Publications by authors named "Alan P Lyss"

29 Publications

  • Page 1 of 1

Closing the Rural Cancer Care Gap: Three Institutional Approaches.

JCO Oncol Pract 2020 07 23;16(7):422-430. Epub 2020 Jun 23.

American Society of Clinical Oncology, Alexandria, VA.

Patients in rural areas face limited access to medical and oncology providers, long travel times, and low recruitment to clinical trials, all of which affect quality of care and health outcomes. Rural counties also have high rates of cancer-related mortality and other negative treatment outcomes. On April 10, 2019, ASCO hosted Closing the Rural Cancer Care Gap, the second event in its State of Cancer Care in America series. The event focused on two aspects of rural cancer care: a review of the major issues and concerns in delivering rural cancer care and a discussion of creative solutions to address rural-nonrural disparities. This article draws from the event and supporting literature to summarize the challenges to delivering high-quality care in rural communities, update ASCO's workforce data on the geographic distribution of oncologists, and highlight 3 institutional approaches to addressing these challenges in diverse rural settings. The experience of the 3 institutions featured in the article suggests that increasing rural patients' access to care requires expanding services and decreasing travel distances, mitigating financial burdens when insurance coverage is limited, opening avenues to clinical trial participation, and creating partnerships between providers and community leaders to address local gaps in care. Because the characteristics of rural communities, health care resources, and patient populations are not homogeneous, rural health disparities require local solutions that are based on community needs, available resources, and trusting and collaborative partnerships.
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http://dx.doi.org/10.1200/OP.20.00174DOI Listing
July 2020

Phase II Single-Arm Study of Preoperative Letrozole for Estrogen Receptor-Positive Postmenopausal Ductal Carcinoma In Situ: CALGB 40903 (Alliance).

J Clin Oncol 2020 04 3;38(12):1284-1292. Epub 2020 Mar 3.

University of California, San Francisco, San Francisco, CA.

Purpose: Primary endocrine therapy for ductal carcinoma in situ (DCIS) as a potential alternative to surgery has been understudied. This trial explored the feasibility of a short-term course of letrozole and sought to determine whether treatment results in measurable radiographic and biologic changes in estrogen receptor (ER)-positive DCIS.

Patients And Methods: A phase II single-arm multicenter cooperative-group trial was conducted in postmenopausal patients diagnosed with ER-positive DCIS without invasion. Patients were treated with letrozole 2.5 mg per day for 6 months before surgery. Breast magnetic resonance imaging (MRI) was obtained at baseline, 3 months, and 6 months. The primary end point was change in 6-month MRI enhancement volume compared with baseline.

Results: Overall, 79 patients were enrolled and 70 completed 6 months of letrozole. Of these, 67 patients had MRI data available for each timepoint. Baseline MRI volumes ranged from 0.004 to 26.3 cm. Median reductions from baseline MRI volume (1.4 cm) were 0.6 cm (61.0%) at 3 months ( < .001) and 0.8 cm (71.7%) at 6 months ( < .001). Consistent reductions were seen in median baseline ER H-score (228; median reduction, 15.0; = .005), progesterone receptor H-score (15; median reduction, 85.0; < .001), and Ki67 score (12%; median reduction, 6.3%; = .007). Of the 59 patients who underwent surgery per study protocol, persistent DCIS remained in 50 patients (85%), invasive cancer was detected in six patients (10%), and no residual DCIS or invasive cancer was seen in nine patients (15%).

Conclusions: In a cohort of postmenopausal women with ER-positive DCIS, preoperative letrozole resulted in significant imaging and biomarker changes. These findings support future trials of extended endocrine therapy as primary nonoperative treatment of some DCIS.
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http://dx.doi.org/10.1200/JCO.19.00510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164489PMC
April 2020

Personalized Management of Chemotherapy-Induced Peripheral Neuropathy Based on a Patient Reported Outcome: CALGB 40502 (Alliance).

J Clin Pharmacol 2020 04 4;60(4):444-452. Epub 2019 Dec 4.

Center for Translational Medicine, University of Maryland, Baltimore, Maryland, USA.

Chemotherapy-induced peripheral neuropathy (henceforth, neuropathy) is often dose limiting and is generally managed by empirical dose modifications. We aimed to (1) identify an early time point that is predictive of future neuropathy using a patient-reported outcome and (2) propose a dose-adjustment algorithm based on simulated data to manage neuropathy. In previous work, a dose-neuropathy model was developed using dosing and patient-reported outcome data from Cancer and Leukemia Group B 40502 (Alliance), a randomized phase III trial of paclitaxel, nanoparticle albumin-bound paclitaxel or ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer. In the current work, an early time point that is predictive of the future severity of neuropathy was identified based on predictive accuracy of the model. Using the early data and model parameters, simulations were conducted to propose a dose-adjustment algorithm for the prospective management of neuropathy in individual patients. The end of the first 3 cycles (12 weeks) was identified as the early time point based on a predictive accuracy of 75% for the neuropathy score after 6 cycles. For paclitaxel, nanoparticle albumin-bound paclitaxel, and ixabepilone, simulations with the proposed dose-adjustment algorithm resulted in 61%, 48%, and 35% fewer patients, respectively, with neuropathy score ≥8 after 6 cycles compared to no dose adjustment. We conclude that early patient-reported outcome data on neuropathy can be used to guide dose adjustments in individual patients that reduce the severity of future neuropathy. Prospective validation of this approach should be undertaken in future studies.
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http://dx.doi.org/10.1002/jcph.1559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064382PMC
April 2020

Pemetrexed, Bevacizumab, or the Combination As Maintenance Therapy for Advanced Nonsquamous Non-Small-Cell Lung Cancer: ECOG-ACRIN 5508.

J Clin Oncol 2019 09 30;37(26):2360-2367. Epub 2019 Jul 30.

Inova Schar Cancer Center, Fairfax, VA.

Purpose: Pemetrexed or bevacizumab is used for maintenance therapy of advanced nonsquamous non-small-cell lung cancer (NSCLC). The combination of bevacizumab and pemetrexed has also demonstrated efficacy. We conducted a randomized study to determine the optimal maintenance therapy.

Patients And Methods: Patients with advanced nonsquamous NSCLC and no prior systemic therapy received carboplatin (area under the curve, 6), paclitaxel (200 mg/m), and bevacizumab (15 mg/kg) for up to four cycles. Patients without progression after four cycles were randomly assigned to maintenance therapy with bevacizumab (15 mg/kg), pemetrexed (500 mg/m), or a combination of the two agents. The primary end point was overall survival, with bevacizumab serving as the control group.

Results: Of the 1,516 patients enrolled, 874 (57%) were randomly assigned after induction therapy to one of the three maintenance therapy groups. With a median follow-up of 50.6 months, median survival with pemetrexed was 15.9 months, compared with 14.4 months with bevacizumab (hazard ratio [HR], 0.86; = .12); median survival with pemetrexed and bevacizumab was 16.4 months (HR, 0.9; = .28); median progression-free survival was 4.2, 5.1 (HR, 0.85; = .06), and 7.5 months (HR, 0.67; < .001) for the three groups, respectively. Incidence of worst grade 3 to 4 toxicity was 29%, 37%, and 51%, respectively, for bevacizumab, pemetrexed, and the combination regimen.

Conclusion: Single-agent bevacizumab or pemetrexed is efficacious as maintenance therapy for advanced nonsquamous NSCLC. Because of a lack of survival benefit and higher toxicity, the combination of bevacizumab and pemetrexed cannot be recommended.
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http://dx.doi.org/10.1200/JCO.19.01006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001786PMC
September 2019

Germline Genetic Variants in GATA3 and Breast Cancer Treatment Outcomes in SWOG S8897 Trial and the Pathways Study.

Clin Breast Cancer 2019 08 6;19(4):225-235.e2. Epub 2019 Mar 6.

Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY. Electronic address:

Introduction: GATA3 is a critical transcription factor in maintaining the differentiated state of luminal mammary epithelial cells. We sought to determine the prognostic and predictive roles of GATA3 genotypes for breast cancer.

Patients And Methods: Twelve single nucleotide polymorphisms (SNPs) were genotyped in 2 breast cancer cohorts, including the SWOG S8897 trial where patients were treated with adjuvant chemotherapy (CAF [cyclophosphamide, doxorubicin, 5-fluorouracil] vs. CMF [cyclophosphamide, methotrexate, 5-fluorouracil]) or untreated, and the observational Pathways Study.

Results: In the S8897 trial, rs3802604 and rs568727 were associated with disease-free survival and overall survival in the treated group, regardless of chemotherapy regimen. The GG genotype of rs3802604 conferred poorer overall survival (adjusted hazard ratio, 2.45; 95% confidence interval, 1.48-4.05) and disease-free survival (adjusted hazard ratio, 1.95; 95% confidence interval, 1.27-2.99) compared with the AA genotype. Similar associations were found for rs568727. In contrast, no association with either SNP was found in the untreated group. Subgroup analyses indicated that these 2 SNPs more strongly influenced outcomes in the patients who also received tamoxifen. However, the associations in the subgroup with tamoxifen treatment were not replicated in the Pathways Study, possibly owing to substantial differences between the 2 patient cohorts, such as chemotherapy regimen and length of follow-up. Results from joint analyses across these 2 cohorts were marginally significant, driven by the results in S8897. Bioinformatic analyses support potential functional disruption of the GATA3 SNPs in breast tissue.

Conclusions: The present study provides some evidence for the predictive value of GATA3 genotypes for breast cancer adjuvant therapies. Future replication studies in appropriate patient populations are warranted.
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http://dx.doi.org/10.1016/j.clbc.2019.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667288PMC
August 2019

Capacity for Cancer Care Delivery Research in National Cancer Institute Community Oncology Research Program Community Practices: Availability of Radiology and Primary Care Research Partners.

J Am Coll Radiol 2017 Dec 19;14(12):1530-1537. Epub 2017 Oct 19.

Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Winston-Salem, North Carolina.

Purpose: Cancer care spans the spectrum from screening and diagnosis through therapy and into survivorship. Delivering appropriate care requires patient transitions across multiple specialties, such as primary care, radiology, and oncology. From the program's inception, the National Cancer Institute Community Oncology Research Program (NCORP) sites were tasked with conducting cancer care delivery research (CCDR) that evaluates structural, organizational, and social factors, including care transitions that determine patient outcomes. The aim of this study is to describe the capacity of the NCORP to conduct multidisciplinary CCDR that includes radiology and primary care practices.

Methods: The NCORP includes 34 community and 12 minority and underserved community sites. The Landscape Capacity Assessment was conducted in 2015 across these 46 sites, composed of the 401 components and subcomponents designated to conduct CCDR. Each respondent had the opportunity to designate an operational practice group, defined as a group of components and subcomponents with common care practices and resources. The primary outcomes were the proportion of adult oncology practice groups with affiliated radiology and primary care practices. The secondary outcomes were the proportion of those affiliated radiology and primary care groups that participate in research.

Results: Eighty-seven percent of components and subcomponents responded to at least some portion of the assessment, representing 230 practice groups. Analyzing the 201 adult oncology practice groups, 85% had affiliated radiologists, 69% of whom participate in research. Seventy-nine percent had affiliated primary care practitioners, 31% of whom participate in research. Institutional size, multidisciplinary group practice, and ownership by large regional or multistate health systems was associated with research participation by affiliated radiology and primary care groups. Research participation by these affiliated specialists was not significantly different between the community and the minority and underserved community sites.

Conclusions: Research relationships exist between the majority of community oncology sites and affiliated radiology practices. Research relationships with affiliated primary care practices lagged. NCORP as a whole has the opportunity to encourage continued and expanded engagement where relationships exist. Where no relationship exists, the NCORP can encourage recruitment, particularly of primary care practices as partners.
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http://dx.doi.org/10.1016/j.jacr.2017.08.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880209PMC
December 2017

Kinetic-Pharmacodynamic Model of Chemotherapy-Induced Peripheral Neuropathy in Patients with Metastatic Breast Cancer Treated with Paclitaxel, Nab-Paclitaxel, or Ixabepilone: CALGB 40502 (Alliance).

AAPS J 2017 09 15;19(5):1411-1423. Epub 2017 Jun 15.

Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity caused by several chemotherapeutic agents. Currently, CIPN is managed by empirical dose modifications at the discretion of the treating physician. The goal of this research is to quantitate the dose-CIPN relationship to inform the optimal strategies for dose modification. Data were obtained from the Cancer and Leukemia Group B (CALGB) 40502 trial, a randomized phase III trial of paclitaxel vs. nab-paclitaxel vs. ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer. CIPN was measured using a subset of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group Neurotoxicity (FACT-GOG-NTX) scale. A kinetic-pharmacodynamic (K-PD) model was utilized to quantitate the dose-CIPN relationship simultaneously for the three drugs. Indirect response models with linear and S drug effects were evaluated. The model was evaluated by comparing the predicted proportion of patients with CIPN (score ≥8 or score ≥12) to the observed proportion. An indirect response model with linear drug effect was able to describe the longitudinal CIPN data reasonably well. The proportion of patients that were falsely predicted to have CIPN or were falsely predicted not to have CIPN was 20% or less at any cycle. The model will be utilized to identify an early time point that can predict CIPN at later time points. This strategy will be utilized to inform dose adjustments to prospectively manage CIPN. Clinicaltrials.gov ID: NCT00785291.
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http://dx.doi.org/10.1208/s12248-017-0101-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711539PMC
September 2017

Anthracyclines in Early Breast Cancer: The ABC Trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology).

J Clin Oncol 2017 Aug 11;35(23):2647-2655. Epub 2017 Apr 11.

Joanne L. Blum, Lina Asmar, Nicholas J. Robert, Joyce A. O'Shaughnessy, Svetislava J. Vukelja, Devchand Paul, and Stephen E. Jones, US Oncology Research; Lina Asmar, McKesson Specialty Health, The Woodlands; Joanne L. Blum and Joyce A. O'Shaughnessy, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas; Svetislava J. Vukelja, Texas Oncology-Tyler, Tyler, TX; Patrick J. Flynn, Charles E. Geyer Jr, Samuel A. Jacobs, Judith O. Hopkins, Louis Fehrenbacher, Alan P. Lyss, Adam M. Brufsky, Sandra M. Swain, Eleftherios P. Mamounas, and Norman Wolmark, National Surgical Adjuvant Breast and Bowel Project/NRG Oncology; Greg Yothers, Jong-Hyeon Jeong, and Linda H. Colangelo, NRG Oncology; Greg Yothers, John-Hyeon Jeong, and Linda H. Colangelo, The University of Pittsburgh; Samuel A. Jacobs, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine; Adam M. Brufsky, Magee-Womens Hospital at University of Pittsburgh Medical Center; Norman Wolmark, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh; Henry Leonidas Gómez, Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Philadelphia, PA; Patrick J. Flynn, Metro-Minnesota Community Oncology Research Consortium, Minneapolis, MN; Charles E. Geyer Jr, Massey Cancer Center, Virginia Commonwealth University, Richmond; Nicholas J. Robert, Virginia Cancer Specialists, Fairfax, VA; Judith O. Hopkins, The Southeastern Medical Oncology Center, Goldsboro, NC; Chau T. Dang, The Alliance, Boston, MA; Chau T. Dang, Memorial Sloan Kettering Cancer Center, New York, NY; Henry Leonidas Gómez, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Louis Fehrenbacher, Kaiser Permanente Oncology Clinical Trials Northern California, Vallejo, CA; Alan P. Liss, Heartland Cancer Research National Cancer Institute Community Oncology Research Program at Missouri Baptist Cancer Center, St Louis, MO; Devchand Paul, Rocky Mountain Cancer Centers, Denver, CO; Sandra M. Swain, MedStar Washington Hospital Center Washington Cancer Institute, and Georgetown University Medical Center, Washington, DC; and Eleftherios P. Mamounas, UF Cancer Center at Orlando Health, Orlando, FL.

Purpose Docetaxel and cyclophosphamide (TC) was superior to doxorubicin and cyclophosphamide (AC) in a trial in early breast cancer. However, activity of TC relative to AC regimens with a taxane (TaxAC) is unknown. Methods In a series of three adjuvant trials, women were randomly assigned to TC for six cycles (TC6) or to a standard TaxAC regimen. US Oncology Research (USOR) 06-090 compared TC6 with docetaxel, doxorubicin, and cyclophosphamide (TAC6). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-46-I/USOR 07132 compared TC6, TAC6, or TC6 plus bevacizumab. NSABP B-49 compared TC6 with several standard AC and taxane combination regimens. Before any analysis of individual trials, a joint efficacy analysis of TC versus the TaxAC regimens was planned, with invasive disease-free survival (IDFS) as the primary end point. Patients who received TC6 plus bevacizumab on NSABP B-46-I/USOR 07132 were not included. A hazard ratio (HR) from a stratified Cox model that exceeded 1.18 for TC6 versus TaxAC was predefined as inferiority for TC6. The prespecified interim monitoring plan was to report for futility if the HR was > 1.18 when 334 IDFS events were observed (50% of 668 events required for definitive analysis). Results A total of 2,125 patients were randomly assigned to receive TC6 regimens and 2,117 patients were randomly assigned to receive TaxAC regimens. The median follow-up time was 3.3 years. There were 334 IDFS events, and the HR for TC6 versus TaxAC was 1.202 (95% CI, 0.97 to 1.49), which triggered early reporting for futility. The 4-year IDFS was 88.2% for TC6 and was 90.7% for TaxAC ( P = .04). Tests for treatment interaction by protocol, hormone receptor status, and nodal status were negative. Conclusion The TaxAC regimens improved IDFS in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer compared with the TC6 regimen.
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http://dx.doi.org/10.1200/JCO.2016.71.4147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549453PMC
August 2017

Randomized Phase III Trial of Paclitaxel Once Per Week Compared With Nanoparticle Albumin-Bound Nab-Paclitaxel Once Per Week or Ixabepilone With Bevacizumab As First-Line Chemotherapy for Locally Recurrent or Metastatic Breast Cancer: CALGB 40502/NCCTG N063H (Alliance).

J Clin Oncol 2015 Jul 8;33(21):2361-9. Epub 2015 Jun 8.

Hope S. Rugo, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; William T. Barry, Alliance Statistics and Data Center, Dana-Farber Cancer Institute; Erica L. Mayer and Eric P. Winer, Dana-Farber Cancer Institute, Boston, MA; Alvaro Moreno-Aspitia and Edith A. Perez, Mayo Clinic, Jacksonville, FL; Alan P. Lyss, Heartland Cancer Research Community Clinical Oncology Program; Michael Naughton, Washington University School of Medicine, St Louis, MO; Constance Cirrincione and Eleanor Leung, Alliance Statistics and Data Center, Duke University, Durham; Lisa A. Carey, University of North Carolina, Chapel Hill, NC; Deborah Toppmeyer, Cancer Institute of New Jersey, New Brunswick, NJ; and Clifford Hudis, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: We compared nab-paclitaxel or ixabepilone once per week to paclitaxel with bevacizumab as first-line therapy for patients with advanced breast cancer (BC) to evaluate progression-free survival (PFS) for nab-paclitaxel or ixabepilone versus paclitaxel.

Patients And Methods: Eligible patients were age ≥ 18 years with chemotherapy-naive advanced BC. Patients were randomly assigned to bevacizumab with paclitaxel 90 mg/m(2) (arm A), nab-paclitaxel 150 mg/m(2) (arm B), or ixabepilone 16 mg/m(2) (arm C), once per week for 3 of 4 weeks. Planned enrollment was 900 patients, which would give 88% power to detect a hazard ratio of 0.73.

Results: In all, 799 patients were enrolled, and 783 received treatment (97% received bevacizumab). Arm C was closed for futility at the first interim analysis (n = 241), and arm A (n = 267) and arm B (n = 275) were closed for futility at the second interim analysis. Median PFS for paclitaxel was 11 months, ixabepilone was inferior to paclitaxel (PFS, 7.4 months; hazard ratio, 1.59; 95% CI, 1.31 to 1.93; P < .001), and nab-paclitaxel was not superior to paclitaxel (PFS, 9.3 months; hazard ratio, 1.20; 95% CI, 1.00 to 1.45; P = .054). Results were concordant with overall survival; time to treatment failure was significantly shorter in both experimental arms v paclitaxel. Hematologic and nonhematologic toxicity, including peripheral neuropathy, was increased with nab-paclitaxel, with more frequent and earlier dose reductions.

Conclusion: In patients with chemotherapy-naive advanced BC, ixabepilone once per week was inferior to paclitaxel, and nab-paclitaxel was not superior with a trend toward inferiority. Toxicity was increased in the experimental arms, particularly for nab-paclitaxel. Paclitaxel once per week remains the preferred palliative chemotherapy in this setting.
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http://dx.doi.org/10.1200/JCO.2014.59.5298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500830PMC
July 2015

Phase III double-blind, placebo-controlled study of gabapentin for the prevention of delayed chemotherapy-induced nausea and vomiting in patients receiving highly emetogenic chemotherapy, NCCTG N08C3 (Alliance).

Cancer 2014 Nov 9;120(22):3575-83. Epub 2014 Jul 9.

Mayo Clinic Rochester, Rochester, Minnesota.

Background: Despite targeted antiemetics, data support an unmet need related to the management of delayed nausea and vomiting (NV). Promising pilot data informed this phase III trial evaluating gabapentin for delayed NV from highly emetogenic chemotherapy (HEC).

Methods: Participants were randomized to receive prophylactic treatment with 20 mg of dexamethasone and a 5HT3 receptor antagonist (RA) on the day of chemotherapy, followed by gabapentin 300 mg twice a day and dexamethasone (dex) or placebo and dex after HEC. Gabapentin/placebo was started the day of chemotherapy and continued through day 5 for the first chemotherapy cycle, whereas dex was titrated down on days 2-4. The primary end point was complete response (CR), defined as no emesis and no use of rescue medications on days 2-6, using an NV diary. The percentages of those in each group with a CR were compared by Fisher's exact test.

Results: Four hundred thirty patients were enrolled in this study. Forty-seven percent of patients in the gabapentin arm and 41% in the placebo arm had a CR (P = .23). Mean number of emesis episodes was <0.5 daily, and mean nausea severity was < 2 (mild). In both arms, patient satisfaction with NV control was greater than 8 (with 10 being perfectly satisfied). There were no significant differences in unwanted side effects.

Conclusions: In this study, gabapentin did not significantly improve delayed NV. Patients were satisfied with the control of their nausea and vomiting irrespective of arm. The use of a 5HT3 RA and dexamethasone provided good control of nausea and vomiting for most patients.
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http://dx.doi.org/10.1002/cncr.28892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221473PMC
November 2014

Trimodality therapy for superior sulcus non-small cell lung cancer: Southwest Oncology Group-Intergroup Trial S0220.

Ann Thorac Surg 2014 Aug 28;98(2):402-10. Epub 2014 Jun 28.

University of California Davis Cancer Center, Sacramento, California.

Background: Although preoperative chemotherapy (cisplatin-etoposide) and radiotherapy, followed by surgical resection, is considered a standard of care for superior sulcus cancers, treatment is rigorous and relapse limits long-term survival. The Southwest Oncology Group-Intergroup Trial S0220 was designed to incorporate an active systemic agent, docetaxel, as consolidation therapy.

Methods: Patients with histologically proven and radiologically defined T3 to 4, N0 to 1, M0 superior sulcus non-small cell lung cancer underwent induction therapy with cisplatin-etoposide, concurrently with thoracic radiotherapy at 45 Gy. Nonprogressing patients underwent surgical resection within 7 weeks. Consolidation consisted of docetaxel every 3 weeks for 3 doses. The accrual goal was 45 eligible patients. The primary objective was feasibility.

Results: Of 46 patients registered, 44 were eligible and assessable; 38 (86%) completed induction, 29 (66%) underwent surgical resection, and 20 (45% of eligible, 69% surgical, and 91% of those initiating consolidation therapy) completed consolidation docetaxel; 28 of 29 (97%) underwent a complete (R0) resection; 2 (7%) died of adult respiratory distress syndrome. In resected patients, 21 of 29 (72%) had a pathologic complete or nearly complete response. The known site of first recurrence was local in 2, local-systemic in 1, and systemic in 10, with 7 in the brain only. The 3-year progression-free survival was 56%, and 3-year overall survival was 61%.

Conclusions: Although trimodality therapy provides excellent R0 and local control, only 66% of patients underwent surgical resection and only 45% completed the treatment regimen. Even in this subset, distant recurrence continues to be a major problem, particularly brain-only relapse. Future strategies to improve treatment outcomes in this patient population must increase the effectiveness of systemic therapy and reduce the incidence of brain-only metastases.
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http://dx.doi.org/10.1016/j.athoracsur.2014.04.129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122593PMC
August 2014

The changing face of research in community practice.

J Oncol Pract 2014 May;10(3):155-60

Michiana Hematology Oncology; Northern Indiana Cancer Research Consortium Community Clinical Oncology Program (CCOP), South Bend, IN; American Society of Clinical Oncology, Alexandria, VA; and Missouri Baptist Cancer Center and Heartland Cancer Research CCOP, Saint Louis, MO.

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http://dx.doi.org/10.1200/JOP.2014.001424DOI Listing
May 2014

The National Cancer Institute-American Society of Clinical Oncology Cancer Trial Accrual Symposium: summary and recommendations.

J Oncol Pract 2013 Nov 15;9(6):267-76. Epub 2013 Oct 15.

National Cancer Institute; Education Network to Advance Cancer Clinical Trials, Bethesda; The EMMES Corporation, Rockville, MD; Delaware Cancer Consortium, Dover; Helen F. Graham Cancer Center, Newark, DE; American Society of Clinical Oncology, Alexandria, VA; Coalition of Cancer Cooperative Groups; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Cancer Information & Support Network, Auburn, CA; Oregon Health & Science University, Portland, OR; Pancreatic Cancer Action Network; Brooklyn Hospital Center, New York, NY; Massachusetts General Hospital, Boston, MA; Duke Clinical Research Institute, Durham; Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC; Michiana Hematology Oncology and Northern Indiana Cancer Research Consortium, South Bend, IN; Barbara Ann Karmanos Cancer Institute, Detroit, MI; University of Arizona Cancer Center, Tucson, AZ; University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland; The Ohio State University, Columbus, OH; University of Alabama at Birmingham, Birmingham, AL; Indiana University Simon Cancer Center, Indianapolis, IN; Heartland Cancer Research CCOP, St. Louis, MO; Meharry Medical College; and Vanderbilt-Ingram Cancer Center, Nashville, TN.

Introduction: Many challenges to clinical trial accrual exist, resulting in studies with inadequate enrollment and potentially delaying answers to important scientific and clinical questions.

Methods: The National Cancer Institute (NCI) and the American Society of Clinical Oncology (ASCO) cosponsored the Cancer Trial Accrual Symposium: Science and Solutions on April 29-30, 2010 to examine the state of accrual science related to patient/community, physician/provider, and site/organizational influences, and identify new interventions to facilitate clinical trial enrollment. The symposium featured breakout sessions, plenary sessions, and a poster session including 100 abstracts. Among the 358 attendees were clinical investigators, researchers of accrual strategies, research administrators, nurses, research coordinators, patient advocates, and educators. A bibliography of the accrual literature in these three major areas was provided to participants in advance of the meeting. After the symposium, the literature in these areas was revisited to determine if the symposium recommendations remained relevant within the context of the current literature.

Results: Few rigorously conducted studies have tested interventions to address challenges to clinical trials accrual. Attendees developed recommendations for improving accrual and identified priority areas for future accrual research at the patient/community, physician/provider, and site/organizational levels. Current literature continues to support the symposium recommendations.

Conclusions: A combination of approaches addressing both the multifactorial nature of accrual challenges and the characteristics of the target population may be needed to improve accrual to cancer clinical trials. Recommendations for best practices and for future research developed from the symposium are provided.
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http://dx.doi.org/10.1200/JOP.2013.001119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3825288PMC
November 2013

The NCI Community Oncology Research Program: what every clinician needs to know.

Am Soc Clin Oncol Educ Book 2013

From the National Cancer Institute, National Institutes of Health, Bethesda, MD; BJC HealthCare, St. Louis, MO; Yale University, New Haven, CT.

Research in the community setting is essential for the translation of advances in cancer research into practice and improving cancer care for all populations. The National Cancer Institute is proposing a new community-based program, NCI Community Oncology Research Program (NCORP), which is the alignment of two existing programs, the Community Clinical Oncology Program, Minority-Based Community Clinical Oncology Program, and their Research Bases, and the National Cancer Institute's Community Cancer Centers Program. NCROP will support cancer control, prevention, treatment, and screening clinical trials and expand its research scope to include cancer care delivery research. Cancer disparities research will be integrated into studies across the continuum of NCORP research. Input from current NCI-funded community investigators provides critical insight into the challenges faced by oncology practices within various organizational structures. Furthermore, these investigators identify the resources, both administrative and clinical, that will be required in the community setting to support cancer care delivery research and to meet the requirements for a new generation of clinical research. The American Society for Clinical Oncology (ASCO) has initiated a forum to focus on the conduct of clinical research in the community setting. Resources are being developed to help practices in managing cancer care in community settings.
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http://dx.doi.org/10.1200/EdBook_AM.2013.33.e84DOI Listing
December 2015

A randomized phase II study of gemcitabine and carboplatin with or without cediranib as first-line therapy in advanced non-small-cell lung cancer: North Central Cancer Treatment Group Study N0528.

J Thorac Oncol 2013 Jan;8(1):79-88

Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.

Introduction: The purpose of this study was to assess the safety and efficacy of gemcitabine and carboplatin with (arm A) or without (arm B) daily oral cediranib as first-line therapy for advanced non-small-cell lung cancer.

Methods: A lead-in phase to determine the tolerability of gemcitabine 1000 mg/m on days 1 and 8, and carboplatin on day 1 at area under curve 5 administered every 21 days with cediranib 45 mg once daily was followed by a 2 (A):1 (B) randomized phase II study. The primary end point was confirmed overall response rate (ORR) with 6-month progression-free survival (PFS6) rate in arm A as secondary end point. Polymorphisms in genes encoding cediranib targets and transport were correlated with treatment outcome.

Results: On the basis of the safety assessment, cediranib 30 mg daily was used in the phase II portion. A total of 58 and 29 evaluable patients were accrued to arms A and B. Patients in A experienced more grade 3+ nonhematologic adverse events, 71% versus 45% (p = 0.01). The ORR was 19% (A) versus 20% (B) (p = 1.0). PFS6 in A was 48% (95% confidence interval: 35%-62%), thus meeting the protocol-specified threshold of at least 40%. The median overall survival was 12.0 versus 9.9 months (p = 0.10). FGFR1 rs7012413, FGFR2 rs2912791, and VEGFR3 rs11748431 polymorphisms were significantly associated with decreased overall survival (hazard ratio 2.78-5.01, p = 0.0002-0.0095).

Conclusions: The trial did not meet its primary end point of ORR but met its secondary end point of PFS6. The combination with cediranib 30 mg daily resulted in increased toxicity. Pharmacogenetic analysis revealed an association of FGFR and VEGFR variants with survival.
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http://dx.doi.org/10.1097/JTO.0b013e318274a85dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4193613PMC
January 2013

Phase 2 trial of paclitaxel polyglumex with capecitabine for metastatic breast cancer.

Am J Clin Oncol 2014 Apr;37(2):167-71

*Division of Hematology/Oncology, Mayo Clinic Arizona, Scottsdale, AZ †Research Services ‡Department of Oncology, Mayo Clinic, Rochester, MN §Department of Pathology, Medcenter One, Bismarck, ND ∥Missouri Baptist Cancer Center, St Louis, MO ¶Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL.

Background: Capecitabine and paclitaxel are established effective treatments, alone and combined with other cytotoxic and targeted agents, for metastatic breast cancer (MBC). Paclitaxel polyglumex (a macromolecular conjugate of paclitaxel bound to poly-L-glutamic acid) has potential advantages over conventional paclitaxel, including little alopecia, short infusion time with no premedication, enhanced tumor permeability/retention effect, and improved tolerability. We therefore examined tolerability and efficacy of paclitaxel polyglumex with capecitabine in patients with MBC.

Patients And Methods: This was a single-stage phase 2 study, with interim analysis conducted with endpoints of tumor response, adverse events (toxicities), time to progression, and overall survival. The main eligibility criteria were: age >18 years, no prior MBC chemotherapy, Eastern Cooperative Oncology Group performance score <2, disease measurable by RECIST criteria, no HER2 overexpression or amplification, no brain metastases or peripheral sensory neuropathy. Treatment consisted of paclitaxel polyglumex (135 mg/m) by intravenous infusion on day 1+capecitabine (825 mg/m) orally twice daily on days 1 to 14, repeated on a 3-week cycle. Forty-one evaluable patients were required to test the null hypothesis that the complete and partial tumor response rate (CR+PR) was at the most 40% against the alternative of at least 60%. Paclitaxel polyglumex+capecitabine would be considered promising in this population if ≥21 responses were observed among first 41 evaluable patients.

Results: Forty-eight patients were enrolled between April 2006 and April 2007; all patients were evaluable. The median number of treatment cycles administered was 6. Eighteen patients [38%; 95% confidence interval (CI), 24%-53%] had a confirmed tumor response (2 CR, 16 PR) by RECIST criteria. Fifteen (38%; 95% CI, 23%-53%) responses occurred in first 41 patients, falling short of prespecified goal of 21 responses. Median duration of tumor response was 13.2 months. Three of the responders were progression free at last follow-up with a median follow-up of 43 months. Median progression-free survival was 5.1 months (95% CI, 4.0-7.6 mo). Six-month progression-free survival was 42% (95% CI, 30%-58%). Median dose level administered was paclitaxel polyglumex (135 mg/m) and capecitabine (825 mg/m) for cycles 1 to 7. Most common severe (grade 3/4) toxicities (at least possibly related to study drug) were: leukopenia 9 (19%), neutropenia 8 (17%), neurosensory 4 (8%), skin reaction-hand/foot 4 (8%), and dyspnea 2 (4%). Forty-six percent (22/47) of patients experienced grade ≥3 toxicity and 8% (4/48) experienced grade ≥4 toxicity. No alopecia was reported.

Conclusions: Although the trial failed to reach goal of 21 confirmed tumor responses among the first 41 evaluable patients, paclitaxel polyglumex and capecitabine is well tolerated and effective in MBC.
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http://dx.doi.org/10.1097/COC.0b013e31826e0550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593738PMC
April 2014

The clinical research team.

J Oncol Pract 2011 May;7(3):188-92

American Society of Clinical Oncology, Alexandria, VA; Michiana Hematology Oncology and Northern Indiana Cancer Research Consortium, South Bend, IN; Clinical Trial Support Unit Hematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada; Missouri Baptist Cancer Center and Heartland Cancer Research, Saint Louis, MO.

Developing and maintaining an exemplary research team is essential to the success of a quality clinical research program.
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http://dx.doi.org/10.1200/JOP.2011.000276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092661PMC
May 2011

Gene polymorphisms in cyclophosphamide metabolism pathway,treatment-related toxicity, and disease-free survival in SWOG 8897 clinical trial for breast cancer.

Clin Cancer Res 2010 Dec;16(24):6169-76

Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

Purpose: There are no established genetic markers for prediction of outcomes after cyclophosphamide (CP)-containing adjuvant therapy for breast cancer. In an ancillary study to a SWOG (Southwest Oncology Group) trial (S8897), we investigated functional polymorphisms in 4 genes in CP pharmacokinetic pathways in relation to hematologic toxicity and disease-free survival (DFS).

Experimental Design: Germline DNA was available from 458 women who were at high risk of relapse and was randomized to CAF (CP, intravenous doxorubicin, and 5-fluorouracil) versus CMF (CP, intravenous methotrexate, and 5-fluorouracil) ± tamoxifen, and from 874 women who had a presumed favorable prognosis and did not receive adjuvant therapy. Odds ratios for grade 3 and 4 hematologic toxicity in the treated group and hazard ratios for DFS associated with selected functional polymorphisms in CYP2B6CYP3A4GSTA1 and GSTP1 were estimated by logistic regression and Cox proportional hazard regression.

Results: Compared with women with AA genotypes, those with at least 1 GSTP1 variant G allele had reduced risk of grade 3 and 4 neutropenia [odds ratios (OR) = 0.63, 95% CI = 0.41-0.97] and leucopenia (OR = 0.59, 95% CI = 0.39-0.89). No other associations between single nucleotide polymorphisms and toxicity or survival were found in the treated or untreated group.

Conclusion: Known genetic variants in genes involved in CP pharmacokinetics may not have major effects on DFS in breast cancer patients. The lower risk of developing high-grade hematologic toxicity among women with variant GSTP1 alleles suggests that genetic markers in combination with clinical factors may be useful in defining a subgroup of women who are less susceptible to adverse hematologic toxicities with CP-containing therapies.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-0281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058716PMC
December 2010

Manganese superoxide dismutase polymorphism, treatment-related toxicity and disease-free survival in SWOG 8897 clinical trial for breast cancer.

Breast Cancer Res Treat 2010 Nov 23;124(2):433-9. Epub 2010 Mar 23.

Department of Cancer and Prevention and Control, Roswell Park Cancer Institute, Elm & Carlton Sts, Buffalo, NY 14263, USA.

To date, the few studies of associations between a functional polymorphism in the oxidative stress-related gene manganese superoxide dismutase (SOD2) and breast cancer survival have been inconsistent. In a homogeneous patient population from a large cooperative group trial Southwest Oncology Group (SWOG) 8897, we evaluated this polymorphism in relation to both treatment-related toxicity and disease-free survival (DFS). Among 458 women who received cyclophosphamide-containing adjuvant chemotherapy, those with variant C alleles, related to higher antioxidant activity, experienced less grade 3-4 neutropenia (OR = 0.52, 95% CI = 0.29-0.92) but had worse DFS (HR = 1.59, 95% CI = 0.99-2.55) than women with TT genotypes. No associations were observed among 874 women who were followed without adjuvant therapy. Our results are consistent with the hypothesis that women with higher SOD2 antioxidant activity may experience less treatment-related toxicity but shorter time to disease recurrence or death after breast cancer adjuvant chemotherapy, supporting the modifying effects of oxidative stress-related enzymes on cancer treatment toxicity and efficacy.
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http://dx.doi.org/10.1007/s10549-010-0840-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2968705PMC
November 2010

Accrual to National Cancer Institute-sponsored non-small-cell lung cancer trials: insights and contributions from the CCOP program.

Clin Lung Cancer 2009 Nov;10(6):410-3

Heartland Cancer Research CCOP, St. Louis, MO 63131, USA.

Background: The Community Clinical Oncology Program (CCOP) has been a success in augmenting accrual to cooperative group research trials from community-based institutions. We analyzed accruals to selected phase II and III cooperative group non-small-lung cancer (NSCLC) trials to determine specific accrual patterns that might guide the implementation of future studies and their application to community settings.

Patients And Methods: Data from each of the adult multispecialty cooperative group trials that studied treatment interventions in NSCLC and completed accrual from 2000 to 2005 were gathered. We tabulated and analyzed information regarding the percentage of total accrual that derived from CCOPs according to cooperative group, extent of disease, trial phase, and modality of treatment.

Results: CCOP contributions did not seem to vary greatly by phase of study or by extent of disease. In general, CCOP accrual to Radiation Therapy Oncology Group trials was lower than for the other cooperative groups. CCOP accrual to multimodality trials, in which systemic treatment was not the primary study question, was poorer. Trials of standard therapy with or without a new therapeutic agent in advanced disease tend to enjoy better accrual.

Conclusion: Multidisciplinary studies in NSCLC provide challenges for CCOPs and will require more effort and greater incentives. CCOP leaders should participate more actively in the design and implementation of cooperative group NSCLC trials in order to maximize their participation.
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http://dx.doi.org/10.3816/CLC.2009.n.077DOI Listing
November 2009

Myeloperoxidase genotypes and enhanced efficacy of chemotherapy for early-stage breast cancer in SWOG-8897.

J Clin Oncol 2009 Oct 14;27(30):4973-9. Epub 2009 Sep 14.

Roswell Park Cancer Institute, Department of Cancer Prevention and Control, Buffalo, NY 14263, USA.

Purpose: Myeloperoxidase (MPO) generates reactive oxygen species and also activates xenobiotics. In a rigorous clinical trial (Southwest Oncology Group SWOG-8897), we examined relationships between genotypes and disease-free survival (DFS) among women treated for breast cancer, as well as those who did not receive adjuvant chemotherapy.

Patients And Methods: Patients were assigned to risk groups according to standard prognostic features; the low-risk group (n = 753 genotyped) received follow-up only, and the high-risk group (n = 401 genotyped) was randomly assigned to adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) or cyclophosphamide, doxorubicin, and fluorouracil (CAF), with or without tamoxifen. DNA from archived normal lymph node tissue was genotyped, and Cox proportional hazard models were used to calculate DFS associated with MPO genotypes.

Results: Among women in the treatment arm, those with MPO G alleles had more than a two-fold reduction in hazard of recurrence (adjusted hazard ratio [HR] for GA genotypes, 0.51; 95% CI, 0.21 to 0.99; HR for GG genotypes, 0.41; 95% CI, 0.21 to 0.77). Effects were greatest among women who were further randomly assigned to tamoxifen (HR for GA genotypes, 0.28; 95% CI, 0.12 to 0.69; HR for GG genotypes, 0.19; 95% CI, 0.08 to 0.45). There were no significant associations between genotypes and DFS among women in the untreated arm, and relationships between genotypes and DFS did not differ by CAF or CMF.

Conclusion: These results, observed in two independent study populations, indicate that high-activity MPO genotypes are associated with better survival among women receiving cyclophosphamide-containing therapy, particularly when followed by tamoxifen therapy. MPO can be inhibited and/or upregulated by commonly used drugs; thus, our findings merit further investigation for optimization of therapeutics for breast cancer.
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http://dx.doi.org/10.1200/JCO.2009.21.8669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799053PMC
October 2009

Nitric oxide synthase variants and disease-free survival among treated and untreated breast cancer patients in a Southwest Oncology Group clinical trial.

Clin Cancer Res 2009 Aug 11;15(16):5258-66. Epub 2009 Aug 11.

Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.

Purpose: Numerous chemotherapeutic agents are cytotoxic through generation of reactive species, and variability in genes related to oxidative stress may influence disease-free survival (DFS). We examined relationships between DFS and variants in NOS3, as well as NQO1, NQO2, and CBR3, among treated and untreated breast cancer patients in a Southwest Oncology Group clinical trial (S8897).

Experimental Design: In the parent trial, women were assigned according to prognostic features; the high-risk group was randomized to cyclophosphamide, i.v. methotrexate, and 5-fluorouracil or to cyclophosphamide, i.v. doxorubicin, and 5-fluorouracil +/- tamoxifen, and the low-risk group did not receive adjuvant therapy. We extracted DNA from normal lymph node tissue and examined functional polymorphisms in NOS3, NQO1, NQO2, and CBR3, in relation to DFS, using Cox proportional hazard model.

Results: There were significant interactions between DFS, adjuvant therapy, and NOS3 Glu298Asp and -786 polymorphisms, alone and in combination (P for interaction = 0.008). When NOS3 genotypes were combined, women with genotypes encoding for lower nitric oxide who received chemotherapy had a >2-fold increase in hazard of progression (hazard ratio, 2.32; 95% confidence interval, 1.26-4.25), whereas there was reduced risk for those who did not receive adjuvant therapy (hazard ratio, 0.42; 95% confidence interval, 0.19-0.95). There were no associations between the other genotypes and DFS in either group.

Conclusion: Variants encoding lower activity of NOS3 may affect outcomes in breast cancer patients, with the direction of risk differing depending on chemotherapy status. These results may mirror the known dual functions of nitric oxide and nitric oxide synthase, depending on oxidative environment.
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http://dx.doi.org/10.1158/1078-0432.CCR-09-0685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745926PMC
August 2009

Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer.

J Clin Oncol 2009 Feb 15;27(4):591-8. Epub 2008 Dec 15.

Massachusetts General Hospital, Center for Thoracic Cancers, 55 Fruit St, Boston, MA 02114, USA.

Purpose: Gemcitabine plus carboplatin (GC) is active as front-line treatment for advanced non-small-cell lung cancer (NSCLC). For patients without progression, timing of second-line chemotherapy for optimum clinical benefit remains uncertain. This phase III, randomized trial assessed the efficacy and safety of docetaxel administered either immediately after GC or at disease progression.

Patients And Methods: The chemotherapy-naïve patients enrolled had either stage IIIB NSCLC with pleural effusion or stage IV NSCLC. Gemcitabine (1,000 mg/m(2)) was administered on days 1 and 8 followed by carboplatin (area under the curve = 5) on day 1. After four 21-day cycles, patients who did not have progression were randomly assigned either to an immediate docetaxel group (docetaxel 75 mg/m(2) on day 1 every 21 days, with maximum of six cycles) or to a delayed docetaxel group. The primary end point was overall survival (OS) measured from random assignment. Additional analyses included tumor response, toxicity, progression-free survival (PFS), and quality of life (QOL).

Results: Enrollment totaled 566 patients; 398 patients completed GC; 309 patients were randomly assigned equally to the two docetaxel treatment groups. Toxicity profiles were generally comparable for the docetaxel groups. Median PFS for immediate docetaxel (5.7 months) was significantly greater (P = .0001) than for delayed docetaxel (2.7 months). Median OS for immediate docetaxel (12.3 months) was greater than for delayed docetaxel (9.7 months), but the difference was not statistically significant (P = .0853). QOL results were not statistically different (P = .76) between docetaxel groups.

Conclusion: We observed a statistically significant improvement in PFS and a nonstatistically significant increase in OS when docetaxel was administered immediately after front-line GC, without increasing toxicity or decreasing QOL.
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http://dx.doi.org/10.1200/JCO.2008.17.1405DOI Listing
February 2009

Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102.

J Clin Oncol 2005 Nov;23(33):8313-21

University of Arkansas for Medical Sciences, Little Rock, AR, USA.

Purpose: We evaluated the efficacy of cyclophosphamide, methotrexate, and fluorouracil (CMF) versus cyclophosphamide, doxorubicin, and fluorouracil (CAF) in node-negative breast cancer patients with and without tamoxifen (TAM), overall and by hormone receptor (HR) status.

Patients And Methods: Node-negative patients identified by tumor size (> 2 cm), negative HR, or high S-phase fraction (n = 2,690) were randomly assigned to CMF, CAF, CMF + TAM (CMFT), or CAF + TAM (CAFT). Cox regression evaluated overall survival (OS) and disease-free survival (DFS) for CAF versus CMF and TAM versus no TAM separately. Two-sided CIs and one-sided P values for planned comparisons were calculated.

Results: Ten-year estimates indicated that CAF was not significantly better than CMF (P = .13) for the primary outcome of DFS (77% v 75%; HR = 1.09; 95% CI, 0.94 to 1.27). CAF had slightly better OS than CMF (85% v 82%, HR = 1.19 for CMF v CAF; 95% CI, 0.99 to 1.43); values were statistically significant in the planned one-sided test (P = .03). Toxicity was greater with CAF and did not increase with TAM. Overall, TAM had no benefit (DFS, P = .16; OS, P = .37), but the TAM effect differed by HR groups. For HR-positive patients, TAM was beneficial (DFS, HR = 1.32 for no TAM v TAM; 95% CI, 1.09 to 1.61; P = .003; OS, HR = 1.26; 95% CI, 0.99 to 1.61; P = .03), but not for HR-negative patients (DFS, HR = 0.81 for no TAM v TAM; 95% CI, 0.64 to 1.03; OS, HR = 0.79; 95% CI, 0.60 to 1.05).

Conclusion: CAF did not improve DFS compared with CMF; there was a slight effect on OS. Given greater toxicity, we cannot conclude CAF to be superior to CMF. TAM is effective in HR-positive disease, but not in HR-negative disease.
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http://dx.doi.org/10.1200/JCO.2005.08.071DOI Listing
November 2005

Induction paclitaxel/carboplatin followed by concurrent chemoradiation therapy for unresectable stage III non-small-cell lung cancer: a limited-access study--CALGB 9534.

Clin Lung Cancer 2005 Jul;7(1):47-53

Department of Medicine, Rhode Island Hospital, Providence, RI, USA.

Background: This phase II cooperative group study of patients with unresectable stage III non-small-cell lung cancer was designed to treat patients with induction chemotherapy with paclitaxel and carboplatin (PC) followed by concurrent chemotherapy with the same chemotherapy plus thoracic irradiation to 66 Gy.

Patients And Methods: All enrolled patients were scheduled to receive 2 cycles of induction PC at conventional doses. All nonprogressing patients were subsequently treated with concurrent chemoradiation, including 7 weekly doses of PC and once-daily thoracic irradiation. The eligibility criteria allowed treatment of an expanded population of patients, unrestricted by previous weight loss.

Results: Despite the fact that 22% of patients had experienced > 5% weight loss in the preceding 6 months, 23 of the 40 eligible patients (58%) responded to the overall regimen. A 3-year failure-free survival rate of 15% and a 3-year overall survival rate of 27% were achieved. The 3-year overall survival rate is consistent with landmark cooperative group results for the combined modality treatment of a more highly selected patient population.

Conclusion: The feasibility of this therapeutic approach in a cooperative group setting and inclusive of patients who were representative of the general population of stage III lung cancer patients was established.
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http://dx.doi.org/10.3816/CLC.2005.n.021DOI Listing
July 2005

Neoadjuvant and adjuvant chemotherapy with doxorubicin and docetaxel in locally advanced breast cancer.

Clin Breast Cancer 2004 Dec;5(5):377-84

Division of Hematology/Medical Oncology, Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65203, USA.

Fifty patients with histologically confirmed stage III breast cancer were enrolled in this study of doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 intravenously infused over 1 hour every 21 days with granulocyte colony-stimulating factor for 4 cycles. This was followed by surgery (mastectomy or lumpectomy) and 4 more cycles of doxorubicin/docetaxel postoperatively, then radiation and tamoxifen as indicated. Forty-six of the 50 patients (92%) completed neoadjuvant chemotherapy, and 38 patients (76%) completed adjuvant chemotherapy. Clinical response (defined as > 50% decrease in size of tumor) was achieved after 2 cycles in 37 patients (74%) and after 4 cycles in 42 of the 46 patients (91%) who finished neoadjuvant chemotherapy. Pathologic complete response (pCR; no pathologic invasive cancer) at the primary site was obtained in 7 of 46 patients (15%); 11 had no residual gross disease but did have microscopic persistence or microscopic complete response (mCR), for a combined pCR and mCR of 18 of 46 patients (39%). No treatment-related deaths occurred, but 3 patients died during treatment: 1 from progressive disease, 1 from a gastrointestinal bleeding, and 1 from unexplained sudden cardiac death. Dose-limiting toxicities were hematologic (grade 3 neutropenia in 5 patients and grade 4 in 23 patients). Congestive heart failure developed in 4 of 50 patients (8%), with a mean decrease in left ventricular ejection fraction (LVEF) of 20% in affected patients and 1 asymptomatic decrease in LVEF of 25%. At last follow-up, 10 patients had died of progressive disease, and 1 each from sudden cardiac death and lower gastrointestinal bleeding. In locally advanced breast cancer, neoadjuvant doxorubicin/docetaxel is a very active regimen that achieved pCR of 15% and a combined pCR and mCR of 39%, for an overall clinical response rate of 91%. Adjuvant chemotherapy was complicated by dropouts and congestive heart failure. This regimen should be used with close monitoring of cardiac function.
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http://dx.doi.org/10.3816/cbc.2004.n.045DOI Listing
December 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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http://dx.doi.org/10.1016/j.ijrobp.2003.10.021DOI Listing
June 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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http://dx.doi.org/10.3816/clc.2002.n.004DOI Listing
February 2002

Weekly, high-dose paclitaxel in advanced lung carcinoma: a phase II study with pharmacokinetics by the Cancer and Leukemia Group B.

Cancer 2003 May;97(10):2480-6

Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84103, USA.

Background: The Cancer and Leukemia Group B conducted a Phase II trial to evaluate the efficacy, toxicity, and pharmacokinetics of paclitaxel administered at a maximum dose density for patients with chemotherapy-naïve, advanced-stage non-small cell lung carcinoma (NSCLC).

Methods: Patients with Stage IIIB/IV or recurrent NSCLC, a performance status (PS) score of 0-1, and no history of chemotherapy exposure were eligible. Paclitaxel, 150 mg/m(2), was administered over 3 hours during Weeks 1-6 of an 8-week cycle. Doses were modified for ANC < 1500/microL or for >or= Grade 2 neuropathy on the day of therapy. Treatment continued until toxicity or disease progression. Pharmacokinetics were assessed at Weeks 1, 3, and 5 of Cycle 1.

Results: Thirty-eight patients (median age, 64 years; range, 31-81 years) were treated. There were 21 males (PS = 0 for 17). Eleven patients had received previous radiation, 2 had brain metastases, 25 had adenocarcinoma, 23 had Stage IV disease, 6 had StageIIIB disease, and 9 had recurrent disease. Grade 3-4 granulocytopenia occurred in 39% of patients. There were no deaths due to toxicity. Grade 2 or 3 neuropathy occurred in 29% and 24% of patients, respectively. Ten (27%) patients had Grade 3 hyperglycemia (glucose concentration > 250 mg/dL). There were 16 partial responses (42%; 95% confidence interval [CI], 26-59%). The median survival period was 12.3 months (95% CI, 7.9-19.6%), and the 1-year and 2-year survival rates were 52% (95% CI, 39-71%) and 26% (95% CI, 15-45%), respectively. Paclitaxel pharmacokinetics were consistent with published values and clearance was not induced. Older age and hyperglycemia were associated with greater neurotoxicity.

Conclusions: Paclitaxel at 150 mg/m(2) per week x 6 every 8 weeks can be administered safely in the cooperative group setting. These Phase II data are comparable to those associated with combination therapy. The weekly dose-dense schedule may be more active than conventional schedules.
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http://dx.doi.org/10.1002/cncr.11375DOI Listing
May 2003