Chemotherapy for Advanced Prostate Cancer: 25 Years Later (2008)

When the article entitled “Doxorubicin, Mitomycin-C, and 5-Fluorouracil (DMF) in the Treatment of Metastatic Hormonal Refractory Adenocarcinoma of the Prostate, With a Note on the Staging of Metastatic Prostate Cancer” was published in the Journal of Clinical Oncology, there was great skepticism that chemotherapy had any role in the treatment of advanced prostate cancer. This was largely based on three justifiable concerns: (1) Elderly prostate cancer patients would neither desire nor tolerate the rigors of chemotherapy. (2) Prostate cancer was inherently resistant to chemotherapy based on its low proliferation rate. (3) Efficacy of chemotherapy could not be assessed based on the lack of measurable disease or other objective measures of patient benefit. Twenty-five years later, the perception that patients with advanced prostate cancer are either unwilling or too infirm to receive chemotherapy is known to be false. Indeed, the strong impression of some early investigators that chemotherapy could effectively palliate cancer-related symptoms such as pain and asthenia was subsequently definitively demonstrated by Slack and Murphy and Tannock et al. Recently reported data from large randomized studies confirm that a significant proportion of patients with far-advanced disease are able to tolerate chemotherapy, and those that are symptomatic are palliated significantly. Finally, randomized trials have demonstrated a survival benefit from docetaxel-based therapy, and thus chemotherapy is now established as a palliative useful tool that modestly alters the natural history of castrate-resistant metastatic prostate cancer. In addition, investigators have made advances in understanding and reducing the severity of the adverse effects of sustained androgen ablation, including use of antiandrogens without testicular suppression, intermittent androgen suppression, and bone-preserving bisphosphonates. These advances allow more patients to tolerate therapy at the time of progression to a castrate-resistant state. Increased awareness of prostate cancer and the emergence of patient advocacy groups demanding care have combined with the advances in the therapeutic armamentarium to overcome the reluctance to use chemotherapy for patients with advanced prostate cancer. While the general perception that castrate-resistant prostate cancer is inherently chemotherapy-resistant has been largely overcome, it remains true that the prolongation of survival in patients with advanced prostate cancer is modest and effective treatment combinations have yet to be developed. Furthermore, and in contrast with other common solid tumors such as breast and bladder cancer, we have no evidence of improved efficacy with the earlier application of chemotherapy in prostate cancer. Optimization of chemotherapy combinations in the setting of advanced cancer followed by the methodical integration in earlier disease settings has been the hallmark of successful therapy development in solid tumors. These milestones have yet to be achieved in prostate cancer. The absence of reported benefit may be a result of the relative paucity of completed large randomized studies. While there are still yet unpublished, ongoing large randomized studies, the published data on early use of chemotherapy is disappointing. Tumor regression observed in the preoperative setting has been a reliable surrogate for chemotherapy efficacy in other solid tumors. The experience to date with preoperative chemotherapy demonstrates little tumor regression in early prostate cancer. If the predictive value of tumor regression also holds true for prostate cancer, then a unique therapy development paradigm will need to be developed. Thus, while advanced, castrate-resistant disease has shown some response to chemotherapy, cumulative experience continues to reinforce the notion that early prostate cancer is refractory to the cytotoxic paradigm. Introduction of the serum prostate-specific antigen (PSA) to monitor disease progression has transformed the care of patents with early prostate cancer. However, serum PSA concentration has not been accepted as a surrogate for patient benefit, and the practice of using PSA concentration to guide clinical decisions in advanced prostate cancer threatens our ability to conduct trials based on more meaningful end points such as objective progression or survival. Although PSA has raised patient awareness, improved detection, and provided a tool for monitoring progression of early-stage prostate cancer, it has not translated into improved efficiency of clinical studies in patients with advanced prostate cancer. Thus, we still have challenges to define objective criteria for outcomes that reliably correlate with survival. Our sense that the distribution of visceral metastases and volume of bone involvement are related to therapy response and patient survival is now amply confirmed and accounted for by morphologic variants that reflect the biologic heterogeneity of prostate cancer. Furthermore, it is reasonable to implicate the bone microenvironment in progression of those prostate cancers with clinical presentations dominated by bone-forming metastases. Several lines of clinical and experimental observations have generated interest in developing strategies to prevent or treat bone metastases. Despite this, the further characterization of patient populations based on the distribution of metastases and the incorporation of markers JOURNAL OF CLINICAL ONCOLOGY C E L E B R A T I N G 2 5 Y E A R S O F J C O VOLUME 26 NUMBER 15 MAY 2