Treatment combination prolonged life in prostate cancer

Treatment combination prolonged life in prostate cancer

20 Jun 2016

A large contemporary analysis of men with metastatic prostate cancer has found that adding radiotherapy to androgen deprivation therapy resulted in substantially better survival than androgen deprivation alone.

With a median follow-up of 5.1 years, giving prostate radiotherapy plus androgen deprivation was associated on univariate analysis with a longer median overall survival of 53 versus 29 months. The effect held in multivariate, propensity score, and landmark analyses -- with the last yielding improved overall survival estimates at 3, 5, and 8 years, reported Chad. G. Rusthoven, MD, of University of Colorado School of Medicine, Denver, and colleagues.

The estimates were 62% versus 43% for 3 years, 49% versus 25% for 5 years, and 33% versus 13% for 8 years. "With all the caveats of retrospective database analyses, this study lends meaningful support to the hypothesis that the primary prostatic tumor may play a fundamental role in metastatic expansion and that effective local therapy might disrupt the complex dynamics between the primary tumor, the microenvironment of secondary organs, and metastatic disease," Rusthoven commented.

Clinical details

Searching the National Cancer Data Base, the investigators identified 6,382 patients (median age 69) diagnosed with new metastatic prostate cancer from 2004 to 2012. The cohort included 5,844 patients (91.6%) receiving androgen deprivation alone and 538 (8.4%) receiving androgen deprivation plus prostate radiotherapy.

Among those receiving the latter, the median time from diagnosis to radiotherapy initiation was 101 days. Radiotherapy use was associated with the following variables: younger median age (66 versus 69 years), better comorbidity scores, lower prostate-specific antigen (PSA) levels, higher tumor stage, zero nodal involvement, treatment at community facilities, and private insurance.

“Radiotherapy remained independently associated with improved overall survival”

With multivariate analysis adjusting for age, year, race, comorbidity score, PSA level, Gleason score, tumor stage, nodal status, chemotherapy administration, treating facility, and insurance status, radiotherapy remained independently associated with improved overall survival. On subset analysis, both radiotherapy to the prostate only and radiotherapy to the prostate plus pelvis were associated with improved overall survival compared with androgen deprivation alone.

In particular:

• A propensity score analysis with matched baseline characteristics demonstrated that adding prostate radiotherapy conferred a superior median overall survival of 55 versus 37 months and a 5-year overall survival of 49% versus 33%.
• No significant difference in survival, however, emerged between patients treated with therapeutic-dose radiotherapy plus androgen deprivation versus prostatectomy plus androgen deprivation during the same time interval. Both therapies were superior to androgen deprivation alone.
• The magnitude of the association between prostate radiotherapy and improved survival was greater for patients with Gleason scores of <8 versus 9-10, and for stage T1-3 versus T4. No significant interactions were observed between radiotherapy and age, PSA level, or nodal stage.

David Beyer, MD, of Arizona Oncology Services in Scottsdale, called the study an interesting departure from the way most oncologists have thought about metastatic prostate cancer. "The historical teaching is that once it's metastatic, it doesn't matter what you do to treat the prostate because it's already somewhere else and therefore it's unnecessary to treat the prostate," he said. "This study actually says there is value in [treating the prostate]. There is benefit in selected patients who have disease outside the prostate. When you treat not just with the hormones but add radiation to the prostate, you get a better outcome."

The study investigators noted that this analysis correlates with preclinical studies suggesting that treating the primary prostatic tumor may impact distant disease and potentially improve survival for men with metastatic disease.

Study limitations-need for further assessment

Despite these promising findings, Rusthoven stressed the need for randomized trials to assess the impact of local prostatic therapy in this setting. He pointed to examples in other disease sites where local therapy has improved overall survival in randomized trials – for example, metastatic renal cell carcinoma – and also instances, such as breast cancer, where potential benefits have been more elusive. "Time will tell whether level I evidence will be attained to support a survival advantage with local therapy for metastatic prostate cancer and, as a result, influence the standard-of-care for this population," Rusthoven said. "If phase 3 trials are ultimately positive, this National Cancer Database analysis will also provide meaningful corroborative data, suggesting the generalizability of improved survival with prostate radiotherapy among patients treated outside the context of clinical trials."

Addressing study limitations, the authors cited its retrospective design, the potential for selection biases and imbalances in unquantified variables. In particular, the performance status and extent of metastatic disease burden could not be controlled for beyond patient- and disease-status surrogates such as age, comorbidities, PSA level, Gleason score, tumor stage, and nodal status. Sites of metastatic spread were unavailable and no data were available regarding specific systemic therapy agents, duration of systemic therapy, salvage therapies, and disease progression endpoints.

"The attenuation of the survival advantage observed with prostate radiotherapy from the overall cohort to the propensity score-matched analysis underscores the importance of controlling for disparities in baseline characteristics," the authors wrote.

This combination approach is not for very high-risk patients

Beyer, who is also an American Society of Radiation Oncology expert in genitourinary cancer, urged caution in the face of these encouraging results. "This is clearly stimulating a lot of hypotheses, but is it enough to say the standard of care across the country should change tomorrow? We're probably not there yet. But there is enough evidence to say, 'There is a serious question here, and somebody needs to take a look at it and needs to take a look at it soon.'"

Beyer also noted that this combination approach is not for very high-risk patients, observing that those with Gleason scores of >8, 9, or 10 did not show the same benefit with radiotherapy. "But for the vast majority of patients, it suggests there is some value," he said. "Clearly, most of the patients had PSAs of 20, 40, 50. These are probably not patients who come in with 20 or 30 separate bone metastases."

It may be that National Cancer Database patients selected for radiation had fewer and less severe metastatic sites, he added. "Based on this study, I wouldn't take the highly symptomatic patient in very poor condition with multiple metastases and offer him radiation. That's probably excessive."

Beyer pointed to the difficulty of changing the standard of care in prostate cancer. "You need large numbers of patients; you need long follow-up," he said. "I think the next step is that somebody needs to reproduce this in a prospective study. Somebody needs to take a look at this and ask whether other things might be confounding the results."

Source: MedPage Today