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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.

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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.

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Both docetaxel and gemcitabine are active against chemotherapy-pretreated non small-cell lung cancer (NSCLC). We previously demonstrated that weekly gemcitabine can be safely combined with monthly docetaxel with promising antineoplastic activity. In a recently completed phase II trial, 38 NSCLC patients failing upfront chemotherapy were treated with gemcitabine 800 mg/m2 on days 1, 8, and 15 and docetaxel 100 mg/m2 on day 1 every 4 weeks. The intent-to-treat response rate was 33% (95% CI: 19%-55%), with one complete and 11 confirmed partial responses. Responses were seen at all disease sites and in 31% of patients refractory to front-line chemotherapy. The median time to disease progression for the responders was 8 months, and two have remained progression-free for longer than a year. Hematological toxicities included grade 4 neutropenia in half of patients, febrile neutropenia in 10%, and grade 3-4 thrombocytopenia in 25%. The most prominent nonhematological toxicity was asthenia. We conclude that this doublet is active and safe, producing durable responses at all disease sites and in patients with platinum-refractory NSCLC.

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PURPOSE: To evaluate the efficacy of a novel multiday schedule of vinorelbine and displatin in patients with advanced NSCLC. PATIENTS AND METHODS: Thirty patients were enrolled, including 27 patients with stage IV disease, and 11 patients with performance status of 2. They received a maximum of four chemotherapy cycles with cisplatin 20 mg/m2/day and vinorelbine 15 mg/m2/day intravenously (i.v.) for four consecutive days, every three weeks, with prophylactic filgrastim. RESULTS: Sixteen patients responded (53%, 95% confidence interval (95% CI): 34%-72%), including two complete and fourteen partial confirmed responses. Median survival for all patients was 8.1 months, with actuarial one-year and two-year survival rates of 40% and 15%. Despite prophylactic filgrastim, the delivered vinorelbine dose intensity of 16.8 mg/m2/week caused febrile neutropenia in 48% of patients (16% of cycles), resulting in one treatment-related death. Common nonhematologic toxicities included delayed emesis, asthenia, and constipation. CONCLUSIONS: This multiday vinorelbine-cisplatin schedule is highly active against advanced NSCLC but results in frequent neutropenic complications. The myelotoxicity and antitumor efficacy of vinorelbine in NSCLC patients may be schedule-dependent.

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PURPOSE: To determine the maximum-tolerated dose of monthly docetaxel combined with fixed-dose weekly gemcitabine and describe the dose-limiting toxicities (DLTs) of the combination. PATIENTS AND METHODS: Patients with refractory solid tumors were treated with gemcitabine days 1, 8, and 15 every 4 weeks at a fixed dose of 800 mg/m2. Two docetaxel administration schedules were studied, with the drug administered either day 1 or day 15 at doses of 45, 60, 75, and 100 mg/m2 per cycle. RESULTS: Forty patients received 132 cycles of chemotherapy. On the day-1 schedule, the maximum-tolerated docetaxel dose was the highest planned dose of 100 mg/m2 with two DLT episodes among 12 patients treated with 34 cycles at this dose level. On the day-15 schedule, delivery of the planned docetaxel doses was not feasible because of thrombocytopenia and hepatic dysfunction. Hematologic toxicities included grade 4 neutropenia in 16 patients, with three episodes of febrile neutropenia; grades 3 to 4 thrombocytopenia in nine patients; and anemia that required RBC transfusions in 10 patients. For patients treated at the highest docetaxel dose level, myelosuppression was not dose limiting and only one of 34 cycles was complicated by febrile neutropenia. The most common nonhematologic toxicities were asthenia, flu-like symptoms, and fluid retention. Antineoplastic activity was noteworthy, with partial responses in nine of 21 patients with pretreated non-small-cell lung cancer (NSCLC; 43%; 95% confidence interval, 22 to 66), in four of seven patients with breast cancer, and in one patient with esophageal adenocarcinoma. CONCLUSION: Gemcitabine 800 mg/m2 days 1,8, and 15 can be safely combined with docetaxel 100 mg/m2 day 1 of a 28-day cycle. The observed antitumor activity warrants phase II evaluation.

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PURPOSE: The primary objectives of the study were to evaluate the efficacy and safety of prolonged oral (PO) etoposide as part of cisplatin-based chemotherapy plus concurrent chest/brain irradiation induction, followed by CAV consolidation, in the treatment of patients with limited-stage small cell lung cancer (SCLC-LD) within a cooperative group setting. METHODS AND MATERIALS: Fifty-six eligible patients with SCLC-LD received three 28-day cycles of cisplatin 50 mg/m2 i.v. (days 1, 8; 29, 36; and 57, 64), PO etoposide 50 mg/m2 (days 1-14, 29-42, and 57-70), and vincristine 2 mg i.v. (days 1, 29, and 57). Thoracic irradiation (TRT) was administered at 1.8 Gy in 25 daily fractions to a total dose of 45 Gy via an AP:PA arrangement, to begin concomitantly with induction chemotherapy. Prophylactic cranial irradiation (PCI) was started on day 15 of induction therapy. Fifteen daily fractions of 2.0 Gy were administered to the entire brain to a total dose of 30 Gy to finish at approximately the same time as TRT. Two 21-day cycles of consolidation cyclophosphamide 750 mg/m2 i.v., doxorubicin 50 mg/m2 i.v., and vincristine 2 mg i.v. (all on days 1 and 22), were given beginning on day 106 or week 16, from the start of induction therapy. RESULTS: Among 56 eligible patients, 93% had SWOG performance status 0-1. All had adequate organ function and had not received prior therapy. The overall confirmed response rate was 46%, including 16% complete responders and 30% partial responders. After a minimum follow-up duration of 17 months, the Kaplan-Meier median progression-free (PFS) and overall survival (OS) were 10 and 15 months, respectively. Two-year survival is 28%. Only 28 of 56 patients (50%) completed chemotherapy per protocol, while 52 of 56 patients (93%) completed radiation per protocol. Eleven patients (20%) discontinued secondary to toxicity and two patients died from treatment. The major toxicity was hematologic. The two deaths were secondary to infection. Of the nonhematologic toxicities, there were 10 cases of pulmonary fibrosis (including one Grade 3) and six cases of pneumonitis (including one Grade 3). CONCLUSION: Concomitant chemoradiation with oral etoposide as part of a platinum-based chemotherapy and TRT induction regimen is toxic. The CR rate is not better than our prior best group-wide experience. The progression-free and overall survival are similar to published trials utilizing short-course i.v. etoposide. As in chemotherapy for extensive-stage SCLC, there is no apparent advantage to prolonged exposure to etoposide, and toxicity resulted in an inferior therapeutic index compared to programs with shortened exposure.

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PURPOSE: Topotecan is a topoisomerase I inhibitor with antitumor activity against hematologic and solid tumor malignancies. We evaluated its activity in refractory and relapsing multiple myeloma patients who had received one prior chemotherapeutic regimen. PATIENTS AND METHODS: Toptecan 1.25 mg/m2/d was administered as a 30-minute infusion for 5 days repeated every 3 weeks. Granulocyte colony-stimulating factor (G-CSF) 5 microg/kg/d subcutaneously was administered after the first course of treatment if neutropenia was dose-limiting. RESULTS: Forty-six patients entered the study, with 43 patients eligible. The major toxicity was granulocytopenia with grade 3 or better occurring in 40 of 43 patients treated; 21 of 43 patients developed grade 3 or greater thrombocytopenia. Other significant toxicity included mild nausea in 23 patients and mild vomiting in 13 patients. The overall response rate (partial response or better) was 16% (95% confidence interval, 7% to 31%), with responses occurring in both relapsed and refractory patients. Responses have lasted 70 to 477+ days, with a median progression-free survival duration of 13 months and median survival time of 28 months. CONCLUSION: Topotecan has activity in refractory and relapsing multiple myeloma. Future investigation of topotecan in multiple myeloma including combination therapy and the study of other topoismerase I inhibitors is warranted.

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BACKGROUND: Teniposide (VM-26) was reported to have activity in small cell lung carcinoma (SCLC). The authors performed a Phase II study of teniposide as a treatment for patients with previously untreated extensive SCLC. METHODS: The study was open to patients with a histologic or cytologic diagnosis of extensive SCLC who had not received prior radiation or chemotherapy. Patients with hematologic values below normal were considered eligible if the impaired bone marrow function was directly attributable to disease involvement. Treatment consisted of teniposide 60 mg/m2 given intravenously (i.v.) on Days 1-5 every 3 weeks. RESULTS: This study opened on September 15, 1988, closed permanently on November 15, 1990, and accrued 45 patients identified at 19 academic, military, and Community Clinical Oncology Program institutions affiliated with the Southwest Oncology Group. Of the 45 registered patients, 41 were eligible. Twenty eight (68%) were males and 13 (32%) were females; the median age was 64 years (minimum, 46 years; maximum, 83 years). Twenty-four patients (59%) had a performance status (PS) on the Zubrod scale of 0-1 and 17 cases (41%) had a PS of 2. Of the 41 eligible patients, 10 had confirmed partial responses (24%) (95% confidence interval, 12-40%). The median survival was 7 months. The significant toxicities noted were Grade 4 leukopenia and/or granulocytopenia, experienced by 15 patients; 1 of these patients also had Grade 4 hyponatremia. One patient died of a respiratory infection. CONCLUSIONS: When administered according to the dosage and schedule selected for this study (60 mg/m2 i.v. on Days 1-5 every 3 weeks), teniposide as a single agent had modest activity in extensive small cell lung carcinoma. The toxicities observed in this study were acceptable.

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BACKGROUND: In patients with advanced esophageal adenocarcinoma, the efficacy and palliative role of systemic chemotherapy are not well defined. The primary objective of this Phase II trial was to evaluate the antitumor activity and toxicity of a multiday chemotherapy schedule of high dose cisplatin and etoposide in patients with unresectable or metastatic esophageal adenocarcinoma. A secondary objective was to assess the efficacy of this regimen in palliating dysphagia. METHODS: Twenty-seven eligible patients with unresectable locoregional or metastatic esophageal adenocarcinoma were treated with cisplatin, 30 mg/m2/day, and etoposide, 60 mg/m2/day, intravenously daily for 5 days, every 3 weeks. After three cycles of chemotherapy, all patients were assessed for response. Patients with responding metastatic disease were given one additional cycle of chemotherapy, and patients with locoregional disease received radiation and concurrent continuous infusion of 5-fluorouracil at 300 mg/m2/day for the duration of radiation therapy. Patients were questioned about dysphagia symptoms initially and then weekly during chemotherapy. RESULTS: The major toxicities included myelosuppression, nausea and vomiting, and peripheral sensory neuropathy, with one treatment-related death. Major responses were observed in 13 patients (48%; 95% confidence intervals, 36-74%), including 5 complete and 8 partial responses. Dysphagia relief occurred in 89% of 18 symptomatic patients within a median time of 16 days. The median survival duration for all patients was 9.8 months, and the actuarial 3-year survival rate was 22%. CONCLUSIONS: Multiday chemotherapy with high dose cisplatin and etoposide is active in patients with advanced esophageal adenocarcinoma. Toxicities associated with this regimen are substantial but manageable.

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BACKGROUND: We wanted to determine factors affecting survival rates of benefits to, and complications in patients with esophageal cancer treated with photodynamic therapy. METHODS: From 1982 to January 1994, we used photodynamic therapy to treat 77 patients with esophageal carcinoma and evaluated survival to July 1994. All patients had failed, refused, or were ineligible for surgical intervention, ionizing radiation therapy, or chemotherapy. RESULTS: The only significant variable affecting survival was clinical stage. Median survival after photodynamic therapy was as follows: all patients, 6.3 months (mean survival, 9.2 months); stage I, not reached; stage II, 12 months; stage III, 6.2 months; and stage IV, 3.5 months. For stages III and IV, a Karnofsky performance status of 70 or higher had a significant effect. For stage III, the median survival was 6.3 months when the Karnofsky performance status was equal to or greater than 70 and 3.5 months when it was less than 70. For stage IV, the median survival was 5.5 months when the Karnofsky performance status was equal to or greater than 70 and 2.5 months when it was lower than 70. Seven stage I patients with no treatment prior to photodynamic therapy had an estimated 5-year survival rate of 62%. Three patients with stage I invasive adenocarcinoma and Barrett's mucosa diagnosed when they underwent endoscopy for dysphagia were alive with no evidence of disease 17, 44, and 59 months after photodynamic therapy. CONCLUSIONS: Photodynamic therapy for esophageal carcinoma caused minimal complications and no procedure-related deaths. Photodynamic therapy can be considered an alternative treatment for patients with Barrett's esophagus with severe dysplasia or patients with stage I carcinoma who are under consideration for operation but are high surgical risks. The length of palliation for patients having "noncurative" treatment was equal to or better than that reported historically for most other treatment regimens.

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We compared health-related quality of life (HQL) measures in 210 patients with metastatic colorectal cancer who were receiving equitoxic regimens of weekly 5-fluorouracil (5-FU) plus leucovorin (LV) or 5-FU alone in a multicenter, placebo-controlled, double-blind, randomized trial. The HQL was assessed during the first 120 days of treatment by the patient-generated functional living index-cancer (FLIC) questionnaire. Also assessed were clinician-generated measures to evaluate physical functioning and suffering: Karnofsky performance status (KPS), body weight, disease symptoms, and hospitalization. No significant difference was detected between treatment groups in HQL or in any measurement of efficacy or toxicity. The number of patients hospitalized was similar in both groups, 35 patients receiving 5-FU-LV, 32 receiving 5-FU-placebo, but those receiving 5-FU-LV were hospitalized longer (450 vs 315 total days). The KPS improved or stabilized in 23% and 37% of patients, respectively. Overall, FLIC scores significantly improved in 27% or remained stable in 62% of all patients; disease symptoms improved in 19-49%; a weight increase of 2 kg or more occurred in 27%. A change in FLIC was not associated with tumor response or improvement in pain, but a decline in FLIC was associated with improved survival. An improvement in KPS or weight was associated with tumor response and strongly correlated with survival. Improvement of pain was associated with a stable or increase in weight, and worsening of pain correlated with lack of tumor response.

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BACKGROUND: The assessment of treatment efficacy in nonsmall cell lung cancer (NSCLC) is limited by the lack of a clear association between clinical response and survival. The prognostic usefulness of treatment-induced tumor-marker declines in NSCLC has not been established. The authors investigated the prognostic significance of treatment-induced declination in tumor marker levels of carcinoembryonic antigen, CA 19-9, and CA 125 in a group of patients with NSCLC treated with a brief course of cisplatin-based chemotherapy. METHODS: Eighty-three patients with NSCLC enrolled on 2 related treatment protocols had pretreatment tumor-marker determinations. Patients were restaged 10 to 12 weeks after study entry, and clinical and marker responses were determined. RESULTS: Thirty-eight patients (46%) had elevated pretreatment tumor markers, 36 (42%) of whom were evaluable for both clinical and marker responses. Pretreatment, the latter 36 individuals had measurable or evaluable disease, and at least one elevated tumor marker (greater than twice normal); posttreatment, they had follow-up measurements of both parameters. Of the 36 patients, 8 had normalization of tumor marker levels, 13 had 50-99% marker level declination, and 15 had less than 50% or no declination. In the same group of 36 patients, there were, 1 patient with complete clinical response, 11 with partial response, 19 with stable disease, and 5 with progressive disease. Marker responses occurred with equal frequency in clinical responders and nonresponders. There was no association between clinical response and survival, but there was a strong association between marker response and survival. CONCLUSIONS: In patients with nonsmall cell lung cancer with elevated pretreatment tumor marker levels, treatment-induced marker level declination can be a surrogate indicator for survival.

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BACKGROUND: Multiple myeloma is considered to be a drug responsive disease; however, there is no cure for this disease and virtually all patients will develop drug resistance. One form of drug resistance that has been documented is the multidrug resistance phenotype or MDR. METHODS: A randomized trial of the combination of vincristine, doxorubicin, and dexamethasone (VAD) and VAD plus oral verapamil (VAD/v) in drug refractory multiple myeloma patients was performed by the Southwestern Oncology Group. Verapamil was used as a chemosensitizing agent to attempt to overcome or prevent MDR and improve the therapeutic outcome. RESULTS: Response rates between the two treatment arms were similar with an overall response rate of 41% for the VAD alone arm and 36% for the VAD/v arm. Overall survival of patients was also similar with a median survival of 10 months for the VAD arm and 13 months for the VAD/v arm. The toxicity profile was also similar for both treatments, with myelosuppression being the dose-limiting toxicity. No significant correlation was observed between expression of P-glycoprotein, serum verapamil levels, and response to therapy. CONCLUSIONS: No beneficial effect was observed from the addition of oral verapamil to the VAD chemotherapy regimen for the treatment of drug-resistant myeloma patients. More effective and less toxic chemosensitizers are needed to study the role of chemosensitizers in reversing MDR in the clinic.

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Didemnin B is a cyclic peptide isolated from the marine tunicate Trididemnin cyanophorum. It is a known potent inhibitor of RNA, DNA and protein synthesis, with activity against the murine B16 melanoma. Fourteen patients with disseminated malignant melanoma were evaluated in a Southwest Oncology Group phase II trial of didemnin B at 4.2 mg/m2 by 30 min i.v. infusion every 28 days (SWOG-8754). Only patients with no prior chemotherapy were eligible; prior radiation therapy, surgery and at most one prior biologic regimen were allowed. Patients with brain metastasis were eligible only if the disease in the brain had been treated and controlled. All patients had to have normal renal and hepatic function and adequate granulocyte and platelet counts, a performance status of 0-2, and bidimensionally measurable disease. Fourteen patients were entered on the study; five received one and nine received two courses of didemnin B. No responses were noted among the 11 patients evaluable for response. Five patients developed unusual but reversible hypersensitivity reactions during the second course of therapy. Other toxicity in this trial was nausea and vomiting and diarrhea, none of severity greater than grade 3. Given the lack of antitumor efficacy and the unusual toxicity, further evaluation of didemnin B in this dose and schedule in malignant melanoma is not warranted.

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The Southwest Oncology Group conducted a trial of VM-26 (teniposide) in patients with advanced gastric cancer. VM-26 60 mg/m2 i.v. infusion over 30-45 minutes was given daily for 5 days every 21 days. Twenty-one eligible patients with measurable disease and a SWOG performance status of 0-2 were analyzed for response and toxicity. Partial responses were seen in 2 of the 21 eligible patients (9.5%). Median survival was 3.8 months. Severe of life-threatening toxicity was observed in 13/21 (62%) patients. This included two drug related deaths related to neutropenic sepsis and seven other patients with grade 4 granulocytopenia (< 500/mm3). Liver dysfunction and hypotension were seen less often and were not dose limiting. Although the modest activity seen was comparable to that of VP-16 (etoposide) as a single agent, the hematologic toxicity observed in this trial would likely preclude further trials of VM-26 (teniposide) in advanced gastric cancer.

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PURPOSE: A prospectively randomized trial was performed to determine whether the combination of fluorouracil (FU) plus leucovorin (FU-LV) administered orally is more effective than equitoxic FU for patients with metastatic colorectal cancer. PATIENTS AND METHODS: A double-blind, placebo-controlled trial design was used to eliminate observer bias. An escalating FU dosing schedule was used to achieve equal toxicity. End points were response, time to treatment failure (TTF), and eight quality-of-life (QL) parameters. A crossover arm allowed FU-treated patients to receive FU-LV combination treatment after treatment failure. RESULTS: Response rate was 32% for FU-LV versus 23% for FU (P = .15). Median TTF was 22 versus 16 weeks (P = .27). Median survival time was 44 versus 54 weeks (P = .26). QL was the same for both treatments, except for days of hospitalization, which was greater for FU-LV (P < .001). Toxicities were similar to those previously reported for FU-LV and FU alone. CONCLUSION: Oral LV-FU produces the same efficacy and toxicity pattern as has been reported for intravenous LV-FU. When FU-LV is compared with equitoxic doses of FU, there is no difference in patient outcome. These results suggest that patients with advanced disease should receive FU at doses adequate to produce toxicity.

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