Eight weeks versus 28 weeks of androgen suppression before radiotherapy produced virtually identical outcomes at 10 years of follow-up in men with intermediate-risk prostate cancer, in the randomized Phase III Radiation Therapy Oncology Group (RTOG) 9910 trial, published in the February 1st issue of the Journal of Clinical Oncology (2015;4:332-339).
The rates of 10-year disease-specific survival, overall survival, cumulative incidence of locoregional progression, distant metastasis cumulative incidence, and antigen-based recurrence cumulative incidence were all equal or within one or two percentage points between the two groups.
But an important question not asked or answered in the trial was whether some men with intermediate-risk prostate cancer can safely avoid androgen suppression entirely prior to radiotherapy. Also, the significance of the trial outcome may be less certain because the dose of radiotherapy used was less than is commonly used today.
RTOG 9910, sponsored by the National Cancer Institute, included 1,489 men with intermediate-risk prostate cancer randomly assigned to either a short-duration androgen-suppression regimen lasting eight weeks, or a prolonged-suppression regimen of 28 weeks. Patients in both groups were then treated with radiotherapy and an additional eight weeks of androgen suppression.
Those in the short-duration group therefore received a total of 16 weeks of androgen suppression, versus 36 weeks in the prolonged-duration group.
In a telephone interview, the first author, Thomas M. Pisansky, MD, Professor of Radiation Oncology at the Mayo Clinic, said that a lower than expected prostate cancer death rate reduced the ability of the results to detect a between-group difference in disease-specific survival. Nevertheless, he and his coauthors concluded that the schedule of eight weeks of androgen suppression before radiotherapy plus eight weeks of androgen suppression during radiotherapy remains a standard of care in men with intermediate-risk prostate cancer.
Accompanying Editorial by Anthony D'Amico
In an accompanying editorial (?JCO 2015;4:301-303), Anthony V. D'Amico, MD, PhD, Professor of Radiation Oncology at Harvard Medical School and Chief of the Department of Genitourinary Radiation Oncology at Brigham and Women's Hospital and Dana-Farber Cancer Institute, questioned whether the trial had the power to show benefit from a longer duration of radiotherapy.
Those concerns were based on the inclusion of men in the trial who had intermediate-risk disease but a favorable prognosis and who may not have needed androgen suppression at all, which D'Amico said diluted the power of the study to measure difference in outcomes.
Intermediate-risk prostate cancer was defined for the purposes of the trial by three sets of specifications: T1b-4, Gleason score 2 to 6, and prostate-specific antigen (PSA) between 10 and 100 ng/mL; or T1b-4, Gleason score 7, and PSA less than 20 ng/mL; or T1b-1c, Gleason score 8 to 10, and PSA less than 20 ng/mL.
Prior androgen-suppression therapy was not allowed unless a luteinizing hormone-releasing hormone analog (LHRHa) was started within 30 days before random assignment and bicalutamide or flutamide was started within 14 days of the LHRHa. Any finasteride was discontinued.
The radiotherapy used was two-dimensional or three-dimensional conformal external technique, but intensity modulation and brachytherapy were not allowed.
The prostate and any extraprostatic tumor extensions received 70.2 Gy in 39 daily fractions. The iliac lymph nodes received 46.8 Gy in 26 fractions, when included.
The median age of the men was 71 years for both groups, ranging from the mid-40s to the mid-80s.
The authors said that prior studies in these men showed that radiotherapy with androgen suppression reduced the risk of death from prostate cancer compared with use of radiotherapy alone.
Results Virtually Identical
For the 752 patients in the short-course androgen-suppression arm and the 747 in the prolonged androgen-suppression arm, a median duration of 9.4 years follow-up showed that the:
- 10-year disease-specific survival rate for the eight-week group was 95 percent, compared with 96 percent for the 28-week group;
- 10-year overall survival rates were 66 percent and 67 percent respectively;
- 10-year cumulative incidences of locoregional progression were six and 4 percent, respectively;
- 10-year distant metastasis cumulative incidences were both six percent; and
- 10-year prostate-specific antigen- based recurrence cumulative incidences were both 27 percent.
In the patients receiving short-term androgen suppression, there were 230 deaths, 29 as a result of prostate cancer and one due to complications of treatment. In the prolonged- treatment group, 220 patients died, 23 from prostate cancer and one from complications of treatment.
The authors acknowledged that the radiotherapy used was the standard more than a decade before the trial concluded and is no longer recommended, so the study may overestimate the incidence of biochemical failure, salvage therapy, and adverse events that might be expected with conformal radiation.
‘Not Convinced about Trial's Conclusions’
D'Amico, though, said he was not convinced about the trial's conclusions: “Whether four months of androgen deprivation is sufficient, or if any androgen deprivation is necessary in men with unfavorable or favorable intermediate-risk prostate cancer, to minimize prostate cancer specific mortality, remains unanswered.”
He said that at this time, withholding androgen-deprivation therapy in men with favorable intermediate-risk prostate cancer, or adding four or six months of androgen deprivation to radiotherapy in men with unfavorable intermediate-risk prostate cancer, are both reasonable options based on the available evidence.
The definition of an intermediate-risk favorable subgroup that he cited, from Memorial Sloan Kettering, is a patient with Gleason 3 + 4 or less and a positive prostate biopsy not exceeding 50 percent and only one intermediate-risk factor excluding 4 + 3.
The intermediate-risk unfavorable subgroup would be patients with Gleason 4 + 3 or at least two intermediate-risk factors or at least one intermediate risk factor and a positive prostate biopsy greater than 50 percent.
“The clinical significance of this subdivision relates to personalizing the use of androgen-deprivation therapy for men with intermediate-risk prostate cancer,” D'Amico said.
In an e-mail exchange, he said that if a significant number of men in the study were in the favorable intermediate-risk group, which is likely based on the very low death rate at 10 years from prostate cancer, then the study loses power (or the ability) to measure a difference in death from prostate cancer between the two randomized treatment arms: “This is true because for men with favorable intermediate-risk prostate cancer, several studies have shown no significant association with a decrease in death from prostate cancer when varying durations of hormonal therapy were added to radiotherapy.
“The most important point is that when you run a trial where the question is whether a longer duration of hormonal therapy will decrease death from prostate cancer, and some men enrolled in the study do not benefit from any hormonal therapy—in this case the favorable intermediate-risk patients—then any benefit from the longer duration of hormonal therapy in men with more advanced (i.e., unfavorable intermediate-risk prostate cancer) gets diluted, and both arms can end up looking the same, whether it is the eight-week or the 28-week hormonal therapy arm.”
“That means this study, instead of having a total of a certain number of patients, really has that number minus the number of people in the subset who do not benefit from any hormonal therapy,” he said. “And that is why the power of the study to measure the difference is decreased.”
D'Amico said it is very possible that patients in the unfavorable intermediate-risk arm—“how many there are in this study we do not know”—may benefit from more hormonal therapy. “We already know that six months prolong survival, and we know that four months prolong survival.” But whether nine months is better than the four months in this study is yet to be told.
D'Amico said he is awaiting the post-randomization analyses of the RTOG 0815 and the GICOR 17 randomized controlled trials within the intermediaterisk subgroups for the latest data.
Commentary's Criteria Not Validated
Pisansky responded to D'Amico's critique in a telephone interview: “Our study tested the duration of androgen suppression with radiotherapy, as well as it has been tested to date, and we did not find any benefit to extending its duration beyond four months. This is simply the most objective way of looking at this study and its findings.
“The only thing that occurred as a consequence of prolonged androgen suppression was more side effects.”
He noted that during the time the study was being prepared for publication, another study looking at short-term versus intermediate-term androgen suppression was published, and this too found no benefit to longer-term use of androgen suppression in intermediate-risk prostate cancer (Denham et al. Lancet Oncology 2014;10:1076-1089).
RTOG 9910 entered approximately 1,500 patients over four years and followed patients for nearly a decade thereafter, he said.
Pisansky said that although D'Amico as the editorial writer did not seem to agree totally with the study's conclusions, the critique appears to be based on information (Zumsteg et al. Eur Urol 2013;64:895-902) that became available well after RTOC 9910 was designed and completed.
Moreover, Pisansky said, that information has not been validated by others (Castle et al. Int J Radiat Oncol Biol Phys. 2013;85:693-699 and Rodrigues et al. Radiother Oncol 2013;109:204-210), nor adopted as a risk stratification scheme for intermediate-risk prostate cancer by any consensus group.
“There is certainly a range of prognoses within intermediate-risk prostate cancer, and there are those patients with more ‘favorable’ versus ‘unfavorable’ outcomes,” Pisansky continued. “However, focusing mainly on stratification based on Gleason grade 3 + 4 and the percentage of positive biopsy to separate ‘favorable’ from ‘unfavorable’ may be premature, as other studies that look at changing the risk stratification for intermediate-risk prostate cancer did not show that the percent of positive biopsy was an important ingredient.”
But RTOG 9910 did provide information on patients with “unfavorable” intermediate-risk disease, Pisansky said, based on the number of risk factors. In fact, the group with multiple intermediate-risk factors and those with what may now be considered high-risk disease made up more than half of the study's patients, and even there the researchers did not observe a benefit to androgen suppression beyond four months' use.
“Even if one were to think that the study should have tested the more prolonged androgen suppression only in the more ‘unfavorable’ intermediate-risk patients, still, more than 7,000 patients would be needed—a monumental task and is simply not realistic,” he said.
RTOG 9910 did not address the question of whether omitting androgen suppression is a reasonable option for intermediate-risk patients, Pisansky said, but noted that a prior RTOG study (Jones et al. NEJM 2011;365:107-118) did show a benefit of four months for androgen suppression in intermediate-risk prostate cancer, as did another study using higher radiation doses.
“We mentioned in our paper that another study, RTOG 0815, is currently accruing patients specifically meant to address the issue that Dr. D'Amico brings up—namely whether certain patients with more favorable intermediate-risk benefit from androgen suppression at all, but results of that study are years off. For the here and now, I think RTOG 9910 is as good as any study can be to answer the question we asked.”
William Oh: Optimal Management of Intermediate-Risk Prostate Cancer Has Long Been Controversial
For a urological oncologist's point of view on RTOG 9910, William K. Oh, MD, Chief of the Division of Hematology and Medical Oncology and Professor of Medicine and Urology at Mount Sinai School of Medicine, was asked for his perspective.
He said the optimal management of intermediate-risk prostate cancer has been controversial for some time because randomized trials have suggested that both increased doses of radiation and concurrent use of androgen-deprivation therapy can have benefit in terms of clinical outcomes.
The report on RTOG 9910 by Pisansky and colleagues suggests that nine months of ADT appears to have no significant advantage over four months of androgen-deprivation therapy in intermediate-risk patients treated with 70.2 Gy of external beam radiation, Oh said.
This was a large study and well conducted, he said, but the standard of care for radiotherapy in intermediate-risk prostate cancer has evolved over the years since that trial began, to include both higher standard doses of radiation as well as better risk stratification of intermediate-risk disease to favorable and unfavorable categories.
“What we can generally say with 9910 is that nine months of androgen deprivation therapy in general will not benefit intermediate-risk patients. But it does not tell us if androgen deprivation therapy is not needed for some lower-risk intermediate patients.”
For that question, he said, RTOG 0815 is asking whether a higher dose of radiation and no androgen-deprivation therapy versus six months of androgen deprivation therapy is of value.
‘Take-Home Message Clear, But Not News’
A radiation oncologist asked to comment, Sabin B. Motwani, MD, Assistant Professor in the Department of Radiation Oncology at Robert Wood Johnson Medical School, Cancer Institute of New Jersey, said RTOG 9910 asked a good question at the time it was initiated.
He noted that the standard of eight weeks neoadjuvant androgen suppression and eight weeks concurrently with radiotherapy had been set previously by RTOG 8610, but this was for locally advanced prostate cancer in the pre-PSA era. Animal data had suggested that extended androgen suppression before radiotherapy was effective and that led to conducting this trial.
“But more than a decade since the initiation of RTOG 9910, we already know that for intermediate-risk prostate cancer there is a survival benefit with androgen suppression from the D'Amico trial and RTOG 9408.
Both trials used eight weeks of neoadjuvant androgen suppression before radiotherapy,” Motwani said. “The total duration of androgen suppression in those trials was six months and four months, respectively. Now the question for intermediate-risk prostate cancer is not necessarily how long the hormone suppression should be given but rather whether it should be given at all, given all the adverse effects of hormonal therapy.”
Motwani also noted that RTOG 9910 used 70 Gy, but in 2015 most radiation oncologists treat to much higher doses, in the range of 78 to 80 Gy.
“RTOG 0815 will provide valuable information in the setting of modern radiation doses, whether six months of androgen suppression is necessary or not in the intermediate risk prostate cancer population.” he said.