Monthly docetaxel and weekly gemcitabine in metastatic breast cancer: a phase II trial.

BACKGROUND: Docetaxel and gemcitabine are active against breast cancer. The purpose of this phase II study was to evaluate the efficacy and safety of monthly docetaxel combined with weekly gemcitabine in patients with chemotherapy-pretreated metastatic breast cancer. PATIENTS AND METHODS: Thirty-nine patients were enrolled, of whom thirty had received prior chemotherapy in the adjuvant setting, seven for metastatic disease, and two for both, including prior anthracycline in 33 patients. Treatment was gemcitabine 800 mg/m2 days 1, 8, 15 and docetaxel 100 mg/M2 on day 1, with cycles repeated every four weeks. RESULTS: Response rate was 79% (95% confidence interval (CI): 63%-91%), with 2 complete and 29 partial responses. Twenty-five of the responders remained progression-free for more than six months. Median survival was 24.5 months. Delivered dose intensity of gemcitabine was lower than expected (63% of planned). The predominant hematologic toxicity was grade 4 neutropenia in 36 patients, complicated by fever in three patients. With the exception of asthenia, severe non-hematological toxicities were infrequent. CONCLUSIONS: Monthly docetaxel, combined with weekly gemcitabine, has significant but manageable hematologic toxicity. Despite frequent dose adjustments, this doublet is very active in metastatic breast cancer, producing a high proportion of durable responses associated with favorable survival.

Evaluation of gemcitabine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Southwest Oncology Group phase II study.

A phase II trial of gemcitabine (Gemzar), a nucleoside analogue with broad activity in solid tumors, was performed in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. A total of 26 eligible patients were registered to receive a dose of 1250 mg/m2 weekly for 3 weeks, followed by a 1 week rest. Toxicity was evaluable in 26 patients. Nausea and vomiting occured in 11 and 6 patients, repectively. Grade 3 or 4 hematologic toxicities were infrequent. Two patients developed neutropenic infections. One patient developed fatal liver failure which was thought due to progressive liver metastases or infection 14 days after a single dose of gemcitabine. There were no objective treatment responses (95% CI 0-13%), with a median survival of 6 months in this highly resistant disease population. Gemcitabine is not considered active enough as monotherapy for further evaluation in this disease population.

Second-line chemotherapy for non-small-cell lung cancer with monthly docetaxel and weekly gemcitabine: a phase II trial.

BACKGROUND: Docetaxel and gemcitabine are active against chemotherapy-pretreated non-small-cell lung cancer (NSCLC). The purpose of this phase II study was to evaluate the efficacy and safety of monthly docetaxel combined with weekly gemcitabine in NSCLC patients failing one prior regimen. PATIENTS AND METHODS: Forty patients were enrolled. Prior chemotherapy was a platinum-based combination in 36 patients, using vinorelbine in 26 patients and etoposide in 10 patients. The other four patients had prior single agents. Tumors were refractory or resistant to front-line therapy in 80% of patients. Treatment was gemcitabine 800 mg/m2 days 1, 8, 15 and docetaxel 100 mg/m2 day 1, with cycles repeated every four weeks. RESULTS: Thirteen patients responded (32.5%; 95% confidence interval (CI): 19%-49%), including one complete and 12 partial responses. Responses were observed at all metastatic sites, with similar response frequencies in platinum-sensitive and platinum-resistant/refractory tumors. The median time to progression for responders was nine months, with two responses lasting longer than a year. Median survival was 8.1 months. Hematologic toxicities included grade 4 neutropenia in 23 patients, with 4 episodes of febrile neutropenia, grade 3-4 thrombocytopenia in 9 patients, and anemia requiring red cell transfusions in 9 patients. With the exception of asthenia, severe non-hematologic toxicities were infrequent. CONCLUSIONS: Monthly docetaxel, combined with weekly gemcitabine, is an active and safe second-line therapy for NSCLC patients.

A phase II trial of topotecan in esophageal carcinoma: a Southwest Oncology Group study (SWOG 9339).

BACKGROUND: Chemotherapeutic treatments containing topoisomerase I inhibitors have shown antitumor activity against a number of solid tumors. Responses have been seen in Phase I trials using topotecan in ovarian, lung, and esophageal cancer. A phase II trial using continuous infusion topotecan was completed to assess activity in esophagus cancer. METHODS: Forty-five eligible patients with locally-advanced or metastatic squamous cell carcinoma or adenocarcinoma of the esophagus received a regimen consisting of 24-hour continuous infusion topotecan at 1.5 mg/m2/day on Days 1, 8, 15, 22 (of 42-day cycle). Patients continued on treatment until evidence of disease progression or unacceptable toxicity. RESULTS: Partial response was demonstrated in 1 patient (2% confirmed response rate). Thirty-six patients progressed during the first cycle of treatment. The median survival was 3 months, and the median progression-free survival was 1 month. Toxicity was mild with only one Grade 4 toxicity reported. CONCLUSIONS: This phase II trial indicates no significant anti-neoplastic activity for topotecan administered in the dose and schedule to patients with squamous cell or adenocarcinoma of the esophagus.

A phase II study of 9-aminocamptothecin in patients with refractory breast cancer.

We evaluated 9-aminocamptothecin (9-AC) in patients with metastatic or locally recurrent breast cancer who were no longer responsive to standard therapy. Patients were treated with 9-AC with a 72-hr continuous infusion given at a dose of 45 micrograms/m2/hr every 2 weeks. Granulocyte colony-stimulating factor 5 micrograms/kg was given subcutaneously for 7-10 days after completion of the treatment. Eighteen patients were treated, with all patients assessable for toxicity and 15 patients assessable for response. There were two partial responses seen in the 15 patients lasting 3.5 and 5 months, respectively. The major toxicity seen was myelosuppression, with 12 patients having grade 3 or greater granulocytopenia with four episodes of significant infectious complications. In addition, significant thrombocytopenia was seen in 14 patients. The other complications commonly seen were nausea and vomiting and alopecia. 9-AC given as a 3-day continuous infusion has limited activity in previously treated metastatic and locally recurrent breast cancer.

Phase II study of edatrexate in advanced head and neck cancer. A Southwest Oncology Group study.

Fifty-two patients with persistent, recurrent and/or metastatic squamous cell cancer of the head and neck were treated with weekly edatrexate, 80 mg/m2. Nine patients had received previous adjuvant or neoadjuvant chemotherapy. Of the 46 eligible patients, two complete responses and one partial response were observed (6%, 95% confidence interval of 1-18%). The most common toxicities were myelosuppression and mucositis, but dermatologic toxicity was also observed in 25% of patients. Edatrexate appears to have limited activity in advanced head and neck cancer.

Treatment of metastatic renal cell carcinoma with recombinant interleukin-2 in combination with vinblastine or lymphokine-activated killer cells.

Fifty patients with metastatic renal cell carcinoma were treated with recombinant interleukin-2 alone or in combination with the antitumor drug vinblastine or lymphokine-activated killer cells. Of 34 evaluable patients treated with intravenous bolus interleukin-2, 1 (3%) had a partial response. Vinblastine increased myelotoxicity but did not enhance response to interleukin-2 in 15 of these patients. Two partial responses were observed among 15 patients treated with lymphokine-activated killer cells in addition to interleukin-2. In 1 patient biopsy documented complete resolution of hepatic metastases lasting for 1 year was observed. All responders had undergone previous nephrectomy and none had multiple sites of metastatic disease. Toxicity was significant and caused termination of therapy in 40% of the patients. Biological therapy using interleukin-2 can result in prolonged responses in renal cell cancer but future trials should be directed at lessening toxicity.

A phase II study of chemotherapy of metastatic colorectal carcinoma with 5-fluorouracil plus cisplatin. A Southwest Oncology Group study.

The combination of 5-fluorouracil and cisplatin has shown encouraging results in single institution pilot studies in colorectal carcinoma. This phase II SWOG study was undertaken to further evaluate this treatment. Cisplatin was administered at a dose of 60 mg/M2 IV day 1, repeated every 21 days. 5-FU was given at a dose of 15 mg/Kg IV days 1, 8, and 15, with cycles repeated every 21 days. Among 47 eligible patients there were no complete responses and only three partial responses for an overall response rate of 6% with a 95% confidence interval of 1% to 18%. Seventeen patients (36%) had stable disease/no response and 22 (47%) progressed. Five patients (10%) had no evaluation and were assumed to have had no response, or were early deaths. Median survival was 9.1 months. Significant hematologic toxicity was seen with grade 3 leukopenia occurring in 11 patients. There were felt to be two deaths definitely related to treatment and two additional deaths possibly treatment related. The combination of 5-FU and cisplatin used in this dose and schedule is an ineffective and toxic regimen for treatment of colorectal carcinoma.

Prognostic factors in multiple myeloma.

The pretreatment characteristics of 265 multiple myeloma patients treated between 1977 and 1983 were evaluated as potential prognostic factors for survival. Patients whose diagnosis was based on bone marrow plasmacytosis (greater than 30%) were noticed to have poorer survival (P less than 0.001). Although classification of patients according to stage has traditionally been used to identify prognostic groups, differences in survival were noted only between Stage III and Stage I or II patients using one of two common staging systems. Multivariate analysis using Cox's proportional hazards model identified the following prognostic factors in order of importance: plasmacytosis (hazard ratio [HR] = 2.2, 95% confidence interval [CI] = 1.49 to 3.27), hypercalcemia (HR = 1.68, CI = 1.22 to 2.32), hypoalbuminemia (HR = 1.51, CI = 1.15 to 1.99), alkaline phosphatase (HR = 1.62, CI = 1.18 to 2.23), hyperuricemia (HR = 1.46, CI = 1.09 to 1.96), and renal insufficiency (HR = 1.48, CI = 1.08 to 2.04). All patients were followed from 2 to 7.5 years and 130 (49%) survived over 2 years. Logistic regression analysis demonstrated that hyperuricemia, hypoalbuminemia, renal insufficiency, plasmacytosis, gender, alkaline phosphatase, and hypercalcemia were significant predictors of 2-year survival. Knowledge of these factors could be of value in predicting prognosis and planning therapy in patients with multiple myeloma.

Synergistic effects of vinblastine and recombinant interferon-beta on renal tumor cell lines.

Potential synergistic interactions between vinblastine (VBL) and recombinant interferon-beta (rIFN-beta) were assessed using median effect analysis. Calculation of the combination index demonstrated values less than 1 (indicating synergy) over a wide range of drug-induced growth inhibition for each of four different renal carcinoma cell lines (RCC). The degree of synergy observed could not be predicted from the morphology, doubling time, or relative sensitivity of the RCC lines to VBL and rIFN-beta. The optimal ratio of VBL to rIFN-beta in the combination appeared to be close to the ratio of the concentrations of each agent which yielded a 50% inhibition of growth. Although simultaneous presence of VBL and rIFN-beta in the culture medium was not required to demonstrate a synergistic effect, the minimum exposure time for rIFN-beta was determined to be 7 days. The uptake but not the egress of tritiated VBL into RCC cells was enhanced after growth for 4 days in 2.25 ng/ml of rIFN-beta. Median effect analysis can be shown to be independent of the mechanism of action of VBL and rIFN-beta and gives an indication of potential synergistic interactions over a wide range of drug effects. This method may prove useful in the selection of combinations of IFNs and antitumor drugs for clinical study.

Concurrent chemotherapy/radiotherapy for limited small-cell lung carcinoma: a Southwest Oncology Group Study.

The Southwest Oncology Group (SWOG) has conducted a phase II study to explore the efficacy and toxicity of initial, concurrent use of radiation therapy with cisplatin, etoposide (VP-16), and vincristine in limited-stage small-cell carcinoma of the lung. Two courses of cisplatin, VP-16, and vincristine chemotherapy were given with concurrent radiotherapy (XRT) to the primary tumor to a total dose of 4,500 cGy. Elective brain XRT was given to all patients concurrent with a third course of cisplatin/VP-16 therapy. Consolidation chemotherapy consisting of vincristine, methotrexate, and VP-16 alternating with Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) and cyclophosphamide, was given for 12 weeks following the initial induction chemotherapy/XRT program. Patients with a complete response had all therapy discontinued. Among 154 eligible patients treated, the complete response rate was 56%, with a partial response rate of 27%. The median survival is 17.5 months with an estimated 30% survival rate at 4 years from initiation of treatment. Combined modality toxicities were acceptable with the predominant toxicity being moderate to severe leukopenia and mild radiation esophagitis. The results of this treatment program appear superior to any previously reported by our group and compare favorably to those in the literature at large.

Effect of interferon alpha, interferon beta, and interferon gamma on the in vitro growth of human renal adenocarcinoma cells.

Interferon-alpha, interferon-beta, and interferon-gamma differ in their antiproliferative effects for several cell lines. Interferons were thus assessed for their activity in inhibiting proliferation of three renal cell carcinoma cell lines. The malignant epithelial phenotype of each of these cell lines was confirmed by electron microscopy, histology, karyotype and tumorigenicity. When compared on an anti-viral unit basis, naturally produced interferon-beta was more effective than natural interferon-alpha for all cell lines and clones. Proliferation of each of the cell lines was inhibited by interferon-gamma. In all cases, removal of interferons from culture media resulted in resumption of the rate of cell growth after a variable delay of 6-10 days. If the antiproliferative effects of interferons predominate in mediating tumor regression, clinical response may depend upon the type of interferon to which the tumor is exposed.

Pulmonary toxicity induced by mitomycin C is highly responsive to glucocorticoids.

The authors have studied five cases of biopsy-proven pulmonary toxicity caused by the administration of mitomycin C (M), vincristine, and cisplatin in 64 patients with advanced non-small cell lung cancer. The clinical triad of progressive dyspnea, rales, and pulmonary infiltrates presented in all five cases. In addition, pulmonary function tests showed hypoxemia (four/five), reduced forced vital capacity (three/four), total lung capacity (two/three), and forced expiratory volume (FEV1) (three/four) and very profound reduction in diffusion capacity (three/three). Transbronchial biopsy for tissue examination was necessary to rule out other causes. Characteristics but nonspecific pathologic changes were documented in all five cases. All the patients responded quickly and dramatically to high-dose glucocorticoids with improvement of hypoxia, dyspnea, exercise tolerance, and sense of well being. In three patients the pulmonary infiltrates cleared. However, abrupt stopping or early withdrawal of steroid resulted in aggravation of dyspnea and pulmonary infiltrate in three cases who improved subsequently with escalation of steroid doses. The authors conclude that the treatment of choice for pulmonary toxicity induced by M or M-containing chemotherapy regimens is a high dose of glucocorticoid and discontinuation of M at once when suspicion is raised.

Phase II evaluation of a combination of mitomycin C, vincristine, and cisplatin in advanced non-small cell lung cancer.

The combination treatment of mitomycin C (M), vincristine (V), and cisplatin (P) (MVP) in 63 patients with advanced non-small cell lung cancer (NSCLC) were evaluated for their potential synergistic cytotoxicity. The overall response rate was 43% (27/63); in the 54 eligible and evaluable patients, the response rate was 50% (27/54). Responses were observed in all cell types and disease sites. Cell type; performance status of 0, 1, or 2; sex; and age younger or older than 60 years did not significantly influence the response rate. However, patients with prior radiation had significantly more treatment failure than those without. The dose-limiting side effects in these 54 patients were myelosuppression (40%), pulmonary fibrosis (9%), peripheral neuropathy (6%), and intractable nausea and vomiting (4%). The degree of leukopenia (P less than 0.01) but not of thrombocytopenia increased significantly in patients who had received prior radiotherapy. One patient died of marked thrombocytopenia and one of fulminant hepatitis. Patients who responded lived significantly longer than those who did not (P less than 0.004). A majority of the responders (82%) also achieved symptomatic palliation. With appropriate dose modification and supportive care, MVP was tolerable. Further trials with this regimen or a modified version are worth consideration.

Chemotherapy-induced remission in a patient with small cell carcinoma of the lung and hairy cell leukemia.

Small cell carcinoma of the lung developed in a patient with previously diagnosed hairy cell leukemia. Treatment with aggressive chemotherapy resulted in a complete response in both diseases lasting 13 months. Recurrence of the leukemia did not occur. This case demonstrates that hairy cell leukemia may be responsive to combination regimens.