Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial (2017)

Type of publication:
Randomised controlled trial

Author(s):
Earl, Helena M; Hiller, Louise; Howard, Helen C; Dunn, Janet A; Young, Jennie; Bowden, Sarah J; McDermaid, Michelle; Waterhouse, Anna K; Wilson, Gregory; *Agrawal, Rajiv; O’Reilly, Susan; Bowman, Angela; Ritchie, Diana M; Goodman, Andrew; Hickish, Tamas; McAdam, Karen; Cameron, David; Dodwell, David; Rea, Daniel W; Caldas, Carlos; Provenzano, Elena; Abraham, Jean E; Canney, Peter; Crown, John P; Kennedy, M John; Coleman, Robert; Leonard, Robert C; Carmichael, James A; Wardley, Andrew M; Poole, Christopher J; tAnGo trial collaborators

Citation:
The Lancet. Oncology, Volume 18, No. 6, p755–769, June 2017

Abstract:
BACKGROUND The tAnGo trial was designed to investigate the potential role of gemcitabine when added to anthracycline and taxane-containing adjuvant chemotherapy for early breast cancer. When this study was developed, gemcitabine had shown significant activity in metastatic breast cancer, and there was evidence of a favourable interaction with paclitaxel. METHOD StAnGo was an international, open-label, randomised, phase 3 superiority trial that enrolled women aged 18 years or older with newly diagnosed, early-stage breast cancer who had a definite indication for chemotherapy, any nodal status, any hormone receptor status, Eastern Cooperative Oncology Group performance status of 0-1, and adequate bone marrow, hepatic, and renal function. Women were recruited from 127 clinical centres and hospitals in the UK and Ireland, and randomly assigned (1:1) to one of two treatment regimens: epirubicin, cyclophosphamide, and paclitaxel (four cycles of 90 mg/m2 intravenously administered epirubicin and 600 mg/m2 intravenously administered cyclophosphamide on day 1 every 3 weeks, followed by four cycles of 175 mg/m2 paclitaxel as a 3 h infusion on day 1 every 3 weeks) or epirubicin, cyclophosphamide, and paclitaxel plus gemcitabine (the same chemotherapy regimen as
the other group, with the addition of 1250 mg/m2 gemcitabine to the paclitaxel cycles, administered intravenously as a 0·5 h infusion on days 1 and 8 every 3 weeks). Patients were randomly assigned by a central computerised deterministic minimisation procedure, with stratification by country, age, radiotherapy intent, nodal status, and oestrogen receptor and HER-2 status. The primary endpoint was disease-free survival and the trial aimed to detect 5% differences in 5-year disease-free survival between the treatment groups. Recruitment completed in 2004 and this is the final, intention-to-treat analysis. This trial is registered with EudraCT (2004-002927-41), ISRCTN (51146252), and ClinicalTrials.gov (NCT00039546).FINDINGS Between Aug 22, 2001, and Nov 26, 2004, 3152 patients were enrolled and randomly assigned to epirubicin, cyclophosphamide, paclitaxel, and gemcitabine (gemcitabine group; n=1576) or to epirubicin, cyclophosphamide, and paclitaxel (control group; n=1576). 11 patients (six in the gemcitabine group and five in the control group) were ineligible because of pre-existing metastases and were therefore excluded from the analysis. At this protocol-specified final analysis (median follow-up 10 years [IQR 10-10]), 1087 disease-free survival events and 914 deaths had occurred. Disease-free survival did not differ significantly between the treatment groups at 10 years (65% [63-68] in the gemcitabine group vs 65% [62-67] in the control group), and median disease-free survival was not reached (adjusted hazard ratio 0·97 [95% CI 0·86-1·10], p=0·64). Toxicity, dose intensity, and a detailed safety substudy showed both regimens to be safe, deliverable, and tolerable. Grade 3 and 4 toxicities were reported at expected levels in both groups. The most common were neutropenia (527 [34%] of 1565 patients in the gemcitabine group vs 412 [26%] of 1567 in the control group), myalgia and arthralgia (207 [13%] vs 186 [12%]), fatigue (207 [13%] vs 152 [10%]), infection (202 [13%] vs 141 [9%]), vomiting (143 [9%] vs 108 [7%]), and nausea (132 [8%] vs 102 [7%]).INTERPRETATION The addition of gemcitabine to anthracycline and taxanebased adjuvant chemotherapy at this dose and schedule confers no therapeutic advantage in terms of disease free survival in early breast cancer, although it can cause increased toxicity. Therefore, gemcitabine has not been added to standard adjuvant chemotherapy in breast cancer for any subgroup.FUNDING Cancer Research UK core funding for Clinical Trials Unit at the University of Birmingham, Eli Lilly, Bristol-Myers Squibb, and Pfizer.

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Gefitinib for oesophageal cancer progressing after chemotherapy (COG): a phase 3, multicentre, double-blind, placebo-controlled randomised trial (2014)

Type of publication:
Randomised Controlled Trial

Author(s):
Dutton SJ,Ferry DR,Blazeby JM,Abbas H,Dahle-Smith A,Mansoor W,Thompson J,Harrison M,*Chatterjee A,Falk S,Garcia-Alonso A,Fyfe DW,Hubner RA,Gamble T,Peachey L,Davoudianfar M,Pearson SR,Julier P,Jankowski J,Kerr R,Petty RD

Citation:
Lancet Oncology, 07 2014, vol./is. 15/8(894-904), 1470-2045;1474-5488 (2014 Jul)

Abstract:
BACKGROUND: Evidence is scarce for the effectiveness of therapies for oesophageal cancer progressing after chemotherapy, and no randomised trials have been reported. We aimed to compare gefitinib with placebo in previously treated advanced oesophageal cancer.METHODS: For this phase 3, parallel, randomised, placebo-controlled trial, eligible patients were adults with advanced oesophageal cancer or type I/II Siewert junctional tumours, histologically confirmed squamous-cell carcinoma or adenocarcinoma, who had progressed after chemotherapy, with WHO performance status 0-2, and with measurable or evaluable disease on CT scan. Participants were recruited from 48 UK centres and randomly assigned (1:1) to gefitinib (500 mg) or matching placebo by simple randomisation with no stratification factors. Patients, clinicians, and trial office staff were masked to treatment allocation. Treatment continued until disease progression, unacceptable toxicity, or patient choice. The primary outcome was overall survival, analysed by intention to treat. This trial is registered, number ISRCTN29580179.FINDINGS: Between March 30, 2009, and Nov 18, 2011, 450 patients were randomly assigned to treatment groups (one patient withdrew consent; 224 patients allocated gefitinib and 225 allocated placebo included in analyses). Overall survival did not differ between groups (median 373 months, 95% CI 323-450, for gefitinib vs 367 months, 95% CI 297-437, for placebo; hazard ratio 090, 95% CI 074-109, p=029). Among the prespecified patient-reported outcomes (110 patients on gefitinib and 121 on placebo completed both baseline and 4 week questionnaires and were included in analyses), odynophagia was significantly better in the gefitinib group (adjusted mean difference -861, 95% CI -1449 to -273; n=227; p=0004), whereas the other outcomes were not significantly improved compared with placebo: global quality of life (269, 95% CI -233 to 772, n=231, p=0293), dysphagia (-318, 95% CI -836 to 200, n=231, p=0228), and eating (-411, 95% CI -996 to 175, n=229, p=0168). Median progression-free survival was marginally longer with gefitinib than it was with placebo (157 months, 95% CI 123-190 in the gefitinib group vs 117 months, 95% CI 107-137 in the placebo group; HR 080, 95% CI 066-096, p=0020). The most common toxicities were diarrhoea (36 [16%] of 224 patients on gefitinib vs six [3%] of 225 on placebo) and skin toxicity (46 [21%] vs two [1%]), both mostly grade 2. The commonest grade 3-4 toxicities were fatigue (24 [11%] vs 13 [6%] patients) and diarrhoea (13 [6%] vs two [1%]). Serious adverse events were reported in 109 (49%) of 224 patients assigned to gefitinib and 101 (45%) of 225 on placebo. 54 (24%) of patients in the gefitinib group achieved disease control at 8 weeks, as did 35 (16%) of patients on placebo (p=0023).INTERPRETATION: The use of gefitinib as a second-line treatment in oesophageal cancer in unselected patients does not improve overall survival, but has palliative benefits in a subgroup of these difficult-to-treat patients with short life expectancy. Future research should focus on identification of predictive biomarkers to identify this subgroup of benefiting patients.FUNDING: Cancer Research UK. Copyright 2014 Elsevier Ltd. All rights reserved.

Link to more details or full-text: http://www.sciencedirect.com/science/article/pii/S1470204514700245