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Dorff T.B.,University of Southern California | Goldman B.,Southwest Oncology Group Statistical Center | Pinski J.K.,University of Southern California | Mack P.C.,University of California at Davis | And 6 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Interleukin-6 (IL-6) facilitates cancer cell survival via pleotrophic effects. We conducted a multicenter phase II study of CNTO328 (siltuximab) as second-line therapy for men with castration-resistant prostate cancer. Experimental Design: Eligible men had castration-resistant prostate cancer treated with one prior chemotherapy. Subjects were treated with 6 mg/kg CNTO328 i.v. every 2 weeks for 12 cycles. Response was assessed after every three cycles. Primary end point was prostate-specific antigen (PSA) response rate defined as a 50% reduction. Accrual was planned in two stages, with 20 eligible patients in the first stage and 40 overall. Plasma cytokines and growth factors were measured by Luminex. Results: Fifty-three eligible subjects had all received prior taxane therapy. Two (3.8%; 95% CI, 0.5-13.0%) had PSA response. None of the 31 patients with measurable disease had a RECIST (Response Evaluation Criteria in Solid Tumors) response but 7 (23%) had stable disease. With median follow-up of 14.8 months, median progression-free survival was 1.6 months (95% CI, 1.6-1.7) and median overall survival was 11.6 months (95% CI, 7.5-19.0). Grade 3/4 toxicities included disseminated intravascular coagulation (1), central nervous system ischemia (1), elevated aspartate aminotransferase (1), gastritis/esophagitis (2), thrombocytopenia (2), pain (2), leukopenia (1), and neuropathy (2). Median baseline IL-6 levels were 12.5 pg/mL (interquartile range, 2.5-41.5). Patients with IL-6 >12.5 pg/mL had worse survival than those with levels <12.5 pg/mL (53% versus 94%; P = 0.02). After treatment, IL-6 levels were >250-fold higher. Thirty-two of 38 patients had a decline in C-reactive protein plasma levels at 6 weeks. Conclusions: CNTO328 resulted in a PSA response rate of 3.8% and a RECIST stable disease rate of 23%. Declining C-reactive protein levels during treatment may reflect biological activity. Despite evidence of CNTO-mediated IL-6 inhibition, elevated baseline IL-6 levels portended a poor prognosis. ©2010 AACR.

Blanchard E.M.,St Elizabeths Medical Center | Moon J.,Southwest Oncology Group Statistical Center | Hesketh P.J.,Lahey Clinic Medical Center | Kelly K.,University of Kansas Medical Center | And 3 more authors.
Journal of Thoracic Oncology | Year: 2011

PURPOSE: This retrospective analysis sought to investigate the safety, feasibility, and outcomes of platinum doublet therapy in patients aged 70 years or older with advanced non-small cell lung cancer compared with patients younger than 70 years who participated in two randomized phase III trials conducted by the Southwest Oncology Group. PATIENTS AND METHODS: Outcomes and toxicity data from fit patients with stage IIIB or stage IV non-small cell lung cancer treated with cisplatin/vinorelbine and carboplatin/paclitaxel were pooled from Southwest Oncology Group trials 9308 (S9308) and 9509 (S9509) and compared with respect to age. RESULTS: A total of 616 patients were available for efficacy analyses, of which 122 (20%) were aged 70 years or older. The median progression-free survival was 4 months in both age groups (p = 0.71), and response rates were similar. Overall survival was significantly higher in the younger patient cohort (median 9 months versus 7 months, p = 0.04). Individual parameters of toxicity were similar in both age groups. CONCLUSION: Although patients aged 70 years or older derived initial benefit from platinum-based therapy, survival was better in younger patients. Additional studies in this growing patient population are needed to develop treatment strategies that minimize toxicity and increase efficacy. Copyright © 2010 by the international Association fot the Study of lung Cancer.

Tsao A.S.,University of Texas M. D. Anderson Cancer Center | Garland L.,Arizona Cancer Center | Redman M.,Southwest Oncology Group Statistical Center | Kernstine K.,Beckman Research Institute | And 2 more authors.
Journal of Thoracic Oncology | Year: 2011

Malignant pleural mesothelioma (MPM) is difficult to measure radiographically due to the nonradial and variable pattern of growth and response to therapy. Inaccurate and inconsistent tumor measurements often compromise results from clinical trials that are dependent on identifying response rate and progression-free survival. In this article, we sought to provide a practical guide through the Southwest Oncology Group on how to measure MPM by the updated RECIST version 1.1 and by modified RECIST. We hope that these steps will provide a simple means by which computed tomography measurements can be consistently performed, minimizing intra- and interobserver variability. With this consistency, we may be able to better estimate the prognosis and response to therapy. With greater utilization, we will be able to better understand the biology of MPM. Copyright © 2011 The International Association for the Study of Lung Cancer.

Hussain M.,University of Michigan | Tangen C.M.,Southwest Oncology Group Statistical Center | Berry D.L.,Dana-Farber Cancer Institute | Higano C.S.,University of Washington | And 18 more authors.
New England Journal of Medicine | Year: 2013

Background: Castration resistance occurs in most patients with metastatic hormone-sensitive prostate cancer who are receiving androgen-deprivation therapy. Replacing androgens before progression of the disease is hypothesized to prolong androgen dependence. Methods: Men with newly diagnosed, metastatic, hormone-sensitive prostate cancer, a performance status of 0 to 2, and a prostate-specific antigen (PSA) level of 5 ng per milliliter or higher received a luteinizing hormone-releasing hormone analogue and an antiandrogen agent for 7 months. We then randomly assigned patients in whom the PSA level fell to 4 ng per milliliter or lower to continuous or intermittent androgen deprivation, with patients stratified according to prior or no prior hormonal therapy, performance status, and extent of disease (minimal or extensive). The coprimary objectives were to assess whether intermittent therapy was noninferior to continuous therapy with respect to survival, with a one-sided test with an upper boundary of the hazard ratio of 1.20, and whether quality of life differed between the groups 3 months after randomization. Results: A total of 3040 patients were enrolled, of whom 1535 were included in the analysis: 765 randomly assigned to continuous androgen deprivation and 770 assigned to intermittent androgen deprivation. The median follow-up period was 9.8 years. Median survival was 5.8 years in the continuous-therapy group and 5.1 years in the inter-mittent- therapy group (hazard ratio for death with intermittent therapy, 1.10; 90% confidence interval, 0.99 to 1.23). Intermittent therapy was associated with better erectile function and mental health (P<0.001 and P = 0.003, respectively) at month 3 but not thereafter. There were no significant differences between the groups in the number of treatment-related high-grade adverse events. Conclusions: Our findings were statistically inconclusive. In patients with metastatic hormonesensitive prostate cancer, the confidence interval for survival exceeded the upper boundary for noninferiority, suggesting that we cannot rule out a 20% greater risk of death with intermittent therapy than with continuous therapy, but too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy resulted in small improvements in quality of life. Copyright © 2013 Massachusetts Medical Society. All rights reserved.

Stopeck A.T.,Arizona Cancer Center | Unger J.M.,Southwest Oncology Group Statistical Center | Rimsza L.M.,Arizona Cancer Center | LeBlanc M.,Southwest Oncology Group Statistical Center | And 6 more authors.
Blood | Year: 2012

S0515 was a phase 2 trial to determine whether the addition of bevacizumab to cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) plus rituximab (R-CHOP) would improve progression-free survival (PFS) without adding significant toxicity in patients with newly diagnosed advanced diffuse large B-cell lymphoma. A total of 73 patients were enrolled. For the 64 eligible patients, median age was 68 years, and 60% had International Prognostic Index scores more than or equal to 3. The observed 1- and 2-year PFS estimates were 77% and 69%, respectively. These PFS estimates were not statistically different from the expected PFS for this population if treated with R-CHOP alone. Grade 3 or higher toxicities were observed in 81% of patients, including 2 grade 5 events. The majority of serious toxicities were hematologic but also included 5 patients with gastrointestinal perforations, 4 patients with thrombotic events, and 11 patients who developed grade 2 or 3 left ventricular dysfunction. Higher baseline urine VEGF and plasma VCAM levels correlated with worse PFS and overall survival. In conclusion, the addition of bevacizumab to R-CHOP chemotherapy was not promising in terms of PFS and resulted in increased serious toxicities, especially cardiac and gastrointestinal perforations. This study is registered at www.clinical trials.gov as #NCT00121199. © 2012 by The American Society of Hematology.

Zonder J.A.,Barbara Ann Karmanos Cancer Institute | Crowley J.,Southwest Oncology Group Statistical Center | Hussein M.A.,Cleveland Clinic | Bolejack V.,Southwest Oncology Group Statistical Center | And 5 more authors.
Blood | Year: 2010

The Southwest Oncology Group conducted a randomized trial comparing lenalidomide (LEN) plus dexamethasone (DEX; n = 97) to placebo (PLC) plus DEX (n = 95) in newly diagnosed myeloma. Three 35-day induction cycles applied DEX 40 mg/day on days 1 to 4, 9 to 12, and 17 to 20 together with LEN 25 mg/day for 28 days or PLC. Monthly maintenance used DEX 40 mg/day on days 1 to 4 and 15 to 18 along with LEN 25 mg/day for 21 days or PLC. Crossover from PLC-DEX to LEN-DEX was encouraged on progression. One-year progression-free survival, overall response rate, and very good partial response rate were superior with LEN-DEX (78% vs 52%, P =.002; 78% vs 48%, P <.001; 63% vs 16%, P <.001), whereas 1-year overall survival was similar (94% vs 88%; P =.25). Toxicities were more pronounced with LEN-DEX (neutropenia grade 3 or 4:21% vs 5%, P <.001; thromboembolic events despite aspirin prophylaxis: 23.5% [initial LEN-DEX or crossover] vs 5%; P <.001). This trial was registered at www.clinicaltrials. gov as #NCT00064038. © 2010 by The American Society of Hematology 2010;.

Fang M.,Fred Hutchinson Cancer Research Center | Fang M.,University of Washington | Storer B.,Fred Hutchinson Cancer Research Center | Estey E.,Fred Hutchinson Cancer Research Center | And 8 more authors.
Blood | Year: 2011

Monosomal karyotype (MK), defined as ≥ 2 autosomal monosomies or a single monosomy in the presence of other structural abnormalities, was confirmed by several studies to convey an extremely poor prognosis in patients with acute myeloid leukemia (AML) with a 4-year overall survival after diagnosis of < 4%. A recent investigation by the Southwest Oncology Group found that the only MK+ patients alive and disease free > 6 years from diagnosis received allogeneic hematopoietic cell transplantation (HCT). To expand this observation, we retrospectively analyzed 432 patients treated with HCT at the Fred Hutchinson Cancer Research Center, 14% of whom were MK+. The 4-year overall survival of patients after HCT was 25% for MK+ AML and 56% for MK- AML (adjusted hazard ratio = 2.29, P < .0001). Among the MK+ patients, complex karyotype was associated with a significantly worse outcome than patients with noncomplex karyotype (adjusted hazard ratio = 2.70, P = .03). Thus, although the prognosis of MK+ patients remains worse than that for MK- patients in the transplantation setting, HCT appears to improve the overall outcome of MK+ patients, especially patients without a complex karyotype. However, the 28% of MK+ patients > 60 years had only a 6% 4-year survival rate after HCT, stressing the need for new approaches in these patients. © 2011 by The American Society of Hematology.

Medeiros B.C.,Stanford University | Othus M.,Stanford University | Othus M.,Southwest Oncology Group Statistical Center | Fang M.,Fred Hutchinson Cancer Research Center | And 4 more authors.
Blood | Year: 2010

Monosomal karyotype (MK), defined as 2 or more monosomies, or a single monosomy in the presence of structural abnormalities, has recently been reported as identifying a distinct subset of acute myeloid leukemia (AML) patients with an extremely poor prognosis. In an effort to confirm this observation, we analyzed the prognostic impact of MK in 1344 AML patients between the ages of 16 and 88 years treated on Southwest Oncology Group protocols. MK was found in 176 (13%) patients. The proportion of patients with MK increased with age, being present in 4% of patients age 30 or younger, but in 20% of those over age 60. Ninety-eight percent of MK cases were within the unfavorable cytogenetic risk category and comprised 40% of this group. The complete remission rate in patients with unfavorable cytogenetics without MK was 34% versus 18% with MK (P < .01). The 4-year overall survival of patients with unfavorable cytogenetics but without MK was 13% in contrast to a 4-year survival of only 3% with MK (P < .01). Thus, MK defines a sizeable subset of patients with unfavorable cytogenetics who have a particularly poor prognosis. © 2010 by The American Society of Hematology.

Iqbal S.,University of Southern California | Goldman B.,Southwest Oncology Group Statistical Center | Fenoglio-Preiser C.M.,University of Cincinnati | Lenz H.J.,University of Southern California | And 4 more authors.
Annals of Oncology | Year: 2011

Background: Lapatinib (GW572016) is a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/ErbB2), which are reported as overexpressed in 15%-45% of gastric cancers, making them potential targets. Patients and methods: The primary objective of this study was to assess response rate. Secondary objectives included overall survival (OS), toxicity, and the relationship of EGFR, ErbB2, and markers of angiogenesis with clinical outcome. Lapatinib was administered to chemonaive metastatic gastric cancer patients at a dose of 1500 mg orally daily for 28 days. Results: The study enrolled 47 patients from February 2005 until May 2006. Four patients (9%) had a confirmed partial response (PR), 1 (2%) had an unconfirmed PR, and 10 (23%) had stable disease. Median (95% confidence interval) time to treatment failure was 1.9 (1.6-3.1) months and OS was 4.8 (3.2-7.4) months. Significant adverse events: one grade 4 cardiac ischemia/infarction, one grade 4 fatigue, and one grade 4 emesis. One treatment-related death was due to central nervous system ischemia. An exploratory analysis of markers revealed gene expression of HER2, interleukin (IL)-8 and genomic polymorphisms IL-8, and vascular endothelial growth factor correlated with OS. Conclusions: Lapatinib is well tolerated, with modest single-agent activity in advanced/metastatic gastric cancer patients. Potential molecular correlatives were identified which warrant further validation.

Sinicrope F.A.,Mayo Medical School | Foster N.R.,Mayo Medical School | Sargent D.J.,Mayo Medical School | O'Connell M.J.,Mayo Medical School | Rankin C.,Southwest Oncology Group Statistical Center
Clinical Cancer Research | Year: 2010

Purpose: Obesity is associated with an increased risk of colon cancer. However, the influence of body mass index (BMI) on the prognosis of colon cancer survivors and its relationship to gender remains unknown. Experimental Design: BMI (kg/m2) was categorized in patients with tumor-node-metastasis stage II and III colon carcinomas (n = 4,381) enrolled in seven randomized trials of 5-fluorouracil-based adjuvant chemotherapy. Cox proportional hazards models were used to determine the association of BMI with disease-free survival (DFS) and overall survival (OS). Results: Among colon cancer patients, 868 (20%) were obese (BMI,≥30 kg/m2), of which 606 were class 1 (BMI, 30-34 kg/m2) and 262 were class 2,3 (BMI, ≥35 kg/m2). Obese versus normal-weight patients were more likely to be younger, have distal tumors, show intact DNA mismatch repair, and have more lymph node metastases (P < 0.017). In a multivariate analysis, BMI was significantly associated with both DFS (P = 0.030) and OS (P = 0.0017). Men with class 2,3 obesity showed reduced OS compared with normal-weight men [hazard ratio, 1.35; 95% confidence interval, 1.02-1.79; P = 0.039]. Women with class I obesity had reduced OS [hazard ratio, 1.24; 95% confidence interval, 1.01-1.53; P = 0.045] compared with normal-weight women. Overweight status was associated with improved OS in men (P = 0.006), and underweight women had significantly worse OS (P = 0.019). BMI was not predictive of therapeutic benefit. Conclusions: Obesity is an independent prognostic variable in colon cancer survivors and shows gender-related differences. These data suggest that obesity-related biological factors can influence clinical outcome. ©2010 AACR.

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