A randomized, phase III multicenter trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin in patients with advanced or metastatic non-small-cell lung cancer.

BACKGROUND: Paclitaxel-carboplatin is used as the standard regimen for patients with advanced or metastatic non-small-cell lung cancer (NSCLC). This trial was designed to compare gemcitabine + carboplatin or gemcitabine + paclitaxel to the standard regimen. PATIENTS AND METHODS: A total of 1135 chemonaive patients with stage IIIB or IV NSCLC were randomly allocated to receive gemcitabine 1000 mg/m(2) on days 1 and 8 plus carboplatin area under the concentration-time curve (AUC) 5.5 on day 1 (GC), gemcitabine 1000 mg/m(2) on days 1 and 8 plus paclitaxel 200 mg/m(2) on day 1 (GP), or paclitaxel 225 mg/m(2) plus carboplatin AUC 6.0 on day 1 (PC). Stratification was based on disease stage, baseline weight loss, and presence or absence of brain metastases. Cycles were repeated every 21 days for up to six cycles or disease progression. RESULTS: Median survival (months) with GC was 7.9 compared with 8.5 for GP and 8.7 for PC. Response rates (RRs) were as follows: GC, 25.3%; GP, 32.1%; and PC, 29.8%. The GC arm was associated with a greater incidence of grade 3 or 4 hematologic events but a lower rate of neurotoxicity and alopecia when compared with GP and PC. CONCLUSIONS: Non-platinum and non-paclitaxel gemcitabine-containing doublets demonstrate similar overall survival and RR compared with the standard PC regimen. However, the treatment arms had distinct toxicity profiles.

Long-term survival results for patients with locally advanced, initially unresectable non-small cell lung cancer treated with aggressive concurrent chemoradiation.

PURPOSE: Patients with locally advanced, initially unresectable non-small cell lung cancer (NSCLC) have a median survival time of 9 to 11 months, a 2-year survival rate of 13%, and a long-term survival rate of 5% to 7% when treated with radical thoracic radiation alone. Because of the preclinical radiosensitizing capabilities of 5-fluorouracil and cisplatin and the therapeutic synergy of etoposide and cisplatin, we combined these agents with full-dose radical thoracic radiation to determine the feasibility and efficacy of this approach in locally advanced NSCLC. METHODS: Patients with clinical stage IIIb and bulky IIIa NSCLC and ECOG performance status 0 or 1 received 5-fluorouracil infusion (640-800 mg/m2/d CVI days 1-5, 29-34), cisplatin (20 mg/m2/d, days 1-5, 29-34), etoposide (50 mg/m2, days 1, 3, 5, 29, 31, 33) and concurrent thoracic radiation (60 Gy/2 Gy/d/30 Fx). Patients with adequate cytoreduction proceeded to surgical resection. RESULTS: From March 1987 to July 1990, 41 patients were enrolled on study; 40 are evaluable. The objective response rate was 90%. Thirteen patients (39%), five with clinical stage IIIb disease and eight with IIIa disease, underwent thoracotomy and resection; three proved to have pathological complete remissions. Ten of 77 chemotherapy courses were complicated by neutropenic fever. Grade 3 or 4 esophagitis occurred in 21 patients (52%). Cardiac ischemia or infarction occurred in two patients (5%). There were seven deaths in the first 6 months in the absence of disease progression. Two-year survival was 38%, 3-year survival 25%, and 4- to 5-year survival 18%. Six patients (15%) remain alive at the median follow-up time of 66 months (range, 64-84). CONCLUSIONS: Despite substantial early morbidity and mortality, concurrent, aggressive chemoradiation produced a long-term survival rate in locally advanced NSCLC comparable to other combined modality approaches. However toxicity, particularly esophagitis and postoperative complications, preclude the use of this regimen in phase III studies. Combined modality approaches for locally advanced, initially unresectable NSCLC have become standard; research must simultaneously focus on ways to enhance efficacy and reduce toxicity.

Phase I trial of recombinant macrophage colony-stimulating factor and recombinant gamma-interferon: toxicity, monocytosis, and clinical effects.

Macrophage colony-stimulating factor (M-CSF) is a known inducer of proliferation and differentiation of cells of the mononuclear phagocyte lineage, and gamma-interferon (gamma-IFN) is a known activator of mononuclear phagocytes. In this Phase I clinical trial of combined therapy with M-CSF and gamma-IFN, 36 patients were treated with 14-day continuous infusions of M-CSF at doses ranging from 10 to 140 micrograms/kg/day. In all but five patients, gamma-IFN was administered by daily s.c. injection on days 8-14 of the M-CSF infusion at doses of 0.05 or 0.1 mg/m2/day. A total of 73 courses of M-CSF and 66 courses of gamma-IFN were administered. The maximally tolerated dose combination was 120 micrograms/kg/day M-CSF, 0.1 mg/m2/day gamma-IFN. The addition of gamma-IFN did not alter the maximally tolerated dose of M-CSF therapy, although some additional toxicities were noted with combined therapy. At the 140-micrograms/kg/day M-CSF dose level, grade 4 thrombocytopenia occurred in 2 of 3 patients, with a median platelet count nadir of 26,000/mm3 after 7-10 days of M-CSF infusion. At this dose level, there was one reversible grade 3 hepatic toxicity, and one grade 3 exacerbation of underlying chronic obstructive lung disease. Peripheral blood monocytosis was observed at all M-CSF dose levels exceeding 40 micrograms/kg/day, approaching 3-fold elevations at the 100-micrograms/kg/day M-CSF dose level. The induction of monocytosis was correlated with the development of thrombocytopenia. At the conclusion of therapy with 100 micrograms/kg/day M-CSF, 0.1 mg/m2/day gamma-IFN, 78% of peripheral blood monocytes expressed the low affinity Fc gamma receptor for aggregated immunoglobulin, Fc gamma RIII (CD16), and CD14 was expressed by only 36% of the cells. This phenotype has been shown previously to be associated with cellular activation. In contrast, 35% of monocytes from patients treated with M-CSF therapy alone at the same dose expressed CD16 and 88% expressed CD14. A partial clinical response was noted in a patient with metastatic renal cell carcinoma, and minor clinical responses were observed in patients with a diffuse/follicular lymphoma, metastatic renal cell carcinoma, and metastatic thymoma. At M-CSF doses exceeding 20 micrograms/kg/day within the maximally tolerated dose range, gamma-IFN did not modulate the ability of M-CSF to reliably induce peripheral blood monocytosis. This study shows that M-CSF and gamma-IFN therapy induces the proliferation and differentiation of circulating mononuclear phagocytes.

Phase II study of low-dose mitomycin in patients with ovarian cancer previously treated with chemotherapy.

Forty-three evaluable patients with ovarian cancer who had failed one or more chemotherapy regimens were treated with mitomycin iv at 28-day intervals. Thirty-six patients with good bone marrow reserve received 10 mg/m2 and seven patients with poor bone marrow reserve received 6.7 mg/m2 initially. Ten patients (23%) responded. Patients with an Eastern Cooperative Oncology Group performance status of 0-1 had better response rates and survivals as compared to patients with a performance status of 2-4 (44% vs 8%; median survival, 8 vs 4 months). The acute hematologic and gastrointestinal toxicity was minimal. No patients developed pulmonary, renal, cardiovascular, or local tissue toxicity.

Phase II study of mitolactol in chemotherapy-refractory metastatic breast cancer.

Thirty-eight evaluable patients with metastatic breast cancer refractory to hormonal therapy and multiple chemotherapy regimens were treated with mitolactol at a dose of 130 mg/m2/day orally for 10 days every 6 weeks. Only one patient, with nodal and chest wall metastases, had a sustained complete regression; two patients had stable disease; and 35 patients had disease progression. The toxicity, which was primarily hematologic, was acceptable.

An effective low-dose mitomycin regimen for hormonal- and chemotherapy-refractory patients with metastatic breast cancer.

Ninety evaluable metastatic breast cancer patients refractory to hormonal therapy and combinations of cyclophosphamide, methotrexate, 5-fluorouracil, and doxorubicin were treated with a low-dose mitomycin regimen, i.e., 10 mg/m2 intravenously every 28 days. In order to minimize thrombocytopenia, dose de-escalations related to platelet counts were made. One patient (1%) had a complete response and 17% had partial responses for a median duration of 4 months. The time to progression for the responders and stabilized patients was similar; however, the responders and stabilized patients lived significantly longer than did the progressors. Hematologic toxicity was minimized because of planned de-escalations in mitomycin dosage. Perivenous ulceration, both immediate and delayed (8%), congestive heart failure (2%), and heart-renal failure with malignant hypertension (2%) resulted in significant morbidity, including two drug-related deaths. Although mitomycin dosages were successfully titrated according to platelet counts in this group of chemotherapy-refractory patients, prolonged use of this drug in adjuvant or early metastatic breast cancer patients is not recommended because of potentially irreversible thrombocytopenia.

Upper hemibody and local chest irradiation as consolidation following response to high-dose induction chemotherapy for small cell bronchogenic carcinoma--a pilot study.

Encouraging results of the combination of upper hemibody irradiation (UHBI) and local chest irradiation (LCI) combined withh standard-dose chemotherapy in patients with extensive small cell bronchogenic carcinoma led us to a second pilot study utilizing the same radiation program combined wit high-dose induction chemotherapy. Fourteen patients with small cell bronchogenic carcinoma, five with extensive disease and nine with localized disease, were treated with cyclophosphamide (1.5 g/m2 iv, Days 1 and 22), lomustine (70 mg/m2 orally, Day 1), and methotrexate (15 mg/m2 twice weekly during Weeks 2, 3, 5, and 6). UHBI (600 rads) was given during Week 6 in a single dose and LCI was given during Week 7 (2000 rads/five fractions) to the tumor and mediastinum. Maintenance chemotherapy began in Week 12 with cyclophosphamide (700 mg/m2 iv every 3 weeks) and lomustine (70 mg/m2 orally every 6 weeks). Twelve patients were evaluable for response and toxicity (eight with limited disease). There were three complete response and seven partial responses after induction chemotherapy. After completion of the consolidation radiation therapy, all 12 patients had a response: six complete responses and six partial responses. Acute toxic effects included nausea and vomiting in eight patients, fever in five, and hypotension and angina in one. Subacute toxic effects included nausea, vomiting, and dehydration in two patients who required hospitalization, prolonged aplasia in one, reversible radiation esophagitis in three. Three patients had radiation pneumonitis including one with bilateral diffuse disease that led to death from respiratory failure. Only two of 12 patients received their maintenance therapy on schedule. Treatment failures occurred within the LCI field in seven patients and in distant metastatic sites in six. The median time to first relapse was 7 months and the median survival was 9 months. Because of toxicity, treatment delays, and poor survival in this group of patients, we cannot recommend this combined modality approach.

Effective control of cisplatin-induced nausea using high-dose steroids and droperidol.

Seventy-three consecutive patients receiving cisplatin-containing chemotherapy regimens were treated with an initial dose of chlorpromazine (25 mg im), droperidol (1 mg iv, then 1 mg sc every 4 hours), and methylprednisolone (250 mg every 4 hours for four doses). Twenty patients received a combination chemotherapy protocol that included cisplatin at a dose of 40 mg/m2 iv (group 1) and 53 patients received a protocol that included cisplatin at a dose of 120 mg/m2 iv (group 2). The median age of all the patients was 58 years. Seventy-five percent of the patients in group 1 and 45% of those in group 2 had no vomiting at all; the remainder had limited and tolerable vomiting. These results in a group of elderly patients compare favorably with trials of other antiemetic programs.

Randomized clinical trial of tamoxifen plus sequential CMF chemotherapy versus tamoxifen alone in postmenopausal women with advanced breast cancer.

Eighty-eight postmenopausal women with metastatic breast cancer, in whom estrogen receptors (ER) were positive or unknown, were treated on a controlled trial to determine the effectiveness of tamoxifen and to assess the therapeutic advantage of sequentially adding low-dose cyclophosphamide-methotrexate-5-fluorouracil (CMF) chemotherapy in tamoxifen responders. Patients with known ER negative status were not studied. After the initial 12-week treatment with tamoxifen alone, 60% of ER positive patients achieved complete or partial response as did 35% in whom ER were unknown. Response status further improved in 18% randomized to continue tamoxifen alone vs 31% in whom CMF was added to tamoxifen. There were no statistically significant differences in time to the development of progressive disease or survival between the ER positive and ER unknown patients or between the tamoxifen and tamoxifen plus CMF groups. We conclude that inability to determine ER status should not prejudice against the use of tamoxifen in postmenopausal patients with advanced breast cancer. No benefit has been demonstrated from the addition of CMF chemotherapy in tamoxifen responders.

Phase III study of ICRF-159 versus 5-FU in the treatment of advanced metastatic colorectal carcinoma.

Thirty-seven previously untreated patients with advanced metastatic colorectal carcinoma were treated in a prospective randomized fashion with either ICRF-159 or 5-FU. The ICRF-159 was administered orally at a dose of 1 g/m2/day for 3 consecutive days every 3 weeks, and the 5-FU was given iv at a dose of 450 mg/m2/day for 5 days every 5 weeks. All patients were evaluated for response and toxic effects after two courses of treatment. All those who failed to meet the criteria for objective response with either a complete remission or a partial response received the other drug in a crossover fashion. Three of the 18 patients (16%) initially treated with 5-FU achieved a partial response while none of the 19 patients initially treated with ICRF-159 achieved a complete or partial response. Nine prior 5-FU-treated patients were crossed over to ICRF-159 and 14 prior ICRF-159-treated patients subsequently received 5-FU. No antitumor response was seen with the secondary agent in this study. The response rate for ICRF-159 (none of 19 patients) predicts that it is unlikely to produce a true response rate of greater than or equal to 20% with a rejection error of less than 5%, making it unsuitable as primary therapy for colon carcinoma. The toxicity of 5-FU was moderate and mainly gastrointestinal while the toxicity of ICRF-159 was severe and mainly hematologic.

An effective low-dose adriamycin regimen as secondary chemotherapy for metastatic breast cancer patients.

Sixty breast cancer patients with hormone-resistant metastatic disease who had progressed after chemotherapy with low-dose cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or with L-phenylalanine mustard underwent treatment with a low-dose Adriamycin regimen,i.e., 20 mg/m2, intravenously on days 1 and 8 every 28 days. Two percent of patients had complete responses; 25%, partial responses; 38%, stabilization; and 35%, progression. The time to progression for the responders was similar to that of the stabilized patients, while the responders and stabilized patients survived significantly longer than did the progressors. Responses were seen in nodal, hepatic, dermal/subcutaneous, bone, pulmonary, and peritoneal metastases. The toxicity was mild: 18% of patients had leukocyte counts of less than 3,000/mm3; 10% had platelet counts of less than 90,000/mm3, 22% experience vomiting; and 33% had hair loss. No patient experienced local venous/subcutaneous toxicity or heart failure. Since this regimen of low-dose Adriamycin appears to be as effective as, but less toxic than, the secondary standard-dose of Adriamycin at 60--75 mg/m2 every three weeks, a randomized trial of low-dose Adriamycin vs. standard-dose Adriamycin should be conducted in metastatic breast cancer patients who have previously undergone chemotherapy.

Tamoxifen plus sequential CMF chemotherapy versus tamoxifen alone in postmenopausal patients with advanced breast cancer: a randomized trial.

Eighty-nine postmenopausal women with metastatic breast cancer, in whom estrogen receptors (ER) were positive or unknown, were treated on a controlled trial to determine the effectiveness of tamoxifen and to assess the therapeutic advantage of sequentially adding low-dose cyclophosphamide-methotrexate-5-fluorouracil (CMF) chemotherapy in tamoxifen responders. Patients with known ER negative status were not studied. After the initial 12 week treatment with tamoxifen alone, 59% of ER positive patients achieved complete or partial response as did 35% in whom ER were unknown. Response status further improved in 18% randomized to continue tamoxifen alone vs. 28% in whom CMF was added to tamoxifen. There were no statistically significant differences in time to the development of progressive disease or survival between the ER positive and ER unknown patients or between the tamoxifen and tamoxifen plus CMF groups. We conclude that inability to determine ER status should not prejudice against the use of tamoxifen in postmenopausal patients with advanced breast cancer. As yet, no benefit has been demonstrated from the addition of CMF chemotherapy in tamoxifen responders.

Low dose chemotherapy of metastatic breast cancer with cyclophosphamide, adriamycin, methotrexate, 5-fluorouracil (CAMF) versus sequential cyclophosphamide, methotrexate, 5-fluorouracil (CMF) and adriamycin.

Seventy-eight advanced breast cancer patients with hormone-resistant disease or visceral metastases were randomized to receive either of two low dose regimens consisting of cyclophosphamide (C), methotrexate (M), 5-fluorouracil (F), and Adriamycin (A) as their initial chemotherapy. One group was treated with CAMF, and the other with CMF until progression, followed by A (CMF leads to A). C was given at 50 mg/m2, po, days 1-14; M at 20 mg/m2, F at 300 mg/m2, and A at 20 mg/m2, iv, days 1 and 8 of each 28-day cycle. The response rates for CAMF vs. CMF did not differ significantly (complete and partial responses-62% vs. 49%; stabilizations-23% vs. 31%). Responses by site of metasis, median times to progression and median survivals were similar for both groups. Poor and good risk partial responders had similar survivals. Twelve percent of CMF patients treated with Adriamycin at the time of progression had partial responses with an associated improved survival. Since CMF is as effective as CAMF, but has less toxicity, low dose therapy with CMF is more acceptable than CAMF as an initial chemotherapy regimen for metastatic breast cancer. Adriamycin may be reserved for subsequent regression induction.

Phase II study of ICRF-159 in refractory metastatic breast cancer.

ICRF-159, at a dose of 300 mg/m2, was given orally every 8 hours for nine doses every 21 days to 40 patients with metastatic breast cancer refractory to hormonal therapy and cyclophosphamide, methotrexate, 5-fluorouracil, and adriamycin chemotherapy. Two patients with soft tissue disease had short-lived partial responses. The hematologic toxicity was severe. Three patients required rbc transfusions. Four patients became septic at the nadir of leukopenia; two of these patients died while leukopenic. Two patients had platelet counts less than 25,000/mm3. All patients who were nonevaluable or who had life-threatening or lethal toxicity were nonambulatory. Since the 19 nonambulatory patients had a median survival of only 1.25 months as compared to 7 months in ambulatory patients, it is recommended that future phase II trials in chemotherapy-refractory breast cancer be limited to ambulatory patients. Although ICRF-159 has minimal antineoplastic effects, it is not recommended for further investigations in metastatic breast cancer, even at more hematologically tolerable doses of 250 mg/m2 every 8 hours for nine doses.