Objective responses to first-line neoadjuvant carboplatin-paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial (2021)

Type of publication:
Journal article

Author(s):
Morgan R.D.; Jayson G.C.; Clamp A.R.; McNeish I.A.; Krell J.; Cook A.D.; James E.C.; Lord R.; Dark G.; Glasspool R.M.; Parkinson C.; Poole C.J.; Hall M.; Gallardo-Rincon D.; Lockley M.; Essapen S.; Summers J.; Anand A.; *Zachariah A.; Williams S.; Jones R.; Scatchard K.; Walther A.; Kim J.-W.; Sundar S.; Ledermann J.A.

Citation:
The Lancet Oncology; Feb 2021; vol. 22 (no. 2); p. 277-288

Abstract:
Background: Platinum-based neoadjuvant chemotherapy followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced-stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase 3 trials, evaluation of response to neoadjuvant chemotherapy using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and cancer antigen 125 (CA125) has not been reported. We describe RECIST and Gynecologic Cancer InterGroup (GCIG) CA125 responses in patients receiving platinum-based neoadjuvant chemotherapy followed by DPS in the ICON8 trial. Method(s): ICON8 was an international, multicentre, randomised, phase 3 trial done across 117 hospitals in the UK, Australia, New Zealand, Mexico, South Korea, and Ireland. The trial included women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, life expectancy of more than 12 weeks, and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO; 1988) stage IC-IIA high-grade serous, clear cell, or any poorly differentiated or grade 3 histological subtype, or any FIGO (1988) stage IIB-IV epithelial cancer of the ovary, fallopian tube, or primary peritoneum. Patients were randomly assigned (1:1:1) to receive intravenous carboplatin (area under the curve [AUC]5 or AUC6) and intravenous paclitaxel (175 mg/m2 by body surface area) on day 1 of every 21-day cycle (control group; group 1); intravenous carboplatin (AUC5 or AUC6) on day 1 and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 2); or intravenous dose-fractionated carboplatin (AUC2) and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 3). The maximum number of cycles of chemotherapy permitted was six. Randomisation was done with a minimisation method, and patients were stratified according to GCIG group, disease stage, and timing and outcome of cytoreductive surgery. Patients and clinicians were not masked to group allocation. The scheduling of surgery and use of neoadjuvant chemotherapy were determined by local multidisciplinary case review. In this post-hoc exploratory analysis of ICON8, progression-free survival was analysed using the landmark method and defined as the time interval between the date of pre-surgical planning radiological tumour assessment to the date of investigator-assessed clinical or radiological progression or death, whichever occurred first. This definition is different from the intention-to-treat primary progression-free survival analysis of ICON8, which defined progression-free survival as the time from randomisation to the date of first clinical or radiological progression or death, whichever occurred first. We also compared the extent of surgical cytoreduction with RECIST and GCIG CA125 responses. This post-hoc exploratory analysis includes only women recruited to ICON8 who were planned for neoadjuvant chemotherapy followed by DPS and had RECIST and/or GCIG CA125-evaluable disease. ICON8 is closed for enrolment and follow-up, and registered with ClinicalTrials.gov, NCT01654146. Finding(s): Between June 6, 2011, and Nov 28, 2014, 1566 women were enrolled in ICON8, of whom 779 (50%) were planned for neoadjuvant chemotherapy followed by DPS. Median follow-up was 29.5 months (IQR 15.6-54.3) for the neoadjuvant chemotherapy followed by DPS population. Of 564 women who had RECIST-evaluable disease at trial entry, 348 (62%) had a complete or partial response. Of 727 women who were evaluable by GCIG CA125 criteria at the time of diagnosis, 610 (84%) had a CA125 response. Median progression-free survival was 14.4 months (95% CI 9.2-28.0; 297 events) for patients with a RECIST complete or partial response and 13.3 months (8.1-20.1; 171 events) for those with RECIST stable disease. Median progression-free survival for women with a GCIG CA125 response was 13.8 months (95% CI 8.8-23.4; 544 events) and 9.7 months (5.8-14.5; 111 events) for those without a GCIG CA125 response. Complete cytoreduction (R0) was achieved in 187 (56%) of 335 women with a RECIST complete or partial response and 73 (42%) of 172 women with RECIST stable disease. Complete cytoreduction was achieved in 290 (50%) of 576 women with a GCIG CA125 response and 30 (30%) of 101 women without a GCIG CA125 response. Interpretation(s): The RECIST-defined radiological response rate was lower than that frequently quoted to patients in the clinic. RECIST and GCIG CA125 responses to neoadjuvant chemotherapy for epithelial ovarian cancer should not be used as individual predictive markers to stratify patients who are likely to benefit from DPS, but instead used in conjunction with the patient’s clinical capacity to undergo cytoreductive surgery. A patient should not be denied surgery based solely on the lack of a RECIST or GCIG CA125 response. Funding(s): Cancer Research UK, UK Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.

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Regression of a spinal schwannoma after Pomalidomide (2020)

Type of publication:
Journal article

Author(s):
Kunnel Jomon M.; Pepper J.; Price R.; *O’Connor N.

Citation:
British Journal of Neurosurgery; Mar 2020 ; p. 1-2

Abstract:
A 77-year old female with a history of neurofibromatosis type 2 (NF2) was diagnosed with a spinal schwannoma that was managed conservatively over a decade. During this time, follow up imaging revealed this lesion had been growing and the patient had become symptomatic from it necessitating surgical decompression. However, the patient had been diagnosed with multiple myeloma and underwent treatment with Pomalidomide chemotherapy which delayed surgery for the spinal schwannoma. Further imaging of the spine revealed significant regression in the size of the spinal schwannoma. This phenomenon has not previously been reported and this report aims to explore the implications of Pomalidomide in patients with NF2 related spinal schwannomas.

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Optimizing chemotherapy for frail and/or elderly patient with advanced gastroesophageal cancer (AGOAC): the GO2 phase III trial (2019)

Type of publication:
Conference abstract

Author(s):
Swinson D.E.; Hall P.; Seymour M.; Lord S.; Marshall H.; Ruddock S.; Cairns D.; Waters J.; Wadsley J.; Falk S.; Roy R.; Joseph M.; Nicoll J.; Vellios Kamposioras K.; Tillett T.; Cummins S.; Grumett S.; Stokes Z.; Waddell T.; *Chatterjee A.; Garcia A.; Allmark C.; Khan M.; Petty R.

Citation:
Journal of Geriatric Oncology; Nov 2019; vol. 10 (no. 6), Supplement 1, S8

Abstract:
Introduction: aGOAC patients are frequently elderly and/or frail.
Objective(s): (i) find the optimum dose of oxaliplatin capecitabine (OCap) for this population; (ii) explore the use of an objective geriatric assessment to individualize dose for maximum overall treatment utility (OTU), a composite of clinical benefit, tolerability, quality of life (QL) and patient value.
Method(s): Patients with aGOAC were eligible if there was uncertainty of the appropriate dose of chemotherapy. Baseline assessment included global QL; symptoms; functional scales; comorbidity; frailty. Randomization was 1:1:1 to dose Level A (Ox 130 mg/m2 d1, Cap 625 mg/m2 bd d1-21, q21d), B (80% Level A) or C (60% Level A). At 9 weeks, patients were scored for OTU. Non-inferiority (vs A) was assessed using PFS, censored at 12 months, with upper boundary HR 1.34 (based on patients’ and clinicians’ discussions), needing 284 PFS events per two-way comparison. In a separate sub-study, when there was uncertainty regarding the use of chemotherapy, patients were randomized between level C and supportive care alone (SCA).
Results and Conclusion(s): 512 patients were randomized, 2014-2017, at 61 UK centers. Age, performance status and frailty were similar in all arms. Non-inferiority of PFS is confirmed for Level B vs A (HR 1.09, CI 0.89-1.32) and for Level C vs A (HR 1.10, CI 0.90-1.33). Level C patients had the least toxicity and best OTU outcomes. When analyzed by baseline age, frailty and PS no group was identified who benefit more from higher treatment doses. A further 46 patients were randomized between chemotherapy and SCA. A non-significant trend to improved survival was observed (HR=0.69, CI 0.32-1.48) and QL deteriorated less with chemotherapy. This is the largest RCT specifically investigating frail and/or elderly aGOAC patients, and should guide future treatment. The lowest dose tested was non-inferior in terms of PFS, produced less toxicity and better overall treatment utility.

Best supportive care (BSC) with or without lowdose chemotherapy (chemo) in frail elderly patients with advanced gastroesophageal cancer (aGOAC): The uncertain randomization of the GO2 phase III trial (2019)

Type of publication:
Conference abstract

Author(s):
Swinson D.; Hingorani M.; Stokes Z.; Dent J.; Guptal K.; *Chatterjee A.; Kamposioras K.; Grumett S.A.; Khan M.; Marshall H.; Ruddock S.; Allmark C.; Katona E.; Howard H.C.; Velikova G.; Lord S.; Hall P.S.; Seymour M.T.

Citation:
Journal of Clinical Oncology; May 2019; vol. 37

Abstract:
Background: Before 2000, trials comparing BSC +/chemo for aGOAC showed overall survival (OS) benefit, but in predominantly fit patients (pts). We have revisited this question in a modern context, using lowdose chemo in a frail population, with comprehensive baseline health and frailty assessment.
Method(s): In the GO2 trial, elderly and/or frail aGOAC pts with a ?certain? indication for chemo were randomised between 3 chemo doses. In this GO2 sub-study, pts with an ?uncertain? indication for chemo were instead randomised to BSC +/- the lowest dose chemo. Pts were eligible if clinician and pt agreed the indication for chemo was uncertain. There was no PS threshold, but eGFR >=30 and bili < 2xULN were required. Baseline assessment included global QL, symptom & functional scales, frailty and comorbidity. Randomisation was 1:1 to BSC alone, or with oxaliplatin 78 mg/m2 d1, capecitabine 375 mg/m2 bd d121 (modified if eGFR 3050 ml/min or bili 1.52.0 xULN), q21d. QL was reassessed after 9 and 18 wks. The primary endpoint analysis was OS, adjusted for baseline factors. The sample size for this exploratory sub-study was not preset, but around 60 pts were anticipated.
Result(s): 558 pts entered GO2 at 61 centres 201417, of whom only 45 pts (8%) at 21 centres entered this uncertain randomisation. This would provide 80% power at p = 0.05 (2tailed) to detect an OS HR of 0.3. OS was shorter in pts with worse baseline PS (p<0.01) or distant mets (p<0.05). OS was not significantly improved with chemo; however we cannot exclude HR >0.32. QL deteriorated less with BSC+chemo than with BSC alone.
Conclusion(s): In this frail, poor PS population, we observed a small survival benefit with chemo but this did not reach statistical significance. Clinicians should carefully consider BSC alone as a valid treatment option for aGOAC pts with poor PS and/or frailty.

Link to full-text [no password required]

Addition of Docetaxel to First-line Long-term Hormone Therapy in Prostate Cancer (STAMPEDE): Modelling to Estimate Long-term Survival, Quality-adjusted Survival, and Cost-effectiveness (2018)

Type of publication:
Journal article

Author(s):
Woods B.S.; Sideris E.; Sculpher M.J.; Sydes M.R.; Gannon M.R.; Parmar M.K.B.; Millman R.; Alzouebi M.; Attard G.; Dearnaley D.P.; Birtle A.J.; Brock S.; Cathomas R.; Chakraborti P.R.; Cook A.; Cross W.R.; Gale J.; Gibbs S.; Graham J.D.; Hughes R.; Jones R.J.; Laing R.; Mason M.D.; Matheson D.; McLaren D.B.; O’Sullivan J.M.; Parikh O.; Parker C.C.; Peedell C.; Protheroe A.; Ritchie A.W.S.; Robinson A.; Russell J.M.; Simms M.S.; *Srihari N.N.; Srinivasan R.; Staffurth J.N.; Sundar S.; Thalmann G.N.; Tolan S.; Tran A.T.H.; Tsang D.; Wagstaff J.; James N.D.

Citation:
European Urology Oncology; Dec 2018; vol. 1 (no. 6); p. 449-458

Abstract:
BACKGROUND: Results from large randomised controlled trials have shown that adding docetaxel to the
standard of care (SOC) for men initiating hormone therapy for prostate cancer (PC) prolongs survival for those with metastatic disease and prolongs failure-free survival for those without. To date there has been no formal assessment of whether funding docetaxel in this setting represents an appropriate use of UK National Health Service (NHS) resources.
OBJECTIVE(S): To assess whether administering docetaxel to men with PC starting long-term hormone therapy is cost-effective in a UK setting.
DESIGN, SETTING, AND PARTICIPANTS: We modelled health outcomes and costs in the UK NHS using data collected within the STAMPEDE trial, which enrolled men with high-risk, locally advanced metastatic or recurrent PC starting first-line hormone therapy. INTERVENTION: SOC was hormone therapy for >=2 yr and radiotherapy in some patients. Docetaxel (75mg/m2) was administered alongside SOC for six three-weekly cycles. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The model generated lifetime predictions of costs, changes in survival duration, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS AND LIMITATIONS: The model predicted that docetaxel would extend survival (discounted quality-adjusted survival) by 0.89 yr (0.51) for metastatic PC and 0.78 yr (0.39) for nonmetastatic PC, and would be cost-effective in metastatic PC (ICER 5514/QALY vs SOC) and nonmetastatic PC (higher QALYs, lower costs vs SOC). Docetaxel remained cost-effective in nonmetastatic PC when the assumption of no survival advantage was modelled.
CONCLUSION(S): Docetaxel is cost-effective among patients with nonmetastatic and metastatic PC in a UK setting. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in patients with nonmetastatic PC, as the opportunity to offer docetaxel at hormone therapy initiation will be missed for some patients by the time more mature survival data are available. PATIENT SUMMARY: Starting docetaxel chemotherapy alongside hormone therapy represents a good use of UK National Health Service resources for patients with prostate cancer that is high risk or has spread to other parts of the body.

Local experience at DGH shows combination Pertuzumab and Herceptin nearly doubles PCR rate of Neo-adjuvant Chemotherapy (NAC) in HER2 positive breast cancer (2018)

Type of publication:
Poster presentation

Author(s):
*Blossom Lake, *Donna Appleton, *Abel Zachariah, *Habib Khan, *Kerry Flemming, *Jennifer Neill, *Laura Pettit

Citation:
Presented at BASO: The Association for Cancer Surgery

Link to poster [PDF]

3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial (2018)

Type of publication:
Randomised controlled trial

Author(s):
Iveson TJ, Kerr RS, Saunders MP, Cassidy J, Hollander NH, Tabernero J, Haydon A, Glimelius B, Harkin A, Allan K, McQueen J, Scudder C, Boyd KA, Briggs A, Waterston A, Medley L, Wilson C, Ellis R, Essapen S, Dhadda AS, Harrison M, Falk S, Raouf S, Rees C, Olesen RK, Propper D, Bridgewater J, Azzabi A, Farrugia D, Webb A, Cunningham D, Hickish T, Weaver A, Gollins S, Wasan HS, Paul J. [SaTH was one of the sites this trial took place at]

Citation:
Lancet Oncology 2018 Apr;19(4):562-578

Abstract:
BACKGROUND: 6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment.
METHODS: The SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres. Patients aged 18 years or older with high-risk stage II and stage III colorectal cancer underwent central randomisation with minimisation for centre, choice of regimen, sex, disease site, N stage, T stage, and the starting dose of capecitabine. Patients were assigned (1:1) to receive 3 months or 6 months of adjuvant oxaliplatin-containing chemotherapy. The chemotherapy regimens could consist of CAPOX (capecitabine and oxaliplatin) or FOLFOX (bolus and infused fluorouracil with oxaliplatin). The regimen was selected before randomisation in accordance with choices of the patient and treating physician. The primary study endpoint was disease-free survival and the non-inferiority margin was a hazard ratio of 1·13. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who started study treatment. This trial is registered with ISRCTN, number ISRCTN59757862, and follow-up is continuing.
FINDINGS: 6088 patients underwent randomisation between March 27, 2008, and Nov 29, 2013. The intended treatment was FOLFOX in 1981 patients and CAPOX in 4107 patients. 3044 patients were assigned to 3 month group and 3044 were assigned to 6 month group. Nine patients in the 3 month group and 14 patients in the 6 month group did not consent for their data to be used, leaving 3035 patients in the 3 month group and 3030 patients in the 6 month group for the intention-to-treat analyses. At the cutoff date for analysis, there had been 1482 disease-free survival events, with 740 in the 3 month group and 742 in the 6 month group. 3 year disease-free survival was 76·7% (95% CI 75·1-78·2) for the 3 month group and 77·1% (75·6-78·6) for the 6 month group, giving a hazard ratio of 1·006 (0·909-1·114, test for non-inferiority p=0·012), significantly below the non-inferiority margin. Peripheral neuropathy of grade 2 or worse was more common in the 6 month group (237 [58%] of 409 patients for the subset with safety data) than in the 3 month group (103 [25%] of 420) and was long-lasting and associated with worse quality of life. 1098 serious adverse events were reported (492 reports in the 3 month group and 606 reports in the 6 month group) and 32 treatment-related deaths occurred (16 in each group).
INTERPRETATION: In the whole study population, 3 months of oxaliplatin-containing adjuvant chemotherapy was non-inferior to 6 months of the same therapy for patients with high-risk stage II and stage III colorectal cancer and was associated with reduced toxicity and improved quality of life. Despite the fact the study was underpowered, these data suggest that a shorter duration leads to similar survival outcomes with better quality of life and thus might represent a new standard of care.
FUNDING: Medical Research Council, Swedish Cancer Society, NETSCC, and Cancer Research UK.

Link to full-text [Open access – no password required]

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An audit of ‘real world’ systemic chemotherapy in breast cancer patients over the age of 70 in one U.K. Cancer Centre (2018)

Type of publication:
Conference abstract

Author(s):
*Choudhary Y.; *Pettit L.; *Khanduri S.

Citation:
European Journal of Surgical Oncology; Mar 2018; vol. 44

Abstract:
Background: Breast cancer incidence among the over 70’s is increasing. Trial data from this age group is not as extensive when compared with younger patients. Co-morbidities are common and may lead to poor tolerance of chemotherapy. Cytotoxic chemotherapy usage in patients over 70 was audited to record toxicity and tolerability.Method: Patients aged >70 years, diagnosed with invasive breast cancer between 01/01/2015 and 31/12/2015 treated with cytotoxic chemotherapy at the Shrewsbury and Telford Hospital NHS Trust were identified from the Somerset database. Clinical information was obtained from an electronic portal. Data collected: demographics, performance status, tumour characteristics, ER/PR and HER2 status, chemotherapy regimen, treatment intent, number of chemotherapy cycles planned, number given, toxicities, and hospital admissions. Data was collected on an excel database.Results: Thirty patients were identified, all female. 26 were between 71 and 75, 2 were between 76 and 80, 2 > 80 years. 20 patients (67%) ER/PR receptor positive. 15 (50%) HER2 positive. The majority 29 (97%) had a performance status of 0/1. Cardiovascular co-morbidities were the most common (57% pre-existing cardiovascular disease). 25 (83%) were treated with adjuvant intent. 15 (50%) were admitted to hospital, 6 (20%) with neutropenic sepsis. 12 (40%) had dose reductions. 21 (70%) completed their planned number of cycles. Chemotherapy was discontinued in 7 (23%) due to toxicity and 1 patient remains on treatment at the time of this audit. There were no patient deaths within 30 days of commencing chemotherapy.Conclusion: Chemotherapy usage in the >70’s was associated with higher risk breast cancer. Despite good baseline performance status, 50% of patients required hospital admission and 27% discontinued treatment due to toxicity. The decision to use chemotherapy must also account for potential toxicities and impact on quality of life. Increased contact with health professionals including tele-consults and increased specialist nurse support, will help to predict and manage toxicity and reduce admissions.

Group pre-assessment for patients undergoing chemotherapy: Our experience at The Royal Shrewsbury Hospital (2017)

Type of publication:
Conference abstract

Author(s):
*Allos B.; *Redgrave R.; *Davies W.; *Chatterjee A.

Citation:
Lung Cancer; Jan 2017; vol. 103, Supplement 1, Page S47

Abstract:
Introduction: Waiting time targets in England and Wales state cancer treatment must commence within 31 days of the treatment plan being agreed. Often, pressures on chemotherapy units, such as low staffing levels and capacity, delays starting chemotherapy. This may impact outcomes. To improve capacity and waiting times we have implemented group pre-assessment (GPAC) for all prospective chemotherapy patients at our trust. Methods: Previously each patient received a 1-hour pre-assessment appointment with a dedicated nurse. For non-urgent patients we have established GPAC clinics since January 2014. These are run three times a week by volunteers in conjunction with one chemotherapy nurse and accommodate 6 patients per session. Patients watch a 25-minute DVD providing general information on chemotherapy in addition to introducing the unit, nurses and general treatment procedures. A unit tour follows this. Each patient receives a diagnosis-specific  tumour pack and the session concludes with a 10-minute one-to-one meeting with a nurse to discuss their personal treatment regime. Results: We pre-assess up to 18 patients a week via GPAC. Since implementation we have reduced nursing hours needed for this service to a maximum of 6 hours per week. From September 2015 to August 2016 a total of 667 patients attended GPAC clinic with 312 nursing hours required. Our unit has consequently saved 355 nursing hours over that time period (Figure 1). Patient satisfaction with the service remains high with 24/25 (96%) of patients surveyed rating the service as good to excellent across five categories. With GPAC initiation, our average chemotherapy waiting time has reduced to 13 days from over 20 days. Conclusion: By initiating GPAC our department has significantly saved nursing hours allowing us to reallocate these to chemotherapy delivery and service development. With increased capacity to treat patients waiting times have been significantly reduced. This has not been to the detriment of patient satisfaction. (Table Presented).

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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