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Biomedical subjects

David R Gandara

Publications and source records attributed to David R Gandara.

At least 19 recordsLinked to original sources
PubMed2006

Phase II study of consolidation paclitaxel after concurrent chemoradiation in poor-risk stage III non-small-cell lung cancer: SWOG S9712.

PURPOSE: A previous Southwest Oncology Group (SWOG) study (S9429) demonstrated efficacy and tolerability of concurrent chemoradiotherapy in poor-risk stage III non-small-cell lung cancer (NSCLC). This study evaluated adding consolidation paclitaxel after chemoradiotherapy for a similar patient cohort. PATIENTS AND METHODS: Patients with histologically/cytologically determined stage III NSCLC were eligible based on performance status (PS) 2 and either low albumin or weight loss more than 10%, poor pulmonary function, or comorbidities precluding cisplatin use. Treatment was carboplatin 200 mg/m2 days 1, 3, 29, and 31, and etoposide 50 mg/m2 days 1 through 4, and 29 to 32. Beginning day 1, thoracic radiation was delivered at 1.8 Gy in 25 fractions plus 16-Gy boost (total dose, 61 Gy). Patients without disease progression received paclitaxel 175 mg/m2 every 21 days for three cycles. RESULTS: Characteristics of 87 eligible patients were age 51 to 82 years; 57% PS 0 to 1, 43% PS 2; and 51% stage IIIA, 49% stage IIIB. Toxicities of concurrent chemoradiotherapy included grade 3 esophagitis (7%) and grade 3/4 neutropenia (43%). Fifty-four assessable patients received paclitaxel consolidation. Four treatment-related deaths occurred during chemoradiotherapy and four occurred during consolidation. Overall response rate was 53%. Median progression free- and overall survival were 6.1 and 10.2 months, respectively. One- and 2-year survival rates were 43% and 25%. CONCLUSION: Compared with a previous SWOG trial in a similar patient population, the addition of consolidation paclitaxel after chemoradiotherapy resulted in increased toxicity without a survival advantage. More PS 2 patients (43% v 18%) enrolled onto S9712, which may explain increased toxicity and lack of benefit. The optimal chemoradiotherapy approach for poor-risk patients remains to be defined.

Aged↗
PubMed2006

Gefitinib therapy in advanced bronchioloalveolar carcinoma: Southwest Oncology Group Study S0126.

PURPOSE: Advanced bronchioloalveolar carcinoma (BAC) is a distinct subtype of non-small-cell lung cancer (NSCLC) for which there is currently no optimal therapy. Based on preclinical and clinical data suggesting relevance of the epidermal growth factor receptor (EGFR) axis in BAC, the Southwest Oncology Group initiated a phase II trial (S0126) to evaluate the EGFR tyrosine kinase inhibitor gefitinib in chemotherapy-naïve and chemotherapy-pretreated patients with advanced BAC. METHODS: A total of 136 eligible and assessable patients (101 untreated, 35 previously treated) received gefitinib 500 mg daily until progression or prohibitive toxicity. RESULTS: The median age was 68.0 years (range, 34.3 to 88.6); 51% were female; 89% had a performance status (PS) of 0% or 1% and 11% had a PS of 2. The Response Evaluation Criteria in Solid Tumors response rate was 17%, with 6% complete responses (CRs) among 69 previously untreated patients with measurable disease, and 9% with no CRs among 22 pretreated patients. Median survival was 13 months for both chemo-naïve (95% CI, 8 to 18) and previously treated patients (95% CI, 6 to 17). Overall survival at 3 years was 23% (95% CI, 14% to 32%). Toxicity consisted mainly of rash and diarrhea, but 2% of patients died of presumed interstitial lung disease. Exploratory subset analyses revealed improved survival among women (P = .031), patients developing a rash (P = .003), never-smokers (P = .061), and patients with a PS of 0 or 1 (P = .015). CONCLUSION: Gefitinib is an active agent in advanced stage BAC. Several subsets demonstrate significantly improved clinical outcomes.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2006

Phase III study of gemcitabine and cisplatin with or without aprinocarsen, a protein kinase C-alpha antisense oligonucleotide, in patients with advanced-stage non-small-cell lung cancer.

PURPOSE: To determine whether aprinocarsen, an antisense oligonucleotide directed against protein kinase C-alpha, when added to the chemotherapy regimen of gemcitabine and cisplatin improved survival in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with previously untreated stage IIIB/IV NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned to either a control arm of gemcitabine 1,250 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1, or experimental arms consisting of the identical chemotherapy plus aprinocarsen 2 mg/kg/d as continuous infusion for 14 days, starting on either day 1 or 3 days before chemotherapy. Cycles were repeated every 21 days. RESULTS: A total of 670 patients were randomly assigned between the control (n = 328) and experimental arms (n = 342). Due to the results from another phase III study of aprinocarsen in NSCLC, further enrollment was stopped, and the study was terminated early. The median number of cycles was four on the control arm and three on the combined experimental arms. Median overall survival was not different between the two groups (control, 10.4 months [95% CI, 8.6 to 12.2]; experimental, 10.0 months [95% CI, 8.4 to 10.8]; P = .613; hazard ratio = 1.05 [95% CI, 0.88 to 1.25]). Response rates (control arm, 35.0%; experimental arms, 28.9%; P = .124) and other time-to-event measures were not significantly different. Grade 3 and 4 toxicities were significantly increased for thrombocytopenia (P < .0001), epistaxis, and thrombosis/embolism in the experimental arms. CONCLUSION: Adding aprinocarsen to gemcitabine and cisplatin regimen did not enhance survival and other efficacy measures in patients with advanced NSCLC.

Adult↗
PubMed2006

A randomized phase II trial of the matrix metalloproteinase inhibitor BMS-275291 in hormone-refractory prostate cancer patients with bone metastases.

BACKGROUND: BMS-275291 is a selective matrix metalloproteinase inhibitor (MMPI) that does not inhibit sheddases implicated in the dose-limiting arthritis of older MMPIs. We conducted a randomized phase II trial of two doses of BMS-275291 (1,200 versus 2,400 mg) in hormone-refractory prostate cancer (HRPC) patients with bone metastases to probe for a dose-response relationship and to assess differential toxicities. Serial serum and urine specimens were collected to assess for markers of bone metabolism. METHODS: The primary end point was 4-month progression-free survival (PFS). Eligibility criteria included documentation of androgen-independent disease (including anti-androgen withdrawal), skeletal metastasis, adequate end-organ function and performance status, and no more than one prior chemotherapy regimen. Patients were randomized to 1,200 mg orally once daily (arm A) or 1,200 mg orally twice daily (arm B). Response was assessed every 56 days. RESULTS: Eighty patients were enrolled: 39 in arm A and 41 in arm B. There were no responders by prostate-specific antigen or measurable disease to treatment. Stable disease was noted at 8 weeks in 39% of patients in arm A and in 17% of patients in arm B. Progression of disease at 8 weeks was seen in 61% of patients in arm A versus 83% of patients in arm B. Median survival time was 21.6 months (95% confidence interval, 17.5; not reached), whereas median PFS time was 1.8 months (95% confidence interval 1.74; 2) for all patients. Patients in arm A had a median survival time that was not reached, whereas patients on arm B has a median survival time of 21 months (P = 0.2). PFS at 4 months favored arm A: 22% versus 10% (log-rank, P = 0.008). Grade 3 toxicities occurred in 5 (13%) patients in arm A and in 9 (22%) patients in arm B. Grade 4 toxicities were uncommon (only 4% of patients): one each of thrombosis, fatigue, and motor neuropathy was seen in the arm B. Bone marker studies showed that baseline serum levels of N-telopeptide, osteocalcin, procollagen I NH2-terminal propeptide, and PICP had prognostic significance for PFS and/or overall survival. CONCLUSIONS: Regardless of dose schedule, BMS-275291 was well tolerated in HRPC patients and had no dose-limiting arthritis. Toxicities differed modestly according to the dose schedule employed. As overall survival and PFS favored the once daily schedule, this dose schedule is recommended for future studies. Baseline markers of bone metabolism may have prognostic value in HRPC patients with bone metastases.

Aged↗
PubMed2006

Phase II trial of gemcitabine plus irinotecan in patients with esophageal cancer: a Southwest Oncology Group (SWOG) trial.

OBJECTIVES: Metastatic esophageal carcinoma is an incurable disease with median survival duration of 6 to 8 months. Based on preclinical data suggesting a dose-dependent synergy between gemcitabine and irinotecan we have conducted a phase II trial in patients with advanced or metastatic esophageal carcinoma. METHODS: Patient eligibility included a diagnosis of squamous cell or adenocarcinoma of the esophagus/gastroesophageal (GE) junction, metastatic or recurrent disease, no CNS metastasis, no prior chemotherapy, prior adjuvant/neoadjuvant chemotherapy was allowed, no prior gemcitabine or irinotecan, performance status of 0 to 2 and adequate organ function. Patients received gemcitabine 1000 mg/m2 and irinotecan 100 mg/m2 given day 1 and day 8, every 3 weeks. The primary end point was the 6-month survival rate. The secondary end point was to assess qualitative and quantitative toxicities. RESULTS: Fifty-seven eligible patients were accrued. There were 4 treatment-related deaths. The primary grade 3 to 4 toxic events were diarrhea, dehydration, neutropenia, thrombocytopenia, anemia, and anorexia; and 4 episodes of grade 3 to 5 febrile neutropenia, 1 fatal. The study was designed to detect a difference between the null hypothesis of 30% 6-month survival and the alternative hypothesis of 50% 6-month survival. The Kaplan-Meier estimate of 6-month survival is 56% (95% CI: 43-69%), with a median of 6.3 months. The median time to progression was 3.7 months. The 6-month progression-free survival estimate is 25% (95% CI: 13-36%). CONCLUSIONS: The length of survival suggests that this combination has benefit similar to platinum containing regimens, however, the toxicity is substantial and is unlikely to prove superior to platinum containing regimens.

Adenocarcinoma↗
PubMed2006

Pharmacodynamic separation of epidermal growth factor receptor tyrosine kinase inhibitors and chemotherapy in non-small-cell lung cancer.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced-stage non-small-cell lung cancer (NSCLC). One potential explanation for this lack of benefit is a negative interaction or antagonism between chemotherapy and EGFR TKIs when delivered concomitantly. Support for this line of reasoning is provided by preclinical data demonstrating that EGFR TKIs induce primarily a cytostatic effect resulting from a G1 cell cycle arrest in cell lines with wild-type EGFR, reducing cell cycle phase-dependent activity of chemotherapy, whereas they induce apoptotic cell death in tumors with EGFR-activating mutations. Because the great majority of NSCLC tumors consist of wild-type EGFR, sequence-specific interactions of EGFR TKI/chemotherapy combinations might negatively influence the efficacy of these regimens in patients with NSCLC. Further evidence is provided by EGFR mutational analysis in patient tumor specimens from the TRIBUTE study. Herein we provide the preclinical and clinical rationale for studies examining the concept of pharmacodynamic separation as a means for overcoming hypothesized antagonism of EGFR TKIs and chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Current status of adjuvant chemotherapy for stage IB non-small-cell lung cancer: implications for the New Intergroup Trial.

Adjuvant chemotherapy after resection of stage II-IIIA non-small-cell lung cancer is now the standard of care based on the results of 3 phase III studies using cisplatin-based regimens, IALT (International Adjuvant Lung Trial), The National Cancer Institute of Canada JBR.10, and ANITA (Adjuvant Navelbine International Trialist Association). The role of adjuvant chemotherapy for stage IB disease remains controversial, even more so now that the updated results from CALGB (Cancer and Leukemia Group B) trial 9633 are statistically negative. CALGB 9633 was the only randomized adjuvant trial to use a carboplatin backbone and focused exclusively on patients with stage IB disease. Initial results, reported in 2004, showed a significant survival advantage with the addition of chemotherapy, but the 2006 updated results are no longer statistically significant. The next large intergroup adjuvant trial in non-small-cell lung cancer will look at bevacizumab in combination with chemotherapy. Because of the recent update, this trial will now limit patients with stage IB disease to those with larger tumors (>or= 4 cm) and will likely include only cisplatin-based regimens.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Aurora kinase inhibitors: a new class of targeted drugs in cancer.

Aurora kinases (A, B, and C) are essential for spindle assembly, centrosome maturation, chromosomal segregation, and cytokinesis. Aurora kinases A and B are overexpressed in many cancers, including non-small-cell lung cancer and mesothelioma. Small-molecule inhibitors selective for aurora kinases have shown promising activity in preclinical tumor models. To date, phase I studies with aurora kinase inhibitors have shown that myelosuppression is the dose-limiting toxicity, and disease stabilization was achieved in a number of tumor types, including non-small-cell lung cancer. Phase II trials are under way in selected tumor types. This article reviews the biology of aurora kinases, their potential role in the treatment of lung cancer, and challenges in the clinical development of this unique class of antineoplastic agents.

Antineoplastic Agents↗
PubMed2006

Long-term survival with concurrent chemoradiation therapy followed by consolidation docetaxel in stage IIIB non-small-cell lung cancer: a phase II Southwest Oncology Group Study (S9504).

PURPOSE: Here we report 5-year survival data from S9504, a Southwest Oncology Group phase II trial evaluating consolidation docetaxel after concurrent cisplatin/etoposide and thoracic radiation therapy in patients with pathologically documented stage IIIB non-small-cell lung cancer. Survival outcomes were compared with a predecessor study (S9019) with identical eligibility, staging criteria, and treatment, excepting docetaxel consolidation. PATIENTS AND METHODS: Treatment consisted of cisplatin 50 mg/m(2) per day on days 1, 8, 29, and 36; etoposide 50 mg/m(2) per day on days 1-5 and 29-33; and concurrent thoracic radiation therapy (total dose, 61 Gy). Consolidation docetaxel (75 mg/m(2) initial dose) started 4-6 weeks after completion of chemotherapy. RESULTS: Concurrent chemotherapy was generally well tolerated, with a low level of radiation-related esophagitis; 2 patients died from pneumonitis. Grade 3/4 neutropenia during consolidation docetaxel was common. At a median follow-up of 71 months, median progression-free survival was 16 months; median survival 26 months; and 3-, 4-, and 5-year survival rates were 40%, 29%, and 29%, respectively. Brain metastasis was the most common site of failure. In the predecessor trial S9019, median survival was 15 months, and 3-, 4-, and 5-year survival rates were 17%, 17%, and 17%, respectively. CONCLUSION: The 5-year survival rate in S9540 of 29% compares favorably with the predecessor trial S9019 and other treatment approaches currently used in this patient population. A phase III trial designed to validate the concept of consolidation docetaxel is presently under way.

Adult↗
PubMed2006

Second-line treatment for advanced-stage non-small-cell lung cancer: current and future options.

Non-small-cell lung cancer is the leading cause of cancer-related death in men and women. Because of its frequent presentation as advanced disease, most non-small-cell lung cancers are treated with palliative systemic therapy. Multiple trials have established the benefit of chemotherapy for palliation and disease control. Of the patients treated with first-line therapy, approximately 30%-40% will subsequently be candidates for second-line treatment. In the past year, pemetrexed and erlotinib have joined docetaxel as the only Food and Drug Administration-approved second-line therapies. Recent phase III trials have also evaluated the use of oral topotecan, polyglutamated paclitaxel, and gefitinib in this setting. In addition, multiple novel agents, including bortezomib, cetuximab, and bevacizumab, are being investigated as single agents or in combination with approved second-line therapies. With the increasing number of therapeutic options for this patient population, patient characteristics and side effect profiles are influencing the therapeutic choices made by physicians. The use of molecular markers to assist in therapeutic decision-making has yet to come to fruition. Research efforts continue to focus on identifying molecular markers and corresponding clinical features that will allow physicians to individualize patients' therapy.

Antineoplastic Agents↗
PubMed2005

Phase III trial of paclitaxel plus carboplatin with or without tirapazamine in advanced non-small-cell lung cancer: Southwest Oncology Group Trial S0003.

PURPOSE: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells. We conducted a phase III clinical trial to determine whether the addition of tirapazamine to paclitaxel and carboplatin offered a survival advantage when used in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Of 396 patients registered, 367 eligible patients were randomly assigned to either arm 1 (n = 181), which consisted of treatment every 21 days with paclitaxel 225 mg/m2/3 h, carboplatin (area under the curve = 6), and tirapazamine 260 mg/m2 in cycle 1 (which was escalated, if tolerable, to 330 mg/m(2) in cycle 2), or arm 2 (n = 186), which consisted of paclitaxel and carboplatin as in arm 1 with no tirapazamine. RESULTS: Patient characteristics were similar between the two arms. There were no statistically significant differences in response rates, progression-free survival, or overall survival. Patients on arm 1 had significantly (P < .05) more abdominal cramps, fatigue, transient hearing loss, febrile neutropenia, hypotension, myalgias, and skin rash and were removed from treatment more often as a result of toxicity than patients in arm 2 (26% v 13%, respectively; P = .003). More than 40% of patients did not have the tirapazamine dose escalated, primarily because of toxicity. The trial was closed early after an interim analysis demonstrated that the projected 37.5% improvement in survival (8 v 11 months median survival) in arm 1 was unachievable (P = .003). CONCLUSION: The addition of tirapazamine to paclitaxel and carboplatin does not result in improved survival in advanced NSCLC compared with paclitaxel and carboplatin alone but substantially increases toxicity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Evaluation of factors affecting awareness of and willingness to participate in cancer clinical trials.

PURPOSE: Annually, only 3% of patients participate in cancer clinical trials (CCTs). Barriers to accrual include lack of CCT awareness and uncertain third-party payer coverage. In January 2002, a California law (Senate Bill 37 [SB37]) required all third-party payers to reimburse patient care costs related to CCTs. We evaluated the level of awareness of patients and/or their family members/friends regarding CCTs and SB37. METHODS: We used both a written survey for patients and/or their family members and friends seen in oncology clinics, and a verbal telephone version for Cancer Information Service callers. We tested for correlations between CCT awareness and SB37 knowledge, and willingness to participate in CCTs. RESULTS: Of 1,188 respondents, 59% were aware of CCTs, 19% knew of SB37, and 36% were very likely to consider a CCT. There were significant positive correlations between CCT awareness and willingness to participate (P < .001, Spearman), and between SB37 knowledge and willingness to participate (P = .001, Pearson chi2). Reduced awareness was seen in respondents who were either black or African American (odds ratio [OR], 0.44; P = .004), Hispanic (OR, 0.56; P = .03), had an annual income less than 25,000 dollars (OR, 0.38; P < .001), or had less than a college degree (OR, 0.12 to 0.53; P < .001 to .013). Reduced willingness to participate in CCTs was seen in black or African American participants (OR, 0.38; P < .001), Asians (OR, 0.44; P < .006), or respondents aged 18 to 24 years (OR, 0.35; P = .002). CONCLUSION: These results support the hypothesis that improving CCT awareness and SB37 knowledge especially among lower income, less educated, and minority patients, may potentially overcome barriers to participation and subsequently increase accrual in California.

Adolescent↗
PubMed2005

Impact of the year 2000 Medicare policy change on older patient enrollment to cancer clinical trials.

PURPOSE: A prior analysis by the Southwest Oncology Group (SWOG) showed that women and African American patients were adequately represented on cancer clinical treatment trials but that older patients were substantially underrepresented. Twenty-five percent of patients > or = 65 years old were enrolled onto SWOG trials from 1993 to 1996, whereas 63% of all patients with cancer were > or = 65 years old. Recognition of this under-representation led to a change in Medicare policy in 2000 to include coverage of routine patient care costs of clinical trials. We conducted an updated analysis of accrual trends. METHODS: The proportions of enrollment onto SWOG treatment trials by sex, race/ethnicity, and age (> or = 65 years) were computed for the years 1997 to 2000; corresponding rates in the United States were derived from US Census and National Cancer Institute Surveillance, Epidemiology, and End results data. Additionally, method of payment data were analyzed over time (1993 to 2003) to assess whether patterns in method of payment changed with the new Year 2000 Medicare policy on clinical trials coverage. RESULTS: The results showed continued adequate representation by sex and race/ethnicity. Older patient accrual on SWOG trials increased significantly since 2000, with 31% of patients > or = 65 years old enrolled from 1997 to 2000 and 38% enrolled from 2001 to 2003 (v 25% from 1993 to 1996). The percentage of patients using Medicare plus supplemental insurance also increased beginning in 2000, whereas the percentage of patients using Medicare alone remained the same. CONCLUSION: Method of payment analyses provided evidence that the Year 2000 Medicare policy change had a positive impact, but only for those patients with supplemental private coverage of coinsurance costs. Improvements in the Medicare payment structure could further increase older patient participation in clinical trials.

Aged↗
PubMed2005

Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a Southwest Oncology Group Study.

PURPOSE: Bronchioloalveolar carcinoma (BAC) and adenocarcinomas with BAC features seem to be increasing in incidence, particularly in younger, never-smoking women. Epidermal growth factor receptor (EGFR) inhibitors demonstrated response rates of 20% to 30% in patients with advanced BAC subtypes, but selection methods for patient therapy are not established. PATIENTS AND METHODS: EGFR and HER2 gene copy numbers were assessed by fluorescence in situ hybridization (FISH) in 81 patients treated with gefitinib 500 mg/d (Southwest Oncology Group protocol S0126) and were correlated to treatment outcome. Tumors were classified into two main strata: FISH-positive (high polysomy/gene amplification) and FISH-negative (disomy/low polysomy). RESULTS: In 81 patients, the median survival time for EGFR/FISH-negative patients was 8 months and not yet reached for FISH-positive patients (but approaching 18 months; hazard ratio [HR] = 2.02; P = .042). Median progression-free survival time for EGFR/FISH-positive patients was 9 months versus 4 months for the FISH-negative patients (HR = 1.67; P = .072). In multivariate analysis, EGFR copy number by FISH remained a significant predictive factor for survival after accounting for smoking status, sex, histology, and performance status. Fifty-five patients were evaluated for response using Response Evaluation Criteria in Solid Tumors Group, and 12 of 19 EGFR/FISH-positive patients (63%) demonstrated disease control versus 14 (39%) of 36 patients in the FISH-negative group (P = .087). No association was found between HER2 gene copy number and response (n = 39 patients) or survival (n = 56 patients; P > .10). CONCLUSION: Increased EGFR gene copy number detected by FISH is associated with improved survival after gefitinib therapy in patients with advanced BAC, suggesting FISH methodology can be used to assess survival potential in patients treated with EGFR tyrosine kinase inhibitors.

Adenocarcinoma↗