Treating Hormone-Refractory Prostate Cancer: The Latest in Evidence-Based Medicine
After conventional first-line hormonal approaches fail in the treatment of stage IV prostate cancer, cytotoxic chemotherapy is typically applied. While several chemotherapy regimens have shown promise in clinical trials, there remains no one standard chemotherapeutic approach for patients with hormone-refractory prostate cancer. However, the armamentarium of systemic chemotherapeutic agents is expanding, and new classes of compounds are showing activity in this setting. One of these agents is the vinca alkaloid vinorelbine (Navelbine, GlaxoSmithKline), which, like estramustine (Emcyt, Pharmacia Corp.), paclitaxel (Taxol, Bristol-Myers Squibb) and docetaxel (Taxotere, Aventis Pharmaceuticals), is an anti-microtubule agent but potentially offers a more favorable side effect profile. Vinca alkaloid regimens, vinorelbine as well as vinblastine (Velban, Eli Lilly), were evaluated in several encouraging studies presented at the 38th Annual Meeting of the American Society of Clinical Oncology (ASCO) held May 18-21, 2002 in Orlando, Florida.
Emerging Chemotherapy Regimen
In a Phase II study reported by Alan J. Koletsky MD, of the Boca Raton Comprehensive Cancer Center, Boca Raton, Florida, vinorelbine in combination with low-dose docetaxel produced an impressive response, without thromboembolic complications or edema1, which can be problematic toxicities associated with estramustine administration.2
The rationale for the study was the single-agent activity of vinorelbine and docetaxel in hormone-refractory prostate cancer and their level of synergy in prostate cancer cell lines and animal models of prostate cancer. The study was designed to assess the efficacy and tolerability of vinorelbine and docetaxel combination chemotherapy in chemotherapy-naпve patients with hormone-refractory prostate cancer exhibiting disease progression despite castrate testosterone levels and after withdrawal from anti-androgens.
Eighteen patients were treated with vinorelbine (20 mg/m2) followed by docetaxel (25 mg/m2) on days 1 and 8 of a 21-day cycle. Response was defined as a decline of > 50% or > 75% from baseline prostate-specific antigen (PSA), or a reduction in bidimensionally measurable disease using standard Phase II criteria. Patient baseline characteristics included a median age of 76 years (range, 60-83 years), median Performance Status > 90, and median PSA of 145 (range, 19-4, 262). Eight patients had prior radiotherapy, and metastatic sites of disease included bone (13), bone plus visceral organs (2), and lymph nodes (2). Patients received a median of 6.5 courses of therapy (range, 2-14).
Dr. Koletsky reported that 9 of 17 evaluable patients (53%) achieved a post-therapy PSA decline of > 50%, while 7 patients (41%) had PSA declines of > 75%. The median PSA decline for all patients was 60.2% (range, 0-99.75%). Objective responses were seen in two of four patients (50%).
The vinorelbine and docetaxel combination was well tolerated and thromboembolic complications and edema were not observed. Grade 4 toxicity was limited to neutropenia in nine patients (53%) and dyspnea in one patient. Four patients (24%) had grade 3 neutropenia and three patients (18%) had grade 3 anemia. Nonhematologic toxicities included grade 3 peripheral neuropathy and constipation in one patient each. There was one possible treatment-related death from pulmonary acute respiratory distress syndrome, advised Dr. Koletsky.
The investigators felt the activity and tolerability of vinorelbine and docetaxel combination chemotherapy demonstrated in hormone-refractory prostate cancer warranted a multicenter randomized trial, which is being planned.
In another Phase II study of vinorelbine and docetaxel reported by Susan Goodin, MD of the Dean and Betty Gallo Prostate Cancer Center/The Cancer Institute of New Jersey/University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, New Brunswick, New Jersey, the combination was judged to be an active combination for first-line treatment of hormone-refractory prostate cancer.3
Dr. Goodin and colleagues treated 30 patients with hormone-refractory prostate cancer with docetaxel 60 mg/m2 on day 1 and vinorelbine 15 mg/m2 on days 1 and 8 of a 21-day cycle, with filgrastim support on days 2-6 and 9-13. Fourteen patients had prior chemotherapy; 9 patients had progressed on chemotherapy (five with prior taxanes) and 5 patients had received chemotherapy in the adjuvant setting of stage D0 disease. A total of 184 cycles of chemotherapy were administered, with patients receiving an average of 6.7 cycles (range, 1-24).
Twenty patients demonstrated a decrease in PSA, the mean decrease being 57.1% (range, 25.8%-90.6%). The mean duration of response was 6.1 months (range, 1-18 months). In the 16 patients who had received no prior chemotherapy, seven patients (44%) demonstrated a > 50% decrease in PSA and 5 patients had stable disease. Among the 14 patients who received prior chemotherapy, 4 patients (29%) demonstrated a > 50% decrease in PSA, including two patients who had progressed on prior chemotherapy and two with prior adjuvant chemotherapy.
The combination of vinorelbine and docetaxel was well tolerated, with two episodes of neutropenic fever, one grade 3 ataxia, one grade 3 neuropathy, and one decrease in Performance Status. Currently, eight patients remain on this regimen, Dr. Goodin reported.
New Meets Traditional
A large study by the Hellenic Cooperative Oncology Group evaluated the addition of vinorelbine to an estramustine-based protocol in hormone-refractory prostate cancer and showed activity, favorable tolerability, and a benefit in terms of Performance Status and pain relief.4 The triplet was studied because preclinical studies have shown that only small concentrations of estramustine phosphate are needed for synergy with mitoxantrone and vinorelbine.
The study included 52 patients with hormone-refractory prostate cancer with a median age of 70 years (range, 49-100). Performance Status was 0/1/2 in 19%, 44% and 19% of patients, respectively, while unknown in 17% of patients. Previous patient treatment consisted of surgery (85%), radiotherapy (33%), and hormonal therapy (88%). Gleason scores were 2-4/5-7/8-10 in 13%, 27% and 15% of patients, respectively, while unknown in 44% of patients. Sites of metastases included bone (79%), lymph nodes (29%), liver (15%), lung (15%), local recurrence (6%), and other sites (8%).
The treatment regimen was estramustine 140 mg three times a day on days 1-3, days 8-10, days 21-23; mitoxantrone 12 mg/m2 intravenously (IV) on days 2 and 22; and vinorelbine 25 mg/m2 IV on days 2, 9, 22, 29. The cycle was repeated every 3 weeks.
PSA declines were noted in 12/52 (23%) of patients, including 4 complete responses and 8 partial responses. With regard to measurable metastatic lesions (also 23% reduction), there were 3 complete responses (lymph nodes, lung and cardiac muscle), and 9 partial responses (bones, lung, liver and lymph nodes), reported G. F. Samelis, MD, from the Hippokration General Hospital, Athens, Greece.
The toxicity related to this regimen was judged manageable with 6% of patients developing febrile neutropenia. Grade 3 and 4 toxicities included anemia (19%), leukopenia (33%), thrombocytopenia (11.5%), fatigue (4%), alopecia (2%), and infection (2%). The median survival was 13.1 months (range, 0.6-19.6 months). The median time to progression was 6.7 months (range, 4.7-8.7 months), Dr. Samelis reported.
"The combination of estramustine, mitoxantrone and vinorelbine seems to be safe, with a response rate of 23% in the PSA and 23% in measurable disease. Responding patients also had a benefit in their Performance Status and pain scale," he said. The results of a randomized, multicenter Phase III trial reported by Hudes et al, strengthened the hypothesis of combining chemotherapeutic agents with anti-microtubule properties.5 The combination of estramustine phosphate and the vinca alkaloid vinblastine was compared to single-agent vinblastine in 193 patients with hormone-refractory prostate cancer.
The treatment regimen was vinblastine 4 mg/m2 IV weekly for 6 weeks (repeated every 8 weeks) alone and in combination with oral estramustine phosphate 600 mg/m2 daily. The combination of estramustine and vinblastine was superior to single-agent vinblastine for endpoints of progression-free survival (3.7 vs. 2.2 months, p < 0.0004) and proportion of patients with sustained ≥ 50% decrease of serum PSA (25.2% vs. 3.2%, p < 0.0001). Median survivals were 12.5 months and 9.4 months, respectively.
The incidence of grade 3/4 granulocytopenia was markedly less for the combination (8% vs. 27%, p < 0.0001), although nausea and edema were more frequent with the combination.
1. Koletsky AJ, Guerra M, Kruglyak E, Radice PA, Kronish L. A Phase II Study of Vinorelbine and Low-Dose Docetaxel in Patients with Hormone-Refractory Prostate Cancer (HRPC). 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 2438.
2. Emcyt Professional Prescribing Information. Pharmacia Corp. Available at: http://www.pharmacia.com. Accessed May 22, 2002.
3. Goodin S, Rao KV, Engle EA, et al. A Phase II Study of Docetaxel and Vinorelbine in Hormone Refractory Prostate Cancer (HRPC) with and without Prior Chemotherapy. 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 2459.
4. Samelis GF, Kalofonos C, Kosmidis P, et al. Phase II Study of Estramustine Phosphate (EMP), Mitoxantrone (MTX) and Navelbine (NVB) in Patients with Hormone Refractory Prostate Cancer [Hellenic Cooperative Oncology Group (HECOG)]. 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 2473.
5. Hudes G, Ross E, Roth B, et al. Improved Survival for Patients with Hormone-Refractory Prostate Cancer Receiving Estramustine-Based Antimicrotubule Therapy: Final Report of a Hoosier Oncology Group and Fox Chase Network Phase III Trial Comparing Vinblastine and Vinblastine plus Oral Estramustine Phosphate. 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, Florida. Abstract 704.