-
[show abstract]
[hide abstract]
ABSTRACT: Cancer and Leukemia Group B conducted a randomized phase II trial to investigate two novel chemotherapy regimens in combination with concurrent thoracic radiation therapy (TRT).
Patients with unresectable stage III non-small-cell lung cancer (NSCLC) were randomly assigned to carboplatin (area under the curve, 5) and pemetrexed (500 mg/m(2)) every 21 days for four cycles and TRT (70 Gy; arm A) or the same treatment with cetuximab administered concurrent only with TRT (arm B). Patients in both arms received up to four cycles of pemetrexed as consolidation therapy. The primary end point was the 18-month overall survival (OS) rate; if the 18-month OS rate was ≥ 55%, the regimen(s) would be considered for further study.
Of the 101 eligible patients enrolled (48 in arm A and 53 in arm B), 60% were male; the median age was 66 years (range, 32 to 81 years); 44% and 35% had adenocarcinoma and squamous carcinoma, respectively; and more patients enrolled onto arm A compared with arm B had a performance status of 0 (58% v 34%, respectively; P = .04). The 18-month OS rate was 58% (95% CI, 46% to 74%) in arm A and 54% (95% CI, 42% to 70%) in arm B. No significant difference in OS between patients with squamous and nonsquamous NSCLC was observed (P = .667). The toxicities observed were consistent with toxicities associated with concurrent chemoradiotherapy.
The combination of pemetrexed, carboplatin, and TRT met the prespecified criteria for further evaluation. This regimen should be studied further in patients with locally advanced unresectable nonsquamous NSCLC.
Journal of Clinical Oncology 08/2011; 29(23):3120-5. · 18.37 Impact Factor
-
Mark A Socinski,
Robert N Raju, Thomas Stinchcombe,
Darren M Kocs,
Linda S Couch,
David Barrera,
Steven R Rousey,
Janak K Choksi,
Robert Jotte,
Debra A Patt,
Phillip O Periman,
Howard R Schlossberg,
Charles H Weissman,
Yunfei Wang,
Lina Asmar,
Sharon Pritchard,
Jane Bromund,
Guangbin Peng,
Joseph Treat,
Coleman K Obasaju
[show abstract]
[hide abstract]
ABSTRACT: Enzastaurin is an oral serine/threonine kinase inhibitor that targets protein kinase C-beta (PKC-β) and the phosphatidylinositol-3-kinase/AKT pathway. This trial assessed pemetrexed-carboplatin ± enzastaurin to docetaxel-carboplatin in advanced non-small cell lung cancer.
Patients with stage IIIB (with pleural effusion) or IV non-small cell lung cancer and performance status 0 or 1 were randomized to one of the three arms: (A) pemetrexed 500 mg/m and carboplatin area under the curve 6 once every 3 weeks for up to 6 cycles with a loading dose of enzastaurin 1125 or 1200 mg followed by 500 mg daily until disease progression, (B) the same regimen of pemetrexed-carboplatin without enzastaurin, or (C) docetaxel 75 mg/m and carboplatin area under the curve 6 once every 3 weeks for up to six cycles. The primary end point was time to disease progression (TTP).
Between March 2006 and May 2008, 218 patients were randomized. Median TTP was 4.6 months for pemetrexed-carboplatin-enzastaurin, 6.0 months for pemetrexed-carboplatin, and 4.1 months for docetaxel-carboplatin (differences not significant). Median survival was 7.2 months for pemetrexed-carboplatin-enzastaurin, 12.7 months for pemetrexed-carboplatin, and 9.2 months for docetaxel-carboplatin (log-rank p = 0.05). Compared with the other arms, docetaxel-carboplatin was associated with lower rates of grade 3 thrombocytopenia and anemia but a higher rate of grade 3 or 4 febrile neutropenia.
There was no difference in TTP between the three arms, but survival was longer with pemetrexed-carboplatin compared with docetaxel-carboplatin. Enzastaurin did not add to the activity of pemetrexed-carboplatin.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 12/2010; 5(12):1963-9. · 4.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Vinflunine is a novel vinca alkaloid with promising single agent clinical activity. Pemetrexed has at least additive activity with other vincas. A phase I trial was undertaken to assess the safety of vinflunine and pemetrexed in patients with refractory solid tumors.
A standard 3-patient cohort dose escalation scheme was used to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the vinflunine/pemetrexed combination. Pemetrexed 500 mg/m(2) was given with vinflunine 280 mg/m(2) (cohort 1), 300 mg/m(2) (cohort 2) or 320 mg/m(2) (cohort 3) on day 1 of a 21-day cycle.
19 patients were enrolled, median age 58 years (range 32 to 77) and had a median of 3 (range 1-6) prior therapies. DLT occurred 1 of 6 pts in cohort 1 (thrombocytopenia, hyponatremia), 2 of 10 pts in cohort 2 (febrile neutropenia, hyponatremia, hyperbilirubinema; febrile neutropenia), and 2 of 3 pts in cohort 3 (febrile neutropenia, hypokalemia; febrile neutropenia). 1 pt in cohort 2 died prior to completion of cycle 1 likely from disease progression. Most common grade 3/4 adverse events were neutropenia (7), leukopenia (5). Febrile neutropenia occurred in 4 patients (21%). No objective responses were seen. Two patients (breast and lung) had prolonged stable disease for 25 and 20 cycles respectively.
Based on this experience we recommend vinflunine 300 mg/m(2) and pemetrexed 500 mg/m(2) in combination every 3 weeks for future study. At these doses, the combination of vinflunine and pemetrexed was tolerable in this heavily pretreated population. Hematologic toxicity, including febrile neutropenia, was prominent.
Investigational New Drugs 10/2009; 29(1):131-6. · 3.36 Impact Factor
-
Thomas E Stinchcombe,
Lydia Hodgson,
James E Herndon,
Michael J Kelley,
M Giulia Cicchetti,
Nithya Ramnath,
Harvey B Niell,
James N Atkins,
Wallace Akerley,
Mark R Green,
Everett E Vokes
[show abstract]
[hide abstract]
ABSTRACT: In Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival and demonstrated no significant benefit from the addition of induction chemotherapy. The primary objective of this analysis was to dichotomize patients into prognostic groups using factors predictive of survival and to investigate whether induction chemotherapy was beneficial in either prognostic group.
A Cox proportional hazard model was used to assess the impact on survival of the following factors: (>or=70 versus <70 years), gender, race, stage (IIIB versus IIIA), hemoglobin (hgb) (<13 versus >or=13 g/dl), performance status (PS) (1 versus 0), weight loss (>or=5% versus <5%), treatment arm, and the interaction between weight loss and hgb.
Factors predictive of decreased survival were weight loss >or=5%, age >or=70 years, PS of 1, and hgb <13 g/dl (p < 0.05). Patients were classified as having >or=2 poor prognostic factors (n = 165) or <or=1 factor (n = 166). The hazard ratio (HR) for overall survival for the patients with >or=2 versus patients with <or=1 was 1.88 [95% confidence interval (CI), 1.49-2.37; p = <0.0001]; median survival times observed were 9 (95% CI, 8-11) and 18 (95% CI, 16-24) months, respectively. There was no significant difference in survival between treatment arms in patients with >or=2 factors (HR = 0.86, 95% CI, 0.63-1.17; p = 0.34) or <or=1 factor (HR = 0.97, 95% CI, 0.70-1.35; p = 0.87).
There is no evidence that induction chemotherapy is beneficial in either prognostic group.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 07/2009; 4(9):1117-25. · 4.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Combined modality treatment is the standard of care for patients (pts) with unresectable stage III non-small cell lung cancer. Dose escalation of radiotherapy is one strategy used to improve locoregional control and survival, but it increases the risk of both early and late treatment related toxicities.
From May 1996 to August 2004, a total of 112 stage III non-small cell lung cancer pts were treated on 4 phase I/II or phase II trials to assess the safety and feasibility of high-dose (60-90 Gy) thoracic conformal radiotherapy. Patients who received >/=66 Gy (n = 88) were included in an analysis of late complications. Late complications were defined as complications that developed or persisted >/=90 days postradiotherapy. The classic lung toxicities of radiation pneumonitis and fibrosis were not included in this analysis.
Of the 88 patients included in this analysis of late complications, 21 patients (24%) developed a late complication and a total of 28 late complications were observed. The late complications were: pulmonary (n = 5; bronchial stenosis [n = 3] and fatal pulmonary hemoptysis [n = 2]), esophageal (n = 6), cardiac (n = 9), osseous (n = 6), and second primary tumor (n = 2). The median survival for all patients enrolled on the 4 trials (with 95% confidence interval [CI]) was 24.7 months (18.1-30.4 months), and the 5-year overall survival (with 95% CI) was 24% (16-32%). Data to assess for radiographic evidence of local progression were available for 99 patients, and the rate of local progression was 43% (95% CI 34-53%).
High-dose thoracic conformal radiotherapy is feasible and results in promising survival outcomes. Late complications occur in a minority of patients.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2009; 4(1):74-9. · 4.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A phase I clinical trial was conducted to determine the safety, pharmacokinetic parameters, and efficacy of orally administered isoflavones (genistein and daidzein, potential cancer chemotherapeutic agents) over a 3-mo period in men with prostate neoplasia. Twenty men, ages 40 and above, with stage B, C, or D adenocarcinoma of the prostate were treated with a multiple-dose regimen of a soy isoflavone formulation (delivering approximately 300 or 600 mg/day genistein and half this much daidzein) for 84 days. The delivered dose of isoflavones was more than 10-fold higher than that typically taken by prostate cancer patients. In men with prostate cancer, relatively minor side effects of chronic isoflavone treatment were observed including some estrogenic effects (breast changes, increased frequency of hot flashes). Serum dehydroepiandrosterone was decreased by 31.7% (P = 0.0004) at the end of treatment. Except for those subjects whose prostate-specific antigen (PSA) values were below 0.4 ng/ml, subjects had a history of increasing PSA levels prior to the trial. This increase continued during the trial both while on soy isoflavones and after treatment was discontinued. On average the rate of rise accelerated after soy isoflavones were discontinued, but that difference did not attain statistical significance. Genistein and daidzein were rapidly cleared from plasma and excreted in urine. Pharmacokinetic data for chronic dose administration were similar to single-dose administration for the isoflavones investigated except that we observed slightly longer circulation time for daidzein.
Nutrition and Cancer 02/2004; 48(2):160-70. · 2.78 Impact Factor
