Showing papers by "David R. Gandara published in 2001"

Randomized Phase III Trial of Paclitaxel Plus Carboplatin Versus Vinorelbine Plus Cisplatin in the Treatment of Patients With Advanced Non–Small-Cell Lung Cancer: A Southwest Oncology Group Trial

Abstract: PURPOSE: This randomized trial was designed to determine whether paclitaxel plus carboplatin (PC) offered a survival advantage over vinorelbine plus cisplatin (VC) for patients with advanced non–small-cell lung cancer. Secondary objectives were to compare toxicity, tolerability, quality of life (QOL), and resource utilization. PATIENTS AND METHODS: Two hundred two patients received VC (vinorelbine 25 mg/m2/wk and cisplatin 100 mg/m2/d, day 1 every 28 days) and 206 patients received PC (paclitaxel 225 mg/m2 over 3 hours with carboplatin area under the curve of 6, day 1 every 21 days). Patients completed QOL questionnaires at baseline, 13 weeks, and 25 weeks. Resource utilization forms were completed at five time points through 24 months. RESULTS: Patient characteristics were similar between the groups. The objective response rate was 28% in the VC arm and 25% in the PC arm. Median survival was 8 months in both arms, with 1-year survival rates of 36% and 38%, respectively. Grade 3 and 4 leukopenia (P = .002...

Prospective Evaluation of Cancer Clinical Trial Accrual Patterns: Identifying Potential Barriers to Enrollment

Abstract: PURPOSE: Well-conducted cancer clinical trials are essential for improving patient outcomes. Unfortunately, only 3% of new cancer patients participate in clinical trials. Barriers to patient accrual in cancer clinical trials must be identified and overcome to increase patient participation. MATERIALS AND METHODS: We prospectively tracked factors that potentially affected patient accrual into cancer clinical trials at the University of California Davis Cancer Center. Oncologists seeing new outpatients were asked to complete questionnaires regarding patient characteristics and the physician’s decision-making on patient eligibility, protocol availability, and patient opinions on participation. Statistical analysis was performed to correlate these parameters with subsequent protocol accrual. RESULTS: There were 276 assessable patients. At the initial visits, physicians did not consider clinical trials in 38% (105/276) of patients principally because of a perception of protocol unavailability and poor performa...

Twenty-Two Years of Phase III Trials for Patients With Advanced Non–Small-Cell Lung Cancer: Sobering Results

Abstract: PURPOSE: To determine the changes in clinical trials and outcomes of patients with advanced-stage non–small-cell lung cancer (NSCLC) treated on phase III randomized trials initiated in North America from 1973 to 1994. PATIENTS AND METHODS: Phase III trials for patients with advanced-stage NSCLC were identified through a search of the National Cancer Institute’s Cancer Therapy Evaluation Program database from 1973 to 1994, contact with Cooperative Groups, and by literature search of MEDLINE. Patients with advanced NSCLC treated during a similar time interval were also examined in the SEER database. Trends were tested in the number of trials, in the number and sex of patients entered on the trials, and in survival over time. RESULTS: Thirty-three phase III trials were initiated between 1973 and 1994. Twenty-four trials (73%) were initiated within the first half of this period (1973 to 1983) and accounted for 5,359 (64%) of the 8,434 eligible patients. The median number of patients treated per arm of the tri...

Randomized Phase III Intergroup Trial of Isotretinoin to Prevent Second Primary Tumors in Stage I Non-Small-Cell Lung Cancer

Abstract: Background: Promising data have suggested that retinoid chemoprevention may help to control second primary tumors (SPTs), recurrence, and mortality of stage I non-smallcell lung cancer (NSCLC) patients. Methods: We carried out a National Cancer Institute (NCI) Intergroup phase III trial (NCI #I91–0001) with 1166 patients with pathologic stage I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy or chemotherapy). Patients were randomly assigned to receive a placebo or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind fashion. Patients were stratified at randomization by tumor stage, histology, and smoking status. The primary endpoint (time to SPT) and the secondary endpoints (times to recurrence and death) were analyzed by log-rank test and the Cox proportional hazards model. All statistical tests were two-sided. Results: After a median follow-up of 3.5 years, there were no statistically significant differences between the placebo and isotretinoin arms with respect to the time to SPTs, recurrences, or mortality. The unadjusted hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95% confidence interval [CI] = 0.78 to 1.49) for SPTs, 0.99 (95% CI = 0.76 to 1.29) for recurrence, and 1.07 (95% CI = 0.84 to 1.35) for mortality. Multivariate analyses showed that the rate of SPTs was not affected by any stratification factor. Rate of recurrence was affected by tumor stage (HR for T2 versus T1 = 1.77 [95% CI = 1.35 to 2.31]) and a treatment-by-smoking interaction (HR for treatment-by-current-versus-neversmoking status = 3.11 [95% CI = 1.00 to 9.71]). Mortality was affected by tumor stage (HR for T2 versus T1 = 1.39 [95% CI = 1.10 to 1.77]), histology (HR for squamous versus nonsquamous = 1.31 [95% CI = 1.03 to 1.68]), and a treatment-by-smoking interaction (HR for treatment-by-currentversus-never-smoking = 4.39 [95% CI = 1.11 to 17.29]). Mucocutaneous toxicity (P<.001) and noncompliance (40% versus 25% at 3 years) were higher in the isotretinoin arm than in the placebo arm. Conclusions: Isotretinoin treatment did not improve the overall rates of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate and subset analyses suggested that isotretinoin was harmful in current smokers and beneficial in never smokers. [J Natl Cancer Inst 2001;93:605–18].

Twice-Weekly Paclitaxel and Weekly Carboplatin With Concurrent Thoracic Radiation Followed by Carboplatin/Paclitaxel Consolidation for Stage III Non–Small-Cell Lung Cancer: A California Cancer Consortium Phase II Trial

Abstract: PURPOSE: Recent studies have suggested the superiority of concurrent chemoradiotherapy and the efficacy of paclitaxel/carboplatin in advanced non–small-cell lung cancer (NSCLC). In view of those results, we sought to examine the safety and efficacy of administration of radiosensitizing paclitaxel twice weekly and carboplatin weekly with concurrent thoracic radiation therapy (XRT) followed by consolidation paclitaxel and carboplatin for stage III NSCLC in a multi-institutional phase II trial. PATIENTS AND METHODS: Induction chemoradiotherapy consisted of paclitaxel 30 mg/m2 delivered intravenously (IV) for 1 hour twice weekly for 6 weeks, carboplatin at a dose based on an area under the concentration-time curve (AUC) of 1.5 mg/mL × min, given IV once weekly for 6 weeks, and concomitant XRT of 1.8 to 2.0 Gy daily for a total of 61 Gy. Patients who achieved a complete response, partial response, or stable disease received two 21-day cycles of consolidation chemotherapy consisting of paclitaxel 200 mg/m2 IV f...

Dolastatin-10 in metastatic melanoma: a phase II and pharmokinetic trial of the California Cancer Consortium.

Abstract: Dolastatin-10 is a novel pentapeptide agentoriginally isolated from the marine molluskDolabella auricularia with amechanism of antitumor activity thatinvolves the inhibition of microtubuleassembly. We performed a Phase II trial ofDolastatin-10, 400 μg/m2, inpatients with advanced melanoma who hadreceived no prior chemotherapy. Dolastatin-10 pharmokinetics wereevaluated in a subset of patients followingcourses 1 and 2. Twelve patients weretreated with a median of 2 cycles ofDolastatin-10, and no patient experiencedan objective response. The only grade >2toxicities were grade 3 neutropeniauncomplicated by infection, occurring in 4patients following the first treatmentcycle. The total systemic clearance andvolume of distribution at steady-state were2.61 ± 1.9 L/h/m2 and 28.4 ± 13 L/m2,respectively. Due toprolonged terminal elimination,Dolastatin-10 plasma concentrations ofgreater than 1 nM were sustained for 24h in all patients studied. Dolastatin-10 is unlikely to havesubstantial activity in the treatment ofmelanoma.

Cisplatin, Etoposide, and Paclitaxel with Granulocyte Colony-Stimulating Factor in Untreated Patients with Extensive-Stage Small Cell Lung Cancer A Phase II Trial of the Southwest Oncology Group ,

Abstract: Purpose: This study was designed to determine the efficacy and toxicity of cisplatin, etoposide, and paclitaxel (PET) in patients with extensive-stage small cell lung cancer (ES-SCLC). Experimental Design: Chemo-naive adult patients with a performance status (PS) of 0–2 and adequate organ function were eligible. Patients received cisplatin 80 mg/m2 i.v., etoposide 80 mg/m-2 i.v., and paclitaxel 175 mg/m2 i.v. over a 3-h period on day 1 followed by etoposide 160 mg/m2 p.o. on days 2 and 3 every 21 days for six cycles. G-CSF 5 μg/kg was injected s.c. on days 4–14. Results: Eighty-eight patients were assessable. The median age was 60 years; 50% were male, 78% had PS of 0–1, 28% had PS of 2, 53% had multiple sites, and 13% had brain involvement. The overall response rate was 57% with 10 (12%) of 84 patients achieving a complete response. Median progression-free survival was 6 months [95% confidence interval (CI), 5–7 months] with a median survival of 11 months (95% CI, 8–13 months) and a 1-year survival rate of 43% (95% CI, 33–54%). Six patients (7%) died from toxicity. Grade 5 toxicity occurred in 3 (14%) of 22 patients (with a PS of 2) versus 3 (5%) of 61 patients (with a PS of 0–1; P , not significant). Grade 4 neutropenia developed in 40% of patients. Grade 3 nonhematological toxicities were primarily nausea (20%), vomiting (16%), and fatigue (14%). Conclusion: The survival result achieved was superior to prior SWOG experiences; however, the toxic death rate was unacceptably high in PS-2 patients. These results provide the largest database for the ongoing randomized Intergroup trial comparing PET to cisplatin+etoposide in PS-0–1 patients with ES-SCLC.

Activity of high-dose toremifene plus cisplatin in platinum-treated non-small-cell lung cancer: A phase II California Cancer Consortium Trial

Abstract: Purpose: Although cisplatin is an important agent in non-small-cell lung cancer (NSCLC), de novo resistance is common and acquired resistance emerges rapidly during therapy. Proposed mediators of platinum resistance include the protein kinase C (PKC) signal transduction pathway and associated c-FOS overexpression. While estrogen administration has been reported to upregulate PKC and c-FOS expression, the triphenylethylenes tamoxifen and toremifene potentiate platinum cytotoxicity by inhibition of PKC. Downregulation of c-FOS expression has been reported to result from PKC inhibition. In view of these findings, we hypothesized that toremifene would reverse platinum resistance and that this interaction would be influenced by tumor estrogen receptor (ER) status. Materialsandmethods: A phase II trial of high-dose toremifene (600 mg orally daily on days 1–7) plus cisplatin (50 mg/m2 intravenously on days 4 and 11) every 28 days in NSCLC patients was conducted. A group of 30 patients with metastatic NSCLC who had been previously treated with platinum-based therapy were enrolled. Results: All of the 30 patients were assessable for toxicity and 28 for tumor response. Therapy was well tolerated with minimal hematologic and non-hematologic toxicity. Common toxicity criteria grade 3 hematologic toxicity was seen in only three patients. Five patients achieved a partial response for an overall response rate of 18% (95% CI 6–37). Median overall survival was 8.1 months (95% CI 5.4–17). To assess PKC, ER, and c-Fos expression by immunohistochemistry, 12 informative pretreatment patient tumor specimens were obtained. Four patient tumor specimens were positive for one or both PKC isoforms (α and e) while c-Fos was overexpressed in three. None of the responding patient tumors exhibited c-FOS or PKC-e overexpression. ER expression was found to be infrequent (8%), contrasting with previous reports in this tumor type. Conclusion: While this phase II study indicates that high-dose toremifene plus cisplatin is feasible, active, and well tolerated in NSCLC patients previously treated with platinum compounds, the mechanism of action remains unclear. Further study of this regimen is warranted.

Neoadjuvant therapy for non-small cell lung cancer.

Abstract: Clinical trials evaluating neoadjuvant or preoperative therapy for locally advanced non-small cell lung cancer (NSCLC) have demonstrated the feasibility, tolerability and activity of this approach. Three randomized trials have reported improved survival in patients with stage III NSCLC treated with preoperative chemotherapy followed by surgical resection compared to surgery alone. Combinations of neoadjuvant chemotherapy plus thoracic radiotherapy have also been investigated, generally resulting in higher rates of pathologic response, but higher toxicity rates as well. The best approach to neoadjuvant therapy remains to be determined and may well be substage dependent. In bulky stage III NSCLC, the role of surgery itself remains unclear and is the subject of an ongoing intergroup trial in the US. Regardless, neoadjuvant therapy has emerged as an important paradigm for clinical research since it serves as an in vivo test of chemosensitivity in patients, and represents a 'window of opportunity' for testing new chemotherapeutic agents and novel strategies. Among the new chemotherapeutic agents being investigated in this setting is docetaxel, one of the most active agents in first- and second-line chemotherapy of NSCLC, and a potent radiosensitizer. Preliminary studies have confirmed the feasibility of integrating docetaxel into neoadjuvant treatment strategies and encouraging results have been reported.

Gemcitabine in combination with new platinum compounds: an update.

Abstract: Combinations of gemcitabine (Gemzar) with cisplatin (Platinol) are among the most active new chemotherapy regimens developed for advanced non-small-cell lung cancer. Carboplatin (Paraplatin) is a platinum analog