Multimodal Therapy May Up Survival in Advanced Prostate Cancer

Kristin Jenkins

October 03, 2018

The largest population-based retrospective study to date comparing multimodal therapies in advanced prostate cancer shows that primary treatment with radical prostatectomy (RP) followed by radiotherapy (RT) offers a significant survival advantage but higher rates of erectile dysfunction and urinary incontinence.

The study, led by Grace L. Lu-Yao, PhD, MPH, of the Sidney Kimmel Cancer Center–Jefferson Health, in Philadelphia, Pennsylvania, was published online September 25 in Cancer.

The analysis of Surveillance, Epidemiology, and End Results–Medicare data from 13,856 men with locally advanced or regionally advanced prostate cancer showed that the adjusted 10-year prostate cancer–specific survival rate was 89% in those treated with RP and RT, compared to 74% in men who received RT plus androgen deprivation therapy (ADT).

The adjusted 10-year overall survival rate was 64% in men who underwent RP plus RT, compared to 48% in those who received RT plus ADT.

At a median follow-up of 14.6 years, this overall survival advantage was present regardless of tumor stage or Gleason score, the researchers say. Men without lymph node metastasis benefited the most, the study showed.

"These data suggest that even men with high-risk disease that is not clinically localized can achieve durable long-term cancer-specific survival and overall survival with multimodal treatment," the authors write. "These findings should be verified with prospective trial data and suggest the need to include a surgical arm in future trials for men with high-risk prostate cancer."

In a statement issued by Jefferson Health, Lu-Yao noted the controversy surrounding multimodal therapies.

"There's a lot of debate about whether to remove the whole prostate and follow up with radiation therapy or, as a second option, to spare the prostate and treat it using radiation therapy plus hormone-blocking therapy," she observed. "Our study suggests that removing the prostate followed by adjuvant radiotherapy is associated with greater overall survival in men with prostate cancer."

Still, improved survival came at a cost to quality of life. The analysis showed that men who underewnt RP plus RT had significantly higher rates of erectile dysfunction compared to men treated with FT and hormone therapy (28% vs 20%; P = .02).

In addition, the rate of urinary incontinence was more than twice as high in men treated with RP plus RT compared to those who underwent RT plus ADT (49% vs 19%; P < .0010). Men treated with RP plus RT also had higher rates of bladder neck contractures and urethral strictures compared to men who underwent RT plus ADT (38% vs 18%).

Although the use of aggressive RT after surgery began more than 2 decades ago, the proportion of men who undergo prostatectomy plus RT has decreased significantly since then, Lu-Yao noted. "There were trade-offs for the survival advantages," she pointed out.

The study showed that of the 2189 deaths in the cohort, 702 were secondary to prostate cancer. By 10 years, most men with T4N1M0 disease had died as a result of prostate cancer, regardless of treatment, the researchers say.

Notably, the analysis revealed that clinicians were not following treatment guidelines for high-risk prostate cancer recommended by the National Comprehensive Cancer Network and the European Association of Urology/European Society for Radiotherapy and Oncology. Both recommend multimodal treatment, including RP and RT, and RT plus ADT.

Rather, researchers discovered that half of the entire cohort had been treated with a single intervention and that 20% of the cohort of men aged 65 years or older had received no treatment at all within 6 months of diagnosis.

"Our data can't tell us the reason for this deviation from guidelines, and further studies are needed," said Lu-Yao. "Prostatectomy is an unpopular treatment," she added.

In men who received multimodal therapy, 6.1% received RP plus RT, and 23.6% were treated with RT plus ADT. Men who were more likely to receive RT plus ADT tended to be older, unmarried, have significantly more comorbidities, and have tumor fixation to adjacent structures.

The analysis also showed that younger men with fewer comorbid conditions and extracapsular extension (T3aN0M0) or seminal vesicle invasion (T3bN0M0) without regional lymph node involvement were more likely to receive RP plus RT. Men with regional lymph node involvement and extracapsular extension or seminal vesicle invasion were also more likely to undergo RP plus RT than RT plus ADT.

"Although we found RP as a primary intervention to be associated with more favorable survival outcomes than RT in this high-risk population, the questions, as other investigators have suggested, should focus not on which modality is best," the authors emphasize. Instead, they say, the focus should be on optimizing treatment timing and intensity and integrating more effective systemic therapies with optimal local treatments.

Local Control Called "Critical"

When approached for comment, Jorge Garcia, MD, director of the advanced prostate cancer research program at the Cleveland Clinic, Ohio, said that with novel agents, "some men with oligometastatic prostate cancer can achieve durable responses, if not cure.

"Traditionally, the standard of care for high-risk prostate cancer without positive nodes in men who elect surgery is radical prostatectomy alone, followed by ether adjuvant radiation therapy or salvage radiation therapy plus ADT at the time of failure," Garcia noted. Most are treated with either high doses of the oral androgen receptor inhibitor bicalutamide (Casodex, AstraZeneca) for 2 years, or ADT with testosterone suppression for 6 months.

For men who elect to have RT instead of surgery, the current standard of care is 2 years of ADT plus RT, he said.

Garcia emphasized the importance of a multidisciplinary approach in men with high-risk prostate cancer. A urologist, a radiation oncologist, and a medical oncology team are needed to maximize treatment outcome in these patients, he said.

Tanya Barauskas Dorff, MD, clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope in Duarte, California, agreed. "Overall, the conclusions fit with the shift in our thinking about local control being critical," she told Medscape Medical News.

The need for multimodal therapy with RP plus RT in patients with locally advanced prostate cancer is becoming increasingly recognized, said Dorff, who is head of the genitourinary cancers program.

"We currently do not view the presence of pelvic lymph nodes as a contraindication to radical prostatectomy, nor to definitive radiation. These patients are better served by multimodal therapy than by ADT alone. This study supports this approach and, if anything, suggests an even greater potential role for radical prostatectomy."

RT plus ADT "remains valuable," she added.

Dorff also noted that cardiovascular morbidity was not greater in men treated with RT plus ADT. "This needs to be understood in the context that many men treated with RP plus RT also received ADT, either together with their radiation or later in the course of their disease," she pointed out. "This remains a side effect issue related to ADT, and patients should be actively monitored for optimization of lipids, blood pressure, and glucose/insulin during ADT."

These data add support to combining therapies for maximum advantage, commented Leonard G. Gomella, MD, chair of the Department of Urology at the Sidney Kimmel Cancer Center – Jefferson Health. He was not involved in the current study.

Gomella emphasized that men with localized prostate cancer with adverse features, such as a high Gleason score or extension outside the prostate, should be considered for multimodal therapy.

Studies investigating the use of surgery, RT, and hormonal therapy in high-risk prostate cancer are producing evidence that multimodal therapies provide benefit in terms of cancer control and progression, Gomella pointed out. Technical changes in surgery and RT over the past decade have limited adverse side effects associated with these therapies, and new tools, such as genomic markers and improved imaging, are making a clinical impact in more aggressive localized disease.

Major clinical improvements in the use of combined therapies have created models of success in other cancers, including lymphoma and bladder cancer, said Gomella. "Radiation therapy combined with hormonal therapy represents a standard for many men with prostate cancer," he said.

The study was funded by the National Cancer Institute, the New Jersey Health Foundation, and the Rutgers Cancer Institute of New Jersey. Dr Lu-Yao has disclosed no relevant financial relationships. Other authors have financial ties to Co-OPKO Health and Merck. Dr Garcia has relationships with Janssen, Sanofi, and Bayer. Dr Dorff has relationships with Exelixis, AstraZeneca, Janssen, Roche, Bayer, Eisai, EMD Serono, Prometheus, and Pfizer. Dr Gomella has disclosed no relevant financial relationships.

Cancer. Published online September 25, 2018. Abstract


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