Capecitabine in hormone-resistant metastatic prostatic carcinoma - a phase II trial.

The objective of the trial is to evaluate the efficacy of capecitabine in patients with metastatic hormone-resistant prostate carcinoma (HRPC), in terms of prostate-specific antigen (PSA) response and clinical benefit (decrease of pain or analgesic score) and its safety profile. In all, 25 patients with HRPC were enrolled on a phase II trial of capecitabine (Xeloda) at a dose of 1250 mg m(-2) orally twice daily on days 1-14 every 21 days. The inclusion criteria were PSA serum levels >3 x upper limit of normal, a WHO performance status 0-2, age <85 years and adequate bone marrow, liver and renal function. In patients with grade 2 or higher haematological toxicity on day 1 of the treatment cycle, therapy was first delayed, and then continued at a lower dose. Trial end points were PSA response and clinical benefit defined by quality of life (QL) data and analgesic consumption. The median age of patients was 70 years (range 54-85 years). A median of three cycles of capecitabine was administered (range 1-8). PSA response was observed in three patients (12%, 95% CI 3-31%), with times to tumour progression of 18, 21 and 35 weeks, respectively. In these patients, the response durations were 12, 17 and 32 weeks, respectively. Minor PSA regression was also seen in two further patients. The median time to tumour progression of all patients was 12 weeks (95% CI 9-15 weeks). Haematological toxicity was minor, with leukopenia grade 3 observed in one patient. There were three deaths during trial treatment, respectively, due to sepsis following mucositis and leukopenia, presumed sepsis with mucositis induced by chemotherapy and concomitant radiotherapy and cerebral dysfunction progressing to coma. Hand-foot syndrome grades 2 and 3 were observed in four patients each. Clinical benefit was observed in five patients (20%, CI 7-41%). Based on toxicity data, we recommend a lower starting dose of 1000 mg x m(-2) orally twice daily. While capecitabine has some activity in HRPC, as suggested by observed PSA responses, we conclude that it is not worthwhile to investigate capecitabine monotherapy in a phase III trial. Combinations of capecitabine with other agents, such as vinorelbine or docetaxel, may prove to be more effective.

Vinorelbine in androgen-independent metastatic prostatic carcinoma--a phase II study.

The purpose of this study was to evaluate the efficacy of vinorelbine treatment in terms of prostate-specific antigen (PSA) response and clinical benefit (decrease of pain or analgesic score for the subgroup of patients with pain), as well as its toxicity in patients with progressive metastatic androgen-independent prostatic carcinoma. 44 patients with prostatic carcinoma progressing after orchiectomy or during treatment with hormonal agents were treated with vinorelbine at a dose of 30 mg/m(2) intravenously (i.v.) on days 1 and 8 of a 21-day cycle. Inclusion criteria were metastatic progressive prostatic carcinoma with prostate-specific antigen (PSA) serum levels >/=3 x upper limit of normal, World Health Organization (WHO) performance status /=2 was observed on the day of scheduled vinorelbine administration. 9 patients received less than three cycles, 6 due to rapid tumour progression. Treatment at day 1 had to be delayed in 13.7% of 183 cycles. Treatment at day 8 had to be omitted in 19.7% of all cycles. Grade >/=3 granulocytopenia occurred in 18% of patients. 4 patients had severe constipation. In 7 patients (15.9%, Confidence Interval (CI) 6.6-30.1%), a PSA response (>/=50% reduction of PSA levels) was observed. Among 8 patients with measurable disease, 3 had partial remission and 1 no change. Median time to PSA progression in 43 assessable patients was 11.9 weeks (range 3-52 weeks). Median duration of PSA response was 14 weeks (9-30 weeks). Clinical benefit was seen in 7 of 31 cases (23%) with baseline pain, there was no association with PSA response. Vinorelbine is a fairly well tolerated drug with a moderate single agent activity in patients with androgen-refractory prostate cancer.

Response and palliation in a phase II trial of gemcitabine in hormone-refractory metastatic prostatic carcinoma. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: In a phase II trial, 43 patients with hormone-refractory prostate cancer were treated with gemcitabine at a dose of 1,200 mg/m2 over 2 hours (later decreased to 1,000 mg/m2 due to hematological toxicity) on days 1, 8 and 15 of a 28 day cycle. PATIENTS AND METHODS: Inclusion criteria were proven tumor progression after hormonal treatment and increased PSA levels, a WHO PS < or = 2, adequate bone marrow reserve, liver and renal function and age < or =, 80 years. Response criteria were based on PSA levels (CR: normalization of PSA, PR: > 50% decrease). Quality of life (QL) was assessed with the EORTC QLQ-C30 on day 1 of each treatment cycle and on day 8 of the first cycle (range of scales 0-100). Physician-rated pain intensity and use of pain medication were assessed at the same timepoints. RESULTS: Hematological toxicity of gemcitabine led to a dose-reduction in 48% of all cycles. Three of forty-three patients (RR = 7%) showed a PSA response: one CR and three PR with time to treatment failure of 8.7, 6.6 and > or = 9.3 months. Seven patients (16%) had stable disease (NC) for a median duration of 7.1 months (range 6.1-11.7 months). There was one case with objective regression of lymph node metastases. Patients reported a considerably impaired health status/QL (n = 41, median = 50) and severe fatigue (n = 41, median = 55.6) at baseline, with no change under treatment. Pain (QLQ-C30) was also severe at baseline (N=41, median=50) but was improved at the end of cycles 1 (n = 33, median change = -16.7, P = 0.0002), 2 (n = 19, median change = -33.3, P = 0.0006), 3 (n = 14, median change = -16.7, P = 0.06) and 4 (n = 9, median change = -33.3, P = 0.04). Patient-rated pain and use of analgesics as combined endpoint yielded palliation for at least 8 weeks in 14 patients (32%). Nine of these patients showed at least stable disease (CR/PR or NC by PSA level), five indicated a benefit in spite of progressive disease. CONCLUSIONS: Gemcitabine in the dose and schedule indicated above has a significant beneficial impact on pain in patients with hormone-refractory prostatic carcinoma despite its limited activity in terms of PSA response and considerable, especially hematological, toxicity.

Prostate specific antigen in as a dynamic model in advanced prostate cancer.

BACKGROUND: Prostate specific antigen doubling time (PSADT) is a prognostic factor after radical prostatectomy, radiation therapy, and hormonal therapy respectively for prostate cancer. However, its role in patients receiving chemotherapy has not been evaluated to date. PATIENTS AND METHODS: Thirty patients (pts.) with hormone resistant prostate cancer were enrolled in a prospective phase II study to receive oral Idarubicin. The drug was administered at a dose of 35 mg on day 1 and 8 of each cycle, and treatment was repeated every 3 weeks. RESULTS: Fully evaluable for response were 26 pts. 13 of these 26 had measurable disease and 3 out of 13 had no change (NC) after therapy. Ten pts. had progression. All 13 pts. with non-measurable disease showed no response. PSA values increased exponentially over time in all pts., except for the 3 pts. with NC, in whom PSA values remained stable. Median PSADT of pts. with a rising PSA was 2.1 months (mean 2.6; range 0.7-6.1). CONCLUSIONS: PSA levels in pts. not responding to treatment with Idarubicin rose in an exponential fashion similar to pts. who were only on hormonal therapy. PSADT should be evaluated in a larger number of hormone resistant prostate cancer pts. as a possible surrogate endpoint.

Effect of carboplatin on response and palliation in hormone-refractory prostate cancer. Swiss Group for Clinical Cancer Research (SAKK).

To assess the efficacy of carboplatin in patients with hormone-refractory prostate cancer in terms of response rate and palliation, the Swiss Group for Clinical Cancer Research (SAKK) conducted this phase II clinical trial (SAKK 08/91). Carboplatin 400 mg/m2 was administered i.v. every 28 days to 27 patients. The prostate-specific antigen (PSA) level was monitored and compared with the clinical response. Tumour response was evaluated according to EORTC criteria. For patients with nonmeasurable disease, response was defined as the absence of progression in any tumour localization, with no increase in PSA and a decrease of at least 2 points in the WHO pain score. Selected aspects of quality of life (QL) and use of analgesics were assessed to describe patients' experience of toxicity and palliation. Only 1 patient with measurable and 2 patients with nonmeasurable disease achieved partial remission or a response according to our criteria. However, 13 of the 27 evaluable patients had some benefit from carboplatin therapy, as indicated by an improvement in performance status, reduction of pain, and stabilization of metastases. There was no clear-cut association between clinical response and PSA level. QL data suggested that carboplatin was relatively well tolerated and confirmed the clinically documented palliation. In particular, from baseline, for at least two consecutive cycles 7 patients reported either an improvement in pain by 1 point or more on a 4-point scale (> or = 33%) without an increase in analgesic intake or a decrease by 50% or more in analgesic intake without an increase in pain. With the dose and schedule used in this study, carboplatin had only limited objective activity in advanced prostate cancer, but induced palliation in about half the patients.

The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: results of a phase III trial. Swiss Group for Clinical Cancer Research (SAKK).

PURPOSE: A wide variety of fluorouracil (FU)-plus-leucovorin (LV) dose schedules are in clinical use for the treatment of advanced colorectal cancer. Only the monthly low-dose LV-plus-FU regimen, as used by the North Central Cancer Treatment Group, has demonstrated a lasting survival benefit as opposed to FU alone (J Clin Oncol 1989; 7: 1407-1417). The Swiss Cancer Group adopted this regimen for a confirmatory phase III trial but used the same dose-intensity of fluorouracil in both treatment arms. PATIENTS AND METHODS: Patients with inoperable or metastatic colorectal cancer were randomized to receive monthly FU 400 mg/m2/day plus LV 20 mg/m2/day as intravenous push daily for five days, or FU alone. RESULTS: Three hundred nine of the 310 patients randomized were eligible and included in the analysis. The objective response rate for patients with measurable disease was 9% with FU alone and 22% with FU-plus-LV (P = 0.0001). The median progression-free survival was 3.9 versus 6.2 months (P = 0.003) and the overall survival 10 versus 12.4 months (P = 0.02). The major prognostic factors for survival were performance status, weight loss, and disease symptoms. WHO > 2 toxicity, consisting of stomatitis (P = 0.001), diarrhea (P = 0.001), and nausea (P = 0.001), was more pronounced for FU-plus-LV, without fatal events. CONCLUSIONS: This is the largest published randomized trial to compare FU-plus-LV to FU alone in advanced colorectal cancer. It confirms the survival benefit obtained from biomodulating monthly FU with low-dose LV. The toxic effects of FU-plus-LV were acceptable to most patients, and they responded well to FU dose reductions. In the absence of an ideal dose-intense FU monotherapy regimen, monthly FU with low-dose LV provides a simple and economical means by which to achieve adequate FU efficacy in the treatment of advanced colorectal cancer.

A phase II study of oral idarubicin as a treatment for metastatic hormone-refractory prostate carcinoma with special focus on prostate specific antigen doubling time. Swiss Group for Clinical Cancer Research, Berne, Switzerland.

BACKGROUND: Treatment of hormone-refractory prostate carcinoma with chemotherapy is purely palliative, and reported response rates have been low. At the time this study was conducted, there was an urgent need for a trial using potentially efficacious drugs, with quality of life (QL), and serial prostate specific antigen (PSA) behavior as endpoints. METHODS: In this Swiss multicenter Phase II study, 30 patients were enrolled to receive oral idarubicin. Patients were administered 35 mg idarubicin on Days 1 and 8 of each cycle, and treatment was repeated every 3 weeks. Assessment was based on response rates, sequential PSA measurements in serum, toxicity, and selected aspects of QL. RESULTS: Twenty-six of 30 patients were evaluable for response, and none of them achieved a response. Three patients had stable disease as their best response, and their PSA levels also remained stable. In all other patients, PSA increased exponentially over time; the median PSA doubling time was 2.1 months (mean, 2.6; range, 0.7-6.1). Toxicity was minimal and consisted mainly of myelosuppression and nausea/vomiting. QL did not change significantly during therapy with regard to general well-being, fatigue, or nausea/vomiting. However, there were improvements in patient-rated and physician-rated pain. CONCLUSIONS: At the dose and schedule used in this study, oral idarubicin showed only minimal efficacy against hormone-refractory prostate carcinoma. In patients who did not respond, PSA doubling times were similar to those in patients who relapsed while receiving only antiandrogen therapy. In future clinical trials, QL and serial PSA behavior should be included in analysis.