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.

Phase II trial of CI-980 in patients with disseminated malignant melanoma and no prior chemotherapy. A Southwest Oncology Group study.

Malignant melanoma is increasing in frequency at a rapid rate in the United States. Metastatic disease is chemoresistant with DTIC considered the most active single agent. CI-980 is a synthetic mitotic inhibitor that blocks the assembly of tubulin and microtubules. It has shown cytotoxic activity against a broad spectrum of murine and human tumor cell tines. CI-980 can cross the blood brain barrier, is effective when given orally or parenterally, and is active against multidrug resistant cell lines overexpressing P-glycoprotein. In this trial, patients with disseminated melanoma with measurable disease, SWOG performance status of 0-1, no prior chemotherapy or immunotherapy for metastatic disease, and adequate hepatic and renal function, were enrolled. Treatment with CI-980 was given by 72 h continuous i.v. infusion at a dose of 4.5 mg/m2/day, days 1-3 every 21 days. Twenty-four patients were registered on this study with no patients ineligible. They ranged in age from 33-78 with performance status of 0 in 15 patients and 1 in 9 patients. Nineteen patients had visceral disease with 12 having liver involvement. There were no confirmed responses. The overall response rate was 0% (95% CI 0%-14%). The median overall survival is eleven months (95% CI 4-14 months). The most common toxicities were hematologic and consisted of leukopenia/granulocytopenia and anemia, with nausea/vomiting and malaise/fatigue/weakness also frequent. CI-980 administered at this dose and schedule has insufficient activity in the treatment of disseminated malignant melanoma to warrant further investigation.

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.

Gender and other survival predictors in patients with metastatic melanoma on Southwest Oncology Group trials.

BACKGROUND: Some studies have suggested that women with metastatic malignant melanoma have a better survival rate than men. However, little is known about the effect of gender on survival in combination with other clinical variables and treatment variables. Thus, an analysis of 813 eligible patients from 15 consecutive Southwest Oncology Group (SWOG) Phase II or III trials evaluating chemotherapy or chemoimmunotherapy for metastatic melanoma was performed. METHODS: A multivariate Cox regression model was used. RESULTS: Poor performance status (P < 0.001), more organ sites with metastases (OSM) (P < 0.001), liver involvement (P < 0.001), and nonliver visceral involvement (P = 0.01) were highly significant predictors of worse survival, whereas the disease free interval (P = 0.08) had borderline significance. After adjustment for all factors, there was no difference in overall survival between men and women (P = 0.19). Women had a longer disease free interval (P = 0.003) and fewer OSM (P = 0.004) at study registration than men. CONCLUSIONS: The current study found that performance status, OSM, and type of visceral involvement were independent predictors of survival in patients with metastic malignant melanoma and should be used as stratification factors in future Phase III trials. However, the current study also found that gender did not appear to be a significant independent predictor of survival for this stage of disease. A longer disease free interval from initial diagnosis and fewer OSMs may partly explain the improved outcome reported for women in selected trials. The study concluded that further investigation of the biologic differences at early stage diagnosis should be undertaken to determine whether women truly have a different pace of disease progression and a different metastatic pattern.

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.

Weekly 1-hour infusion of paclitaxel. Clinical feasibility and efficacy in patients with hormone-refractory prostate carcinoma.

BACKGROUND: Preclinically, paclitaxel given according to an intense bolus schedule has significant antitumor activity against human prostate carcinoma cell lines in SCID mice. The authors evaluated the feasibility and efficacy of weekly 1-hour infusion of paclitaxel in patients with metastatic hormone-refractory prostate carcinoma (HRPC). METHODS: A total of 18 patients with progressive metastatic HRPC were enrolled. Patients had to have no prior chemotherapy. Paclitaxel was infused weekly at a dose of 150 mg/m(2) over 1 hour for 6 weeks every 8 weeks. RESULTS: Eighteen patients with a median age of 68.5 years and a median prostate specific antigen (PSA) level of 82 ng/mL (range, 2.17-3196 ng/mL) were enrolled. The median number of prior hormone treatments was 2, and 12 patients on antiandrogens completed antiandrogen withdrawal. Ten of eighteen patients had bone-only metastasis and eight had metastasis to bone with lymph node and/or visceral metastasis. Seventeen patients received a total of 31 cycles (157 courses) and 1 patient refused chemotherapy. All patients were included in response evaluation. Of the 8 [corrected] patients with measurable disease, 4 achieved a major response, with 1 complete response (in the lung) and 3 partial responses (1 in the liver and 2 in the lymph nodes). Seven of eighteen patients (39%) had a PSA decline of >/=50%. The major high grade toxicity was peripheral neuropathy, with 6 patients (35%) developing Grade 3 toxicity. CONCLUSIONS: Weekly 1-hour paclitaxel has activity in patients with HRPC. The major toxicity is peripheral neuropathy. The minimal myelosuppressive effects make a modified schedule (lower doses on the same schedule or a shorter schedule of the same dose) attractive for future combination chemotherapy trials.

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.

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.

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 evaluation of all-trans-retinoic acid plus interferon alfa-2a in stage IV melanoma: a Southwest Oncology Group study.

BACKGROUND: Interferon alfa has modest but definite activity in the treatment of metastatic melanoma and is the only agent currently available for adjuvant therapy of high-risk resected disease. A variety of retinoic acid derivatives have been shown to be synergistic with interferon alfa in vitro and in vivo, with nonoverlapping toxicities. If promising combinations of interferon alfa and retinoids could be developed for melanoma patients, they would have clinical relevance for the treatment of advanced as well as localized disease. PURPOSE: To determine the efficacy and toxicity of a combination of interferon alfa-2a and all-trans-retinoic acid in patients with measurable metastatic melanoma, the South-west Oncology Group conducted a phase II clinical trial. PATIENTS AND METHODS: Fifty-seven patients with measurable metastatic melanoma (American Joint Committee on Cancer stage IV) were entered; five patients were unevaluable. Treatment consisted of oral all-trans-retinoic acid (37.5 to 75 mg/m2 orally twice daily for 21 days followed by 7 days' rest) plus subcutaneously administered interferon alfa-2a (6 MU/m2 three times a week). RESULTS: Two complete and three partial responses were observed among 52 evaluable patients, for an objective response rate of 10% (95% confidence interval 3% to 21%). Responses were seen only in patients with pulmonary, nodal, or subcutaneous metastases, and lasted from 4 to 23+ months. Median survival for the 52 patients was 8 months. Side effects were tolerable but significant, with one case of grade IV anemia and 92% of patients experiencing at least grade II toxicity. Flu-like symptoms were the most commonly reported side effects. There was one case of grade III hyperlipidemia. CONCLUSION: The combination of recombinant human interferon alfa-2a with all-trans-retinoic acid did not result in a greater percentage of objective responses or a longer overall survival than that associated with interferon alfa alone. This combination cannot be recommended for further evaluation in melanoma in either the advanced disease or the adjuvant settings.

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 trial of recombinant human interleukin-4 in patients with disseminated malignant melanoma: a Southwest Oncology Group study.

Malignant melanoma is increasing in incidence in this country. Metastatic disease generally responds poorly to most chemotherapy drugs. Immunologic and biologic agents have shown some activity in this disease. Interleukin 4 (IL-4) is a cytokine produced by activated T-lymphocytes with pluripotent activities including growth inhibition of various tumor cell lines in vitro and immune- mediated tumor growth inhibition in in vivo animal tumor models. In this phase II trial, patients with advanced malignant melanoma with no prior systemic therapy for metastatic disease and Southwest Oncology Group performance status 0-1 were treated with recombinant human IL-4 at a dose of 5 micrograms/kg/day by daily subcutaneous injection days 1-28 followed by a 7-day rest period, after which the cycle was repeated. Thirty-six patients were registered to this study. Two patients were ineligible by study criteria. Among the 34 eligible patients, there was 1 complete response, 0 partial responses, 2 stable/no responses, 27 increasing disease/progression, 1 early death, and 3 patients whose assessment was inadequate to determine response. The overall estimated response rate was 3% (1 of 34) with a 95% confidence interval 0.1-15%. The duration of the complete response is 421+ days. Thirty-one of the 34 eligible patients have died. The estimated median survival is 6 months (95% confidence interval 4-9 months). The most common toxicities were elevated liver function tests, nausea/vomiting/diarrhea, malaise/fatigue, edema, headache, myalgias/arthralgias, and fever/chills. Despite promising preclinical growth inhibitory and immunomodulatory effects, IL-4 in this dose and schedule showed only low antitumor activity. Alternative methods and routes of administration or combinations of IL-4 with other cytokines might produce greater antitumor effects.

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.

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.

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.

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.