Maughan T.S.,University of Cardiff |
Adams R.A.,University of Cardiff |
Smith C.G.,University of Cardiff |
Meade A.M.,Medical Research Council Clinical Trials Unit |
And 17 more authors.
The Lancet | Year: 2011
Background In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in fi rst-line treatment of advanced colorectal cancer with the aim of assessing eff ect on overall survival. Methods In this randomised controlled trial, patients who were fi t for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fl uoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fl uoropyrimidine therapy (capecitabine or infused fl uouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF, and EGFR status were done. The trial is registered, ISRCTN27286448. Findings 1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not diff er between treatment groups (median survival 17•9 months [IQR 10•3-29•2] in the control group vs 17•0 months [9•4-30•1] in the cetuximab group; HR 1•04, 95% CI 0•87-1•23, p=0•67). Similarly, there was no eff ect on progressionfree survival (8•6 months [IQR 5•0-12•5] in the control group vs 8•6 months [5•1-13•8] in the cetuximab group; HR 0•96, 0•82-1•12, p=0•60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0•049). Grade 3 and higher skin and gastrointestinal toxic eff ects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival diff ers by somatic mutation status irrespective of treatment received: BRAF mutant, 8•8 months (IQR 4•5-27•4); KRAS mutant, 14•4 months (8•5-24•0); all wild-type, 20•1 months (11•5-31•7). Interpretation This trial has not confi rmed a benefi t of addition of cetuximab to oxaliplatin-based chemotherapy in fi rst-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefi t in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in fi rstline chemotherapy in patients with widespread metastases cannot be recommended. © 2011 Elsevier Ltd.
Adams R.A.,University of Cardiff |
Meade A.M.,Medical Research Council Clinical Trials Unit |
Seymour M.T.,University of Leeds |
Wilson R.H.,Queens University of Belfast |
And 16 more authors.
The Lancet Oncology | Year: 2011
Background: When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. Methods: COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1·162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. Findings: 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15·8 months (IQR 9·4-26·1) in arm A and 14·4 months (8·0-24·7) in arm C (hazard ratio [HR] 1·084, 80% CI 1·008-1·165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19·6 months (13·0-28·1) in arm A and 18·0 months (12·1-29·3) in arm C (HR 1·087, 0·986-1·198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400 000 per μL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0·96 (95% CI 0·80-1·15, p=0·66), versus 1·54 (1·17-2·03, p=0·0018) in patients with a raised platelet count (p=0·0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand-foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. Interpretation: Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break. Funding: Cancer Research UK. © 2011 Elsevier Ltd.
Development of a label-free LC-MS/MS strategy to approach the identification of candidate protein biomarkers of disease recurrence in prostate cancer patients in a clinical trial of combined hormone and radiation therapy
Morrissey B.,University College Dublin |
O'Shea C.,St Lukes Institute of Cancer Research |
Armstrong J.,St Lukes Institute of Cancer Research |
Rooney C.,University College Dublin |
And 4 more authors.
Proteomics - Clinical Applications | Year: 2013
Purpose: Combined hormone and radiation therapy (CHRT) is one of the principle curative regimes for localised prostate cancer (PCa). Following treatment, many patients subsequently experience disease recurrence however; current diagnostics tests fail to predict the onset of disease recurrence. Biomarkers that address this issue would be of significant advantage. Experimental design: Label-free LC-MS/MS for protein biomarker discovery and MRM for targeted confirmation were applied to patient serum samples accrued in a non-interventional clinical trial of CHRT. Results: Analysis of time-matched patient samples from a patient with disease recurrence compared with a time match disease-free individual supported the identification of 287 proteins. Of these, 141 proteins were quantified, 95 proteins changed in their expression (P ≤ 0.05 and ≥1.5-fold change) and of these 16 were selected for MRM confirmation. The protein expression changes observed in the label-free LC-MS/MS and MRM analysis were found to be highly correlated (R2 = 0.85). Conclusions and clinical relevance: The establishment of a clinical trial to support the acquisition of samples and development of a pipeline for MS-based biomarker discovery and validation should contribute to the identification of a serum protein signature to predict or monitor the outcome of treatment of patients with PCa. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Smyth L.,St Vincents University Hospital |
Watson G.,St Vincents University Hospital |
Walsh E.M.,All Ireland Co operative Oncology Research Group |
Kelly C.M.,All Ireland Co operative Oncology Research Group |
And 13 more authors.
Breast Cancer Research and Treatment | Year: 2015
The 21-gene test is a validated multi-gene diagnostic test that predicts chemotherapy (CT) benefit in oestrogen receptor positive (ER+), lymph node-negative (N0) breast cancer (BC) patients (pts). Ireland was the first public health care system to reimburse this test in Europe. Study objectives were to assess the impact of this test on decision-making and to analyse the economic impact of testing. Between October 2011 and February 2013, a national, retrospective, cross-sectional observational study of ER+, N0 BC pts tested with the 21-gene test was conducted. Surveyed breast medical oncologists, provided the assumption for the decision impact analysis that grade (G) 1 pts would not have received CT before testing and G2/3 pts would have received CT before testing. Descriptive statistical analyses were performed. 592 pts were identified; Low, intermediate and high recurrence score were identified in 53, 36 and 10 % pts, respectively. 384 (70 %) pts had G2, 129 (22 %) G3 and 76 (13 %) G1 tumours. Post testing, 345 pts (59 %) experienced a change in CT decision; 339 changed to hormone therapy alone and 6 advised to receive CT. 172 (30 %) pts received CT, 12 (3.9 %) of pts with low scores, 108 (50.9 %) of intermediate risk and 50 (90.9 %) of pts with high risk scores. Net reduction in CT use was 58 % and net savings achieved were €793,565. Since public reimbursement, the introduction of the 21-gene test has resulted in a significant reduction in chemotherapy administration and cost savings for the Irish public healthcare system. © 2015, Springer Science+Business Media New York.
Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial
Eiermann W.,Red Cross |
Eiermann W.,All Ireland Co operative Oncology Research Group |
Eiermann W.,Hospital Universitario San Carlos |
Eiermann W.,Mount Medical Center |
And 212 more authors.
Journal of Clinical Oncology | Year: 2011
Purpose: Anthracyclines, taxanes, and alkylating agents are among the most active agents in treatment of adjuvant breast cancer (BC), but the optimal schedule for their administration is unknown. We performed an adjuvant trial to compare the sequential regimen of doxorubicin with cyclophosphamide (AC) followed by docetaxel (ie, AC>T) with the combination regimen of TAC. Patients and Methods: Women with node-positive, human epidermal growth factor receptor 2-nonamplified, operable BC were stratified by number of axillary nodes and hormone receptor status and were randomly assigned to adjuvant chemotherapy with six cycles of TAC (75/50/500 mg/m 2 every 3 weeks) or four cycles of AC (60/600 mg/m 2 every 3 weeks) followed by four doses of docetaxel at 100 mg/m 2 every 3 weeks (AC>T). After completion of chemotherapy, radiation therapy was given as indicated, and patients with hormone receptor (HR) -positive disease received adjuvant hormonal therapy with tamoxifen and/or aromatase inhibitors. Results: In 30 months, 3,298 patients were enrolled (n = 1,649 in each arm). The major baseline characteristics were well balanced between the groups. At a median follow-up of 65 months, estimated 5-year disease-free survival rates were 79% in both groups (log-rank P = .98; hazard ratio [HR], 1.0; 95%CI, 0.86 to 1.16), and 5-year overall survival rates for both arms were 88% and 89%, respectively (log-rank P = .37; HR, 0.91; 95% CI, 0.75 to 1.11). TAC was associated with more febrile neutropenia and thrombocytopenia, and AC>T was associated with more sensory neuropathy, nail changes, and myalgia. The incidence of neutropenic infection was similar in both groups. Conclusion: The sequential and combination regimens incorporating three drugs were equally effective but differed in toxicity profile. © 2011 by American Society of Clinical Oncology.