DEBATE FOR CHEMOTHERAPY FOR NON-METASTATIC PROSTATE CANCER

Although the use of upfront chemotherapy in metastatic castration-resistant prostate cancer (CRPC) has recently been established, for nonmetastatic disease its use is more controversial and there is no consensus.

Now experts argue the case for and against the early use of chemotherapy in nonmetastatic CRPC in a pair of articles published online November 3 in JAMA Oncology.

Tackling the "pro" side of the debate, Evan Y. Yu, MD, and Daniel W. Lin, MD, both from the University of Washington School of Medicine in Seattle, argue that despite the controversy surrounding overdiagnosis and overtreatment of prostate cancer, there is also another matter to consider: undertreatment.

Even though most men with prostate cancer die with the disease rather than of it, the authors note that the natural history of prostate cancer is quite heterogeneous.

In addition, 26,000 men die of the disease every year in the United States, which emphasizes the importance of selecting appropriate patients for aggressive intervention.

Dr Yu and Dr Lin point out that 2 large randomized trials (the E3805 study/CHAARTED trial  [N Engl J Med. 2015;373:737-746] and the STAMPEDE trial [Lancet. 2016;387:1163-1177]) have shown a survival benefit when chemotherapy was added to androgen deprivation therapy (ADT) for hormone-sensitive metastatic prostate cancer.

One of these trials (STAMPEDE) included a subset of 1200 patients with high-risk nonmetastatic prostate cancer. As previously reported by Medscape Medical News, the difference in survival was not as pronounced as in metastatic disease and did not reach statistical significance, but these survival data are still immature. The addition of docetaxel did prolong the event-free survival by "a substantial amount," the authors point out.

The authors also emphasize that the term "nonmetastatic" itself "is frequently a misnomer. For example, a patient with an increasing PSA [prostate-specific antigen] level after radical prostatectomy either harbors residual disease in the prostatic fossa, has microscopic metastases, or both."

But this group represents a large, heterogenous population, and it would be "naive and irresponsible to propose the use of chemotherapy for all nonmetastatic PC [prostate cancer] patients," they note.

"It is now clear there is benefit to early docetaxel with ADT in patients with PC; the challenge is identifying patients in earlier disease states who have life-limiting PC and are apt to benefit from early chemotherapy, rather than succumb to other competing causes of mortality," they write.

The authors add that they are not yet using chemotherapy on a regular basis in the postprostatectomy adjuvant setting "because conflicting data exists from recently presented trials."

Evidence Weak to Support Chemotherapy

Taking the con side of the debate, Julie N. Graff, MD, Joshi J. Alumkal, MD, Tomasz Beer, MD, from Oregon Health and Science University in Portland, agree that recent trials that include patients with nonmetastatic disease have shown encouraging results for the use of docetaxel in that setting.

However, they point out that while results of the STAMPEDE, GETUG-12 (Lancet Oncol. 2015;16:787-794), and RTOG-0521 (J Clin Oncol. 2015;33[suppl]:abstract LBA5002) trials all showed significant improvements in various measures of failure-free survival (FFS) in patients who received docetaxel-based chemotherapy plus ADT compared with ADT alone, an overall survival benefit with docetaxel was not observed in the GETUG-12 trial or the nonmetastatic subset of the STAMPEDE trial.

An early analysis showed that the RTOG-0521 trial showed a statistically significant but modest improvement in overall survival, but that appeared to be influenced by a decrease in non–prostate cancer deaths, they point out.

Additionally, two other studies (VA CSP 533 [J Urol. 2016;195:e107] and SPCG12 [J Clin Oncol. 2016;34(suppl):abstract 5001]) also reported on the use of docetaxel without ADT in patients with nonmetastatic prostate cancer, and neither showed an improvement in FFS.

Drs Graff, Alumkal, and Beer reiterate that even though the FFS data for the three studies of chemotherapy plus ADT are encouraging, "overall survival data are necessary to fully understand the benefit of docetaxel chemotherapy in the adjuvant or biochemical recurrence setting."

Other considerations are the acute and long-term toxic effects of docetaxel, and the uncertain benefits of chemotherapy need to be weighed against the known harms. "In addition to neuropathy, chemotherapy treatment may lead to cognitive declines in domains such as attention, memory, and processing speed even 10 to 20 years after treatment," they write. "Such long-term outcomes are of particular concern when docetaxel use is contemplated in earlier stages of the disease wherein 10- to 20-year survival may be quite possible."

As for now, it is premature to conclude that docetaxel will benefit patients with high-risk localized prostate cancer or biochemical recurrence, they conclude. "Demonstration of overall survival improvements along with acceptable long-term toxic effects will be necessary to confirm that the use of docetaxel in the adjuvant or biochemical recurrence setting will improve outcomes for men with prostate cancer," they write.