Trial Of Adjuvant Chemotherapy Research Articles

Aspirin and COX-2 inhibitor use in patients with stage III colon cancer.

We conducted a prospective, observational study of aspirin and COX-2 inhibitor use and survival in stage III colon cancer patients enrolled in an adjuvant chemotherapy trial. Among 799 eligible patients, aspirin use was associated with improved recurrence-free survival (RFS) (multivariable hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.28 to 0.95), disease-free survival (DFS) (HR = 0.68, 95% CI = 0.42 to 1.11), and overall survival (OS) (HR = 0.63, 95% CI = 0.35 to 1.12). Adjusted HRs for DFS and OS censored at five years (in an attempt to minimize misclassification from noncancer death) were 0.61 (95% CI = 0.36 to 1.04) and 0.48 (95% CI = 0.23 to 0.99). Among 843 eligible patients, those who used COX-2 inhibitors had multivariable HRs for RFS, DFS, and OS of 0.53 (95% CI = 0.27 to 1.04), 0.60 (95% CI = 0.33 to 1.08), and 0.50 (95% CI = 0.23 to 1.07), and HRs of 0.47 (95% CI = 0.24 to 0.91) and 0.26 (95% CI = 0.08 to 0.81) for DFS and OS censored at five years. Aspirin and COX-2 inhibitor use may be associated with improved outcomes in stage III colon cancer patients.

Molecular Markers Identify Subtypes of Stage III Colon Cancer Associated With Patient Outcomes

Categorization of colon cancers into distinct subtypes using a combination of pathway-based biomarkers could provide insight into stage-independent variability in outcomes. We used a polymerase chain reaction-based assay to detect mutations in BRAF (V600E) and in KRAS in 2720 stage III cancer samples, collected prospectively from patients participating in an adjuvant chemotherapy trial (NCCTG N0147). Tumors deficient or proficient in DNA mismatch repair (MMR) were identified based on detection of MLH1, MSH2, and MSH6 proteins and methylation of the MLH1 promoter. Findings were validated using tumor samples from a separate set of patients with stage III cancer (n = 783). Association with 5-year disease-free survival was evaluated using Cox proportional hazards models. Tumors were categorized into 5 subtypes based on MMR status and detection of BRAF or KRAS mutations which were mutually exclusive. Three subtypes were MMR proficient: those with mutations in BRAF (6.9% of samples), mutations in KRAS (35%), or tumors lacking either BRAF or KRAS mutations (49%). Two subtypes were MMR deficient: the sporadic type (6.8%) with BRAF mutation and/or or hypermethylation of MLH1 and the familial type (2.6%), which lacked BRAF(V600E) or hypermethylation of MLH1. A higher percentage of MMR-proficient tumors with BRAF(V600E) were proximal (76%), high-grade (44%), N2 stage (59%), and detected in women (59%), compared with MMR-proficient tumors without BRAF(V600E) or KRAS mutations (33%, 19%, 41%, and 42%, respectively; all P < .0001). A significantly lower proportion of patients with MMR-proficient tumors with mutant BRAF (hazard ratio = 1.43; 95% confidence interval: 1.11-1.85; Padjusted = .0065) or mutant KRAS (hazard ratio = 1.48; 95% confidence interval: 1.27-1.74; Padjusted < .0001) survived disease-free for 5 years compared with patients whose MMR-proficient tumors lacked mutations in either gene. Disease-free survival rates of patients with MMR-deficient sporadic or familial subtypes was similar to those of patients with MMR-proficient tumors without BRAF or KRAS mutations. The observed differences in survival rates of patients with different tumor subtypes were validated in an independent cohort. We identified subtypes of stage III colon cancer, based on detection of mutations in BRAF (V600E) or KRAS, and MMR status that show differences in clinical and pathologic features and disease-free survival. Patients with MMR-proficient tumors and BRAF or KRAS mutations had statistically shorter survival times than patients whose tumors lacked these mutations. The tumor subtype found in nearly half of the study cohort (MMR-proficient without BRAF(V600E) or KRAS mutations) had similar outcomes to those of patients with MMR-deficient cancers.

Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features

Differences exist between the proximal and distal colon in terms of developmental origin, exposure to patterning genes, environmental mutagens, and gut flora. Little is known on how these differences may affect mechanisms of tumorigenesis, side-specific therapy response or prognosis. We explored systematic differences in pathway activation and their clinical implications. Detailed clinicopathological data for 3045 colon carcinoma patients enrolled in the PETACC3 adjuvant chemotherapy trial were available for analysis. A subset of 1404 samples had molecular data, including gene expression and DNA copy number profiles for 589 and 199 samples, respectively. In addition, 413 colon adenocarcinoma from TCGA collection were also analyzed. Tumor side-effect on anti-epidermal growth factor receptor (EGFR) therapy was assessed in a cohort of 325 metastatic patients. Outcome variables considered were relapse-free survival and survival after relapse (SAR). Proximal carcinomas were more often mucinous, microsatellite instable (MSI)-high, mutated in key tumorigenic pathways, expressed a B-Raf proto-oncogene, serine/threonine kinase (BRAF)-like and a serrated pathway signature, regardless of histological type. Distal carcinomas were more often chromosome instable and EGFR or human epidermal growth factor receptor 2 (HER2) amplified, and more frequently overexpressed epiregulin. While risk of relapse was not different per side, SAR was much poorer for proximal than for distal stage III carcinomas in a multivariable model including BRAF mutation status [N = 285; HR 1.95, 95% CI (1.6-2.4), P < 0.001]. Only patients with metastases from a distal carcinoma responded to anti-EGFR therapy, in line with the predictions of our pathway enrichment analysis. Colorectal carcinoma side is associated with differences in key molecular features, some immediately druggable, with important prognostic effects which are maintained in metastatic lesions. Although within side significant molecular heterogeneity remains, our findings justify stratification of patients by side for retrospective and prospective analyses of drug efficacy and prognosis.

Abstract 283: Biomarker search using gene expression databases in a phase III, controlled clinical trial of postoperative adjuvant chemotherapy for stage III colon cancer (acts-cc): Correlation between gene expression and DNA copy number

Abstract Background: The ACTS-CC trial is a randomized, controlled phase III study designed to validate the noninferiority of S-1 to UFT/LV as adjuvant chemotherapy for stage III colon cancer and rectosigmoid cancer. A prospective biomarker search was performed as an auxiliary study of the ACTS-CC trial, using formalin-fixed, paraffin-embedded (FFPE) specimens obtained from 892 patients. The gene expression levels of 5-FU metabolizing enzymes and folate metabolizing enzymes and alterations of genome-wide copy numbers in tumor have been reported (2012 and 2013 Annual Meetings of AACR). In the present study, we performed correlation analyses of gene expression and DNA copy number data to characterize colorectal cancer and to prepare for a pre-planned analysis of predictive or prognostic biomarkers. Methods: FFPE specimens for this biomarker study were obtained after receiving informed consent from 892 (gene expression analysis) or 795 (DNA copy number analysis) of 1535 patients enrolled between April 2009 and January 2010. Macro-dissections were performed to extract total RNA and genomic DNA from 10-μm-thick FFPE specimens of colon cancer. Gene expression levels of 11 enzymes (TS, DPD, TP, OPRT, FPGS, GGH, DHFR, MTHFR, MTHFD, FOLRA, GART) related to 5-FU and folic acid metabolism were studied according to the Danenberg Tumor ProfileTM method (Shirota, Y. JCO 2001). Somatic copy-number alterations in cancer were analyzed by high-density SNP array analysis (Human 250K StyI array, Affymetrix, Santa Clara, CA). To detect copy-number alterations, the scanned image CEL files were imported into Partek Genomics Suite v6.6 (Partek Inc., St. Louis, MO, USA). We compared mRNA level, gene copy number and genome-wide segment copy number across a total of 161 colorectal cancers. Results: Gene expression levels were successfully estimated in 521-808 samples (84.0-90.0%, median 89.4%). Genome-wide DNA copy numbers profiles of 161 samples were obtained by GeneChip. Extracted genomic DNA from 616 of 777 samples that were not subjected to microarray analysis served as validation samples. Frequencies of copy number gain (&amp;gt;2.3) ranged from 0% to 57% for 11 genes, whereas frequencies of copy number loss (&amp;lt;1.7) ranged from 24.8% to 87%. Among 11 genes, the DNA copy numbers of GART, GGH, MTHFD1, and FPGS most strongly correlated with mRNA expression: correlation coefficients of these genes were 0.48, 0.45, 0.42, and 0.41, respectively. Gene expressions of OPRT or TP were influenced not only by their own DNA copy numbers but also by other genomic segments of 20q or 18q on genome-wide analysis. Conclusions: Gene expression of folate metabolizing enzymes positively correlated with DNA copy numbers in patients with stage III colorectal cancer. Such correlations may merit further evaluation to identify potential biomarkers. Citation Format: Hiroyuki Uetake, Toshiaki Ishikawa, Megimi Ishiguro, Shigeyuki Matsui, Kenichi Sugihara, ACTS-CC Study Group. Biomarker search using gene expression databases in a phase III, controlled clinical trial of postoperative adjuvant chemotherapy for stage III colon cancer (acts-cc): Correlation between gene expression and DNA copy number. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 283. doi:10.1158/1538-7445.AM2014-283

Abstract 5545: Rare genetic variation association with neurotoxicity and infection in breast cancer patients enrolled in PG-SNPS

Abstract The genetic architecture underlying individual variation in susceptibility to severe toxicity to chemotherapeutic agents is not yet fully understood. We used a gene-based omnibus test to investigate the role of rare genetic variation in severe neurosensory toxicity and infection. Samples from a breast cancer pharmacogenetics study (PG-SNPS), were genotyped using the Illumina Human Exome Beadchip array. Early breast cancer patients treated with adjuvant and neo-adjuvant chemotherapy trials were recruited into PG-SNPS. Clinical data relating to their chemotherapy-related toxicities was collected prospectively. The National Cancer Institute Common Toxicity Criteria (NCI CTC version 2) was used to assess toxicities. For each of the toxicities, a case-control analysis was conducted using the Rare Admixture Maximum Likelihood method(1). RAML is an omnibus test that looks at joint effects of multiple variants on a phenotype. The test considers the probability that a given variant is associated with severe toxicity, the average effect of the associated variants within a gene on severe toxicity, and the expected standard error of this effect. Patients were considered as taxane-related neurosensory cases, if they had a CTC grade of ≥ 2 and as infection cases if they have a CTC grade of ≥ 3. For both analyses variants with minor allele frequency less than 2% were included. Only patients treated with paclitaxel were included in the neurosensory analysis. In this analysis we included 1,127 patients, 333 of which were considered cases. We tested variants in 14,762 genes exome-wide. The gene LRRTM3 was associated with severe neurosensory toxicity (p-value=5.5 x 10-4). LRRTM3 is a protein-coding gene with strong links to the maintenance and development of the nervous system. Patients exposed to specific adjuvant/neo-adjuvant breast cancer combination chemotherapy regimens with paclitaxel, epirubicin, methotrexate, cyclophosphamide, 5fluorouracil or gemcitabine, were included in the infection analysis (2,3,4). These included 1,564 patients, 583 of which were considered cases. We tested 15,161 genes exome-wide for association with severe infection. The top associated gene was FKBP5 with a p-value of 7 x 10-5. This gene has a role in immunoregulation and encodes a protein which binds to the immunosuppressants FK506 and rapamycin. These genes may be of future interest as candidate genes within pharmacodynamic pathways. 1. Tyrer JP, Guo Q, Easton DF, Pharoah PD. The admixture maximum likelihood test to test for association between rare variants and disease phenotypes. BMC Bioinformatics 2013;14:177. 2. NEAT trial - ClinicalTrials.gov Identifier NCT00003577 3. tAnGo trial - ClinicalTrials.gov Identifier NCT00039546 4. Neo-tAnGo trial - ClinicalTrials.gov Identifier NCT00070278 Citation Format: Ailith Pirie, Jean Abraham, Kyriaki Michailidou, Jonathan Tyrer, Leila Dorling, Joe Dennis, Helena Earl, Carlos Caldas, Paul Pharoah. Rare genetic variation association with neurotoxicity and infection in breast cancer patients enrolled in PG-SNPS. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5545. doi:10.1158/1538-7445.AM2014-5545

Is Marital/Partner Status Associated With Survival in Patients With Resectable Pancreatic Cancer Treated With Adjuvant Postoperative Multi-Modality Therapy?: Results of Secondary Analysis of RTOG 9704

Two recently published studies based on analyses of Surveillance, Epidemiology, and End Results (SEER) data disclosed a statistically significant survival advantage for married/partnered patients with pancreatic cancer. However, the SEER data base does not contain detailed treatment information and therefore neither study specifically looked at survival in patients with resected pancreatic cancer who underwent combined modality adjuvant therapy. Since the impact of marital/partner status on survival in this cohort of aggressively treated patients has not been reported, this study was undertaken. A secondary analysis of RTOG 97-04, a phase III clinical trial of post-operative adjuvant chemotherapy and chemo-radiation therapy for patients with resected pancreatic carcinoma, was performed. Socio-demographic co-variables analyzed with respect to survival included gender (male vs female), age (<60 years vs ≥ 60 years), and marital status (married/partnered vs single). Survival analysis was performed using the product limit method and compared using the log rank test. Multivariable analysis was performed using the Cox proportional hazards regression model. Of the 531 patients enrolled in RTOG 97-04, complete socio-demographic data was available for 451. At the time of the secondary analysis 368 (82%) of the patients had died. Median patient age was 61 years (range 33 to 85 years), 271 (74%) were married/partnered, and 256 (56%) were male. Multivariable analysis disclosed that marital/partner status was not statistically significantly (p = 0.52) associated with overall survival. This secondary analysis of data from RTOG 97-04 demonstrated no association between marital/partner status and survival in patients with resected pancreatic cancer who received adjuvant post-operative chemo-radiation therapy. This finding suggests that while married patients with pancreatic cancer in general have a survival advantage, being married/partnered does not provide a survival advantage for patients with resected pancreatic cancer who undergo aggressive post-operative adjuvant multi-modality therapy.

576P - Pharmacogenetic Profiling for Toxicity of Oxaliplatin and Fluoropyrimidines. Final Report from an Ancillary Protocol to the Tosca (Three or Six Colon Adjuvant) Trial

ABSTRACT Aim: A number of germline polymorphisms have shown promising predictive role for chemotherapy related toxicity in colorectal cancer patients. However, large-scale validation trials are necessary before pharmacogenetic findings are incorporated into clinical practice. We investigated 17 polymorphisms in 11 genes for their association with toxicity of fluoropyrimidines and oxaliplatin (TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT, GSTP, GSTM, ABCC1, ABCC2) in colorectal cancer patients enrolled in a prospective randomized trial of adjuvant chemotherapy. Methods: TOSCA is a non-profit, Italian, multicentre, randomized, non-inferiority phase III study conducted in high-risk stage II and stage III colorectal cancer patients treated with 6 or 3 months of either FOLFOX-4 or XELOX adjuvant chemoterapy. A planned sample of patients was accrued in the ancillary pharmacogenetic study. The primary endpoint was the evaluation of the relationship of genetic polymorphisms with occurrence of grade 3-4 CTCAE toxicity event (grade 2-4 for neurotoxicity). Results: From July 2007 to October 2011, 531 patients were enrolled from 26 experimental centres (194 patients in 6-month FOLFOX-4 arm, 194 patients in 3-month FOLFOX-4 arm, 74 patients in 6-month XELOX arm, 69 patients in 3-month XELOX arm). Grade ≥3 neutropenia and grade >2 neurotoxicity events occurred in 150 (29%) and in 132 patients (24.8%), respectively. Diarrhea grade > 3 events occurred in 34 (6.5%) patients. None of the studied polymorphisms showed clinically relevant association with toxicity. Conclusions: In the studied population, we ruled out a strong predictive role of known genetic variants for toxicity. Future investigations should address novel polymorphisms emerging from genome-wide association studies. Disclosure: All authors have declared no conflicts of interest.

Accuracy of Predefined Hypotheses in Colon Cancer Adjuvant Phase III Trials: Observations and Recommendations

Adjuvant colon cancer trials compare survival of patients receiving either a standard, approved regimen or a new investigational treatment after curative surgical resection of tumor. The target accrual of trials is on the basis of the statistical power required to reveal survival benefit, and depends on predefined hypotheses regarding the expected results for the control group and the differences in treatment effects between the control and the investigational group. In this review we assess the validity of predefined hypotheses in phase III adjuvant trials of colon cancer treatment published between 1988 and 2012. Correlation between expected and observed results was weak for both the control and the investigational groups in the colon cancer trials. Three-year disease-free survival (DFS) was found to be the most reliable endpoint for assessing different fluoropyrimidine-based and oxaliplatin-based regimens, despite a Will Rogers effect associated with the latter. In recent colon cancer adjuvant trials, correlation between DFS and overall survival was weaker than in previous trials performed when only fluoropyrimidines were available for treatment, both in the adjuvant and metastatic setting. This finding is mainly the result of increased survival obtained with new therapy for patients who relapse after adjuvant therapy. Our observations further support the use of three-year DFS as the primary endpoint of adjuvant chemotherapy trials enrolling patients with stage III colon cancer.

Neoadjuvant chemotherapy in localized resectable stomach cancer

In localized resectable stage II or III gastric cancer, D2 dissection has been accepted as the standard surgical method worldwide. The Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer and Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer phase III trials have demonstrated that systemic adjuvant chemotherapy can significantly improve recurrence-free survival (RFS) and overall survival (OS) after D2 dissection with absolute survival benefit of 10% to 15% compared with surgery alone. Addition of radiation or intensification of adjuvant chemotherapy has been tried in localized resectable gastric cancer for further improvements of RFS and OS as well. However, addition of radiation after D2 dissection was proven to play no or only a minimal role at its best in reduction of loco-regional recurrences as well as distant metastases. The results of recent large-scale adjuvant trials suggest that more intensified adjuvant treatment including multiple chemotherapeutic agents would not likely induce a better result. For this reason, addition of neoadjuvant chemotherapy to current standard of care may be the only plausible strategy to improve long-term outcomes in localized resectable gastric cancer, and clinical trials of neoadjuvant chemotherapy are now ongoing in gastric cancer.

Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: Final results of JCOG0205

BackgroundNSABP C-06 demonstrated the non-inferiority of oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) to weekly fluorouracil and folinate (5-FU/LV) with respect to disease-free survival (DFS) for stage II/III colon cancer. This is the first report of JCOG0205, which compared UFT/LV to standard 5-FU/levofolinate (l-LV) for stage III colorectal cancer patients who have undergone Japanese D2/D3 lymph node dissection. MethodsPatients were randomised to three courses of 5-FU/l-LV (5-FU 500mg/m2, l-LV 250mg/m2 on days 1, 8, 15, 22, 29, 36 every 8weeks) or five courses of UFT/LV (UFT 300mgm−2day−1, LV 75mg/day on days 1–28 every 5weeks). The primary end-point was DFS. The sample size was 1100 determined with one-sided alpha of 0.05, power of 0.78 and non-inferiority margin of hazard ratio of 1.27. This trial is registered with UMIN-CTR (C000000193). FindingsBetween February 2003 and November 2006, 1,101 patients (1092 eligible patients) were randomised to 5-FU/l-LV (n=550) or UFT/LV (n=551). Median age: 61years, colon/rectum: 67%/33%, number of positive nodes ⩽3/>3: 73%/27%, stage IIIa/IIIb: 75%/25%. The hazard ratio of DFS was 1.02 (91.3% confidence interval, 0.84–1.23), demonstrating the non-inferiority of UFT/LV (P=0.0236). Five-year overall survival (87.5%) was higher than that in NSABP C-06 (69.6%). Grade 3/4 toxicities were 8.4% neutropenia in 5-FU/l-LV and 8.7% alanine aminotransferase elevation in UFT/LV, respectively. The incidences of diarrhoea (9.6% versus 8.5%) and anorexia (4.0% versus 3.7%) were similar between the two arms. No treatment-related deaths were reported. InterpretationAdjuvant UFT/LV is non-inferior to standard 5-FU/l-LV with respect to DFS. UFT/LV should be an oral treatment option for patients with stage III colon cancer who have undergone Japanese D2/D3 lymph node dissection.

Sugar-sweetened beverage intake and cancer recurrence and survival in CALGB 89803 (Alliance).

BackgroundIn colon cancer patients, obesity, sedentary lifestyle, and high dietary glycemic load have been associated with increased risk of cancer recurrence. High sugar-sweetened beverage intake has been associated with obesity, diabetes, and cardio-metabolic diseases, but the influence on colon cancer survival is unknown.MethodsWe assessed the association between sugar-sweetened beverage consumption on cancer recurrence and mortality in 1,011 stage III colon cancer patients who completed food frequency questionnaires as part of a U.S. National Cancer Institute-sponsored adjuvant chemotherapy trial. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazard models.ResultsPatients consuming ≥2 servings of sugar-sweetened beverages per day experienced an adjusted HR for disease recurrence or mortality of 1.67 (95% CI, 1.04–2.68), compared with those consuming <2 servings per month (P trend = 0.02). The association of sugar-sweetened beverages on cancer recurrence or mortality appeared greater among patients who were both overweight (body mass index ≥25 kg/m2) and less physically active (metabolic equivalent task-hours per week <18) (HR = 2.22; 95% CI, 1.29–3.81, P trend = 0.0025).ConclusionHigher sugar-sweetened beverage intake was associated with a significantly increased risk of cancer recurrence and mortality in stage III colon cancer patients.

Germline mutations in DNA repair genes in women with ovarian, peritoneal, or fallopian tube cancer treated on GOG protocols 218 and 262

Objectives: GOG218 and GOG262 were trials of adjuvant chemotherapy following debulking surgery for advanced ovarian, peritoneal, and fallopian tube cancers. Our objective was to deeply sequence germline DNA from patients treated on these protocols for mutations in 47 DNA repair genes to determine the frequency and spectrum of inherited mutations in a large group of ovarian cancer patients.

Overall survival result and outcomes by KRAS, BRAF, andDNA mismatch repair in relation to primary tumor site in colon cancers from a randomized trial of adjuvant chemotherapy: NCCTG (Alliance) N0147.

3525 Background: We report mature overall survival (OS) data in stage III colon cancers from a phase III trial of adjuvant mFOLFOX6 ± cetuximab. Biomarkers were analyzed in relation to primary tumo...

A phase III trial of adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: Outback (ANZGOG0902/GOG0274/RTOG1174).

TPS5632 Background: Cervical cancer is a global health problem and the most common cause of cancer-related death among women in developing nations. Despite the recently developed cervical cancer va...

Serum biomarker analysis of WJOG4107: A randomized phase II trial of adjuvant chemotherapy with S-1 versus CDDP+S-1 for resected stage II-IIIA non-small cell lung cancer (NSCLC).

Serum biomarker analysis of WJOG4107: A randomized phase II trial of adjuvant chemotherapy with S-1 versus CDDP+S-1 for resected stage II-IIIA non-small cell lung cancer (NSCLC).

Adjuvant chemotherapy for advanced endometrial cancer.

Approximately 13% of women diagnosed with endometrial cancer present with advanced stage disease (International Federation of Gynecology and Obstetrics (FIGO) stage III/IV). The standard treatment of advanced endometrial cancer consists of cytoreductive surgery followed by radiation therapy, or chemotherapy, or both. There is currently little agreement about which adjuvant treatment is the safest and most effective. To evaluate the effectiveness and safety of adjuvant chemotherapy compared with radiotherapy or chemoradiation, and to determine which chemotherapy agents are most effective in women presenting with advanced endometrial cancer (FIGO stage III/IV). We searched the Cochrane Gynaecological Cancer Collaborative Review Group's Trial Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 10 2013), MEDLINE and EMBASE up to November 2013. Also we searched electronic clinical trial registries for ongoing trials. Randomised controlled trials (RCTs) of adjuvant chemotherapy compared with radiotherapy or chemoradiation in women with FIGO stage III and IV endometrial cancer. Two review authors selected trials, extracted data, and assessed trials for risk of bias. Where necessary, we contacted trial investigators for relevant, unpublished data. We pooled data using the random-effects model in Review Manager (RevMan) software. We included four multicentre RCTs involving 1269 women with primary FIGO stage III/IV endometrial cancer. We considered the trials to be at low to moderate risk of bias. All participants received primary cytoreductive surgery. Two trials, evaluating 620 women (83% stage III, 17% stage IV), compared adjuvant chemotherapy with adjuvant radiotherapy; one trial evaluating 552 women (88% stage III, 12% stage IV) compared two chemotherapy regimens (cisplatin/doxorubicin/paclitaxel (CDP) versus cisplatin/doxorubicin (CD) treatment) in women who had all undergone adjuvant radiotherapy; and one trial contributed no data.Overall survival (OS) and progression-free survival (PFS) was longer with adjuvant chemotherapy compared with adjuvant radiotherapy (OS: hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.57 to 0.99, I² = 22%; and PFS: HR 0.74, 95% CI 0.59 to 0.92, I² = 0%). Sensitivity analysis using adjusted and unadjusted OS data, gave similar results. In subgroup analyses, the effects on survival in favour of chemotherapy were not different for stage III and IV, or stage IIIA and IIIC (tests for subgroup differences were not significant and I² = 0%). This evidence was of moderate quality. Data from one trial showed that women receiving adjuvant chemotherapy were more likely to experience haematological and neurological adverse events and alopecia, and more likely to discontinue treatment (33/194 versus 6/202; RR 5.73, 95% CI 2.45 to 13.36), than those receiving adjuvant radiotherapy. There was no statistically significant difference in treatment-related deaths between the chemotherapy and radiotherapy treatment arms (8/309 versus 5/311; Risk Ratio (RR) 1.67, 95% CI 0.55 to 5.00).There was no clear difference in PFS between intervention groups in the one trial that compared CDP versus CD (552 women; HR 0.90, 95% CI 0.69 to 1.17). We considered this evidence to be of moderate quality. Mature OS data from this trial were not yet available. Severe haematological and neurological adverse events occurred more frequently with CDP than CD.We found no trials to include of adjuvant chemotherapy versus chemoradiation in advanced endometrial cancer; however we identified one ongoing trial of this comparison. There is moderate quality evidence that chemotherapy increases survival time after primary surgery by approximately 25% relative to radiotherapy in stage III and IV endometrial cancer. There is limited evidence that it is associated with more adverse effects. There is some uncertainty as to whether triplet regimens offer similar survival benefits over doublet regimens in the long-term. Further research is needed to determine which chemotherapy regimen(s) are the most effective and least toxic, and whether the addition of radiotherapy further improves outcomes. A large trial evaluating the benefits and risks of adjuvant chemoradiation versus chemotherapy in advanced endometrial cancer is ongoing.

Hospital-based health care use correlates with incidence of adverse events among elderly Medicare patients treated in adjuvant chemotherapy trials (Alliance 70802)

Medicare claims can be useful in chemotherapy-related comparative effectiveness research (CER) estimating survival, but methods for estimating patients' treatment morbidity are currently lacking. We sought to determine if patients' health care use in the claims is a marker of treatment morbidity. For 249 elderly Medicare patients with breast or colon cancer who were treated in two adjuvant clinical trials, we merged patients' National Cancer Institute Common Toxicity Criteria for Adverse Events (CTC AEs) trial data with their contemporaneous Medicare claims. We estimated associations of patients' grade ≥3 CTC AE counts and their use of two types of hospital-based health care in claims (i.e., emergency room (ER) visits and hospitalizations). ER visits and hospitalizations were significantly positively associated with grade ≥3 CTC AE counts incurred by patients during the study. Eight percent of patients without any grade ≥3 CTC AEs had one or more hospitalizations during the observation period compared to 43% of patients with three or more grade ≥3 CTC AEs (p<0.01). Those who were hospitalized at least once had more than three times the rate of grade ≥3 CTC AEs (IRR 3.70, 95% CI: 2.53-5.40) compared to those who were not. With each hospitalization, the daily incidence rate of any grade ≥3 CTC AE more than doubled (IRR 2.10, 95% CI: 1.54-2.86). Because hospitalization is strongly associated with clinically significant toxicity it may be a useful outcome for Medicare claim-based CER comparing treatment morbidity for elderly patients receiving different adjuvant chemotherapy regimens.

Excess adiposity and survival in patients with colorectal cancer: a systematic review

Excess adiposity is an established risk factor for incident colorectal cancer (CRC) but whether this association extrapolates to poorer survival is unclear. We undertook a systematic review to examine relationships between measures of adiposity and survival in patients with CRC. For distinction, we included pre-diagnosis exposure and CRC-related mortality. We performed dose-response meta-analyses and assessed study quality using eight domains of bias. Six study categories were identified based on (i) timing of adiposity measurement relative to survival analysis time zero and (ii) clinical setting. Several types of adiposity measurements were reported; body mass index (BMI) was the commonest. For pre-diagnosis cohorts, baseline BMI negatively impacted on CRC-related mortality in men only (risk estimate per 5 kg m(-2) = 1.19, 95% confidence intervals: 1.14-1.25). The other groups were pre-diagnosis BMI but diagnosis as time zero; population-based cohorts; treatment cohorts; observational analyses within adjuvant chemotherapy trials; patients with metastatic CRC - each had several biases (e.g. treatment selection, reverse causality) and sources of confounding (e.g. chemotherapy 'capping'). Overall, there was insufficient evidence for a strong link between adiposity and survival. These findings demonstrate an important principle: an established link between an exposure (here, adiposity) and increased cancer incidence does not necessarily extrapolate into an inferior post-treatment outcome.

Significance of TP53 mutations as predictive markers of adjuvant cisplatin-based chemotherapy in completely resected non-small-cell lung cancer

Adjuvant cisplatin-based chemotherapy only marginally improves survival in patients with completely resected non-small-cell lung cancer (NSCLC). We have evaluated the predictive value of mutations in TP53, encoding the tumour suppressor p53, in the International Adjuvant Lung Cancer Trial (IALT), a randomized trial of adjuvant cisplatin-based chemotherapy against observation. TP53 (exons 4–8) was sequenced in 524 archived specimens of IALT patients with a median follow-up of 7.5 years. Predictive analyses were based on Cox models adjusted for clinical and pathological variables. P-values ≤0.01 were considered as significant. Mutations were detected in 221 patients (42%) and had no predictive value for the effect of chemotherapy (interaction between TP53 and treatment: p = 0.17 for Overall Survival (OS); p = 0.06 for Disease-Free Interval, (DFS)). However, among patients with mutations, outcome appeared worse in treatment compared to observation arms (HR for OS = 1.36 (95% CI [0.97–1.31), p = 0.08; DFS = 1.40 (95% CI [1.01–1.95]), p = 0.04). When grouping mutations into classes according to predicted effects on protein structure, the tendency towards worse outcomes was restricted to “structure” mutations affecting residues of the hydrophobic core that are not located at the p53 protein-DNA interface (HR for death in this class vs wild-type T53 = 1.66; 95% CI [1.10–2.52], p = 0.02). Overall, TP53 mutations are not significant predictors of outcome in this trial of cisplatin-based chemotherapy, although a specific class of structural mutations may be associated with a tendency towards worse outcomes upon treatment.

Hospital-based health care use correlates with incidence of adverse events among elderly Medicare patients treated in adjuvant chemotherapy trials (Alliance 70802)

Hospital-based health care use correlates with incidence of adverse events among elderly Medicare patients treated in adjuvant chemotherapy trials (Alliance 70802)