Hormone Blockers Can Prolong Life if Prostate Cancer Recurs
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NY Times February 1, 2017
Men whose prostate cancer comes back after surgery are more likely to survive if, along with the usual radiation, they also take drugs to block male hormones.
The finding, published Wednesday in The New England Journal of Medicine, comes from a long-running study that experts say will help clarify treatment for many patients.
After surgery to remove the prostate, more than 30 percent of men have a recurrence, and until now there has not been clear evidence about the best way to stop the disease from killing them. Most are given radiation, but prescribing drugs to counter the effects of male hormones has been inconsistent.
The study, paid for by the National Cancer Institute, showed that among men who received radiation and hormonal treatment, 76.3 percent were still alive after 12 years, compared to 71.3 percent who had radiation alone.
At 12 years, the men who had both treatments were also much less likely to have died from their prostate cancer - 5.8 percent versus 13.4 percent - or to have the cancer spread around their bodies - 14.5 percent versus 23 percent.
"This is a big deal," said Dr. Ian M. Thompson Jr., of the Christus Santa Rosa Health System in San Antonio, who was not part of the study but wrote an editorial accompanying it.
"There are so many things we do in prostate cancer that we don't know if they make a big difference in survival. This is one of the things where now we can say for sure."
He added that he hoped the findings would change medical practice.
The medical term for blocking male hormones is chemical castration, and the treatments can cause hot flashes, sexual problems and other side effects. So to put a man through it, said Dr. Anthony L. Zietman, an author of the study, "you'd better have some decent justification."
Dr. David F. Penson, the chairman of urologic surgery at Vanderbilt University Medical Center, said the study "gives more credence to the concept that you have to treat the whole patient," rather than just irradiating the area where the cancer used to be.
He said the idea of blocking hormones in men like those in the study was finding its way into medical practice.
About 161,360 new cases of prostate cancer and 26,730 deaths are expected in the United States in 2017, according to the American Cancer Society.
The average age at diagnosis is 66. Globally, there were 1.1 million cases and 307,000 deaths in 2012, the most recent data available from the World Health Organization.
The study, begun in 1998 and led by Dr. William U. Shipley, a radiation oncologist at the Massachusetts General Hospital, had an ambitious goal: to follow the patients long enough to find out whether hormone-blocking treatment would affect their survival.
Prostate cancer grows slowly, so it took well over a decade for answers to emerge. Researchers and patients from 150 sites in North America participated. The patients were 760 men who had their prostates removed for cancer that had not spread, but who then had a sign of recurrence - a rise in their blood levels of prostate-specific antigen, or PSA, a protein associated with prostate cancer. The men in the study had PSAs of 0.2 to 4 nanograms per milliliter.
"That's just like the first wisp of smoke," said Dr. Zietman, who is a professor of radiation oncology at Massachusetts General Hospital and Harvard Medical School. "There'll be fire someday."
The fire might take five, 10 or 15 years to break out, but Dr. Zietman said, "Many are in their 50s or 60s, and will live long enough to get into trouble."
The traditional practice for a rising PSA after surgery has been to give radiation, which targets only the pelvis.
The idea of the study was to add hormonal treatment, which might stop minute clumps of cancer that had spread to other parts of the body.
All the men in the study had radiation for six and a half weeks. For two years, half also received a hormone-blocking drug, bicalutamide, and the other half were given placebos. They were followed, on average, for about 13 years.
"This is the first trial that's shown, if you follow these patients long enough, there is a real difference," Dr. Zietman said. "More people survive 15 years later."
Men who had more aggressive cancers - reflected by higher PSA readings after surgery and by the pathology and surgical reports on their tumors - had the most to gain from the hormone-blocking treatment.
The results do not mean that every man with a rising PSA after surgery should have hormone treatment, Dr. Zietman said. Men 75 or older may not need it, because they may die from other causes before the cancer can catch up with them.
"But if they're younger and with a longer life expectancy, treatment is reasonable," he said.
Bicalutamide causes men to develop breasts and potentially other problems, and the high dose given in the study is no longer used in the United States.
Other hormone-blocking drugs like Lupron have mostly taken its place, and may be even more effective, Dr. Zietman said. The study proved the concept that hormone blocking increases survival, he added, so other drugs that do the same thing should also help patients live longer.
Another study in progress in Canada and Europe uses the newer drugs, and is trying to determine whether taking them for six months, rather than two years, might be enough.
Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer
NEJM Feb 8 2017
William U. Shipley, M.D., Wendy Seiferheld, M.S., Himanshu R. Lukka, M.D., Pierre P. Major, M.D., Niall M. Heney, M.D., David J. Grignon, M.D., Oliver Sartor, M.D., Maltibehn P. Patel, M.D., Jean-Paul Bahary, M.D., Anthony L. Zietman, M.D., Thomas M. Pisansky, M.D., Kenneth L. Zeitzer, M.D., Colleen A.F. Lawton, M.D., Felix Y. Feng, M.D., Richard D. Lovett, M.D., Alexander G. Balogh, M.D., Luis Souhami, M.D., Seth A. Rosenthal, M.D., Kevin J. Kerlin, M.D., James J. Dignam, Ph.D., Stephanie L. Pugh, Ph.D., and Howard M. Sandler, M.D., for the NRG Oncology RTOG*
N Engl J Med 2017
Salvage radiation therapy is often necessary in men who have undergone radical prostatectomy and have evidence of prostate-cancer recurrence signaled by a persistently or recurrently elevated prostate-specific antigen (PSA) level. Whether antiandrogen therapy with radiation therapy will further improve cancer control and prolong overall survival is unknown.
In a double-blind, placebo-controlled trial conducted from 1998 through 2003, we assigned 760 eligible patients who had undergone prostatectomy with a lymphadenectomy and had disease, as assessed on pathological testing, with a tumor stage of T2 (confined to the prostate but with a positive surgical margin) or T3 (with histologic extension beyond the prostatic capsule), no nodal involvement, and a detectable PSA level of 0.2 to 4.0 ng per milliliter to undergo radiation therapy and receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after radiation therapy. The primary end point was the rate of overall survival.
The median follow-up among the surviving patients was 13 years. The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (hazard ratio for death, 0.77; 95% confidence interval, 0.59 to 0.99; P=0.04). The 12-year incidence of death from prostate cancer, as assessed by means of central review, was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (P<0.001). The cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (P=0.005). The incidence of late adverse events associated with radiation therapy was similar in the two groups. Gynecomastia was recorded in 69.7% of the patients in the bicalutamide group, as compared with 10.9% of those in the placebo group (P<0.001).
The addition of 24 months of antiandrogen therapy with daily bicalutamide to salvage radiation therapy resulted in significantly higher rates of long-term overall survival and lower incidences of metastatic prostate cancer and death from prostate cancer than radiation therapy plus placebo. (Funded by the National Cancer Institute and AstraZeneca;
Patients with localized prostatic cancer are often treated with radical prostatectomy. More than 30% of such patients will subsequently have recurrence. This recurrence manifests first as a rising serum level of prostate-specific antigen (PSA),1-3 termed biochemical recurrence. Large, retrospective studies suggest that salvage radiation therapy after biochemical recurrence may be associated with long-term freedom from cancer recurrence.4,5 However, 50% of the patients who are treated with salvage radiation therapy will have further disease progression, particularly when there are aggressive disease features.4-7
The combination of radiation therapy and either androgen-deprivation therapy or antiandrogen therapy prolongs survival among some men with an intact prostate.8-11 Thus, this combination treatment represents a rational approach to prolong metastasis-free survival and overall survival among men with a postoperative recurrence. In randomized trials, the oral agent bicalutamide, an androgen-receptor blocker, at a dose of 150 mg daily has been shown to be effective against prostate cancer.11,12 Accordingly, the NRG Oncology Radiation Therapy Oncology Group (formed by merging the National Surgical Adjuvant Breast and Bowel Cancer Project, the Radiation Therapy Oncology Group [RTOG], and the Gynecologic Oncology Group) designed a randomized, double-blind, placebo-controlled trial (RTOG 9601) to evaluate whether the addition of antiandrogen therapy for 24 months during and after salvage radiation therapy could prolong overall survival, as compared with radiation therapy plus placebo. Since the initiation of the trial, high-dose bicalutamide has been superseded by injectable gonadotropin-releasing hormone (GnRH) agonists in therapy, but the hypothesis tested in this trial remains very relevant. A planned interim analysis of the trial in 2010 showed that bicalutamide was associated with significantly lower rates of biochemical recurrence and distant metastases than placebo.13 The primary end point of the protocol of this trial, the overall survival rate, can now be reported.
Characteristics of the Patients
From March 1998 through March 2003, a total of 840 patients underwent randomization (Figure 1). A total of 79 patients were ineligible (1 did not sign the consent form) and 1 withdrew consent, leaving 760 eligible patients for evaluation (384 patients in the bicalutamide group and 376 in the placebo group). The two groups were well balanced with respect to demographic and tumor-related characteristics (Table 1). The median age of the patients was 65 years, and the median PSA level at trial entry was 0.6 ng per milliliter. The median follow-up among the surviving patients was 13 years. The median interval between surgery and the first detectable PSA level was 1.4 years, and the median interval between surgery and trial entry was 2.1 years.
Radiation-therapy review was used to evaluate the total radiation dose, field borders, fractionation, and field administration in a randomly selected subgroup of patients, given that standard techniques were being used. Adherence to the protocol was well balanced between the two trial groups, with 64.8% of the patients treated per protocol, 30.8% treated with an acceptable variation, and 4.4% treated with an unacceptable variation. The percentage of patients who adhered to the assigned regimen, which was defined as continuing to take the tablets for at least 18 months, was 69.8% in the bicalutamide group and 74.7% in the placebo group. At 24 months (the treatment duration designated by the protocol), the adherence rates were 67.2% and 68.6%, respectively.
The end-point results at 12 years are shown in Figure 2 and Figure 3 and in Table 2. A total of 21 patients in the bicalutamide group died from prostate cancer, as compared with 46 in the placebo group (Table S2 in the Supplementary Appendix). The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (hazard ratio for death, 0.77; 95% confidence interval [CI], 0.59 to 0.99; two-sided P=0.04) (Figure 2A). The 12-year incidence of death from prostate cancer was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (hazard ratio, 0.49; 95% CI, 0.32 to 0.74; P<0.001) (Figure 2C).
The cumulative incidence of distant metastases at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (hazard ratio, 0.63; 95% CI, 0.46 to 0.87; P=0.005) (Figure 2D). The cumulative incidence of a second biochemical recurrence at 12 years was 44.0% in the bicalutamide group, as compared with 67.9% in the placebo group (hazard ratio, 0.48; 95% CI, 0.40 to 0.58; P<0.001) (Fig. S1B in the Supplementary Appendix).
Multivariate analyses of overall survival showed that the significant negative prognostic factors were assignment to the placebo group, a PSA level of more than 1.5 ng per milliliter at trial entry, a Gleason score for prostate cancer of 8 to 10 on the basis of pathological testing, a Karnofsky performance-status score of 80 or 90, and an age of 65 years or more (Table S3 in the Supplementary Appendix). Other stratification variables (the PSA nadir after surgery, positive surgical margin, and whether short-term androgen-deprivation therapy had been given before surgery) did not meet prespecified significance levels and were not part of the final model. The rates of local disease progression and any form of disease progression including a second biochemical recurrence were all lower in the bicalutamide group than in the placebo group (Table S4 in the Supplementary Appendix).
There was no significant between-group difference in the risk of non–disease-specific death (Table 2). There were no significant between-group differences in the rates of early urinary, bowel, or hematologic reactions. Late genitourinary adverse events of grade 3 occurred in 7.0% of the patients in the bicalutamide group and in 6.0% of those in the placebo group; grade 4 events occurred in 0.3% and 0.8%, respectively. Late grade 2 hepatic toxic effects occurred in 1.6% of the patients in the bicalutamide group and in 0.8% of those in the placebo group; grade 3 effects occurred in 0.8% and 0.3%, respectively. The rate of cardiovascular deaths that were reported as adverse events was not significantly higher in the bicalutamide group than in the placebo group. Details are provided in Tables S5, S6, and S7 in the Supplementary Appendix.
The rates of hot flashes of grade 1, 2, and 3 were similar in the two groups: grade 1 hot flashes were reported in 16.6% of the patients in the bicalutamide group, grade 2 in 4.5%, and grade 3 in 0.8%; the corresponding values in the placebo group were 14.1%, 2.9%, and 0%. In contrast, gynecomastia of grade 1 was reported in 42.4% of the patients in the bicalutamide group, grade 2 in 23.6%, and grade 3 in 3.7% (resulting in 69.7% of the patients in the bicalutamide group having gynecomastia); the corresponding values in the placebo group were 8.8%, 2.1%, and 0% (resulting in 10.9% of the patients in the placebo group having gynecomastia) (P<0.01 for all comparisons). Although the rate of gynecomastia was significantly higher in the bicalutamide group than in the placebo group, this finding was not significantly linked as an explanation in patients taking less than the full course of oral tablets.
Post hoc subgroup analyses were performed according to well-known prognostic factors. These factors included the PSA level at trial entry, the Gleason score for prostate cancer, and whether the tumor margins were positive (Table 1). The greatest overall survival benefit was seen in subgroups of patients with more aggressive prostate cancer, such as those with a high PSA level at trial entry (1.5 to 4.0 ng per milliliter) or a Gleason score of 7. Few patients in the trial had a Gleason score of 8, 9, or 10; the difference in overall survival within this subgroup did not reach statistical significance (Figures 2B and Figure 3). Patients with positive surgical margins also appeared to have a larger benefit than those with negative surgical margins (Fig. S1A in the Supplementary Appendix). With the exception of PSA level, interaction tests did not indicate a significant differential benefit in subgroups that were defined according to these factors. A similar lower rate of distant metastases in the bicalutamide group was also seen among patients with a Gleason score of 8 to 10, those with a PSA level of 1.5 to 4.0 ng per milliliter at trial entry, and those with positive surgical margins (Table 2, and Fig. S2 in the Supplementary Appendix). A significant variation in the extent of benefit across subgroups was not found.
This randomized trial showed that the addition of 24 months of bicalutamide to salvage radiation therapy resulted in higher rates of overall survival and other important end points among surgery-treated patients with persistent or recurrent disease that was detected only because of an abnormal PSA level. Because of the relatively slow nature of prostate-cancer progression, a median follow-up of more than a decade was necessary to observe this benefit. The 12-year overall survival benefit with antiandrogen therapy was accompanied by significantly lower rates of disease-specific death, distant metastases, and second biochemical recurrence. Multivariate analysis showed that the factors predicting higher rates of overall survival included assignment to the bicalutamide group, a lower PSA level at trial entry (1.6 to 4.0 ng per milliliter), and younger patient age (<65 years). The between-group differences in other stratification variables (PSA nadir after surgery, positive surgical margin, and whether short-term androgen-deprivation therapy had been given before surgery) were not significant for differences in overall survival. Given the lower rate of death (absolute difference, 5.0 percentage points) and the lack of evidence of higher other-cause mortality in the bicalutamide group than in the placebo group, we calculated that 20 patients would need to be treated with bicalutamide to avoid one death over a 12-year period.24
These gains were achieved without the exacerbation of early or late bladder, bowel, hematologic, or hepatic effects, for which the rates were low in the two groups. Bicalutamide was not associated with a significantly higher risk of cardiac death or serious hepatotoxic effects. Cardiovascular mortality was similar in the two groups, as was seen in three previous RTOG phase 3 trials assessing the use or nonuse of androgen-deprivation therapy.25-27 However, only data on cardiac events that were reported as adverse events were collected, which may have introduced an ascertainment bias.
Wirth and colleagues reported the results of the Early Prostate Cancer Program, a series of randomized, double-blind trials comparing 150 mg of bicalutamide with placebo.28 They found that the rates of cardiovascular death were low and similar in the bicalutamide group and the placebo group (3.5% and 3.1%, respectively). In contrast, they found significant differences between the bicalutamide group and the placebo group in the rates of gynecomastia (68% vs. 8%) and patients' withdrawal from the trial or stopping of the tablets because of gynecomastia (17% vs. 1%). The double-blind design of the Early Prostate Cancer Program trials, like ours, did not allow for preemptive measures to minimize gynecomastia.
The gains in overall and metastasis-free survival in this trial may be greater among patients whose disease had particular prognostic features - namely, patients with higher Gleason scores (8 to 10), a higher PSA level at trial entry (0.7 to 4.0 ng per milliliter), or positive surgical margins. Although this post hoc risk analysis is hypothesis-generating, it also suggests that patients with a lower Gleason score (≤7), a PSA level of less than 0.7 ng per milliliter, or negative surgical margins may have less benefit from the addition of antiandrogen therapy to salvage radiation therapy.
Now, 20 years after this trial was designed, GnRH agonists have superseded bicalutamide as the first-choice hormonal therapy with radiation therapy, and bicalutamide at the 150-mg dose level is not approved for this purpose. Randomized trials involving patients with nonmetastatic disease have shown that high-dose bicalutamide and GnRH agonists have similar systemic anticancer efficacy.11,12,28 As such, our trial presents proof of principle that the addition of hormone-based therapy to salvage radiation therapy is associated with significant and clinically important lower rates of prostate-cancer metastases and death. The fully enrolled RADICALS-HD (Radiotherapy and Androgen Deprivation in Combination after Local Surgery) trial in the United Kingdom and the GETUG-16 (Group d'Etude des Tumeurs UrogEnitales 16) trial in France are examining the role of contemporary androgen-deprivation therapy in the context of salvage radiation therapy, and these two trials may provide additional insights as these data mature.29,30
In conclusion, the addition of an antiandrogen agent to salvage radiation therapy resulted in higher rates of overall, disease-specific, and metastasis-free survival than radiation therapy plus placebo among patients who were treated for biochemical (PSA) recurrence of prostate cancer after radical prostatectomy. The higher rate of overall survival with antiandrogen therapy than with placebo became evident in the second decade after therapy.