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Hall J.S.,University of Manchester | Iype R.,University of Manchester | Armenoult L.S.C.,University of Manchester | Taylor J.,University of Manchester | And 7 more authors.
International Journal of Radiation Oncology Biology Physics

Purpose: To investigate the relationship between human papillomavirus (HPV) genotype and outcome after radiation therapy and intrinsic radiosensitivity. Methods and Materials: HPV genotyping was performed on cervix biopsies by polymerase chain reaction using SPF-10 broad-spectrum primers, followed by deoxyribonucleic acid enzyme immunoassay and genotyping by reverse hybridization line probe assay (LiPA25) (version 1) (n=202). PapilloCheck and quantitative reverse transcription-polymerase chain reaction were used to genotype cervix cancer cell lines (n=16). Local progression-free survival after radiation therapy alone was assessed using log-rank and Cox proportionate hazard analyses. Intrinsic radiosensitivity was measured as surviving fraction at 2 Gy (SF2) using clonogenic assays. Results: Of the 202 tumors, 107 (53.0%) were positive for HPV16, 29 (14.4%) for HPV18, 9 (4.5%) for HPV45, 23 (11.4%) for other HPV genotypes, and 22 (10.9%) were negative; 11 (5.5%) contained multiple genotypes, and 1 tumor was HPV X (0.5%). In 148 patients with outcome data, those with HPVα9-positive tumors had better local progression-free survival compared with α7 patients in univariate (P<.004) and multivariate (hazard ratio 1.54, 95% confidence interval 1.11-1.76, P=.021) analyses. There was no difference in the median SF2 of α9 and α7 cervical tumors (n=63). In the cell lines, 9 were α7 and 4 α9 positive and 3 negative. There was no difference in SF2 between α9 and α7 cell lines (n=14). Conclusion: The reduced radioresponsiveness of α7 cervical tumors is not related to intrinsic radiosensitivity. © 2013 Elsevier Inc. Source

Yap B.K.,Christie National Health Service Foundation Trust | Murby B.,Foundation Medicine
Journal of Clinical Endocrinology and Metabolism

Context: Published studies of thyroid stunning due to preablation 131I scanning in the treatment of differentiated thyroid cancer after thyroidectomy had shown inconsistent clinical impact. Objective: The objective of the study was to evaluate the clinical outcome in patients who were given a low diagnostic 131I activity (1.1 mCi or 40 MBq) 6 days prior to radioiodine ablation (RAI). Design/Setting: Two cohorts of patients were treated in a cancer referral center in 2004-2011. The eligibility criteria were as follows: 1) diagnosis of differentiated thyroid cancer; 2) total or near total thyroidectomy; 3) no distant metastasis; and 4) receiving 82.4 mCi or greater (3050 MBq) therapeutic 131I activity. Patients/Interventions: Three hundred five consecutive patients treated in 2004-2008 (group A) had a diagnostic activity 1.1 mCi of 131I prior to RAI. The second cohort treated in 2009-2011 (group B) consisted of 237 patients who did not undergo diagnostic 131I scanning prior to RAI. Main Outcome Measures: The tumor recurrence rate at 3 years and quantitative assessment using diagnostic whole-body radioiodine scans and TSH-stimulated thyroglobulin levels at 3-12 months after RAI were measured. Results: The 3-year recurrence-free survival rates were 96.4% in both groups, with 4.3% in group A and 3.4% in group B having tumor recurrence (P = .91). The ablation success rates measured by diagnostic whole-body radioiodine scans were 97.6% and 100% and by stimulated thyroglobulin were 85.3% and 85.8% in group A and B, respectively (P = .62). Conclusions: The use of low diagnostic 131I activity (1.1 mCi) given 6 days prior to RAI was safe and convenient without adversely affecting the long-term clinical outcome. Copyright © 2014 by the Endocrine Society. Source

Shaw A.T.,Massachusetts General Hospital | Kim D.-W.,Seoul National University | Nakagawa K.,Kinki University | Seto T.,National Kyushu Cancer Center Fukuoka | And 19 more authors.
New England Journal of Medicine

BACKGROUND: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK ) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. METHODS: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. CONCLUSIONS: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.) Copyright © 2013 Massachusetts Medical Society. Source

Ramalingam S.S.,Emory University | Blackhall F.,Christie National Health Service Foundation Trust | Krzakowski M.,Maria Curie Sklodowska University | Barrios C.H.,Pontifical Catholic University of Rio Grande do Sul | And 13 more authors.
Journal of Clinical Oncology

Purpose: This randomized, open-label trial compared dacomitinib (PF-00299804), an irreversible inhibitor of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, with erlotinib, a reversible EGFR inhibitor, in patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods: Patients with NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, no prior HER-directed therapy, and one/two prior chemotherapy regimens received dacomitinib 45 mg or erlotinib 150 mg once daily. Results: One hundred eighty-eight patients were randomly assigned. Treatment arms were balanced for most clinical and molecular characteristics. Median progression-free survival (PFS; primary end point) was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (hazard ratio [HR] = 0.66; 95% CI, 0.47 to 0.91; two-sided P = .012); in patients with KRAS wild-type tumors, median PFS was 3.71 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (HR = 0.55; 95% CI, 0.35 to 0.85; two-sided P = .006); and in patients with KRAS wild-type/EGFR wild-type tumors, median PFS was 2.21 months for patients treated with dacomitinib and 1.84 months for patients treated with erlotinib (HR = 0.61; 95% CI, 0.37 to 0.99; two-sided P = .043). Median overall survival was 9.53 months for patients treated with dacomitinib and 7.44 months for patients treated with erlotinib (HR = 0.80; 95% CI, 0.56 to 1.13; two-sided P = .205). Adverse event-related discontinuations were uncommon in both arms. Common treatment-related adverse events were dermatologic and gastrointestinal, predominantly grade 1 to 2, and more frequent with dacomitinib. Conclusion: Dacomitinib demonstrated significantly improved PFS versus erlotinib, with acceptable toxicity. PFS benefit was observed in most clinical and molecular subsets, notably KRAS wild-type/EGFR any status, KRAS wild-type/EGFR wild-type, and EGFR mutants. © 2012 by American Society of Clinical Oncology. Source

Neoptolemos J.P.,University of Liverpool | Stocken D.D.,University of Birmingham | Bassi C.,University of Verona | Ghaneh P.,University of Liverpool | And 24 more authors.
JAMA - Journal of the American Medical Association

Context: Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer. Objective: To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer. Design, Setting, and Patients: The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up. Interventions: Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m2, intravenous bolus injection, followed by fluorouracil, 425 mg/m2 intravenous bolus injection given 1-5 days every 28 days) (n=551) or gemcitabine (1000 mg/m2 intravenous infusion once a week for 3 of every 4 weeks) (n=537) for 6 months. Main Outcome Measures: Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life. Results: Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (χ1 2=0.7; P=.39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P<.001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups. Conclusion: Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer. Trial Registration: clinicaltrials.gov Identifier: NCT00058201. ©2010 American Medical Association. All rights reserved. Source

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