1. Susman, Ed

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SAN FRANCISCO-A three-pronged anti-prostate cancer attack for men at high-risk for recurrence after surgery appears to extend the time of freedom from disease progression, researchers reported here at the American Society for Radiation Oncology Annual Meeting.

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In the preliminary Radiation Therapy Oncology Group 0621 trial, 73 percent of patients survived the critical three-year post-prostatectomy period without evidence of cancer progression, fulfilling the study's primary endpoint, said Mark Hurwitz, MD, Professor of Radiation Oncology at Thomas Jefferson University.


"In light of these very favorable findings, Phase III trials assessing the use of androgen-deprivation therapy and chemotherapy with radiation in this high-risk population are clearly warranted," he said in his oral presentation.

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The goal of the single-arm study was to determine if the addition of androgen-deprivation therapy plus docetaxel chemotherapy to the standard adjuvant radiation therapy would improve the historical freedom from progression rate from 50 percent of these at-risk patients to at least 70 percent at three years. "The study endpoint was met," Hurwitz said.


"Prostatectomy benefits many but certainly not all patients," he continued, explaining that the researchers sought to find ways to improve outcomes following prostatectomy for men who were clearly at higher risk of recurrence-particularly to determine if systemic therapy would improve outcomes.


"Failure within three years of prostatectomy is associated with increased risk of prostate cancer-specific mortality," Hurwitz said. "While adjuvant radiation will benefit most patients, there clearly are subgroups at high risk of failure despite surgery and radiation."


For the study, Hurwitz and colleagues recruited 80 patients of whom 74 met all the eligibility criteria, enrolled from 2008 through 2010.


To be eligible for the study, post-prostatectomy nadir prostate specific antigen (PSA) had to be greater than 0.2 ng/ml, and the tumor Gleason score had to have been 7 or greater. Men were also eligible if their nadir PSA was 0.2 ng/ml or less and they were diagnosed with Gleason 8 or greater prostate cancer and the patients also were diagnosed with Stage pT3a or greater-meaning extracapsular extension of the cancer.


Hurwitz said that the eligibility was based on previous cooperative group studies that identified men most likely to have disease progression within three years of surgery.


At the three-year time point, 20 events had occurred among the men, which translated to a freedom from progression rate of 73 percent. Failure was defined as a PSA value of at least 0.4 ng/ml, the use of non-protocol hormones, clinical failure, or death within three years.


After a median follow-up of 4.4 years, 26 events were recorded: "Not surprisingly, the initial failure was biochemical in nature," Hurwitz said. Of the 26 events, 24 were defined as biochemical failure; two first events were the emergence of distant metastases.


"With less than five years of follow-up, 11 of our patients experienced distant metastasis and there were two prostate cancer specific deaths," he said. One other patient died from non-prostate cancer causes. The researchers did not observe any cases of local-regional progression.


In a multivariate analysis, PSA nadir was associated with freedom from progression, and both PSA nadir and Gleason score were associated with biochemical failure.


Cost in Adverse Events

The systemic treatments did come with a cost in adverse events, Hurwitz reported. More than 50 of the 74 patients in the trial experienced Grade 3 or 4 neutropenia and leukopenia. However, he said, "most of these adverse events were anticipated and were manageable without long-term sequelae. These were laboratory and not clinically-based toxicities. Rates of febrile neutropenia and infection were low.


"There did not seem to be long-term toxicity with the addition of docetaxel and androgen-deprivation therapy," he said. He noted that the use of docetaxel in the study was based on Phase III trials that indicated the effectiveness of the taxane in treatment of metastatic prostate cancer.



In commenting on the study, Kenneth Roberts, MD, Professor of Radiation Oncology at Yale University School of Medicine, said in an interview: "This trial is hypothesis generating, suggesting that the addition of docetaxel to high-risk individuals after prostatectomy for prostate cancer who would otherwise be getting adjuvant radiation seems to improve survival.


"This needs to be moved forward into a randomized trial," he added. "These results are compared with historical controls and there are lots of pitfalls with those comparisons."

MARK HURWITZ, MD. MA... - Click to enlarge in new windowMARK HURWITZ, MD. MARK HURWITZ, MD: "The take-away message is that the patients in this study had, by and large, more significant risk factors than those in other series."

Study Specifics

In the trial, all patients received six months of androgen deprivation followed eight weeks later with the start of radiation treatment. The radiation dose was 66.6 Gy delivered in fractions of 1.8 Gy. "Three to six weeks later, the initiation of docetaxel for a total of six cycles was begun, using the regimen for metastatic disease," he said.


In the RTOG 0621 study he was reporting, patients were treated with docetaxel dosed at 75 mg/m2 on day 1 of a 21-day cycle. The patients had a median age of 62; 61 of the patients had Gleason scores of 8 to10, and 41 men or 55 percent of the total in the trial were diagnosed with a Gleason score of 9; 40 men were diagnosed with Stage pT3b, and 58 percent had positive margins following surgery.


"The take-away message is that the patients in this study had, by and large, more significant risk factors than those in other series," Hurwitz said. He noted that in a previous SWOG study, about 12 percent of men had Gleason scores of 8 or greater compared with 82 percent in this study. In addition, 47 percent of the men had a nadir PSA higher than 0.2 ng/ml.


The study was supported by grants from the National Cancer Institute and sanofi-aventis.