral bias, concern about toxicity, lack of a consistent survival benefit seen in the updated randomized trials, or a growing preference for salvage radiation at time of biochemical failure."
Howard Sandler, MD, FASTRO, Ronald H. Bloom Chair in Cancer Therapeutics and professor and chair, Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California, provided additional insights into these factors.
With respect to patient preference, Dr Sandler told Medscape Medical News: "Patients aren't being referred to a radiation oncologist for a discussion."
"Sure, some patients will prefer not to receive radiation, but unless they've met with a specialist in radiation, how can they make an informed decision?," he asked.
Dr Efstathiou agreed and questioned whether men are even routinely being presented the option. Studies such as that by him and his colleagues, however, cannot answer this question, he indicated.
"Most cancers require a multidisciplinary and multimodal therapy approach. With high-risk prostate cancer patients, we have to be honest and counsel patients that they may not be cured with a single modality treatment, such as RP alone," Dr Efstathiou told Medscape Medical News.
"We have to have that discussion and should not make the choice for patients without the discussion," he added.
But according to Dr Zelefsky, "not every high-risk patient will fail after surgery," and he suggested that patients should be not be exposed to radiotherapy if they do not need it.
Dr D'Amico agreed. He explained to Medscape Medical Newsthat data from a Duke University study suggest that a patient with a Gleason score of 7, extracapsular extension, and negative margins may be watched, whereas a patient with a Gleason score of 8, extracapsular extension, and a positive margin would be referred for adjuvant RT, given their relatively higher risk for subsequent failure.
"The results of the current study suggest that this is what is happening," he added.
Dr D'Amico explained that at academic centers, urologists typically refer men for a discussion of adjuvant radiotherapy if they have at least two of the three standard high-risk features — extracapsular extrusion, seminal vesicle invasion, and positive surgical margins. Men who have these factors are much more likely to be referred for a discussion about radiotherapy if they have a Gleason score of 8 to 10 vs 7 or less, given the higher absolute risk for recurrence.
He was not too surprised that community centers were more likely to offer men adjuvant RT compared with academic centers. "Academic centers may be more aware of the controversy sparked by the three randomized studies, where all show a prolongation in progression-free survival, but only one shows a survival benefit," he told Medscape Medical News.
Therefore, many clinicians treating men with RP for prostate cancer have adopted a risk-adapted approach to who gets referred for a discussion of adjuvant RT. "The higher the risk of recurrence, the higher the likelihood of these men being referred to receiving adjuvant RT following RP," he said.
"Based on the study from Duke University, it appears that one can follow men with an ultrasensitive PSA and only one high-risk feature (extracapsular extension or a positive surgical margin) and a Gleason score of less than 7, and provide salvage RT at the earliest sign of biochemical recurrence — when the PSA exceeds 0.10 ng/mL," Dr D'Amico told Medscape Medical News.
Dr Zelefsky agrees. "If the PSA is watched carefully and radiotherapy is administered when it becomes a detectable and rising value, the disease is likely being picked up in an early state, and the survival outcome is not likely compromised," he said.
Senior author Dr Efstathiou agreed with this practice, but only up to a point. He emphasized that this practice is not as evidence-based as is at least discussing adjuvant RT on the basis of existing completed prospective randomized trials. In addition, he highlighted the fact that the analysis that his group has just reported shows that men with the highest risk for recurrence (having more than two high-risk features) did not all receive adjuvant RT.
In their discussion, the study authors emphasize that a patient who is younger than 60 years with no comorbidities, pT3-4 disease, a positive margin, and Gleason 8-10 histology was found in their analysis to have received postoperative radiotherapy only 32.3% of the time.
"Given that such a patient is at the highest risk of recurrence and is also most likely to benefit from postoperative radiotherapy with a projected long life expectancy, these low rates raise concern that a significant proportion of patients are not receiving maximally curative treatment," they write.
Indeed, Dr D'Amico indicated that these observations suggest that practicing clinicians may have gone too far in not offering adjuvant radiotherapy to all men with several high-risk features.
Dr D'Amico and Dr Zelefsky told Medscape Medical News that randomized trials are under way to investigate whether there are any differences for the patient if early salvage radiotherapy is used compared with immediate postoperative radiotherapy.
They indicated that the results of these ongoing randomized trials will clarify these issues in the near future.
Uncertainty Over Timing
There is some uncertainty in clinical practice concerning the timing of when radiotherapy should be delivered after a radical prostatectomy, as recently reported by Medscape Medical News. The question is whether radiotherapy should be delivered soon after surgery (adjuvant radiotherapy) or whether clinicians should wait until there is a biochemical recurrence, as shown by a rise in PSA levels (salvage radiotherapy).
The authors of the current study indicate that their data did not show a rise in radiotherapy use in the period between 6 months to 5 years post surgery, suggesting that salvage radiotherapy following early relapse does not necessarily explain the declining use of immediate postoperative radiotherapy.
Dr Efstathiou agreed that the crux of the issue in clinical practice seems to be adjuvant vs early salvage radiotherapy. However, he indicated that until the trial results of early salvage vs adjuvant radiotherapy are available, adjuvant radiotherapy should at least be discussed and considered in the clinical management of men with high-risk features of prostate cancer after surgery. This is evidence- and consensus-based, he said.
Indeed, a long-term follow-up of one of the three randomized studies (EORTC 22911) that supports the use of adjuvant radiotherapy shows a benefit for young men with positive margins, but not for men older than 70 years, he pointed out.
"For older men with one high-risk feature (such as focal extracapsular extension) and other comorbidities, close observation with consideration of early salvage only when and if the PSA becomes detectable is appropriate," Dr Efstathiou said.
He added that when utilizing salvage therapy, however, it should be conducted early, when the PSA is confirmed to be detectable at a level of 0.1 ng/mL or higher.
"Emerging data suggest that the lower the PSA, the better the outcomes when employing salvage radiation," he said.
Dr Efstathiou told Medscape Medical News: "One does want to avoid overtreatment in those patients who may never fail or never realize the benefits of postoperative radiation, but at least having the discussion of the pros and cons of such postoperative options, including timing of therapy (adjuvant vs salvage), allows for informed decision making."
The authors and radiation oncologists interviewed have reported no relevant financial relationships.
Eur Urol. Published online April 20, 2015. Abstract
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