Phase II evaluation of oral estramustine and oral etoposide in hormone-refractory adenocarcinoma of the prostate.

PURPOSE: Estramustine and etoposide (VP-16) have been demonstrated to inhibit the growth of prostate cancer cells in experimental models. This led us to evaluate the effectiveness of this combination in the treatment of patients with metastatic prostate carcinoma refractory to hormone therapy. PATIENTS AND METHODS: Estramustine 15 mg/kg/d and VP-16 50 mg/m2/d, were administered orally in divided doses for 21 days. Patients were then taken off therapy for 7 days and the cycle then repeated. Therapy continued until evidence of disease progression. RESULTS: Forty-two patients have been enrolled onto this trial with a minimum of 40 weeks follow-up. Of 18 patients with measurable soft tissue disease, three demonstrated a complete response (CR) and six a partial response (PR) for longer than 2 months. Of these 18 patients, pretreatment prostate-specific antigen (PSA) levels decreased by at least 75% in five men (28%) and by at least 50% in nine (50%). The median survival duration has not been reached in those patients who demonstrated a response either by soft tissue or PSA criteria. Of 24 patients with disease limited to bone, six (25%) demonstrated improvement and nine (38%) demonstrated stability in their bone scans. Five men (21%) demonstrated a decrease of at least 75% in pretreatment PSA levels and 14 (58%) demonstrated at least a 50% decrease; the median survival duration has not been reached in these patients. Pretreatment performance status is an important predictor of survival. CONCLUSION: We conclude that the combination of estramustine and VP-16 is an active oral regimen in hormone-refractory prostate cancer.

Implications of microscopic satellites of the primary and extracapsular lymph node spread in patients with high-risk melanoma: pathologic corollary of Eastern Cooperative Oncology Group Trial E1690.

PURPOSE: To correlate the presence of extracapsular spread (ECS) of regional nodal metastases, and micrometastasis near the primary tumor, with disease outcome in the intergroup study E1690 in relation to the impact of recombinant interferon-alfa (rIFN alpha)-2b. PATIENTS AND METHODS: E1690 included 642 patients with American Joint Committee on Cancer stage IIB or III cutaneous melanoma. Patients were randomized into high- and low-dose rIFN alpha-2b treatment arms and an observation arm. Pathologic slides were reviewed for selected parameters from at least half of the subjects in all three arms. Evaluation of the primary tumor included notations regarding ulceration, mitotic activity, thickness, microscopic satellites (MS), and nodal ECS on a standardized pathology form. These data were collated in relation to relapse-free survival (RFS) and overall survival (OS) at 50 months' follow-up and studied using Cox regression analysis. RESULTS: Ulceration, mitotic activity, thickness, and size of tumor-bearing lymph nodes did not show a statistically significant correlation with either OS or RFS across all treatment arms. The presence of MS was correlated with RFS (P =.0008) and OS (P =.05). ECS correlated with RFS (hazard ratio = 1.44, P =.032) but not OS (P =.11). CONCLUSION: The presence of MS (in 6% [18 of 308 patients]) had a significant adverse impact on both RFS (P =.0008) and OS (P =.053). Ulceration, mitotic activity, thickness, and number of positive lymph nodes had no significant effect on OS in this subset study (univariate or multivariate Cox analysis). The presence of ECS in lymph nodes had a significant adverse effect on RFS (P =.032) but not on OS.

High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190.

PURPOSE: Pivotal trial E1684 of adjuvant high-dose interferon alfa-2b (IFNalpha2b) therapy in high-risk melanoma patients demonstrated a significant relapse-free and overall survival (RFS and OS) benefit compared with observation (Obs). PATIENTS AND METHODS: A prospective, randomized, three-arm, intergroup trial evaluated the efficacy of high-dose IFNalpha2b (HDI) for 1 year and low-dose IFNalpha2b (LDI) for 2 years versus Obs in high-risk (stage IIB and III) melanoma with RFS and OS end points. RESULTS: A total of 642 patients were enrolled (608 patients eligible), of whom a majority (75%) had nodal metastasis (50% had nodal recurrence). Unlike E1684, E1690 allowed entry of patients with T4 (> 4 mm) deep primary tumors, regardless of nodal dissection, and 25% of the patients entered onto this trial had deep primary tumors (compared with 11% in E1684). At 52 months' median follow-up, HDI demonstrated an RFS benefit exceeding that of LDI compared with Obs. The 5-year estimated RFS rates for the HDI, LDI, and Obs arms were 44%, 40%, and 35%, respectively. The hazards ratio for the intent-to-treat analysis of HDI versus Obs was 1.28 (P(2) =.05); for LDI versus Obs, it was 1.19 (P(2) =.17). By Cox analysis, the impact of HDI on RFS achieved significance (P(2) =.03). The RFS benefit was equivalent for node-negative and node-positive patients. Neither HDI nor LDI has demonstrated an OS benefit compared with Obs at this time. A major improvement in the median OS of patients in the E1690 Obs arm was noted in comparison with E1684 (6 years v 2.8 years). An analysis of salvage therapy for patients who relapsed on E1690 demonstrated that a significantly larger proportion of patients in the Obs arm received IFNalpha-containing salvage therapy compared with the HDI arm; this therapy was unavailable to patients during E1684, and patients with undissected regional nodes were not included in E1684. This study did not specify therapy at recurrence. Analysis of treatments received at recurrence demonstrated significantly more frequent use of IFNalpha2b at relapse from Obs than from HDI, which may have confounded interpretation of the survival benefit of assigned treatments in E1690. CONCLUSION: The results of the intergroup E1690 trial demonstrate an RFS benefit of IFNalpha2b that is dose-dependent and significant for HDI by Cox multivariable analysis.

Outpatient biochemotherapy with interleukin-2 and interferon alfa-2b in patients with metastatic malignant melanoma: results of two phase II cytokine working group trials.

PURPOSE: The Cytokine Working Group performed a randomized phase II trial of two outpatient biochemotherapy regimens to identify an outpatient regimen with high antitumor activity and less toxicity than inpatient regimens which might be compared with chemotherapy or inpatient biochemotherapy regimens in future phase III trials. PATIENTS AND METHODS: Eighty-one patients with metastatic malignant melanoma received dacarbazine 250 mg/m(2)/d intravenously (IV) and cisplatin 25 mg/m(2)/d IV on days 1, 2, and 3, plus interferon (IFN) alfa-2b 5 mU/m(2) subcutaneously (SC) on days 6, 8, 10, 13, and 15, given every 28 days. Interleukin-2 (IL-2) was given daily on days 6 to 10 and 13 to 15. In group 1, IV IL-2 was given at 18.0 MU/m(2), and in group 2, SC IL-2 was given at 5.0 mU/m(2). RESULTS: In group 1 (IV IL-2), there were five complete responses (CRs) and 11 partial responses (PRs) among 44 patients (objective response rate [ORR], 36%; 95% confidence interval [CI], 22% to 51%). In group 2 (SC IL-2), there was one CR and five PRs among the 36 patients (ORR, 17%; 95% CI, 4% to 29%). The median survival was 10.7 months in group 1 and 7.3 months in group 2. Eleven patients in group 1 and four patients in group 2 remain alive as of the last follow-up. Toxicities in both groups were similar. No patient required hospitalization for neutropenic fever. CONCLUSION: Biochemotherapy has activity in these outpatient regimens with acceptable toxicity. The antitumor activity observed with the IV IL-2 regimen seems similar to that of inpatient biochemotherapy regimens. If inpatient biochemotherapy regimens develop an established role in the management of melanoma, future phase III trial comparisons with this outpatient IV IL-2 regimen would be appropriate.

Phase II study of carmustine, dacarbazine, cisplatin, and tamoxifen in advanced melanoma: a Southwest Oncology Group study.

PURPOSE: The combination of carmustine (BCNU), dacarbazine (DTIC), cisplatin (DDP), and tamoxifen (Tam) has been reported in small series to provide a response rate of 50%, but with significant myelosuppression and risk of thromboembolic complications. We performed this phase II study to assess the antitumor activity and important toxicities of this combination in the cooperative group setting. PATIENTS AND METHODS: Seventy-nine eligible patients were treated with BCNU 150 mg/m2/d, every 6 weeks, DTIC 220 mg/m2/d on days 1 to 3 every 3 weeks, DDP 25 mg/m2/d on days 1 to 3 every 3 weeks, and Tam 20 mg orally daily throughout treatment. Treatment cycles were repeated every 6 weeks in responding or stable patients for a maximum duration of 1 year. RESULTS: Twelve objective responses were achieved (response rate 15%, 95% confidence interval 8%-25%). Five responses were complete (CR) and seven were partial (PR). The median response duration was 8+ (range, 4-19+) months, (16+ [4-19+] for CR and 8+ [4-11] for PR), and the median survival of the entire group was 9 months. The toxicities were predominantly neutropenia and thrombocytopenia. Four patients developed thromboembolic events. Two patients died while on protocol therapy, one with complications of neutropenia, and the other with disease progression. CONCLUSION: The activity of this regimen is in the range reported for single agents or DTIC plus DDP, and the addition of BCNU and Tam appears to increase toxicity. We do not recommend this combination for routine treatment of advanced melanoma or as the control arm in randomized studies of combination therapy.

Phase II trial of biochemotherapy with interferon alpha, dacarbazine, cisplatin and tamoxifen in metastatic melanoma: a Southwest Oncology Group trial.

The therapeutic benefit of adding interferon alpha (IFNalpha) to established single-agent and combination chemotherapy regimens for the treatment of metastatic melanoma has not been proven. We designed the present study to estimate the response rate of IFNalpha, dacarbazine, cisplatin and tamoxifen in patients who had not been treated with systemic therapy for advanced disease. Using a schedule similar to that which had previously been shown to favor IFNalpha plus dacarbazine over dacarbazine alone, we treated patients with an "induction" regimen of IFNalpha, 15 mU m(-2) day(-1) intravenously 5 days/week for 3 weeks. Following induction, schedules of IFNalpha, 5 mU m(-2) day(-1) subcutaneously three times a week, and tamoxifen, 10 mg orally twice a day, were begun. Dacarbazine, 250 mg m(-2) day(-1) and cisplatin 33 mg m(-2) day(-1) for 3 consecutive days were repeated every 4 weeks, and subcutaneous IFNalpha and oral tamoxifen were continued until the discontinuation of chemotherapy. We treated 25 patients (18 men and 7 women, median age 52 years) and observed only 1 objective response (response rate 4%, 95% confidence interval 0.1%-20%). The toxicities of the regimen consisted of moderate myelosuppression and constitutional side-effects. On the basis of the low antitumor activity of this regimen, we do not recommend it for further study or for use as standard therapy of metastatic melanoma.

A phase II trial of oral diethylstilbesterol as a second-line hormonal agent in advanced prostate cancer.

OBJECTIVES: To test the use of 1 mg/day of oral diethylstilbesterol (DES) as a treatment for patients with advanced prostate cancer who had failed primary hormonal therapy. Approximately 40,000 men this year will experience first-line hormonal therapy failure for their metastatic prostate cancer. At this time there is no standard therapy for men whose first-line hormonal manipulation has failed. This clinical problem has been exacerbated by the use of prostate-specific antigen (PSA) as a proved biomarker to follow disease progression. Patients who are experiencing hormonal therapy failure now present with a rising PSA, and virtually all are asymptomatic. The dilemma of how to treat these patients represents a new clinical problem for the medical oncologist and urologist that needs to be answered. METHODS: We conducted a Phase II trial of oral DES in 21 patients. Patients were followed for response by PSA criteria and toxicity. A decrease in two serial measurements of PSA of greater than 50% from baseline was judged to be a partial response. RESULTS: Nine of 21 patients achieved a PSA response (43% response rate with 95% confidence intervals of 22% to 64%) leading to early cessation of this Phase II trial. Eight of 13 patients (62%) who had only one prior hormone manipulation that failed demonstrated a PSA response, whereas only 1 of 8 patients (13%) who had received two or more hormone treatments responded (P = 0.07). The median follow-up is 82 weeks (range 8 to 122) among 16 surviving patients. The survival rate at 2 years is 63% (95% confidence interval 41% to 99%). CONCLUSIONS: DES appears to be an active agent for second-line hormone therapy for metastatic prostate cancer. Because it has been taken off the market for economic reasons, DES should be considered for development under the orphan drug strategy.

Alteration of dacarbazine pharmacokinetics after interleukin-2 administration in melanoma patients.

In an effort to improve the treatment of metastatic malignant melanoma, we evaluated the sequential administration of the chemotherapeutic agent dacarbazine (DTIC) and the biological response modifier interleukin-2 (rIL-2) in a phase I-II study. Since the combination of biological response modifiers and chemotherapeutic agents could alter drug disposition, we evaluated the pharmacokinetics of DTIC and its major metabolite, 5-amino-imidazole 4-carboxamide (AIC), before and after rIL-2 administration. DTIC (1 g/m2, 24-h i.v. infusion) was given on day 1 and rIL-2 (2-4 million Cetus units/m2, 30-min i.v. injection), on days 15-19 and 22-26 of each course of therapy. The second DTIC dose was given on day 29, i.e., 3 days after the last rIL-2 administration. DTIC and AIC were assayed by reversed-phase HPLC. DTIC plasma levels showed a significant decrease after rIL-2 administration as compared with DTIC values obtained in the same patients before rIL-2 administration. DTIC area under the curve (AUC) values obtained after rIL-2 were lower than those obtained on day 1 before rIL-2 administration (P = 0.02). After rIL-2, the total body clearance (ClT) was increased (P = 0.04), as was the volume of distribution at steady state (Vss; P = 0.02). The decrease in AUC after rIL-2 administration became more pronounced as the rIL-2 dose was increased (P = 0.03). No significant difference was detected in the elimination phase of DTIC when half-lives obtained before and after rIL-2 administration were compared; the mean half-lives were 0.7 and 2.8 h for the alpha- and beta-phases, respectively. The model-independent mean residence time was 3.4 h. The plasma AUC for the metabolite AIC did not charge after rIL-2 administration. AIC biphasic plasma elimination was also similar after rIL-2 administration, with alpha- and beta-half-lives of 0.7 and 11.4 h, respectively. Urinary excretion of DTIC and AIC did not differ after rIL-2 administration; the overall DTIC excretion was 39% of the dose over 48 h, and AIC urinary excretion was 25% of the DTIC dose. The observed decrease in the DTIC plasma AUC after rIL-2 administration appears to be due to an increase in the volume of distribution, since other factors such as half-lives, urinary excretion, and metabolism were not significantly altered. The clinical consequences of the rIL-2-DTIC interaction remain difficult to assess based on presently available data, but this drug interaction should be taken into consideration in the development of future chemo-immunotherapy regimens that include high-dose rIL-2.

Comparison of patient characteristics and outcome between a single-institution phase II trial and a cooperative-group phase II trial with identical eligibility in metastatic melanoma.

Differences in overall survival and response rates are often noted when promising single-institution phase II treatment regimens are evaluated in a cooperative group setting. One reason for this discrepancy may be the differences in patient characteristics at the time of registration. In the metastatic melanoma literature, the prognostic factors for survival that are most frequently identified are the number of metastatic sites, visceral involvement, performance status, liver involvement, and possibly the disease-free interval and gender. A prognostic factor for response appears to be sites of involvement. A comparison of patient characteristics and outcome was conducted for patients entered in similar phase II melanoma trials at a single institution versus those in a cooperative group. Sixty-four patients at Wayne State University (WSU) were compared with 96 patients who had nearly identical eligibility criteria and were registered in the Southwest Oncology Group (SWOG). All patients were receiving comparable phase II treatments for metastatic melanoma. Southwest Oncology Group patients were significantly older (p < 0.001), had worse performance status (p = 0.03), had more visceral involvement (p = 0.001), and were more likely to have two or more metastatic sites (p = 0.02). No significant differences in gender (p = 0.55), absence or presence of liver involvement (p = 0.12), or disease-free interval were noted. These disparities, despite similar eligibility, may partly explain the observed differences in survival (WSU median = 10 months, SWOG median = 7 months; p = 0.13) and response rates (WSU = 31%, SWOG = 15%; p = 0.02) between the two groups of patients. Investigators should report these important patient characteristics in treatment reports. These differences highlight the difficulty in comparing single-institution and cooperative-group phase II trials, even with comparable patient eligibility. This serves to emphasize the need for well-designed phase III trials when comparing treatment approaches and stratification for the prognostic factors identified.

Metastatic melanoma from intraocular primary tumors: the Southwest Oncology Group experience in phase II advanced melanoma clinical trials.

Ocular melanoma is an uncommon malignancy that, in the presence of metastatic disease, has a poor prognosis for response to treatment and survival. Patients with ocular melanoma are often excluded from clinical trials because of the impression that these patients have a poorer response rate to treatment with anticancer agents and poorer survival, possibly related to the predominance of the liver as a site of metastasis. Sixty-four eligible patients with advanced melanoma arising from ocular primary tumors were entered into seven phase II clinical trials of anticancer therapy activated by the Southwest Oncology Group (SWOG) during the 1980s. Eligible patients with nonocular primaries entered into these trials (420 patients) served as a comparison group for survival, pretreatment characteristics, and response rates. Multivariate Cox model analysis of survival data (with survival from the time of study registration as the primary end-point) was conducted. Among the 484 patients observed, patients with ocular melanoma were older than those with nonocular primary tumors and were more likely to have visceral metastasis, metastasis to the liver, and only one metastatic site at registration, primarily to viscera and liver. The median overall survival after registration to study for both groups was 5 months. There was no significant difference in overall survival between patients with ocular melanoma and those with nonocular melanoma after adjusting for a number of prognostic factor (p = 0.43). Furthermore, the overall objective response rate of patients with ocular melanoma in these studies was not significantly different from that achieved in the nonocular group (9% vs. 11%; p = 1.00). Patients with advanced ocular or nonocular melanoma have similar response rates and survival in this series of cooperative group phase II trials. Patients with ocular primaries should not be excluded from investigational studies in advanced melanoma.

Phase II chemoprevention trial of oral fenretinide in patients at risk for adenocarcinoma of the prostate.

Prostate cancer is the most common cancer diagnosed in American men. The need to find effective means of preventing this disease is clear. Vitamin A and its analogues (retinoids) act as transcriptional regulators within the nucleus and have been tested as both preventative and therapeutic agents in human malignancy. Fenretinide (N-4-hydroxyphenyl retinamide) (4HPR) has been found to be relatively nontoxic in preclinical experiments and early clinical trials. Its toxicity and feasibility for use as a chemoprevention agent in men at high risk for prostate cancer was evaluated in this study. Twenty-two patients were entered into a clinical trial that involved taking 4HPR for twelve 28-day cycles. Eight patients with negative prestudy biopsies had positive prostate biopsies prior to or at the time of their 12th cycle evaluation. This led to early closure of the study. 4HPR was well-tolerated, and no major toxicities were associated with its use. The significance of this study is limited due to small sample size. Chemoprevention studies such as this can be difficult to complete because of the commitment required of otherwise healthy individuals; nevertheless additional dosages and schedules for 4HPR administration merit further investigation.

A phase II evaluation of oral tamoxifen and intermittent intravenous vinblastine in hormone-refractory adenocarcinoma of the prostate.

Hormone refractory prostate carcinoma is an incurable disease. Therapy affecting the tissue matrix at the level of the cytoskeleton has been demonstrated to inhibit prostate cancer growth. In vivo and in vitro evidence demonstrated vinblastine and tamoxifen to be agents that would interact to inhibit prostate cancer growth by microtubule inhibition. This study evaluated the effectiveness of these agents in combination in 22 patients with metastatic hormone refractory prostate cancer. Patients received tamoxifen 20 mg twice daily continuously plus vinblastine 4 mg/m2 on days 1, 8, 15, 22, 28, and 35 every 49 days. Disease response was assessed after the first two cycles of therapy. No partial or complete responses were definitively identified. Only 23% of participants received two or more full cycles of therapy. Major toxicities included grade 1-3 leukopenia (73%), grade 2-3 anemia (64%), and two participants experienced a grade 3/4 thrombocytopenia. Only two participants experienced a greater than 50% decrease in serum PSA, one of which may have been attributed to a flutamide withdrawal syndrome. We conclude that the dosage and schedule of vinblastine and tamoxifen used in this study is inactive in the treatment of metastatic hormone refractory prostate cancer.

The addition of tamoxifen to dacarbazine and cisplatin in metastatic malignant melanoma. A phase II trial of the Southwest Oncology Group, (SWOG-8921).

Based on the reports of substantial improvement in the response rate w ith the addition of tamoxifen to a multiagent chemotherapy regimen for metastatic melanoma, Southwest Oncology Group (SWOG)-8921 was initiated. A prior regimen (SWOG-8804) of dacarbazine (DTIC) 750 mg/m(2) i.v. day 1 and cisplatin 100 mg/m(2) day 1 repeated every 3 weeks produced a 13% response rate in patients with metastatic melanoma without brain metastasis. SWOG-8921 using identical chemotherapy and schedule added tamoxifen 10 mg twice daily. There were 55 eligible patients registered, median age 52, with 37 men and 18 women. Fifty (91%) patients had evidence of visceral metastasis at registration. There were 10 responders (2 complete and 8 partial responses) for an 18% response rate (95% CI, 9-31%). The response rate in women was 28% (95% CI, 10-53%; in men, 14% (95% CI, 5-29%). Tamoxifen has produced a small increase in the response rate when added to the present combination and schedule of chemotherapy. Further Phase III trials will be necessary to assess whether there is a statistical advantage to the use of tamoxifen when combined with chemotherapy and whether there are statistical differences between men and women.

Rationale for intergroup trial E-3695 comparing concurrent biochemotherapy with cisplatin, vinblastine, and DTIC alone in patients with metastatic melanoma.

PURPOSE: The modest activity of chemotherapy and biologic agents in the treatment of advanced metastatic melanoma has prompted investigators to consider combinations of chemotherapy and biologic agents (i.e., biochemotherapy) as a way of improving response rates and survival. Although biochemotherapy has generated a great deal of interest over the last several years, and these regimens have produced high response rates in single-institution phase II trials, they have yet to demonstrate a significant survival benefit in randomized trials compared with either chemotherapy or biotherapy alone. METHODS: The available literature regarding the clinical experience with single- and multiagent chemotherapy, immunotherapy, and biochemotherapy was reviewed. RESULTS: Treatment of metastatic melanoma with either single-agent or combination chemotherapy regimens is clearly suboptimal; the majority of responses are partial and of short duration. In contrast, interleukin (IL)-2 produces long-term durable complete remission in a subset of patients. Over 1,000 patients have been treated with IL-2-based biochemotherapy regimens in single-institution phase II trials, and response rates have ranged from 40% to 60%. Most encouraging have been the durable responses observed in 10% to 20% of patients in most of these trials. Large databases, including two meta-analyses, have confirmed the substantial improvement in response rate associated with biochemotherapy regimens that include both IL-2 and interferon alfa (IFN-alpha) compared with chemotherapy or biotherapy alone. Biochemotherapy is currently being evaluated in randomized controlled trials to determine if this treatment strategy can provide a survival benefit compared with current standard treatments. A pilot study at Beth Israel Deaconess Medical Center has demonstrated the feasibility of administering a modification of a concurrent biochemotherapy regimen, initially described by Legha et al, consisting of cisplatin, vinblastine, and dacarbazine (CVD) plus IL-2 and IFN-alpha in the cooperative group setting. CONCLUSION: These studies provided the rationale for intergroup trial E-3695, which is currently randomizing patients to concurrent biochemotherapy with CVD plus IL-2 and IFN-alpha versus CVD alone.

Biochemotherapy for melanoma.

Systemic therapy for advanced melanoma includes chemotherapy, either with dacarbazine (DTIC) alone or a multiagent combination chemotherapy, and biologic therapy with recombinant interferon-alpha and/or interleukin-2. However, none of these treatment options has produced long-term control of the disease except on rare occasions. Combined chemo-immunotherapy (biochemotherapy) has shown high objective response rates (approximately 50%) and a significant though small proportion of long-term complete responders in metastatic melanoma. It has, however, been associated with greater toxicity. Overall results of sequential versus concurrent biochemotherapy are similar, but the toxicity appears to be less severe in patients treated with the concurrent regimen. At this time, biochemotherapy is under evaluation in a well-designed prospective, randomized trial to identify whether there is benefit to this strategy, compared with chemotherapy alone.

Phase II trial of recombinant interleukin-1 beta in patients with metastatic renal cell carcinoma.

Interleukin-1 (IL-1) plays a central role in the immune system, partly by stimulating the production of interleukin-2 (IL-2) and other cytokines by lymphocytes. In preclinical studies, recombinant interleukin-1 (rIL-1 beta) has shown antitumor activity. We conducted a phase II trial to evaluate the efficacy of rIL-1 in metastatic renal cell carcinoma (RCC). rIL-1 beta was given at a dose of 50 ng/kg i.v. daily for 5 days on a 28-day schedule. Nineteen patients were registered; 16 completed two cycles and were evaluable for response. There were no complete or partial responses to treatment. Toxicity was generally mild and typically involved grades I and II fever, rigors, hypotension, and weight gain. Severe neurologic toxicity was seen in two patients, grade IV seizures were seen in one, and grade III somnolence was seen in another. Analysis of soluble IL-2 receptor (sIL-2r) levels revealed an increase from a mean pretreatment level of 4,567 pg/ml to a mean of 6,124 pg/ml posttreatment (p < 0.001). The mean pretreatment IL-6 level was 51 pg/ml, increased to 84 pg/ml posttreatment (p < 0.05). Patients with bulky disease had higher sIL-2r levels, and patients with tumor fevers had higher IL-6 and sIL-2r levels than patients without fever did. A neutrophilic leukocytosis and a mild thrombocytosis were observed in response to rIL-1 beta administration. We conclude that rIL-1 beta in this dose and schedule is inactive in metastatic RCC.

Oral etoposide in the treatment of hormone-refractory prostate cancer.

BACKGROUND: Hormone-refractory prostate cancer generally remains a chemotherapy-resistant tumor and therefore warrants the continued evaluation of promising agents. METHODS: Twenty-two eligible patients with hormone-refractory prostate cancer were treated with oral etoposide at a dosage of 50 mg/m2/day for 21 days in a 28-day cycle. Response was evaluated using standard solid tumor response criteria. RESULTS: There were two partial responses of 6 and 14 months' duration, respectively. Two patients had disease stabilization, one for 6 months and one for 12 months. Median survival was 31 weeks, with an overall 1-year survival of 30%. Reversible alopecia and myelosuppression were the primary toxicities noted. CONCLUSIONS: Single-agent oral etoposide has minimal activity in patients with hormone-refractory prostate cancer.