Debunking the Myths of Chemotherapy in Prostate Cancer

By Jorge A. Garcia, MD, FACP

Jorge A. Garcia, MD, FACP

During the past five years, treatment options for men with advanced prostate cancer (PCa) have changed dramatically with the introduction of immunotherapy, novel adrenal and androgen receptor targeted agents, and the use of alpha emitters.

Despite the uniqueness of some of these approaches, the role of chemotherapy in the management of this disease has gained momentum with the recent results from a large North American intergroup trial. ECOG 3805, also known as the ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED), evaluated the role of upfront chemotherapy in men with metastatic disease who need androgen deprivation therapy (ADT).

The evolving view of chemotherapy in PCa

Historically, the use of chemotherapy in PCa has faced significant challenges. Among these, determining which specialist should have responsibility for patient oversight has been the biggest challenge. Should patients with advanced disease be managed by urologists or medical oncologists? When should a urologist refer a patient to a medical oncologist?

Although these questions can be answered in many ways, there is now recognition that men with advanced PCa benefit from a multidisciplinary treatment approach. Fueling the debate is the fact that chemotherapy has traditionally been reserved for men with advanced disease who become castration-resistant — a patient population managed by medical oncology.

Myths surrounding chemotherapy relate to its side effects and potential detrimental impact on quality of life (QOL), its supposedly questionable activity in PCa and the perception that it should be used as the last treatment choice after everything else has failed. It certainly did not help that trials in the late 1990s evaluating mitoxantrone-based chemotherapy in castration-resistant disease failed to show survival benefit.

Chemotherapy improves overall survival in castration-resistant prostate cancer

Perhaps one of the most important years in PCa was 2004, when two well-conducted, randomized phase 3 clinical trials (SWOG 9916 and TAX327) evaluating docetaxel-based chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC) led to the Food and Drug Administration’s approval of this regimen for CRPC.

Treatment with docetaxel not only improved overall survival (OS) but led to effective tumor burden reduction, prostate specific antigen (PSA) declines and improvement in QOL in those men with symptomatic disease. In fact, the median OS in the long-term follow-up analysis for the TAX327 trial is 19.2 months for docetaxel-treated patients versus 16.3 months for those receiving mitoxantrone. As important was the fact that the side effect profile was manageable and similar to that of chemotherapy agents used to treat other solid tumors.

More recently, the utility of second-line chemotherapy with cabazitaxel, a semisynthetic taxane derivative developed for its activity in patients with resistance to docetaxel, was demonstrated in the international TROPIC trial. This phase 3 trial evaluated this novel taxane against mitoxantrone in mCRPC patients who have progressed on docetaxel. Men treated with cabazitaxel had an increased OS compared with those treated with mitoxantrone (hazard ratio [HR] 0.70, 95% CI 0.59-0.83, median survival 15.1 versus 12.7 months).

The results of these trials have clearly changed the thinking about systemic chemotherapy in CRPC and have debunked some of the myths that discouraged this approach for many years.

Now the issues we face are of even greater magnitude. An improved understanding of the biology of CRPC coupled with the availability of newer agents has challenged the approach that one treatment fits all. As a result, questions about patient selection, the appropriate timing for treatment, the mechanisms of resistance and the best treatment sequence are the focus of additional research.

Should chemotherapy be a last treatment choice?

The simple answer to this complex question is NO. Some of the most dramatic findings ever published in PCa are the recent results of ECOG 3805, a randomized phase 3 study of androgen deprivation therapy (ADT) +/- 6 cycles of docetaxel chemotherapy in men with hormone-naïve metastatic PCa. Cleveland Clinic participated in the ECOG 3805 trial.

The rationale for the trial’s design was simple: Attack de novo testosterone-independent clones early, allowing ADT to keep PCa in remission longer.

More than 790 men with metastatic PCa in need of ADT were randomized to either ADT alone or chemotherapy and ADT. Patients were stratified based on extent of metastases (high versus low volume), age, Eastern Cooperative Oncology Group performance status, use of agents to prevent skeletal-related events (SREs), use of anti-androgens and prior adjuvant ADT. The primary endpoint of the study was OS. Standard secondary endpoints included rate of PSA undetectability at six and 12 months, time to CRPC, safety and QOL at 12 months.

The OS for the entire cohort was 57.6 months versus 44 months favoring the docetaxel + ADT arm (HR 0.61; p = 0.003). Similarly the OS in men with high-volume disease (defined as visceral disease and/or four or more bone metastases with at least one beyond pelvis and vertebral column) was 49.2 months versus 32.2 months in favor of the chemotherapy +ADT arm (HR 0.60; p = 0.0006). Nearly twice as many patients achieved an undetectable PSA at six and 12 months in the chemotherapy arm (27.5 percent vs. 14 percent and 22.7 percent vs. 11.7 percent, respectively; p < 0.0001), and the time to CRPC was also greater for those in the combination arm (14.7 months vs. 20.7 months; p < 0.0001).

As one would expect, patients in the chemotherapy arm experienced more toxicities compared with those on ADT alone; however, these toxicities were docetaxel-related and similar to those commonly observed when this agent is utilized in the CRPC setting.

These data continue to support the importance of chemotherapy in men with PCa. They debunk the myth that late treatment is better and clearly establish the use of upfront chemotherapy for selected men with advanced disease (even prior to the development of castration-resistant disease) as a new standard of care.

Dr. Garcia is a staff member of Cleveland Clinic Glickman Urological & Kidney Institute’s Department of Urology and of the Department of Hematology and Medical Oncology.