Improved results with the addition of interferon alfa-2b to dacarbazine in the treatment of patients with metastatic malignant melanoma.

Sixty-four patients with histologically confirmed metastatic malignant melanoma were entered on a prospectively controlled randomized trial. Patients received dacarbazine (DTIC) alone or DTIC plus interferon (IFN) alfa-2b. Patients were reasonably balanced with respect to age, sex, performance status (PS), site of metastases, and number of metastatic sites. Objective response (complete plus partial remission [CR + PR]) was documented in six patients on DTIC and in 16 patients on DTIC plus IFN alfa-2b. Median time to treatment failure (TTF) and median survival are significantly better on the combination arm, with some long-term CRs observed. More toxicity was encountered in the combination arm, which was acceptable except in three patients where treatment was discontinued because of IFN toxicity.

Factors predicting for response, time to treatment failure, and survival in women with metastatic breast cancer treated with DAVTH: a prospective Eastern Cooperative Oncology Group study.

Six hundred twenty-four women with metastatic breast cancer were entered on Eastern Cooperative Oncology Group (ECOG) study EST 2181. Patients were treated with mitolactol, doxorubicin, vincristine (DAV), tamoxifen, and fluoxymesterone (DAVTH). Nine patients were canceled, and 114 were ineligible (half because of concomitant diseases). Among the 501 eligible patients, the overall response rate was 54% (14% complete response and 5% not assessable). The median time to treatment failure (TTF) was 9.0 months, and the median survival was 20.9 months. Multivariate models were fit on a randomly chosen half of the eligible cases and then verified on the other half. About half of the variables that were significant in the models remained significant in the verification data set. In the verification data set the variables that remained significantly associated with lower probability of response were three or more organ sites of disease and lack of nodal metastases; the variables associated with a significantly shorter TTF were liver metastases, estrogen receptor (ER)-negativity, and prior adjuvant therapy. The variables associated with significantly shorter survival were liver metastases, ER negativity, three or more organ sites of disease, and prior adjuvant chemotherapy. None of the variables in the data set had a significant influence on toxicity. The 125 patients aged over 65 years did not have worse toxicity or worse prognosis than younger patients. Ineligible patients had significantly less response but virtually identical TTF curves, survival curves, and toxicities. Therefore, patient discriminants are of paramount importance in predicting the outcome of treatment. Many of the current criteria for eligibility for entry on study may not be justified.

Reinduction with the same cytostatic treatment in patients with metastatic breast cancer: an Eastern Cooperative Oncology Group study.

PURPOSE: To investigate the therapeutic value of reinduction with the same cytostatic treatment that had been used in induction treatment for women with metastatic breast cancer. MATERIALS AND METHODS: One hundred six women with metastatic breast cancer were given dibromodulcitol (mitolactol), doxorubicin, vincristine, tamoxifen, and fluoxymesterone (DAVTH) for 6 months of induction treatment, then randomized to receive one of two chemotherapy regimens if they had obtained an induction partial response (PR) or no change (NC), or to receive observation versus chemotherapy if they had obtained an induction complete response (CR). Patients were then retreated with DAVTH reinduction after relapse. RESULTS: Seventy-four patients were eligible or had minor reasons for ineligibility. Severe or life-threatening toxicity was documented in 46%, and lethal toxicity in 4%. Eighteen percent had a response on reinduction (zero of 16 induction nonresponders, 15% induction PR, 44% induction CR). The median time to treatment failure (TTF) from reinduction was 3 months, and the median survival duration from reinduction was 14 months. In a logistic model, factors associated with more reinduction responses were observation after induction CR (P = .002) and age greater than 55 years (P = .04). Time since induction was not significant. CONCLUSION: Reinduction of response after treatment failure remains a therapeutic problem. The need for better salvage treatment underlines the importance of developing new regimens.

Treatment of metastatic breast cancer in premenopausal women using CAF with or without oophorectomy: an Eastern Cooperative Oncology Group Study.

One hundred thirty-one premenopausal women with metastatic breast cancer who had received no prior systemic treatment for metastases were entered on study. Patients without prior chemotherapy with estrogen receptor (ER)-positive and ER-unknown disease were randomized to receive cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, OH), and 5-fluorouracil (CAF) or surgical oophorectomy followed directly by CAF (O + CAF). ER-negative patients without prior chemotherapy were directly assigned to treatment with CAF. Among randomized patients 83% have responded, and 37% have achieved a complete remission. Among ER-negative patients the complete response rate was 38%, and the complete plus partial response rate was 70%. Characteristics significantly associated with a longer time to treatment failure were age 45 or over, one or two organ sites, and performance status O. The median survival time of ER-positive patients treated with CAF is 29 months, and with O + CAF it has not yet been reached, whereas for ER-unknown patients the equivalent survival times are 41 months and 43 months respectively. For ER-negative patients treated with CAF the median survival time is 17 months. Characteristics associated with significantly longer survival among randomized patients were age 35 or over (P = .009) and only one or two organ sites involved (P = .02). Neither treatment (P = .33) nor ER status (P = .70) was significant.

Phase II trial of doxorubicin and docetaxel plus granulocyte colony-stimulating factor in metastatic breast cancer: Eastern Cooperative Oncology Group Study E1196.

PURPOSE: The purpose of this multi-institutional phase II trial was to evaluate the efficacy and toxicity of doxorubicin and docetaxel plus granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer. The primary objective was to determine whether the combination produced a response rate of at least 50%. PATIENTS AND METHODS: Fifty-four patients with metastatic breast cancer received doxorubicin (60 mg/m(2) by intravenous [IV] injection) followed 1 hour later by docetaxel (60 mg/m(2) by IV infusion over 1 hour) every 3 weeks for up to eight cycles. All patients also received G-CSF. RESULTS: Objective response occurred in 29 (57%) of 51 eligible patients (95% confidence interval [CI], 42% to 70%), including three patients who had a complete response (6%; 95% CI, 1% to 16%). The median response duration was 7 months (95% CI, 6.0 to 15.0 months), median time to treatment failure was 7. 6 months (95% CI, 6.2 to 9.9 months), and the median survival was 27. 5 months (95% CI, 21.5 months to upper limit not reached). The median cumulative doxorubicin dose was 395 mg/m(2) (range, 60 to 480 mg/m(2)). Fifteen patients (28%) were documented to have a decrease in the left ventricular ejection fraction below normal, and three patients (6%; 95% CI, 1% to 15%) developed congestive heart failure. CONCLUSION: Using criteria that we had defined a priori, the doxorubicin-docetaxel regimen as used in this study was sufficiently active and tolerable to justify a phase III comparison with doxorubicin-cyclophosphamide in early-stage breast cancer.

Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study.

PURPOSE: To investigate the response rate, time to treatment failure (TTF), overall survival, and toxicity in patients with metastatic melanoma treated with dacarbazine alone, dacarbazine plus interferon (IFN), dacarbazine plus tamoxifen (TMX), or dacarbazine plus IFN plus TMX. MATERIALS AND METHODS: Two hundred seventy-one patients (258 were eligible) were randomized in a 2 x 2 factorial design to receive one of the above treatments. The trial was designed to detect a 50% improvement in survival with 83% power. RESULTS: Nine complete (CRs) and 18 partial responses (PRs) were observed in the patients who received treatments that contained IFN compared with four CRs and 18 PRs in the patients who received treatments that did not contain IFN. Five CRs and 20 PRs occurred in patients treated with TMX compared with eight CRs and 16 PRs in those treated without TMX. Response differences were nonsignificant. The overall median TTF was 2.6 months, and the overall median survival was 8.9 months. There was no significant difference in TTF or survival among any of the different treatments. Poor performance status (PS), hepatic metastases, and weight loss were significant adverse prognostic factors. Twenty-three patients had a TTF greater than 20 months, and these durable responses were evenly distributed among the treatment arms. Significantly more severe and life-threatening toxic events occurred with treatments that contained IFN. CONCLUSION: Neither IFN, TMX, nor the combination significantly improved the response rate, TTF, or survival when added to dacarbazine, but IFN significantly increased toxicity.

Phase II trial of doxorubicin and paclitaxel plus granulocyte colony-stimulating factor in metastatic breast cancer: an Eastern Cooperative Oncology Group Study.

PURPOSE: Several groups have reported that the combination of doxorubicin plus paclitaxel given as a 3-hour intravenous (IV) infusion for up to eight cycles produces a high response rate (> 80%) and complete response rate (> 20%) in metastatic breast cancer, but is also complicated by a 20% incidence of congestive heart failure (CHF). The purpose of this phase II trial was to evaluate the antineoplastic activity of the regimen in a multi-institutional setting and to reduce the incidence of cardiotoxicity by limiting treatment to a maximum of six cycles. PATIENTS AND METHODS: Fifty-two patients with advanced breast cancer received doxorubicin (60 mg/m(2) by IV injection) followed 15 minutes later by paclitaxel (200 mg/m(2) by IV infusion over 3 hours) every 3 weeks for four to six cycles. RESULTS: Objective responses occurred in 25 of 48 assessable patients (52%; 95% confidence interval [CI], 38% to 66%), including four complete responses (8%; 95% CI, 0% to 16%). The median cumulative doxorubicin dose given was 240 mg/m(2) (range, 132 to 360 mg/m(2)). Eleven patients (21%) were documented as having a decrease in the LVEF below normal, including three patients (6%; 95% CI, 0% to 12%) who developed CHF. CONCLUSION: The doxorubicin/paclitaxel regimen that we used is unlikely to produce an objective response rate of more than 70% and a complete response rate of more than 20% in patients with metastatic breast cancer, and proved to be excessively cardiotoxic for use in the adjuvant setting.

Prognostic value of histologic grade and proliferative activity in axillary node-positive breast cancer: results from the Eastern Cooperative Oncology Group Companion Study, EST 4189.

PURPOSE: The identification of a subset of patients with axillary lymph node-positive breast cancer with an improved prognosis would be clinically useful. We report the prognostic importance of histologic grading and proliferative activity in a cohort of patients with axillary lymph node-positive breast cancer and compare these parameters with other established prognostic factors. PATIENTS AND METHODS: This Eastern Cooperative Oncology Group laboratory companion study (E4189) centered on 560 axillary lymph node-positive patients registered onto one of six eligible clinical protocols. Flow cytometric (ploidy and S-phase fraction [SPF]) and histopathologic analyses (Nottingham Combined Histologic Grade and mitotic index) were performed on paraffin-embedded tissue from 368 patients. RESULTS: Disease recurred in 208 patients; in 161 (77%), within the first 5 years. Mitotic index and grade were associated with both ploidy and SPF (P

Effect of chemotherapy with or without buserelin on serum hormone levels in premenopausal women with breast cancer.

Serial determinations of serum oestradiol (E2), follicle-stimulating hormone (FSH) and luteinising hormone (LH) were done to assess the effect of chemotherapy, with or without a gonadotropin-releasing hormone analogue, buserelin, on ovarian function in 147 premenopausal women treated for breast cancer. Cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) plus buserelin was given to 81 women with metastatic disease, and 66 women were randomised to adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with buserelin or CMF alone. Baseline mean E2 of patients treated with cytostatics plus buserelin fell from premenopausal levels and remained low while patients were on study. E2 levels remained at premenopausal values in patients treated with CMF alone. Downregulation of FSH and LH occurred with cytostatics plus depot buserelin, but fluctuated with the nasal administration; on CMF alone, FSH and LH levels increased. Buserelin plus cytostatics more effectively caused ovarian ablation than cytostatic treatment alone. Depot buserelin was more effective than nasal buserelin.

Current treatment options for malignant melanoma.

The incidence of malignant melanoma has increased at an alarming rate over the past few decades. Indications are that it will continue to rise in the foreseeable future. Primary prevention of malignant melanoma through education of the general public regarding the hazards of sun exposure is important in an attempt to reduce the incidence of the disease in the future. It can, however, be expected to take many years before a decrease in the number of cases of this disease is seen. Until such time, the medical oncologist will be faced with an increasing number of referrals for both adjuvant therapy and treatment of metastatic disease. Many agents have been investigated as possible postsurgical adjuvant therapies in patients with malignant melanoma. To date, inteferon-alpha (IFN-alpha) given initially intravenously in high doses followed by subcutaneous therapy for 1 year, is the only treatment that has been shown to increase disease-free and overall survival in patients with high-risk melanomas. Patients falling into this group should still, wherever possible, be enrolled in prospectively randomised clinical trials. Although the prognosis for patients with metastatic melanoma remains poor, some progress in the management of this disease has been made. It has not yet been conclusively proven that combination chemotherapy yields superior results to single agent dacarbazine (DTIC) [which has for many years formed the cornerstone of therapy]. Immunotherapy involving IFNs and interleukin-2 (IL-2) alone or in combination has yielded similar results to those achieved with chemotherapy alone. The combination of chemotherapy plus immunotherapy appears to hold promise, with high response rates and often durable remissions reported, albeit at the expense of considerable treatment-related toxicity. Novel therapies including tumour vaccines and gene therapy also hold promise for the future management of this disease.

Postmenopausal breast cancer. Drug therapy in the 1990s.

In summarising current drug treatment strategies for postmenopausal women with breast cancer, it is essential to emphasise that we are dealing with a group of diseases that are treatable, and that appropriate treatment decisions will give longer disease-free intervals for patients with early breast cancer, and better control with better survival for patients with advanced (i.e. locally advanced and/or metastatic) disease. Women greater than 65 years of age have a predictably better response to hormone treatment versus women less than 65 years of age. Hormone treatment may, therefore, be considered as primary treatment or as adjuvant treatment after limited surgery. Hormone treatment is also the treatment of first choice for elderly patients with advanced disease. For middle-aged women (45 to 65 years of age), various patient factors are important in predicting the value of treatment. Estrogen receptor (ER) status is prognostic of survival irrespective of treatment. Patients with ER-positive disease have a better prognosis than those with ER-negative disease, both in the adjuvant setting and in the face of metastatic disease. This is because ER-positive tumours tend to grow slower. The availability of the serotonin type 3 (5-hydroxytryptamine;5-HT3) antagonists, which effectively control nausea and vomiting in most patients, make chemotherapy combinations more acceptable, and combination chemotherapy can more readily be considered as first treatment option both as adjuvant treatment and for treatment of advanced disease. For patients with organ metastases there is no doubt that combined chemotherapy treatment is indicated.

Fludarabine: a phase II trial in patients with previously treated low-grade lymphoma.

The aim of the study was to investigate the therapeutic activity of Fludarabine in patients with low-grade non-Hodgkin's lymphoma (LG-NHL) no longer responding to standard treatment. In this Phase II study patients were treated with Fludarabine 25 mg/m2 intravenously daily for 5 days repeated at 28-day intervals. Twenty-two patients with LG-NHL, no longer responding to standard treatment, were entered in the study. Among twenty-one evaluable patients, seven had a complete and six a partial response. The median time to treatment failure and survival time are 4.6 months and >28.0 months, respectively. The most important toxicity was hemogram suppression, which was usually manageable but occasionally severe. Fludarabine is not only an active agent with definite therapeutic value in patients with treatment-resistant LG-NHL, but effective and well tolerated in patients no longer responding to standard treatment.

Extended survival in 80 patients with operable, locoregionally recurrent breast cancer treated with chemotherapy.

Locoregional recurrence is a harbinger of disseminated disease, and historically the estimated 5-year survival when treated with local therapy only varies between 21% and 37%. The role of systemic treatment after local treatment is unclear at present. The authors investigated the results of systemic chemotherapy for these patients after complete local surgical resection. Data on 80 patients were evaluable for toxicity, time to treatment failure (TTF), and survival. Sixty-four patients received doxorubicin-based treatments, four received methotrexate-based combinations, and 12 received tamoxifen only. Among the 68 patients treated with cytostatics, there were two possible treatment-related deaths. Two patients developed grade 3 neutropenia, four developed grade 3 vomiting, and 42 had grade 2 toxicity. The 2- and 5-year disease free survival at a mean follow-up period of 5.5 years were 56% and 38%, respectively. The projected median TTF was 32 months (95% confidence interval, 23-82). Two- and 5-year overall survival were 86% and 62%, respectively, with a projected median survival of 93 months (7.75 years; 95% confidence interval, 64-177). These results show systemic therapy improved TTF and survival for patients with stage IV, no-evidence-of-disease breast cancer. Randomized studies are needed to confirm these findings and define optimal therapy.

High-dose medroxyprogesterone acetate plus mitomycin-C or vindesine in the treatment of advanced breast cancer.

Forty women with metastatic breast cancer were randomized to receive either mitomycin-C (MMC) (21 patients) or vindesine (19 patients) with high dose medroxyprogesterone acetate (MPA). Response rates were not significantly different (33% for MPA and MMC and 28% for MPA and vindesine); the duration of response was better for patients receiving the MMC combination (median of 10.5 months versus 6 months for those on the vindesine combination).

A randomized trial of mitomycin-C (M) versus mitomycin-C plus high-dose medroxyprogesterone acetate (MMPA) in the treatment of patients with advanced breast cancer.

Seventy-six women with previously treated breast cancer were randomized to receive mitomycin (M) or M plus high-dose oral medroxyprogesterone acetate (MMPA). Patients were balanced with respect to age, performance status, hormone receptor status, previous treatment, and number of metastatic sites. There were more patients with visceral metastases in the M arm of the study. Side effects were tolerable and not significantly different for the two regimens. No life-threatening toxicity occurred. Objective response was documented in 4 of 37 patients on M and 11 of 39 on MMPA. On M the median time to treatment failure (TTF) was 3 months, and median survival was 7.8 months. On MMPA the median TTF was 4.4 months, and median survival was 9.7 months. There was a tendency for higher response and longer TTF and survival on MMPA, but statistical significance was not reached (p = 0.09).

Treatment of squamous cell esophageal cancer with topotecan: an Eastern Cooperative Oncology Group Study (E2293).

Seventeen patients with enhanced measurable squamous cell carcinoma of the esophagus were treated with topotecan 1.5 mg/m2 daily for 5 days repeated every 21 days. Toxicity was severe, with 1 death from myelotoxicity and 10 patients with life-threatening myelotoxicity. Severe gastrointestinal toxicity consisting of vomiting was also seen in three patients. No response was seen in any of the patients in the study. Topotecan given in this manner has no activity in squamous cell carcinoma of the esophagus.

A randomized study of radiotherapy alone versus radiotherapy plus 5-fluorouracil and platinum in patients with inoperable, locally advanced squamous cancer of the esophagus.

Squamous cell cancer of the esophagus is the most common cancer among black South African males, and 60% of patients present with localized inoperable disease. Combined chemoradiotherapy has been reported to be superior to radiotherapy alone for localized inoperable esophageal cancer in North American patients. A study was carried out to determine if this was also applicable to South African patients, who present with more advanced disease. From September 1991 through June 1995, 70 patients with locally advanced (T3N0-1M0) squamous cancer of the esophagus were prospectively randomized to receive radiotherapy alone or radiotherapy combined with cisplatin and 5-fluorouracil. There was no statistically significant survival difference between the two groups. The median survival was 144 days in the group receiving radiotherapy alone, and 170 days in the group receiving radiotherapy combined with chemotherapy (p = 0.42). The degree of weight loss before initiation of therapy had a significant effect on survival regardless of the treatment arm. Radiotherapy in combination with chemotherapy, as administered in this study for South African patients with locally advanced, inoperable squamous cancer of the esophagus, is no better than radiotherapy alone.

21-day oral etoposide for metastatic breast cancer: a phase II study and review of the literature.

Previous studies of etoposide for metastatic breast cancer commonly used bolus regimens given over a short period of time and included heavily pretreated patients. Results were poor. Chronic oral regimens would be expected to be superior to bolus doses based on pharmacologic studies and patients with less previous chemotherapy would be expected to have higher response rates. We studied the efficacy of oral etoposide at a dose of 50 mg/m2/day for 21 days of a 28-day cycle in good-risk patients with metastatic breast cancer. Healthy patients (Eastern Cooperative Oncology Group performance status 0, 1, or 2) who had not received chemotherapy for at least 1 year before study entry were selected for therapy. Thirty-four patients were entered; three patients were ineligible and one was cancelled. Thirty patients were available for analysis of response. One complete response and eight partial responses were documented (response rate, 30%; 95% confidence interval, 15-49%). A higher response rate was observed in those patients who never received chemotherapy compared with those who had received prior chemotherapy (57 vs. 6%, p = 0.004). There were two treatment-related deaths, both owing to myelosuppression and infection. We found long-term administration of oral etoposide to have a reasonable response rate for metastatic breast cancer (30%). Our response rate was comparable to those of other published studies of long-term oral etoposide regimens for metastatic breast cancer. Response rates in single-arm studies have generally been higher for long-term oral regimens than those for bolus regimens. We also found the regimen to be significantly toxic, an observation that may be underemphasized in the earlier literature.

Experience with interferon alpha 2b combined with dacarbazine in the treatment of metastatic malignant melanoma.

A prospectively randomized trial was undertaken to compare dacarbazine (DTIC) alone with DTIC plus interferon in patients with metastatic malignant melanoma. Of the 73 patients who entered on the study, 36 were randomized to receive DTIC alone and 37 were randomized to receive the combination DTIC plus interferon. The two sections were well balanced. There was more toxicity on the combination section, but no life threatening toxicity. The overall response rate for patients on DTIC was 20% (two complete and five partial responses) (95% CI 7-39%) and for patients on DTIC plus interferon was 50% (13 complete and four partial responses) (95% CI 26-72%) (p = 0.007). The median time to treatment failure, was significantly more in favour of the combination treatment (9 versus 2.5 months; p < 0.01, Mantel-Cox). The median survival of 16.7 versus 8 months was in favor of the combination treatment (p < 0.01). The reasons for the improved results with the combination treatment are discussed. The Eastern Cooperative Oncology Group is currently, based on the results of this study, investigating the role of interferon combinations in metastatic malignant melanoma.