Κυριακή, 5 Φεβρουαρίου 2017

ANTIANDROGEN COMBINED WITH RT FOR RECURRENT PROSTATE CANCER

Adding antiandrogen therapy to radiotherapy as a salvage treatment for men with biochemical recurrence following prostatectomy improves outcomes. It extends overall survival (OS) and reduces the risk for both metastatic disease and death from prostate cancer at 12 years compared with radiation alone, final results from the Radiation Therapy Oncology Group (RTOG) 9601 trial indicate.
"Surgery is a very common treatment for men with localized prostate cancer but more than 30% of them will have recurrent disease, so we specialists in genitourinary oncology have been working to address this problem for a long time," corresponding author William Shipley, MD, professor of radiation oncology, Harvard Medical School, Boston, Massachusetts, said in a statement.
"This study's findings — that adding antiandrogen therapy to the radiation typically used against recurrence reduces the incidence of metastasis, death from prostate cancer and overall deaths — will change the standard of care for patients experiencing a postoperative recurrence," Dr Shipley predicted.
The study was published online February 2 in the New England Journal of Medicine.
The RTOG 9601 trial was designed some 20 years ago, and the antiandrogen used in this trial was bicalutamide. Since then, it has largely been replaced by gonadotropin-releasing hormone (GnRH) agonist drugs, such a leuprolide. However, the investigators argue that the results remain relevant.
"Randomized trials involving patients with nonmetastatic disease have shown that high-dose bicalutamide and GnRH agonists have similar systemic anticancer efficacy," the investigators state.
"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," they add.
The author of an accompanying editorial, Ian Thompson Jr, MD, president, Christus Medical Center Hospital, San Antonio, Texas, agrees with the study authors that GnRH agonists — also known as luteinizing hormone– releasing hormone (LHRH) agonists or LHRH-based agents — have a similar effect as bicalutamide in the setting of prostate cancer. 
"Most folks will look at this and instead of thinking, 'Bicalutamide for 2 years significantly improves the cure rate with salvage radiation,' will think 'Androgen deprivation therapy for 2 years significantly improves the cure rate with salvage radiation,'" Dr Thompson told Medscape Medical News in an email.
"My best guess is that if GnRH agonists are used in lieu of bicalutamide, the results will be similar, if not better," he added
Had to Wait for Overall Survival Results 
An interim report of the same trial released in 2011 showed that the addition of bicalutamide, 150 mg/day for 24 months during and after salvage radiation therapy, significantly improved freedom from prostate-specific antigen (PSA) progression at 7 years (P < .0001) and reduced the incidence of metastatic prostate cancer (P < .041) compared with radiation therapy alone.
However, the primary endpoint of the trial was overall survival (OS), and as such, RTOG 9601 required an additional 5 years of follow-up to achieve its primary goal.
"Eligible patients had all undergone radical prostatectomy with lymphadenectomy and had disease that was originally assessed, on the basis of pathological testing, as tumor stage T2 (confined to the prostate but also with a positive surgical margin) or T3 (with histologic extension of tumor beyond the prostatic capsule) without nodal involvement," Dr Shipley and coauthors noted.
Additionally, PSA levels must have risen to 0.2 to 4.0 ng/mL 8 weeks or more after men had undergone surgery.
A total of 760 patients were available for evaluation: 384 assigned to bicalutamide for 24 months and 376 assigned to placebo. After randomization, all men received salvage radiation within 12 weeks, which they received in addition to radiotherapy.
"The median age of the patients was 65 years, and the median PSA level at trial entry was 0.6 ng per milliliter," study authors write.
Men waited a median of 2.1 years between their original surgery and study enrollment, but the median interval between surgery and their first detectable PSA level was shorter, at only 1.4 years.
Findings at 12 Years 
At 12 years, results showed that the addition of bicalutamide to salvage radiation improved OS by 23% compared with placebo. It also reduced death from prostate cancer by 51% as well as the cumulative incidence of distant metastases by 37%, again compared with the control group.
The addition of bicalutamide also reduced the risk for a second biochemical recurrence at 12 years by 52% compared with salvage radiation alone.
Table. 12-Year Endpoints in the RTOG 9601 Trial (Salvage Radiotherapy With or Without Antiandrogen Treatment)
EndpointSalvage Radiation Therapy Plus Bicalutamide (%)Salvage Radiation Therapy Alone (%)PValue
Overall survival76.371.3.04
Death from prostate cancer5.813.4<.001
Distant metastases14.523.0.005
Second biochemical recurrence44.067.9<.001

"There were no significant between-group differences in the rates of early urinary, bowel, or hematologic reactions," the investigators report. Rates of grade 3 late genitourinary adverse events were numerically higher at 7% in the bicalutamide group compared with 6% of placebo controls, but rates of grade 4 adverse events were very low in both groups at 0.3% and 0.8%, respectively.
Reports of hot flashes as a side effect of antiandrogen therapy were not all that common and were similar in both groups, Dr Shipley pointed out.
On the other hand, over 42% of men receiving bicalutamide reported grade 1 gynecomastia, almost 24% reported grade 2, and about 4% reported grade 3. All grades of gynecomastia were significantly higher among antiandrogen recipients than placebo controls (P < .01 for all comparisons).
Reassuringly, even given for 2 years, bicalutamide did not increase the risk for cardiac death or hepatotoxicity.
When to Implement Salvage Therapy? 
In his editorial, Dr Thompson notes that several large-scale clinical trials are underway in which investigators are aiming to identify which high-risk patients with PSA recurrence are most likely to benefit from androgen deprivation therapy and, if so, how long that therapy should be administered.
In the meantime, Dr Thompson worries that in the real-world clinical setting, radiation therapy is often delayed until PSA levels continue to climb.
"We know that salvage radiation can lead to long-term disease-free control and that the higher the PSA at the inception of radiation, the lower the long-term disease-free control is," Dr Thompson said. 
"The problem is that there is a wide degree of variation in implementation of radiation, with some physicians starting it immediately when the PSA becomes detectable and others waiting until higher levels are seen," he added. 
However, as Dr. Thompson emphasized, if the PSA continues to rise without treatment, there is a risk that at least some patients will progress to metastatic disease, at which point salvage radiation will not be effective. 
"The number needed to treat with the nonsteroidal antiandrogen drug bicalutamide to prevent one death from prostate cancer was 20 [over a 12-year follow-up]," Dr Thompson notes.
"And you have to compare this number to the original treatment itself, surgery, you need to treat 25 to 35 men to prevent one death," he added in his email.
"In this case, simply adding 2 years of androgen deprivation therapy has an even greater impact [than surgery]:  so, it truly is a high-impact observation," Dr Thompson said.
But, as he also cautioned, the only way that findings from RTOG 9601 will benefit patients is if clinicians offer salvage radiation plus androgen deprivation therapy as soon as PSA levels start to declare themselves again and not wait until levels climb higher, at which point the "[current] findings are moot," as Dr Thompson emphasized.
The study was sponsored by the National Cancer Institute and AstraZeneca. Dr Shipley reports having held stock in PFS Genomics (he no longer holds the stock). Other RTOG 9601 investigators report a number of conflicts of interest, which are disclosed at the end of the published article. Dr Thompson has disclosed no relevant financial relationships.
N Engl J Med. 2017;376:417-428, 484-485. 

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