Chemotherapy of Hormone Refractory Disease
By prostate Doc at 23 September, 2008, 7:43 pm
Historically, hormone refractory prostate cancer has been viewed as a condition minimally responsive to cytotoxic agents. This view is largely based on data generated before the mid-1990s using single agents or combinations of drugs. Doxorubicin, cyclophosphamide, vinblastine, cisplatin, fluorouracil, mitoxantrone, and estramustine have all been shown to have objective response rates <15%.
As a single agent, only estramustine is approved by the Food and Drug Administration (FDA) for the treat- ment of hormone refractory disease. Not only do these agents suffer from low re- sponse rates, they are particularly poorly tolerated in this group of frail, often poor performance status patients. Patients with hormone refractory disease are often eld- erly and much of their marrow has been irradiated making hematologic toxicity more likely. They often have comorbid medical conditions, and bony metastasis, if present, are often painful. Until the discovery and widespread use of PSA, objective assess- ment of response has been problematic. Several studies, both retrospective and pro- spective have demonstrated that a decline in PSA of at least 50% from baseline correlates with an objective response and may correlate with overall survival. In determining the activity of a therapy, a 50% PSA decline can be a useful surrogate marker. Ultimate utility of a given treatment still requires prospective, randomized comparisons. The combination of mitoxantrone, a synthetic anthracenedione similar in struc- ture and activity to doxorubicin but less toxic, and prednisone was recently studied. Patients receiving the combination were compared to those receiving prednisone alone. The combination of mitoxantrone (12 mg/m2 ever y three weeks) and pred- nisone (10 mg/day) resulted in a highly significant improvement in palliation of symptoms (predominately bone pain) which led to the approval of this combina- tion by the FDA. While the amount and duration of symptom palliation was both statistically and clinically significant, there was no impact of this therapy on overall survival. The median survival of both groups was 10 months, identical to historical median survivals. More recent approaches have focussed on combined antimicrotublar therapy. Estramustine, vincristine, vinblastine, etoposide, and vinorelbine all prevent micro- tubule assembly during mitosis. The taxanes, docetaxel, and paclitaxel stabilize mi- crotubules and inhibit microtubule disassembly. In vitro, the microtubule spindle inhibitors and taxanes are highly synergistic. The taxanes also inactivate bcl-2, an antiapoptotic protein expressed in 66% of hormone refractory prostate tumors. A number of clinical studies have been conducted employing estramustine and addi- tional agents, some of which are summarized below. Estramustine doses and sched- ules vary widely . All of these regimens have response rates in the 40-60% range, which exceed those of older agents or combinations. The biochemical (PSA) and objective re- sponse rates appear to correlate. While these are all phase II studies, there is a sugges- tion that the historical median survival of 6-10 months may have been improved upon. The optimal dose and schedule of estramustine is not known. Two prospec- tive, randomized studies in symptomatic, hormone refractory patients have been initiated. One study will compare docetaxel and estramustine given once every three weeks to mitoxantrone and prednisone given every three weeks. The second study will compare docetaxel and prednisone, given either weekly or once ever y three weeks to mitoxantrone and prednisone. Both studies will look at response rates, quality of life, toxicity and overall survival. A recently repor ted randomized phase II study comparing mitoxantrone and prednisone to estramustine, prednisone and either weekly or every three week docetaxel. Response, time to progression and toxicity all favor the taxane containing arms. 14 Non-estramustine-based regimens have also been studied. Based on available data, it is not possible to conclude whether the activity of these combinations is equivalent to regimens which contain estramustine. At this time, it appears that docetaxel is the single most active agent in the treatment of hormone refractory disease. Chemotherapy offers definite promise to patients with this disease, but any impact on survival remains to be demonstrated.
No comments yet.