Publications by authors named "Dorothy Watson"

24 Publications

  • Page 1 of 1

An initial genetic analysis of gemcitabine-induced high-grade neutropenia in pancreatic cancer patients in CALGB 80303 (Alliance).

Pharmacogenet Genomics 2019 08;29(6):123-131

Duke Cancer Institute.

Objectives: One of the standard of care regimens for advanced pancreatic cancer is gemcitabine-based chemotherapy. The efficacy of gemcitabine is limited by dose-limiting hematologic toxicities especially neutropenia. Uncovering the variability of these toxicities attributed to germline DNA variation is of great importance.

Patients And Methods: CALGB 80303 was a randomized study in advanced pancreatic cancer patients treated with gemcitabine with or without bevacizumab. The study protocol included genotyping of genes of gemcitabine disposition (CDA, DCTD, SLC29A1, SLC28A1, and SLC29A2), as well as a genome-wide analysis. The clinical phenotype was time to early high-grade neutropenia event accounting for progression or death or other treatment-terminating adverse events as competing for informative events. The inference was carried out on the basis of the association between genotype and cause-specific hazard of a neutropenic event.

Results: The primary analyses were carried out on the basis of 294 genetically estimated European pancreatic cancer patients. For CDA rs2072671 (A>C), AC and CC patients had a lower risk of neutropenia than AA patients (P=0.01, hazard ratio: 0.61, 95% confidence interval: 0.41-0.89). For SLC28A1 rs3825876 (G>A), AA patients have a higher risk of neutropenia than GA and GG patients (P=0.02, hazard ratio: 1.51, 95% confidence interval: 1.06-2.16). CDA rs2072671 was associated with increased mRNA expression in whole blood in three studies (P=2.7e-14, 6.61e-62, and 9.70e-65). In the genome-wide analysis, variants in TGFB2 were among the top hits (lowest P=1.62e-06) but had no effect in luciferase assays.

Conclusion: This is the first genetic analysis of gemcitabine-induced neutropenia using a competing risk model in a prospective randomized clinical study has proposed a potentially novel mechanism of the protective effect of the CDA rs2072671 variant. Further confirmation is needed.
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August 2019

Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy.

Clin Cancer Res 2016 Oct 3;22(19):4890-4900. Epub 2016 May 3.

UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Personalized Medicine Institute, Moffitt Cancer Center, Tampa, Florida.

Purpose: Discovery of SNPs that predict a patient's risk of docetaxel-induced neuropathy would enable treatment individualization to maximize efficacy and avoid unnecessary toxicity. The objectives of this analysis were to discover SNPs associated with docetaxel-induced neuropathy and mechanistically validate these associations in preclinical models of drug-induced neuropathy.

Experimental Design: A genome-wide association study was conducted in metastatic castrate-resistant prostate cancer patients treated with docetaxel, prednisone and randomized to bevacizumab or placebo on CALGB 90401. SNPs were genotyped on the Illumina HumanHap610-Quad platform followed by rigorous quality control. The inference was conducted on the cumulative dose at occurrence of grade 3+ sensory neuropathy using a cause-specific hazard model that accounted for early treatment discontinuation. Genes with SNPs significantly associated with neuropathy were knocked down in cellular and mouse models of drug-induced neuropathy.

Results: A total of 498,081 SNPs were analyzed in 623 Caucasian patients, 50 (8%) of whom experienced grade 3+ neuropathy. The 1,000 SNPs most associated with neuropathy clustered in relevant pathways including neuropathic pain and axonal guidance. An SNP in VAC14 (rs875858) surpassed genome-wide significance (P = 2.12 × 10, adjusted P = 5.88 × 10). siRNA knockdown of VAC14 in stem cell-derived peripheral neuronal cells increased docetaxel sensitivity as measured by decreased neurite processes (P = 0.0015) and branches (P < 0.0001). Prior to docetaxel treatment, VAC14 heterozygous mice had greater nociceptive sensitivity than wild-type litter mate controls (P = 0.001).

Conclusions: VAC14 should be prioritized for further validation of its potential role as a predictor of docetaxel-induced neuropathy and biomarker for treatment individualization. Clin Cancer Res; 22(19); 4890-900. ©2016 AACR.
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October 2016

Participation in Cancer Pharmacogenomic Studies: A Study of 8456 Patients Registered to Clinical Trials in the Cancer and Leukemia Group B (Alliance).

J Natl Cancer Inst 2015 Oct 9;107(10). Epub 2015 Jul 9.

Personalized Medicine, Mission Cancer Care, Mission Health, Asheville, NC (LGD); Biostatistics Core, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, NC (AMD); Alliance Statistics and Data Center, Duke University, Durham, NC (formerly the Cancer and Leukemia Group B Statistical and Data Management Center, Duke University, Durham, NC) (KO); GlaxoSmithKline, Research Triangle Park, NC (DW); Independent contractor, Williamsville, NY (KD); Department of Medicine and Center for Personalized Therapeutics, University of Chicago, Chicago, IL (PNF, MJR); DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center, Tampa, FL (HLM).

Background: Clinically annotated specimens from cancer clinical trial participants offer an opportunity for discovery and validation of pharmacogenomic findings. The purpose of this observational study is to better understand patient/institution factors that may contribute to participation in the pharmacogenomic component of prospective cancer clinical trials.

Methods: Patient demographic information (age, sex, self-reported race) and institutional characteristics (CALGB/CTSU site, "diversity," and accrual) were evaluated for 8456 patients enrolled in seven CALGB phase III studies with a pharmacogenomic component. All statistical tests were two-sided.

Results: The majority of patients (81%) consented to participate in the pharmacogenomic component. However, in a multivariable analysis, site (CALGB vs CTSU) and "institutional diversity" (percent minority cancer patients on national trials) were statistically significantly associated with participation. For both whites and nonwhites, patients from CALGB sites were more likely to participate compared with patients from CTSU sites (whites: odds ratio [OR] = 2.26, 95% confidence interval [CI] = 1.68 to 3.04, P < .001; nonwhites: OR = 1.79, 95% CI = 1.52 to 2.11, P < .001). However, as "institutional diversity" increased, the likelihood of participation in the pharmacogenomics component decreased for both white (OR = 0.94, 95% CI = 0.91 to 0.97, P < .001) and nonwhite patients (OR = 0.90, 95% CI = 0.81 to 1.00, P = .05).

Conclusions: Most clinical trial cancer patients across geographical, racial, and practice settings are willing to participate in pharmacogenomic studies. However, to promote equitable benefit to the larger cancer community, optimization of both patient and institutional participation are needed. Institutional factors may be even more compelling than patient demographics. Prospective studies are needed to identify and address barriers/incentives to participation in pharmacogenomic research at the patient, clinician, and institutional levels.
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October 2015

A pharmacogenetic study of aldehyde oxidase I in patients treated with XK469.

Pharmacogenet Genomics 2014 Feb;24(2):129-32

aDepartment of Medicine, The University of Chicago, Chicago, Illinois bDepartment of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, USA.

XK469 (NSC 697887) is a selective topoisomerase II β inhibitor eliminated mainly by aldehyde oxidase I (AOX1). We performed a candidate gene study to investigate whether AOX1 genetic variation contributes to interindividual variability in XK469 clearance. Forty-one AOX1 single nucleotide polymorphisms (SNPs) and seven liver expression quantitative trait loci were genotyped in White patients with advanced refractory solid tumors (n=59) and leukemia (n=33). We found a significant decrease in clearance (τ=-0.32, P=0.003) in solid tumor patients with rs10931910, although it failed to replicate in the leukemia cohort (τ=0.18, P=0.20). Four other AOX1 SNPs were associated with clearance (P=0.01-0.02) in only one of the two cohorts. Our study provides a starting point for future investigations on the functionality of AOX1 SNPs. However, variability in XK469 clearance cannot be attributed to polymorphisms in AOX1.
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February 2014

Autologous transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia achieves outcomes similar to allogeneic transplantation: results of CALGB Study 10001 (Alliance).

Haematologica 2014 Jan 27;99(1):111-5. Epub 2013 Sep 27.

Allogeneic stem cell transplantation is the standard approach to Philadelphia chromosome positive acute lymphoblastic leukemia. We hypothesized that imatinib plus sequential chemotherapy will result in significant leukemia cell cytoreduction in patients with Philadelphia chromosome positive acute lymphoblastic leukemia, allowing collection of normal hematopoietic stem cells uncontaminated by residual BCR/ABL1(+) lymphoblasts and thus reduce the likelihood of relapse after autologous stem cell transplantation for patients under 60 years of age without sibling donors. We enrolled 58 patients; 19 underwent autologous and 15 underwent allogeneic stem cell transplantation on study. Imatinib plus sequential chemotherapy resulted in reverse-transcriptase polymerase chain reaction-negative stem cells in 9 patients and remained minimally positive in 4 (6 were not evaluable). Overall survival (median 6.0 years vs. not reached) and disease-free survival (median 3.5 vs. 4.1 years) were similar between those who underwent autologous and those who underwent allogeneic stem cell transplantation. We conclude that autologous stem cell transplantation represents a safe and effective alternative for allogeneic stem cell transplantation in Philadelphia chromosome positive acute lymphoblastic leukemia patients without sibling donors ( identifier:00039377).
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January 2014

Comparison of performance status with peak oxygen consumption in operable patients with non-small-cell lung cancer.

Respirology 2014 Jan;19(1):105-8

Division of Respiratory Medicine, Rockyview Hospital, University of Calgary, Calgary, Alberta, Canada.

Background And Objective: In this era of increasing options for treatment of 'surgical' lung cancer patients, preoperative physiologic assessment of accurate patient selection is becoming more important. The variability in an objective measure of cardiorespiratory fitness (peak oxygen consumption (VO2peak )) across performance in operable non-small-cell lung cancer (NSCLC) patients enrolled in the Cancer and Leukemia Group B trial was compared.

Methods: Using a cross-sectional design, 392 NSCLC patients underwent an incremental cardiopulmonary cycling exercise test to symptom limitation with expired gas analysis to determine VO2peak . Performance status (PS) was assessed using the Eastern Cooperative Oncology Group (ECOG) tool.

Results: There was a significant decrease in VO2peak across increasing ECOG categories (P < 0.0001). However, there was a large range in VO2peak for any given ECOG category with overlap between categories (ECOG 0: 5.0-31.5 mL/kg/min; ECOG 1: 4.3-24.8 mL/kg/min; ECOG 2: 8.9-21.9 mL/kg/min; ECOG 3; 3.3-11.7 mL/kg/min).

Conclusions: PS scoring systems do not provide a sensitive measure of functional status. Objective measures such as VO2peak may be a useful in the clinical management of oncology patients.
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January 2014

Integration of cell line and clinical trial genome-wide analyses supports a polygenic architecture of Paclitaxel-induced sensory peripheral neuropathy.

Clin Cancer Res 2013 Jan 30;19(2):491-9. Epub 2012 Nov 30.

Sections of Hematology/Oncology and Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.

Purpose: We sought to show the relevance of a lymphoblastoid cell line (LCL) model in the discovery of clinically relevant genetic variants affecting chemotherapeutic response by comparing LCL genome-wide association study (GWAS) results to clinical GWAS results.

Experimental Design: A GWAS of paclitaxel-induced cytotoxicity was conducted in 247 LCLs from the HapMap Project and compared with a GWAS of sensory peripheral neuropathy in patients with breast cancer (n = 855) treated with paclitaxel in the Cancer and Leukemia Group B (CALGB) 40101 trial. Significant enrichment was assessed by permutation resampling analysis.

Results: We observed an enrichment of LCL cytotoxicity-associated single-nucleotide polymorphisms (SNP) in the sensory peripheral neuropathy-associated SNPs from the clinical trial with concordant allelic directions of effect (empirical P = 0.007). Of the 24 SNPs that overlap between the clinical trial (P < 0.05) and the preclinical cytotoxicity study (P < 0.001), 19 of them are expression quantitative trait loci (eQTL), which is a significant enrichment of this functional class (empirical P = 0.0447). One of these eQTLs is located in RFX2, which encodes a member of the DNA-binding regulatory factor X family. Decreased expression of this gene by siRNA resulted in increased sensitivity of Neuroscreen-1(NS-1; rat pheochromocytoma) cells to paclitaxel as measured by reduced neurite outgrowth and increased cytotoxicity, functionally validating the involvement of RFX2 in nerve cell response to paclitaxel.

Conclusions: The enrichment results and functional example imply that cellular models of chemotherapeutic toxicity may capture components of the underlying polygenic architecture of related traits in patients.
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January 2013

A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101.

Clin Cancer Res 2012 Sep 27;18(18):5099-109. Epub 2012 Jul 27.

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 1550 4th Street RH584E, San Francisco, CA 94158-2911, USA.

Purpose: Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for the development of this toxicity.

Experimental Design: A prospective pharmacogenetic analysis of patients with primary breast cancer, randomized to the paclitaxel arm of CALGB 40101, was used to identify genetic predictors of the onset and severity of sensory peripheral neuropathy. A genome-wide association study in 855 subjects of European ancestry was conducted and findings were replicated in additional European (n = 154) and African American (n = 117) subjects.

Results: A single nucleotide polymorphism in FGD4 was associated with the onset of sensory peripheral neuropathy in the discovery cohort [rs10771973; HR, 1.57; 95% confidence interval (CI), 1.30-1.91; P = 2.6 × 10(-6)] and in a European (HR, 1.72; 95% CI, 1.06-2.80; P = 0.013) and African American (HR, 1.93; 95% CI, 1.13-3.28; P = 6.7 × 10(-3)) replication cohort. There is also evidence that markers in additional genes, including EPHA5 (rs7349683) and FZD3 (rs10771973), were associated with the onset or severity of paclitaxel-induced sensory peripheral neuropathy.

Conclusions: A genome-wide association study has identified novel genetic markers of paclitaxel-induced sensory peripheral neuropathy, including a common polymorphism in FGD4, a congenital peripheral neuropathy gene. These findings suggest that genetic variation may contribute to variation in development of this toxicity. Validation of these findings may allow for the identification of patients at increased risk of peripheral neuropathy and inform the use of an alternative to paclitaxel and/or the clinical management of this toxicity.
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September 2012

Measuring population mental health and social well-being.

Int J Public Health 2012 Apr 3;57(2):421-30. Epub 2011 Nov 3.

Health Promotion Research Centre, National University of Ireland, 16 Distillery Road, Galway, Ireland.

Objectives: This paper examines the relationships between indicators of positive and negative dimensions of mental health, social well-being and physical health.

Methods: The paper reports on data collected in the third National Survey of Lifestyle, Attitudes and Nutrition (SLÁN 2007), a cross-sectional survey conducted with a representative sample of 10,364 Irish adults. The survey included measures of positive mental health and non-specific psychological distress from the SF-36 questionnaire, together with measures of social well-being, subjective health, and selected health behaviours.

Results: Positive mental health is predicted by lower levels of loneliness and higher levels of social support. Better self-rated health, positive health behaviours and lower GP consultation rates are associated with higher levels of positive mental health. Lower levels of social well-being, were found to be the strongest predictors of negative mental health.

Conclusions: Social well-being and health behaviours correlate with both positive and negative mental health. These findings highlight the need to endorse comprehensive approaches to population mental health promotion. The inclusion of both positive and negative mental health indicators in future population health surveys is supported by the findings.
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April 2012

Peak oxygen consumption and long-term all-cause mortality in nonsmall cell lung cancer.

Cancer 2010 Oct;116(20):4825-32

Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.

Background: Identifying strong markers of prognosis is critical to optimize treatment and survival outcomes in patients with nonsmall cell lung cancer (NSCLC). The authors investigated the prognostic significance of preoperative cardiorespiratory fitness (peak oxygen consumption [VO(2peak)]) among operable candidates with NSCLC.

Methods: By using a prospective design, 398 patients with potentially resectable NSCLC enrolled in Cancer and Leukemia Group B 9238 were recruited between 1993 and 1998. Participants performed a cardiopulmonary exercise test to assess VO(2peak) and were observed until death or June 2008. Cox proportional models were used to estimate the risk of all-cause mortality according to cardiorespiratory fitness category defined by VO(2peak) tertiles (<0.96 of 0.96-1.29/>1.29 L/min⁻¹) with adjustment for age, sex, and performance status.

Results: Median follow-up was 30.8 months; 294 deaths were reported during this period. Compared with patients achieving a VO(2peak) <0.96 L/min⁻¹, the adjusted hazard ratio (HR) for all-cause mortality was 0.64 (95% confidence interval [CI], 0.46-0.88) for a VO(2peak) of 0.96 to 1.29 L/min⁻¹, and 0.56 (95% CI, 0.39-0.80) for a VO(2peak) of >1.29 L/min⁻¹) (P(trend) = .0037). The corresponding HRs for resected patients were 0.66 (95% CI, 0.46-0.95) and 0.59 (95% CI, 0.40-0.89) relative to the lowest VO(2peak) category (P(trend) = .0247), respectively. For nonresected patients, the HRs were 0.78 (95% CI, 0.34-1.79) and 0.39 (95% CI, 0.16-0.94) relative to the lowest category (P(trend) = .0278).

Conclusions: VO(2peak) is a strong independent predictor of survival in NSCLC that may complement traditional markers of prognosis to improve risk stratification and prognostication.
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October 2010

Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups.

J Clin Oncol 2008 Nov 22;26(31):5043-51. Epub 2008 Sep 22.

Tufts Medical Center, Division of Medical Oncology, Tufts-NEMC, Boston, MA 02111, USA.

Purpose: Adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC) is now accepted on the basis of several randomized clinical trials (RCTs) that demonstrated improved survival. Although there is strong evidence that adjuvant chemotherapy is effective in stages II and IIIA NSCLC, its utility in stage IB disease is unclear. This report provides a mature analysis of Cancer and Leukemia Group B (CALGB) 9633, the only RCT designed specifically for stage IB NSCLC.

Patients And Methods: Within 4 to 8 weeks of resection, patients were randomly assigned to adjuvant chemotherapy or observation. Eligible patients had pathologically confirmed T2N0 NSCLC and had undergone lobectomy or pneumonectomy. Chemotherapy consisted of paclitaxel 200 mg/m(2) intravenously over 3 hours and carboplatin at an area under the curve dose of 6 mg/mL per minute intravenously over 45 to 60 minutes every 3 weeks for four cycles. The primary end point was overall survival.

Results: Three hundred-forty-four patients were randomly assigned. Median follow-up was 74 months. Groups were well-balanced with regard to demographics, histology, and extent of surgery. Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths. Survival was not significantly different (hazard ratio [HR], 0.83; CI, 0.64 to 1.08; P = .12). However, exploratory analysis demonstrated a significant survival difference in favor of adjuvant chemotherapy for patients who had tumors > or = 4 cm in diameter (HR, 0.69; CI, 0.48 to 0.99; P = .043).

Conclusion: Because a significant survival advantage was not observed across the entire cohort, adjuvant chemotherapy should not be considered standard care in stage IB NSCLC. Given the magnitude of observed survival differences, CALGB 9633 was underpowered to detect small but clinically meaningful improvements. A statistically significant survival advantage for patients who had tumors > or = 4 cm supports consideration of adjuvant paclitaxel/carboplatin for stage IB patients who have large tumors.
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November 2008

Interruptions of once-daily thoracic radiotherapy do not correlate with outcomes in limited stage small cell lung cancer: analysis of CALGB phase III trial 9235.

Lung Cancer 2008 Oct 25;62(1):92-8. Epub 2008 Mar 25.

SUNY Upstate Medical University, Radiation Oncology Department, 750 E. Adams Street, Syracuse, NY 13210, United States.

Purpose: Retrospective data suggests prolonging the time to complete thoracic radiotherapy (TRT) may negatively impact tumor control and survival in limited stage small cell lung cancer (LSCLC). We examined the association between TRT duration and outcomes on a prospective phase III study.

Material And Methods: This review included 267 patients who received protocol TRT on a phase III CALGB LSCLC study assessing the addition of tamoxifen to standard chemo-radiotherapy. TRT, to a planned dose of 50Gy in 2Gy daily fractions, was initiated with the fourth chemotherapy cycle. TRT interruptions were mandated for hematologic toxicity (granulocytes<1000/mm3 or platelets<75,000/mm3) and esophageal toxicity (dysphagia necessitating intravenous hydration).

Results: TRT interruptions > or =3 days occurred in 115 patients (43%), most frequently during the 4th week of TRT, and did not differ between treatment arms. Hematologic toxicity and esophageal toxicity were the most frequent indications for interrupting TRT. Variables including advanced age (>70 years), gender, race, or radiotherapy treatment volume did not predict for TRT interruptions. Overall survival (OS) and local tumor control did not correlate with the administration of TRT interruptions or with TRT duration.

Conclusion: Toxicity mandated interruptions of conventional dose, once-daily, TRT may not adversely affect outcomes for patients receiving TRT concurrent with chemotherapy (cycle 4) for LSCLC. The implications for accelerated or high dose TRT regimens are not clear.
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October 2008

Phase II trial of weekly dose-dense paclitaxel in extensive-stage small cell lung cancer: cancer and leukemia group B study 39901.

J Thorac Oncol 2008 Feb;3(2):158-62

State University of New York Upstate Medical University, Syracuse, New York 13210, USA.

Introduction: Paclitaxel is an active agent in extensive-stage (ES) small cell lung cancer (SCLC). Nevertheless, the optimal schedule is uncertain. A dose-dense schedule was previously evaluated in a Cancer and Leukemia Group B study of patients with non-SCLC, resulting in a 42% response rate and median survival of 12.3 months. Because of these promising results, this dose and schedule of paclitaxel was evaluated in patients with ES-SCLC.

Methods: Patients were eligible for this phase II trial (Cancer and Leukemia Group B 39901) if they had documented ES-SCLC, no prior chemotherapy, and performance status of 0 to 2. Paclitaxel was administered as an intravenous infusion at 150 mg/m2 over 3 hours weekly for 6 consecutive weeks every 8 weeks.

Results: Thirty-six patients with median age of 65 were enrolled. Of them 25 were men and 33 with a performance status 0 to 1. A median of two 8-week cycles were delivered. The percent of patients with grade 3/4 toxicity included neutropenia 22%, anemia 9%, febrile neutropenia 6%, fatigue 20%, sensory neuropathy 26%, motor neuropathy 11%, and dyspnea 17%. There were two treatment-related deaths, both from pneumonitis. The overall response rate was 33% (3% complete response and 30% partial response). Median progression-free and overall survivals were 3.7 and 9.2 months, respectively. One-year progression-free and overall survivals were 17% and 36%, respectively.

Conclusions: For patients with ES-SCLC, dose-dense weekly paclitaxel was associated with fairly mild hematologic toxicity. Nevertheless, nonhematologic toxicities, including neuropathy, fatigue, and dyspnea required frequent dose delays and reductions. The overall response rate is disappointing and much lower than that seen with standard platinum-based combinations. Paclitaxel in this dose and schedule should not be used as front-line therapy for patients with ES-SCLC.
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February 2008

Preoperative exercise Vo2 measurement for lung resection candidates: results of Cancer and Leukemia Group B Protocol 9238.

J Thorac Oncol 2007 Jul;2(7):619-25

Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

Introduction: A stepwise approach to the functional assessment of lung resection candidates is widely accepted, and this approach incorporates the measurement of exercise peak Vo2 when spirometry and radionuclear studies suggest medical inoperability. A new functional operability (FO) algorithm incorporates peak exercise Vo2 earlier in the preoperative assessment to determine which patients require preoperative radionuclear studies. This algorithm has not been studied in a multicenter study.

Methods: The CALGB (Cancer and Leukemia Group B) performed a prospective multi-institutional study to investigate the use of primary exercise Vo2 measurement for the prediction of surgical risk. Patients with known or suspected resectable non-small cell lung cancer (NSCLC) were eligible. Exercise testing including measurement of peak oxygen uptake (Vo2), spirometry, and single breath diffusion capacity (DLCO) was performed on each patient. Nuclear perfusion scans were obtained on selected high-risk patients. After surgery, morbidity and mortality data were collected and correlated with preoperative data. Mortality and morbidity were retrospectively compared by algorithm-based risk groups.

Results: Three hundred forty-six patients with suspected lung cancer from nine institutions underwent thoracotomy with or without resection; 57 study patients did not undergo thoracotomy. Patients who underwent surgery had a median survival time of 30.9 months, whereas patients who did not undergo surgery had a median survival time of 15.6 months. Among the 346 patients who underwent thoracotomy, 15 patients died postoperatively (4%), and 138 patients (39%) exhibited at least one cardiorespiratory complication postoperatively. We found that patients who had a peak exercise Vo2 of <65% of predicted (or a peak Vo2/kg <16 ml/min/kg) were more likely to suffer complications (p = 0.0001) and were also more likely to have a poor outcome (respiratory failure or death) if the peak Vo2 was <15 ml/min/kg (p = 0.0356). We also found a subset of 58 patients who did not meet FO algorithm criteria for operability, but who still tolerated lung resection with a 2% mortality rate.

Conclusions: Our data provide multicenter validation for the use of exercise Vo2 for preoperative assessment of lung cancer patients, and we encourage an aggressive approach when evaluating these patients for surgery.
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July 2007

Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B.

J Clin Oncol 2007 May 2;25(13):1698-704. Epub 2007 Apr 2.

University of Chicago, Chicago, IL, USA.

Purpose: Standard therapy for unresectable stage III non-small-cell lung cancer includes concomitant chemoradiotherapy. In Cancer and Leukemia Group B 39801, we evaluated whether induction chemotherapy before concurrent chemoradiotherapy would result in improved survival.

Patients And Methods: Between July 1998 and May 2002, 366 patients were randomly assigned to arm A, which involved immediate concurrent chemoradiotherapy with carboplatin area under the concentration-time curve (AUC) of 2 and paclitaxel 50 mg/m2 given weekly during 66 Gy of chest radiotherapy, or arm B, which involved two cycles of carboplatin AUC 6 and paclitaxel 200 mg/m2 administered every 21 days followed by identical chemoradiotherapy. The accrual goal was 360 patients.

Results: Thirty-four percent of patients were female, 66% were male, and the median age was 63 years. Grade 3 or 4 toxicities during induction chemotherapy on arm B consisted mainly of neutropenia (18% and 20%, respectively). During concurrent chemoradiotherapy, there was no difference in severity of in-field toxicities of esophagitis (grade 3 and 4 were, respectively, 30% and 2% for arm A v 28% and 8% for arm B) and dyspnea (grade 3 and 4 were, respectively, 11% and 3% for arm A v 15% and 4% for arm B). Survival differences were not statistically significant (P = .3), with a median survival on arm A of 12 months (95% CI, 10 to 16 months) versus 14 months (95% CI, 11 to 16 months) on arm B and a 2-year survival of 29% (95% CI, 22% to 35%) and 31% (95% CI, 25% to 38%). Age, weight loss before therapy, and performance status were statistically significant predictive factors.

Conclusion: The addition of induction chemotherapy to concurrent chemoradiotherapy added toxicity and provided no survival benefit over concurrent chemoradiotherapy alone. The median survival achieved in each of the treatment groups is low, and the routine use of weekly carboplatin and paclitaxel with simultaneous radiotherapy should be re-examined.
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May 2007

Medulloblastoma and birth date: evaluation of 3 U.S. datasets.

Arch Environ Health 2004 Jan;59(1):26-30

Department of Radiation Oncology and Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.

Studies from Norway and Japan have found a higher incidence of medulloblastoma related to births that occur in the fall. The authors sought further evidence concerning this association. For 122 patients in a Duke University database and 90 patients from the Central Cancer Registry of North Carolina, the frequency distribution of birth dates by month was statistically significantly different from the expected North Carolina distribution (p = 0.04 and 0.06). For 75 patients from California Surveillance, Epidemiology, and End Results (SEER) data, the frequency distribution of birth dates by month was marginally different from the expected U.S. distribution (p = 0.14). For 922 patients from national SEER data, the frequency distribution of birth dates by month was not statistically significantly different from the expected U.S. distribution (p = 0.54). Subgroup analysis suggests seasonality of birth dates is most significant for patients aged 5-14 yr diagnosed with medulloblastoma.
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January 2004

Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732.

J Clin Oncol 2005 Jun;23(16):3752-9

University of Tennessee, Memphis, TN 31187, USA.

Purpose: To determine, in a randomized comparison, whether the addition of paclitaxel to etoposide and cisplatin improves the time to progression and overall survival in patients with extensive small-cell lung cancer (SCLC) compared with standard etoposide and cisplatin and to compare the regimens' toxicity.

Patients And Methods: Eligible patients (N=587) with untreated extensive SCLC were randomly assigned to receive either cisplatin 80 mg/m2 on day 1 and etoposide 80 mg/m2 on days 1 through 3 administered every 3 weeks for six cycles (EP) or cisplatin 80 mg/m2 on day 1, paclitaxel 175 mg/m2 over 4 hours on day 1, and etoposide 80 mg/m2 on days 1 to 3 followed by recombinant human granulocyte colony-stimulating factor on days 4 to 18 administered every 3 weeks for six cycles (PET).

Results: Reporting of demographics, response, and survival included 565 patients, of whom 282 were randomly assigned to receive EP and 283 were assigned to receive PET. Overall response rates were 68% for the EP arm and 75% for the PET arm. Median failure-free survival time was 5.9 months for the EP arm and 6 months for the PET arm (P = .179). Median overall survival time was 9.9 months for patients on EP and 10.6 months for patients on PET (P = .169). Toxic deaths occurred in 2.4% of the patients on EP and 6.5% of patients on PET.

Conclusion: PET did not improve the time to progression or survival in patients with extensive SCLC compared with EP alone and was associated with unacceptable toxicity.
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June 2005

Gefitinib in patients with malignant mesothelioma: a phase II study by the Cancer and Leukemia Group B.

Clin Cancer Res 2005 Mar;11(6):2300-4

Department of Medicine, Washington University School of Medicine, 4960 Children's Place, Suite 108, St. Louis, MO 63110, USA.

Purpose: The Cancer and Leukemia Group B conducted a phase II study of gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, in patients with previously untreated malignant mesothelioma.

Experimental Design: Eligible patients had unresectable pleural or peritoneal mesothelioma, measurable disease, no prior therapy, and performance status 0-1 by Cancer and Leukemia Group B criteria. Gefitinib (500 mg p.o.) was administered once a day for 21 days. Patients underwent restaging after every two cycles. Therapy was continued until disease progression or unacceptable toxicity.

Results: The most common grade 3 toxicities were diarrhea (16%) and nausea (12%). Of 43 patients enrolled, 1 patient (2%) had a complete response, 1 patient (2%) had a partial response, 21 (49%) had stable disease lasting two to eight cycles, 15 (35%) had progressive disease, and 5 (12%) had early deaths. One-year survival was 32% [95% confidence interval (CI), 21-50%]. Median survival and failure-free survival were 6.8% (95% CI, 3.5-10.3) and 2.6 months (95% CI, 1.5-4.0), respectively. The 3-month failure-free survival was 40% (95% CI, 25-56%). EGFR expression score by immunohistochemistry done in 28 patients was categorized as low (EGFR 1+ or 2+) or high (EGFR 3+) expression: 97% had EGFR overexpression (2+ or 3+). The median and 3-month failure-free survival were 3.6 months and 40% for those patients with low EGFR expression compared with 8.1 and 40% for those with high EGFR expression.

Conclusions: Although 97% of patients with mesothelioma had EGFR overexpression, gefitinib was not active in malignant mesothelioma. EGFR expression does not correlate with failure-free survival.
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March 2005

Lack of trastuzumab activity in nonsmall cell lung carcinoma with overexpression of erb-B2: 39810: a phase II trial of Cancer and Leukemia Group B.

Cancer 2005 Apr;103(8):1670-5

Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242-1099, USA.

Background: The overexpression of HER-2 occurs in a minority of patients with nonsmall cell lung carcinoma. Trastuzumab, which is a monoclonal antibody to HER-2, is an effective treatment in some women with breast carcinomas that overexpress HER-2, as demonstrated by immunohistochemistry. The objective of this Phase II study was to determine whether trastuzumab would effect responses in patients with nonsmall cell lung carcinoma who had tumors that overexpressed HER-2.

Methods: Patients were required to have Stage IIIB or Stage IV nonsmall cell lung carcinoma and tumors with 2+ or 3+ expression of HER-2, as determined with immunohistochemistry, and they may have received up to 1 prior chemotherapy regimen. Trastuzumab at a dose of 4 mg/kg was given intravenously on Week 1; then, weekly doses of 2 mg/kg were given. Response revaluation was performed every 8 weeks.

Results: Among 209 screened patients, 24 patients (11%) had tumors with 2+ or 3+ expression of HER-2. One patient achieved a partial response, and one patient experienced a treatment-related death due to pulmonary toxicity.

Conclusions: Single-agent trastuzumab did not exhibit significant clinical activity against nonsmall cell lung carcinoma when HER-2 expression levels were measured by immunohistochemistry.
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April 2005

Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730).

J Clin Oncol 2005 Jan;23(1):190-6

The Mount Sinai Comprehensive Cancer Center, 4306 Alton Rd, Miami Beach, FL, USA.

Purpose: We compared the efficacy of combination chemotherapy versus single-agent therapy in patients with advanced non-small-cell lung cancer.

Patients And Methods: A total of 561 eligible patients were randomly assigned to receive paclitaxel alone or in combination with carboplatin.

Results: The response rate was 17% in the paclitaxel arm and 30% in the carboplatin-paclitaxel arm (P < .0001). Median failure-free survival was 2.5 months in the paclitaxel arm and 4.6 months in the carboplatin-paclitaxel arm (P = .0002). Median survival times were 6.7 months (95% CI, 5.8 to 7.8) and 8.8 months (95% CI, 8.0 to 9.9), and 1-year survival rates were 32% (95% CI, 27% to 38%), and 37% (95% CI, 32% to 43%), respectively. The overall survival distributions were not statistically different: hazard ratio = 0.91 (95% CI, 0.77 to 1.17; P = .25). Hematological toxicity and nausea were more frequent in the combination arm, but febrile neutropenia and toxic deaths were equally low in both arms. There was no significant survival difference in elderly patients. Performance status 2 patients treated with combination chemotherapy had a better survival rate than those treated with single-agent therapy (P = .019).

Conclusion: Combination chemotherapy improves response rate and failure-free survival compared with single-agent therapy, but there was no statistically significant difference in the primary end point of overall survival. The results in elderly patients were similar to younger patients. Performance status 2 patients had a superior outcome when treated with combination chemotherapy.
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January 2005

A phase II trial of 6-hydroxymethylacylfulvene (MGI-114, irofulven) in patients with relapsed or refractory non-small cell lung cancer.

Lung Cancer 2004 Sep;45(3):387-92

Department of Medicine, Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas Street, P.O. Box 250955, Charleston, SC 29425, USA.

Purpose: To assess the efficacy and toxicity of 6-hydroxymethylacylfulvene (HMAF; MGI-114, irofulven) as therapy for relapsed or refractory non-small cell lung cancer.

Methods: A two-stage phase II design was employed separately for refractory and relapsed patients to differentiate between ineffective treatment (response rate < or =10%) and active treatment (response rate > or =30%). Eligible patients received HMAF 11 mg/m2 per day intravenously over 5 min on days 1-5, with cycles repeated every 28 days.

Results: Thirty-six patients (15 relapsed; 21 refractory) were treated, and no responses were seen.

Toxicity: Grade 3 neutropenia and grade 3 thrombocytopenia each occurred in 11% of the patients. Grade 3 nausea occurred in 47%; grade 3-4 vomiting in 42%. Twenty-two percent developed grade 3 fatigue. Eleven percent developed grade 3 hallucinations.

Conclusions: HMAF, administered at this dose and schedule, is not active as salvage therapy for relapsed or refractory non-small cell lung cancer.
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September 2004

70 Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808.

Int J Radiat Oncol Biol Phys 2004 Jun;59(2):460-8

Department of Radiation Oncology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.

Purpose: To prospectively evaluate the feasibility of delivering 70 Gy once-daily thoracic radiotherapy (TRT), concurrent with chemotherapy, in the treatment of limited-stage small-cell lung cancer (L-SCLC).

Materials And Methods: Eligible patients received two cycles of induction paclitaxel (175 mg/m(2) on Day 1) and topotecan (1 mg/m(2) on Days 1-5) with granulocyte colony stimulating factor support, followed by three cycles of carboplatin (area under the curve = 5 on Day 1) and etoposide (100 mg/m(2) on Days 1-3). TRT (70 Gy, 2 Gy/fx/7 weeks) was initiated with the first cycle of carboplatin and etoposide. Prophylactic cranial irradiation was offered to patients achieving a complete response or good partial response.

Results: Ninety percent of patients (57 of 63) proceeded to protocol TRT. There was one treatment-related fatality. Nonhematologic Grade 3/4 toxicities affecting more than 10% of patients, during or after TRT, were dysphagia (16%/5%) and febrile neutropenia (12%/4%). The response rate to all therapy was 92% and the median overall survival is 22.4 months (95% confidence interval 16.1, infinity ). Twenty-eight patients remain alive with a median follow-up of 24.7 months.

Conclusion: 70 Gy once-daily TRT can be delivered safely in the cooperative group setting for patients with L-SCLC. Initial efficacy data are encouraging. The hypothesis that high-dose once-daily TRT results in comparable or improved survival compared with twice-daily accelerated TRT warrants testing in a Phase III trial.
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June 2004

Capecitabine in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (39807).

Lung Cancer 2004 May;44(2):251-9

The Ohio State University Comprehensive Cancer Center, 320 West 10th Avenue, Columbus, OH 43210-1240, USA.

Purpose: The CALGB performed a phase II multicenter study to evaluate the activity of oral capecitabine in patients with malignant mesothelioma (CALGB 39807).

Patients And Methods: Between November 15, 2000 and August 31, 2001, 27 patients with mesothelioma were enrolled in this study. Capecitabine was administered at 2500 mg/m(2) per day divided in two doses for 14 days followed by a seven-day break. Cycles were repeated every 21 days with restaging performed every two cycles and therapy continuing for up to six cycles. One patient withdrew from the study prior to receiving therapy and is removed from further analysis. Eligibility criteria included no prior treatment, PS 0-1 by CALGB criteria and histologically documented mesothelioma.

Patient Characteristics: gender; male 19 (73%), female seven; median age 70 (range 40-81); histology: epithelial 15 (58%), mixed eight (31%), unclassified three; site of origin pleura, 25 (96%); weight loss in previous six months of more than 10% in seven (27%), symptoms longer than six months in five (19%).

Results: One patient (4%) had a confirmed PR while 10 (38%) achieved SD for 2-6 cycles. Ten patients (38%) had PD as their best response. There were three patients unevaluable for response and two early deaths. Median survival and failure free survival were 4.9 (95% CI 4-10.8) and 2.4 (95% CI 1.5-4.2) months respectively with a one-year survival of 23% (95% CI 11-49%). Grade three or greater toxicities encountered by at least 10% of patients included lymphopenia (12%), fatigue (12%), dehydration (12%) and diarrhea (15%). Three patients (12%) had grade three skin toxicity or hand-foot syndrome. One patient died of treatment related toxicity during cycle one.

Conclusion: The antitumor activity of capecitabine is insufficient to warrant further exploration in patients with malignant mesothelioma.
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May 2004

Novel doublets in extensive-stage small-cell lung cancer: a randomized phase II study of topotecan plus cisplatin or paclitaxel (CALGB 9430).

Clin Lung Cancer 2002 Feb;3(3):205-10; discussion 211-2

Missouri Baptist Medical Center, St. Louis, MO 63131, USA.

Chemotherapy for extensive-stage small-cell lung cancer (E-SCLC) produces high response rates and improved survival but few cures. We tested three new regimens for E-SCLC that might merit further investigation in a subsequent phase III trial. Cancer and Leukemia Group B 9430 was a randomized phase II study evaluating 4 treatment arms in 57 evaluable, previously untreated E-SCLC patients. Each arm consisted of the following: Arm 1: cisplatin plus topotecan; Arm 2: cisplatin plus paclitaxel; Arm 3: paclitaxel 230 mg/m2 plus topotecan; and Arm 4: paclitaxel 175 mg/m2 plus topotecan. Because of an accrual time difference, Arm 2 will not be discussed in this manuscript. Arm 1 (12 patients) produced 1 complete response (CR, 8%) and an overall response rate (ORR) of 42%. Toxicity was excessive, with 3 deaths (25%). Arm 3 (13 patients) produced no CRs, 7 partial responses (PRs, 54%), median survival of 13.8 months, and failure-free survival (FFS) of 7.41 months, with 3 toxic deaths (25%). Among 32 evaluable patients on Arm 4, there were 2 CRs (6%) and 20 PRs (63%) for an ORR of 69%, median survival of 9.9 months, FFS of 5.21 months, and 1-year survival of 40%. There was 1 possible treatment-related death (3%). Topotecan plus cisplatin, in the doses and schedule employed, produced excessive toxicity and modest efficacy in E-SCLC patients. Paclitaxel (230 mg/m2 on day 1) plus topotecan (1 mg/m2 on days 1-5) produced excessive toxicity that was ameliorated with an attenuated paclitaxel dose (175 mg/m2). With the latter regimen (Arm 4) in patients with a performance status of 0/1, CR rates, FFS, overall survival, and 1-year survival were similar to standard etoposide plus cisplatin chemotherapy. Further exploration of topoisomerase inhibitors and taxanes in SCLC patients is warranted.
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February 2002