- Email: [email protected]
Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control
Annals of Oncology Advance Access published April 8, 2014 1
Chronicle: Results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (Xelox) versus control.
Key Message: "Locally advanced rectal cancer is conventionally treated with preoperative chemoradiation, but has a high risk of distant recurrence. The Chronicle trial did not detect a significant difference in DFS or OS for adjuvant XELOX compared to surgery alone following chemoradiation. The difficulty in recruitment, high acute levels of toxicity and poor compliance to adjuvant chemotherapy, all support the need for trials that test the role of neoadjuvant chemotherapy."
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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R. Glynne-Jones1, N. Counsell2, P. Quirke3, N. Mortensen4, A. Maraveyas5, H.M. Meadows2, J. Ledermann2, D. Sebag-Montefiore3 1 Mount Vernon Centre for Cancer Treatment, London, UK 2 CRUK & UCL Cancer Trials Centre, London, UK 3 University of Leeds, Leeds, UK 4 University of Oxford, Oxford, UK 5 Castle Hill Hospital, Hull, UK Corresponding Author: Dr R Glynne-Jones, Tel: +44 (0) 1923 844767, Fax: +44 (0) 1923 844 138, E-mail: [email protected]
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Abstract Background: In stage III colon cancer oxaliplatin/5FU-based adjuvant chemotherapy (FOLFOX) improves disease-free survival (DFS) and overall survival (OS). In rectal adenocarcinoma following neoadjuvant chemoradiation (CRT), we examined the benefit of postoperative adjuvant capecitabine and oxaliplatin (XELOX) chemotherapy.
Results: The study closed prematurely in 2008 because of poor accrual. Only 113 patients were randomly assigned to either observation (n=59) or XELOX (n=54). Compliance was poor, 93% allocated chemotherapy started and 48% completed 6 cycles. Protocolised dose reductions in XELOX were 39%, and levels of G3/G4 toxicity 40%. After a median follow-up of 44.8 months, 16 patients (27%) in the observation arm had relapsed or died compared with 12 patients (22%) in XELOX. The 3-year DFS rate was 78% with XELOX and 71% with observation (hazard ratio [HR] for DFS=0.80; 95% CI: 0.38-1.69; p=0.56). The 3-year OS for XELOX and observation were 89% and 88% respectively (HR for OS=1.18; 95% CI: 0.43-3.26; p=0.75). Conclusions: The observed improvement in DFS for adjuvant XELOX and similar OS were not statistically significant, as expected given the small number of patients and consequent low power. Our findings support the need for trials that test the role of neoadjuvant chemotherapy. Key words: Rectal adenocarcinoma, preoperative chemoradiation, metastatic disease, adjuvant chemotherapy, capecitabine, oxaliplatin.
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Methods: Eligible patients were randomly assigned following fluoropyrimidine-based CRT and curative resection to observation or 6 cycles of XELOX. The primary endpoint was DFS; secondary endpoints were acute toxicity and OS. 390 patients were required in each arm, to detect an improvement in 3-year DFS from 40% to 50.5%, with 85% power and two-sided 5% significance level.
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Introduction Postoperative 5-Fluorouracil (5FU)-based adjuvant chemotherapy improves overall survival (OS) in stage III colon cancer1. Oxaliplatin added to 5FU-based chemotherapy improves disease-free survival (DFS) and OS2,3, and is considered an international standard for stage III colon cancer.
Locally advanced rectal cancer (LARC) has a high risk of local and distant
Network Guidelines, recommend a FOLFOX regimen as postoperative chemotherapy in patients with stage III or adverse histology following chemoradiation and surgery4,5,6,7,8,9. The validity of this strategy has been questioned10. Trials which directly examined adjuvant 5FU alone after chemoradiation, have provided no evidence for its efficacy11,12,13,.
The CHRONICLE trial aimed to evaluate postoperative adjuvant chemotherapy following neoadjuvant chemoradiation (NCRT) in LARC. The trial examined whether six cycles of capecitabine and oxaliplatin (XELOX) over 4 months would improve DFS and OS compared to surgical follow-up alone. We report the results of acute toxicity and compliance in addition to DFS and OS.
Patients and Methods The Chronicle trial was approved by institutional ethics committees of participating centres and monitored by an Independent Data Monitoring (IDMC) and Trial Steering Committee (TSC). Six-monthly review of recruitment was prospectively defined to assess the feasibility of obtaining a clinically worthwhile result, if accrual was lower than anticipated.
Eligibility Eligible patients were aged >18 years, with histologically confirmed rectal adenocarcinoma, located <15cm from the anal verge, or below the peritoneal reflection. Surgery was performed before randomisation, to start chemotherapy within 12 weeks of surgery. Before enrolment patients received preoperative fluoropyrimidine-based chemoradiation, minimum total dose 45Gy. Patients may
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recurrence. Many oncologists, and the European and National Comprehensive Cancer
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have had up to a 12-week maximum of neoadjuvant fluoropyrimidine-based chemotherapy.
Other eligibility criteria included WHO performance status 0-1, adequate hematologic, renal, and hepatic function, complete resection of the primary tumour, a negative circumferential margin (CRM>1mm), and no evidence of metastatic disease. Definitive histology at surgery required ypT0-T4, N0-N2.
resections, and for significant cardiac disease, CNS disorders, known peripheral neuropathy, moderate/severe renal impairment, and pregnancy or lactation.
Treatment Patients were randomised to observation alone (Observation arm) or XELOX capecitabine (1000mg/m2 orally twice daily days 1-14) and oxaliplatin (130mg/m2 day 1) as a two-hour infusion (XELOX arm) as indicated in the CONSORT diagram (FIGURE 1). A total of 6 three-weekly cycles were intended. Dose modifications for toxicity were defined in the protocol.
Assessments Pre-treatment evaluation included: CT scans of chest, abdomen and pelvis; demographic data, medical history, physical examination, ECG, carcino-embryonic antigen (CEA) determination; height, weight, vital signs, WHO performance status, haematology, and blood chemistry.
Adverse events were monitored during and for 28 days after study treatment. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria, version 3.0. Neurotoxicity was monitored up to 3 years post-randomisation.
Follow-up Patients were evaluated clinically every three weeks following randomisation until 4 months, then three-monthly until the end of the second year, six-monthly until the end of the fifth year and then annually. Colonoscopy was recommended prior to surgery or within 3 months after surgery, and thereafter every third year. Abdo-pelvic CT
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Patients were excluded in the presence of metastatic disease (M1), R1 or R2
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scans or ultrasound and chest x-ray or thoracic CT were to be performed at 6, 12, 18, 24, 36 and 48 months post-randomisation. CEA levels were measured every 3 months (starting 6 months post-randomisation) for the first 3 years and every 6 months thereafter. Assessments were made for local relapse, distant metastases, late toxicity, second cancers and death. Patients were flagged at the UK Office of National Statistics to capture death notification.
Patients were randomly assigned 1:1 between trial arms using permuted blocks, stratified by surgeon and pathological nodal status.
The primary endpoint was DFS, defined as the time from randomisation to relapse, development of a new cancer or death, whichever occurred first. 390 patients were required in each arm to detect an improvement in 3-year DFS from 40% to 50.5% (equivalent to a hazard ratio of 0.75), with 85% power and two-sided 5% significance level. With allowance for loss to follow-up, the target sample size was 800 patients in total, assuming an enrolment and follow-up period of 3 years.
If an advantage was observed for postoperative chemotherapy, it was planned to explore whether it was consistent across various subgroups described in the statistical analysis plan. Secondary endpoints were OS, measured from date of randomisation until death from any cause, incidence rates of acute toxicity and compliance to treatment.
Hazard ratios with 95% confidence intervals (CIs) were calculated using the Cox proportional hazards model. Survival curves are presented using the Kaplan-Meier method. Patients were censored using the date they were last seen if no event had occurred. Analysis was performed on an intention-to-treat (ITT) basis, unless otherwise specified, and generated using SAS software version 9.3, (SAS Institute, Cary NC).
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Statistical Analysis
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Results
Accrual Between 2004 and 2008, 113 patients were randomised; TABLE 1 shows the baseline characteristics. After 4 years of slower-than-anticipated accrual, the trial was terminated early on the recommendation of the IDMC.
54 patients were randomly assigned to XELOX and 59 to the observation arm. At least one cycle of study treatment was received by 50 patients (92.6%). The planned six cycles of chemotherapy were received by only 26 (48.1%). Twenty-one (38.9%) had a dose reduction and 21 (38.9%) had a dose delay; TABLE 2. Median total oxaliplatin dose received was 601mg/m2, compared with a per-protocol six-cycle dose of 780mg/m2. Median total capecitabine dose received was 96,923mg/m2, compared with a per-protocol six-cycle dose of 168,000mg/m2.
Therapy after relapse was received by 9 (16.7%) XELOX and 15 (25.4%) patients in the observation arm. Post-relapse, in the XELOX and observation arms respectively, 6 (11.1%) and 7 (11.9%) patients received chemotherapy, 4 (7.4%) and 7 (11.9%) received surgery, 2 (3.7%) and 2 (3.4%) received palliative care, 1 (1.9%) and 1 (1.7%) received radiotherapy, and 1 (1.9%) XELOX patient was offered a different trial.
Toxicity Fifty (92.6%) XELOX patients received at least 1 cycle of treatment – defined as the safety population. Twenty (40.0% of the safety population) reported grade 3 or higher toxicity; TABLE 3. Three (6.0%) reported a grade 4 toxicity (sensory neuropathy (n=2) and diarrhoea (n=1)). There was one treatment-related death from diarrhoea.
Nine patients reported a grade 3/4 adverse event during follow-up. Six XELOX patients reported 8 late toxicities: bowel obstruction (G4, n=1), malignant fistula (G4, n=1), neuropathy (G3, n=2), impaired bladder function (G3, n=1), pulmonary embolism (G3, n=1), pain (G3, n=1), and blepharospasm (G3, n=1). Three patients in
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Compliance
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the observation arm reported 3 late toxicities: angina (G3, n=1), back pain (G3, n=1), and poor bowel control (G3, n=1).
Efficacy The median follow-up was 44.8 months, censoring those who had died. Only two local recurrences have been observed. There were 16 (27.2%) observation and 12 (22.2%) XELOX patients who had relapsed or died, with 3-year DFS of 71.3% and
p=0.56), in favour of XELOX (FIGURE 2A). The observed 3-year DFS rates were higher than expected (40-50% from the sample size calculation), and the hazard ratio was close to the target value of 0.75. The HR after adjusting for factors that are imbalanced in Table 1 was 0.84 (95% CI: 0.37-1.93, p=0.69).
Fifteen patients died, 7 observation (11.9%; rectal cancer (n=6), rectal & breast cancer with brain metastases (n=1)) and 8 XELOX (14.8%; rectal cancer (n=6), chemotherapy-related (n=1), pharyngeal tumour (n=1)), with 3-year OS of 87.8% and 88.8% respectively. The HR for OS was 1.18 (95% CI: 0.43-3.26; p=0.75) in favour of observation only (FIGURE 2B). The HR after adjusting for factors that appear imbalanced in Table 1 was 1.42 (95% CI: 0.44-4.52, p=0.55).
Discussion
The Chronicle trial is unique in comparing XELOX postoperatively against observation alone in LARC treated with preoperative chemoradiation. Results show that after a median follow-up of 44.8 months, the 3-year DFS rate was 78% with XELOX and 71% with observation (HR for DFS, 0.80; 95% CI: 0.38-1.69; p=0.56). Hence no statistically significant benefit of adjuvant XELOX chemotherapy was found, but the study was underpowered with only 113 patients reducing the planned power of 85% to <20% for the primary endpoint.
We did not specify baseline clinical stage as an eligibility criterion; following the CR07 trial, most patients in the UK with resectable LARC received short course preoperative radiotherapy (5x5Gy). Chemoradiation tended to be given for fixed or unresectable cancers.
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77.5% respectively. The hazard ratio (HR) for DFS was 0.80 (95% CI: 0.38-1.69;
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Based on results of a meta-analysis in colon cancer14, it is assumed chemotherapy should start as soon as possible following surgery, and not be delayed beyond 3 months. In the Chronicle study, the median time from surgery to randomisation was 8 weeks. Compliance to postoperative chemotherapy was poor. Only 26 patients (48.1%) received the planned six cycles. This finding is consistent with other studies.
and mature follow-up of individuals within the trial.Yet few patients were actually accrued from a large number of recruiting centres, which meant that patients receiving XELOX were not well-matched for individual prognostic factors versus those in the observation arm. In particular, the two study groups differed slightly in the number of patients achieving a pathological CR, because patients were randomly assigned using blocked stratification by nodal status and surgeon (82 surgeons, for only 113/800 patients). However, outcomes are similar even after adjusting for these differences.
By restricting eligibilty to patients with a CRM>1mm, we selected patients with more favourable outcomes because non-responders to CRT were effectively excluded. This factor might explain the paucity of relevant events such as low local recurrence rate.
The evidence-base for postoperative adjuvant chemotherapy in LARC is scanty. A phase III Japanese trial of oral UFT15 in 274 patients, suggests an advantage to postoperative adjuvant chemotherapy in rectal cancer although no NCRT was given and surgery involved bilateral lateral pelvic lymph node dissection. A recent metaanalysis16 of 21 randomised controlled trials in 9221 patients, examined postoperative chemotherapy and showed a significant benefit in terms of DFS (HR=0.75,CI: 0.680.83) and OS (HR=0.83, CI: 0.76-0.91) for patients with rectal cancer administered postoperative fluoropyrimidine-based chemotherapy (without oxaliplatin) as compared to observation alone. However, only 3 studies11,17,18 included patients who had received preoperative radiotherapy. In the largest EORTC 22921 study11,19 in 1011 patients with T3/T4 resectable there was no significant benefit in terms of DFS or OS from the addition of postoperative FUFA.
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The Chronicle trial benefits from high levels of complete data, pathologic verification,
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A Korean study randomised 320 patients (161 to 5FU, 159 to FOLFOX) with ypstage II and III rectal cancer following CRT20. After a median follow-up of 22.5 months, estimated 2-year DFS rate was 82.0% in FOLFOX and 69.4% in the 5FU arm (HR=0.46; 95% CI, 0.28-0.76, p=0.002).
There is a well-recognised problem of delivery and compliance to chemotherapy following preoperative CRT and surgery, because of slow recovery and healing, poor patients10,11,21. The Chronicle trial demonstrates only 48% of patients allocated chemotherapy completed 6 cycles. In contrast, compliance to chemotherapy in the preoperative setting is high22 and delivered more easily than postoperative23, enabling full systemic doses of chemotherapy to be delivered at an early stage rather than a delay of up to 18 weeks associated with CRT.
Unpublished studies The Eastern Cooperative Oncology Group (E3201) trial closed after 225 patients of the planned 3150 had been enrolled, when the GI Intergroup developed an alternative trial with bevacizumab (E5204). An updated analysis24 showed no difference in OS between patients who received 5FU alone, oxaliplatin-based or irinotecan-based adjuvant therapy. The follow-on E5204 trial aimed to randomise 2100 patients between modified FOLFOX 6 with or without bevacizumab but closed in 2009. The PETACC 6 (1094 patients)25 and the German ARO/CAO/AIO-04 trials (1259 patients)26 may provide further evidence regarding the role of postoperative FOLFOX (ARO/CAO/AIO-04) or XELOX (PETACC 6) versus adjuvant 5FU/capecitabine alone.
The Dutch CKTO/2003-16/PROCTOR/SCRIPT study initially randomised patients after short course preoperative radiotherapy (5x5Gy) to capecitabine or control, but was amended to include preoperative chemoradiation. Preliminary results in 470 of the 840 originally intended patients, show the 3-year DFS was 67.4% for chemotherapy versus 66.1% for observation (HR 0.835, 95% CI: 0.61-1.13 p=0.24)27.
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tolerance, marked dose reductions and patient reluctance – affecting at least 40% of
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In Chronicle there were sufficient centres open, but the high rate of refusals to take part reflects lack of equipoise on the part of oncologists and strong preferences by patients for no further treatment following CRT. This is a well-recognised problem in non-blinded randomised trials and is unlikely to be due to a specific feature of rectal cancer.
The Chronicle trial did not detect a significant difference in DFS or OS for adjuvant XELOX. No definitive conclusion can be drawn from a trial with inadequate numbers, poor compliance and insufficient statistical power. We remain unsure of the advantage of additional adjuvant chemotherapy following CRT, either in terms of 5FU alone or combined with oxaliplatin, and of specific subgroups who might benefit most/least. Although unable to provide a definitive result, this trial in terms of the hazard ratio of 0.80 for DFS (95% CI: 0.38-1.69), can contribute to future reviews and meta-analyses.
The poor compliance to oxaliplatin containing chemotherapy in the postoperative setting following chemoradiation therefore supports the hypothesis that neoadjuvant chemotherapy – as piloted in the UK BACCHUS Study (NCT01650428) and the US NCCTG N1048 PROSPECT trial (NCT01515787) - might prove a more effective strategy.
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Conclusion
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Acknowledgements The Chronicle trial was conducted across the National Cancer Research Network, and funded by Cancer Research UK - grant award no C10568/A4148. We would like to acknowledge Wendy Wood and Patricia Henley for trial coordination. Capecitabine and Oxaliplatin were supplied free of charge by Roche and Sanofi-Aventis respectively.
Sothi, Alexandra Hospital (Redditch); Dr McDonald, Beatson Oncology Centre; Dr Geh, Birmingham Heartlands Hospital; Dr Susnerwala, Blackpool Victoria Hospital; Dr Falk, Bristol Royal Infirmary; Dr Lowdell, Charing Cross Hospital; Dr Myint, Clatterbridge Hospital; Dr Sebag-Montefiore, Cookridge Hospital; Dr Wadsley, Doncaster Royal Infirmary; Dr Sizer, Essex County Hospital; Dr Biswas, Furness General Hospital; Dr Glaholm, Good Hope Hospital; Dr Soomal, Ipswich Hospital; Dr Churn, Kidderminster Hospital; Dr Hartley, Manor Hospital; Dr Glynne-Jones, Mount Vernon Hospital; Dr Osborne, North Devon District Hospital; Dr Bridgewater, Princess Alexandra Hospital; Dr Maraveyas, Princess Royal Hospital; Dr Geh, Queen Elizabeth Hospital (Birmingham); Dr Dobrowsky, Queen Elizabeth Hospital (Gateshead); Dr Kulkarni, Queen's Hospital; Dr Whillis, Raigmore Hospital; Dr Wilson, Royal Albert Edward Infirmary; Dr Osborne, Royal Devon and Exeter Hospital; Dr Biswas, Royal Lancaster Infirmary; Dr Awwad, Royal Shrewsbury Hospital; Dr Hamilton, Scarborough Hospital; Dr Hamid, Scunthorpe General Hospital; Dr Bateman, Southampton General Hospital; Dr Tsang, Southend Hospital; Dr Myint, Southport and Formby DGH; Dr Cottrill, St Bartholomew's Hospital; Dr O'Callaghan, St Mary's Hospital (Portsmouth); Dr Pedley, Sunderland Royal Hospital;
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Recruiting hospitals and investigators: Dr Samuel, Aberdeen Royal Infirmary; Dr
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Dr Ledermann, UCLH (Middlesex Hospital); Prof Maughan, Velindre Hospital; Dr Riddle, West Middlesex University Hospital; Dr Wadsley, Weston Park Hospital; Dr Hochhauser, Whittington Hospital; Dr Weaver, Wycombe Hospital; Dr Falk, Yeovil Hospital.
RGJ has received honoraria and research funding from Roche, Sanofi-Aventis and
All remaining authors have declared no conflicts of interest.
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Merck KgaA. DSM has received research funding from Roche and Sanofi-Aventis.
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References 1. Moertel CG, Fleming TR, Macdonald JS et al., Levamisole and fluorouracil for adjuvant chemotherapy of resected colon carcinoma. New Engl J Med. 1990;322: 352-358 2. Kuebler JP, Wieand HS, O’Connell MJ et al., Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 2007;25(16):2198204
4 NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990;264(11):1444-50. 5. Minsky BD, Röedel C, Valentini V. Combined modality therapy for rectal cancer. Cancer J. 2010;16(3):253-61. 6. Glimelius B. Adjuvant chemotherapy in rectal cancer—an issue or a nonissue? Ann Oncol. 2010;21(9):1739-41 7. Schmoll H, Van Cutsem E, Stein A et al., ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol. 2012;23(10):2479-516 8. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Rectal Cancer Version 4.2013 ncrn.org . (last accessed 15/2/2013) 9. Benson AB 3rd, Bekaii-Saab T, Chan E,et al., Rectal cancer. J Natl Compr Canc Netw. 2012 Dec 1;10(12):1528-64 10. Bujko K, Glynne-Jones R, Bujko M. Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials. Ann Oncol 2010;21(9):1743-50. 11. Bosset JF, Collette L, Calais G et al. Chemotherapy with pre-operative radiotherapy in rectal cancer. NEJM, 2006;355:1114-23 12. Cionini L, Sainato A, De Paoli A et al. Final results of randomized trial on adjuvant chemotherapy after preoperative chemoradiation in rectal cancer. Radiother Oncol. 2010;96 (Suppl 1):S113–S114 (Abstr) 13. Bosset JF, Calais G, Mineur L, et al., Preoperative radiotherapy (preop RT) in rectal cancer: Impact of chemotherapy on the outcome—Long-term results of the randomized 22921 phase III trial of EORTC. J Clin Oncol 2013;31: (suppl;abstr 3560)
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3. André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27:3109–3116.
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14. Biagi JJ, Raphael MJ, Mackillop WJ, et al., Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis. JAMA 2011;305:2335–2342. 15. Akasu T, Moriya Y, Ohashi Y,et al., Adjuvant chemotherapy with uraciltegafur for pathological stage III rectal cancer after mesorectal excision with selective pelvic lymphadenectomy: A multicentre randomised controlled trial. Jpn J Clin Onc 2006;36(4)237-244
17. Quasar Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 2007;370(9604):2020-29 18. Glimelius B, Dahl O, Cedermark B, et al., Adjuvant Chemotherapy in colorectal cancer: a joint analysis by the Nordic Gastrointectinal Tumour Adjuvant Therapy Group. Acta Oncol 2005;44(8):904-12 19. Bosset JF, Calais G, Mineur L,et al., EORTC Radiation Oncology Group. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014;15(2):184-90 20. Hong Y, Nam B, Jung K et al., Adjuvant chemotherapy with oxaliplatin/5fluorouracil/leucovorin (FOLFOX) versus 5-fluorouracil/leucovorin (FL) in patients with locally advanced rectal cancer after preoperative chemoradiotherapy followed by surgery: A randomized phase II study (The ADORE). J Clin Oncol 2013;31: (suppl;abstr 3570) 21. Sauer R, Becker H, Hohenberger W et al.; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351:1731–1740. 22. Chau I, Brown G, Cunningham D et al., Neoadjuvant Capecitabine and Oxaliplatin Followed by Synchronous Chemoradiation and Total Mesorectal Excision in Magnetic Resonance Imaging –Defined Poor-Risk Rectal Cancer. J Clin Oncol 2006;24:668-674 23. Fernández-Martos C, Pericay C, Aparicio J, et al., Phase II, Randomized Study of Concomitant Chemoradiation Followed by Surgery and Adjuvant Capecitabine Plus Oxaliplatin (CAPOX) Compared With Induction CAPOX Followed by Concomitant Chemoradiation and Surgery in Magnetic Resonance Imaging-Defined, Locally Advanced Rectal Cancer: Grupo Cancer de Recto 3 Study. J Clin Oncol. 2010;28(5):859-65. 24. Nimeiri HS, Feng Y, Catalano PJ et al, Intergroup randomized phase III study of postoperative irinotecan, 5-fluorouracil, and leucovorin versus oxaliplatin, 5-
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16. Petersen SH, Harling H, Kirkeby LT, Wille-Jørgensen P, Mocellin S. Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev. 2012 Mar 14;3:CD004078.
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fluorouracil, and leucovorin versus 5-fluorouracil and leucovorin for patients with stage II or III rectal cancer receiving either preoperative radiation and 5-fluorouracil or postoperative radiation and 5-fluorouracil: ECOG E3201—An updated survival analysis. J Clin Oncol 2013; 31:(suppl; Abstract e14711) 25. Schmoll H-J, Haustermans K, Price TJ, et al., Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: First results of the PETACC-6 randomized phase III trial. J Clin Oncol 2013;31:(suppl;abstr 3531)
27. Breugom AJ, van den Broek CBM, van Gijn W et al., The value of adjuvant chemotherapy for rectal cancer patients after preoperative radiotherapy or chemoradiation and TME-surgery. Results of the PROCTOR/SCRIPT study. Eur J Cancer 2013;49(S3) The European Cancer Congress 2013, Amsterdam LBA.
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26. Rödel C, Liersch T, Becker H,et al., German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012 Jul;13(7):679-87.
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CONSORT diagram
Figure 2.
(A) Disease-free and (B) overall survival curves according to treatment arms in all patients – ITT Population
Table 1.
Baseline Characteristics – ITT Population
Table 2.
Compliance to Chemotherapy – ITT Population
Table 3.
Reported Grade 3 or 4 Toxicities – Safety Population
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Figure 1.
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Table 1.
Baseline Characteristics – ITT Population
Variable
Capecitabine + Oxaliplatin
median (IQR)
median (IQR)
58.0 (52.0 – 65.0) 9.2 (7.4 – 11.4) 8.9 (7.1 – 10.6) 8.7 (7.3 – 10.6)
59.0 (55.0 – 66.0) 8.7 (7.1 – 11.7) 8.5 (7.1 – 11.9) 8.9 (7.0 – 10.6)
No. Gender Female Male WHO performance status 0 1 Tumour site Lower (0 – 4.9cm) Middle (5 – 9.9cm Upper (10 – 15cm) Tumour stage (ypT) T0 T1 T2 T3 T4 Nodal status (ypN) N0 N1 N2 Surgical technique Abdomino-perineal resection Anterior resection Low Hartmann's Other Missing
(%)
(n = 54)
No.
(%)
20 39
(33.9) (66.1)
10 44
(18.5) (81.5)
37 22
(62.7) (37.3)
33 21
(61.1) (38.9)
30 16 13
(50.9) (27.1) (22.0)
25 17 12
(46.3) (31.5) (22.2)
1 2 14 38 4
(1.7) (3.4) (23.7) (64.4) (6.8)
8 2 15 27 2
(14.8) (3.7) (27.8) (50.0) (3.7)
31 23 5
(52.4) (39.0) (8.5)
44 7 3
(81.5) (13.0) (5.6)
21 31 3 3 1
(36.2) (53.4) (5.2) (5.2)
25 27 0 1 1
(47.2) (50.9) (0.0) (1.9)
NB: the apparent imbalance for some of the baseline characteristics (e.g. gender) is due to chance: patients were randomly assigned by blocked stratification using nodal status and surgeon, but with 82 surgeons there were many randomisation ‘cells’, and with only 113 recruited patients out of the target of 800, this method of randomisation can produce chance imbalances.
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Age at random assignment, years Time from chemotherapy to surgery, weeks Time from radiotherapy to surgery, weeks Time from surgery to randomisation, weeks
Follow-up only (n = 59)
Table 2.
Compliance to Chemotherapy – ITT Population
Variable
Capecitabine + Oxaliplatin
Cycle
(n = 54) No.
(%)
0 1 2 3 4 5 6 missing
3 12 3 2 5 2 26 1
(5.6) (22.2) (5.6) (3.7) (9.3) (3.7) (48.1) (1.9)
Dose delay
1 2 3 4 5 6
6 1 6 9 9 4 21
(11.1) (1.9) (11.1) (16.7) (16.7) (7.4) (38.9)
1 2 3 4 5 6
8 3 2 6 4 1 21
(14.8) (5.6) (3.7) (11.1) (7.4) (1.9) (38.9)
Any dose delay
Dose reduction
Any dose reduction
median (IQR) Total dose Capecitabine given, mg/m2 Total dose Oxaliplatin given, mg/m2
96923 (28290, 160000) 601 (130, 769)
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Number of cycles received
Table 3.
Reported Grade 3 or 4 Toxicities – Safety Population
Variable
(n = 50) No.
(%)
20*
(40.0) (16.0) (12.0) (8.0) (8.0) (6.0) (6.0) (2.0) (2.0) (2.0) (2.0) (2.0) (2.0)
8 6 4 4 3 3 1 1 1 1 1 1
* Grade 4 = 3 patients (6.0%): Diarrhoea (n=1), Neuropathy:sensory (n=2)
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Any toxicity (each patient counted once) Diarrhoea Fatigue Nausea Neuropathy:sensory Hand-Foot reaction Vomiting Anorexia Clumsiness Febrile neutropenia Granulocytes Pain - abdomen Paraesthesiae/dyaesthesiae
Capecitabine + Oxaliplatin
Chronicle: Results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (Xelox) versus control.
Key Message: "Locally advanced rectal cancer is conventionally treated with preoperative chemoradiation, but has a high risk of distant recurrence. The Chronicle trial did not detect a significant difference in DFS or OS for adjuvant XELOX compared to surgery alone following chemoradiation. The difficulty in recruitment, high acute levels of toxicity and poor compliance to adjuvant chemotherapy, all support the need for trials that test the role of neoadjuvant chemotherapy."
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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R. Glynne-Jones1, N. Counsell2, P. Quirke3, N. Mortensen4, A. Maraveyas5, H.M. Meadows2, J. Ledermann2, D. Sebag-Montefiore3 1 Mount Vernon Centre for Cancer Treatment, London, UK 2 CRUK & UCL Cancer Trials Centre, London, UK 3 University of Leeds, Leeds, UK 4 University of Oxford, Oxford, UK 5 Castle Hill Hospital, Hull, UK Corresponding Author: Dr R Glynne-Jones, Tel: +44 (0) 1923 844767, Fax: +44 (0) 1923 844 138, E-mail: [email protected]
2
Abstract Background: In stage III colon cancer oxaliplatin/5FU-based adjuvant chemotherapy (FOLFOX) improves disease-free survival (DFS) and overall survival (OS). In rectal adenocarcinoma following neoadjuvant chemoradiation (CRT), we examined the benefit of postoperative adjuvant capecitabine and oxaliplatin (XELOX) chemotherapy.
Results: The study closed prematurely in 2008 because of poor accrual. Only 113 patients were randomly assigned to either observation (n=59) or XELOX (n=54). Compliance was poor, 93% allocated chemotherapy started and 48% completed 6 cycles. Protocolised dose reductions in XELOX were 39%, and levels of G3/G4 toxicity 40%. After a median follow-up of 44.8 months, 16 patients (27%) in the observation arm had relapsed or died compared with 12 patients (22%) in XELOX. The 3-year DFS rate was 78% with XELOX and 71% with observation (hazard ratio [HR] for DFS=0.80; 95% CI: 0.38-1.69; p=0.56). The 3-year OS for XELOX and observation were 89% and 88% respectively (HR for OS=1.18; 95% CI: 0.43-3.26; p=0.75). Conclusions: The observed improvement in DFS for adjuvant XELOX and similar OS were not statistically significant, as expected given the small number of patients and consequent low power. Our findings support the need for trials that test the role of neoadjuvant chemotherapy. Key words: Rectal adenocarcinoma, preoperative chemoradiation, metastatic disease, adjuvant chemotherapy, capecitabine, oxaliplatin.
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Methods: Eligible patients were randomly assigned following fluoropyrimidine-based CRT and curative resection to observation or 6 cycles of XELOX. The primary endpoint was DFS; secondary endpoints were acute toxicity and OS. 390 patients were required in each arm, to detect an improvement in 3-year DFS from 40% to 50.5%, with 85% power and two-sided 5% significance level.
3
Introduction Postoperative 5-Fluorouracil (5FU)-based adjuvant chemotherapy improves overall survival (OS) in stage III colon cancer1. Oxaliplatin added to 5FU-based chemotherapy improves disease-free survival (DFS) and OS2,3, and is considered an international standard for stage III colon cancer.
Locally advanced rectal cancer (LARC) has a high risk of local and distant
Network Guidelines, recommend a FOLFOX regimen as postoperative chemotherapy in patients with stage III or adverse histology following chemoradiation and surgery4,5,6,7,8,9. The validity of this strategy has been questioned10. Trials which directly examined adjuvant 5FU alone after chemoradiation, have provided no evidence for its efficacy11,12,13,.
The CHRONICLE trial aimed to evaluate postoperative adjuvant chemotherapy following neoadjuvant chemoradiation (NCRT) in LARC. The trial examined whether six cycles of capecitabine and oxaliplatin (XELOX) over 4 months would improve DFS and OS compared to surgical follow-up alone. We report the results of acute toxicity and compliance in addition to DFS and OS.
Patients and Methods The Chronicle trial was approved by institutional ethics committees of participating centres and monitored by an Independent Data Monitoring (IDMC) and Trial Steering Committee (TSC). Six-monthly review of recruitment was prospectively defined to assess the feasibility of obtaining a clinically worthwhile result, if accrual was lower than anticipated.
Eligibility Eligible patients were aged >18 years, with histologically confirmed rectal adenocarcinoma, located <15cm from the anal verge, or below the peritoneal reflection. Surgery was performed before randomisation, to start chemotherapy within 12 weeks of surgery. Before enrolment patients received preoperative fluoropyrimidine-based chemoradiation, minimum total dose 45Gy. Patients may
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recurrence. Many oncologists, and the European and National Comprehensive Cancer
4
have had up to a 12-week maximum of neoadjuvant fluoropyrimidine-based chemotherapy.
Other eligibility criteria included WHO performance status 0-1, adequate hematologic, renal, and hepatic function, complete resection of the primary tumour, a negative circumferential margin (CRM>1mm), and no evidence of metastatic disease. Definitive histology at surgery required ypT0-T4, N0-N2.
resections, and for significant cardiac disease, CNS disorders, known peripheral neuropathy, moderate/severe renal impairment, and pregnancy or lactation.
Treatment Patients were randomised to observation alone (Observation arm) or XELOX capecitabine (1000mg/m2 orally twice daily days 1-14) and oxaliplatin (130mg/m2 day 1) as a two-hour infusion (XELOX arm) as indicated in the CONSORT diagram (FIGURE 1). A total of 6 three-weekly cycles were intended. Dose modifications for toxicity were defined in the protocol.
Assessments Pre-treatment evaluation included: CT scans of chest, abdomen and pelvis; demographic data, medical history, physical examination, ECG, carcino-embryonic antigen (CEA) determination; height, weight, vital signs, WHO performance status, haematology, and blood chemistry.
Adverse events were monitored during and for 28 days after study treatment. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria, version 3.0. Neurotoxicity was monitored up to 3 years post-randomisation.
Follow-up Patients were evaluated clinically every three weeks following randomisation until 4 months, then three-monthly until the end of the second year, six-monthly until the end of the fifth year and then annually. Colonoscopy was recommended prior to surgery or within 3 months after surgery, and thereafter every third year. Abdo-pelvic CT
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Patients were excluded in the presence of metastatic disease (M1), R1 or R2
5
scans or ultrasound and chest x-ray or thoracic CT were to be performed at 6, 12, 18, 24, 36 and 48 months post-randomisation. CEA levels were measured every 3 months (starting 6 months post-randomisation) for the first 3 years and every 6 months thereafter. Assessments were made for local relapse, distant metastases, late toxicity, second cancers and death. Patients were flagged at the UK Office of National Statistics to capture death notification.
Patients were randomly assigned 1:1 between trial arms using permuted blocks, stratified by surgeon and pathological nodal status.
The primary endpoint was DFS, defined as the time from randomisation to relapse, development of a new cancer or death, whichever occurred first. 390 patients were required in each arm to detect an improvement in 3-year DFS from 40% to 50.5% (equivalent to a hazard ratio of 0.75), with 85% power and two-sided 5% significance level. With allowance for loss to follow-up, the target sample size was 800 patients in total, assuming an enrolment and follow-up period of 3 years.
If an advantage was observed for postoperative chemotherapy, it was planned to explore whether it was consistent across various subgroups described in the statistical analysis plan. Secondary endpoints were OS, measured from date of randomisation until death from any cause, incidence rates of acute toxicity and compliance to treatment.
Hazard ratios with 95% confidence intervals (CIs) were calculated using the Cox proportional hazards model. Survival curves are presented using the Kaplan-Meier method. Patients were censored using the date they were last seen if no event had occurred. Analysis was performed on an intention-to-treat (ITT) basis, unless otherwise specified, and generated using SAS software version 9.3, (SAS Institute, Cary NC).
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Statistical Analysis
6
Results
Accrual Between 2004 and 2008, 113 patients were randomised; TABLE 1 shows the baseline characteristics. After 4 years of slower-than-anticipated accrual, the trial was terminated early on the recommendation of the IDMC.
54 patients were randomly assigned to XELOX and 59 to the observation arm. At least one cycle of study treatment was received by 50 patients (92.6%). The planned six cycles of chemotherapy were received by only 26 (48.1%). Twenty-one (38.9%) had a dose reduction and 21 (38.9%) had a dose delay; TABLE 2. Median total oxaliplatin dose received was 601mg/m2, compared with a per-protocol six-cycle dose of 780mg/m2. Median total capecitabine dose received was 96,923mg/m2, compared with a per-protocol six-cycle dose of 168,000mg/m2.
Therapy after relapse was received by 9 (16.7%) XELOX and 15 (25.4%) patients in the observation arm. Post-relapse, in the XELOX and observation arms respectively, 6 (11.1%) and 7 (11.9%) patients received chemotherapy, 4 (7.4%) and 7 (11.9%) received surgery, 2 (3.7%) and 2 (3.4%) received palliative care, 1 (1.9%) and 1 (1.7%) received radiotherapy, and 1 (1.9%) XELOX patient was offered a different trial.
Toxicity Fifty (92.6%) XELOX patients received at least 1 cycle of treatment – defined as the safety population. Twenty (40.0% of the safety population) reported grade 3 or higher toxicity; TABLE 3. Three (6.0%) reported a grade 4 toxicity (sensory neuropathy (n=2) and diarrhoea (n=1)). There was one treatment-related death from diarrhoea.
Nine patients reported a grade 3/4 adverse event during follow-up. Six XELOX patients reported 8 late toxicities: bowel obstruction (G4, n=1), malignant fistula (G4, n=1), neuropathy (G3, n=2), impaired bladder function (G3, n=1), pulmonary embolism (G3, n=1), pain (G3, n=1), and blepharospasm (G3, n=1). Three patients in
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Compliance
7
the observation arm reported 3 late toxicities: angina (G3, n=1), back pain (G3, n=1), and poor bowel control (G3, n=1).
Efficacy The median follow-up was 44.8 months, censoring those who had died. Only two local recurrences have been observed. There were 16 (27.2%) observation and 12 (22.2%) XELOX patients who had relapsed or died, with 3-year DFS of 71.3% and
p=0.56), in favour of XELOX (FIGURE 2A). The observed 3-year DFS rates were higher than expected (40-50% from the sample size calculation), and the hazard ratio was close to the target value of 0.75. The HR after adjusting for factors that are imbalanced in Table 1 was 0.84 (95% CI: 0.37-1.93, p=0.69).
Fifteen patients died, 7 observation (11.9%; rectal cancer (n=6), rectal & breast cancer with brain metastases (n=1)) and 8 XELOX (14.8%; rectal cancer (n=6), chemotherapy-related (n=1), pharyngeal tumour (n=1)), with 3-year OS of 87.8% and 88.8% respectively. The HR for OS was 1.18 (95% CI: 0.43-3.26; p=0.75) in favour of observation only (FIGURE 2B). The HR after adjusting for factors that appear imbalanced in Table 1 was 1.42 (95% CI: 0.44-4.52, p=0.55).
Discussion
The Chronicle trial is unique in comparing XELOX postoperatively against observation alone in LARC treated with preoperative chemoradiation. Results show that after a median follow-up of 44.8 months, the 3-year DFS rate was 78% with XELOX and 71% with observation (HR for DFS, 0.80; 95% CI: 0.38-1.69; p=0.56). Hence no statistically significant benefit of adjuvant XELOX chemotherapy was found, but the study was underpowered with only 113 patients reducing the planned power of 85% to <20% for the primary endpoint.
We did not specify baseline clinical stage as an eligibility criterion; following the CR07 trial, most patients in the UK with resectable LARC received short course preoperative radiotherapy (5x5Gy). Chemoradiation tended to be given for fixed or unresectable cancers.
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77.5% respectively. The hazard ratio (HR) for DFS was 0.80 (95% CI: 0.38-1.69;
8
Based on results of a meta-analysis in colon cancer14, it is assumed chemotherapy should start as soon as possible following surgery, and not be delayed beyond 3 months. In the Chronicle study, the median time from surgery to randomisation was 8 weeks. Compliance to postoperative chemotherapy was poor. Only 26 patients (48.1%) received the planned six cycles. This finding is consistent with other studies.
and mature follow-up of individuals within the trial.Yet few patients were actually accrued from a large number of recruiting centres, which meant that patients receiving XELOX were not well-matched for individual prognostic factors versus those in the observation arm. In particular, the two study groups differed slightly in the number of patients achieving a pathological CR, because patients were randomly assigned using blocked stratification by nodal status and surgeon (82 surgeons, for only 113/800 patients). However, outcomes are similar even after adjusting for these differences.
By restricting eligibilty to patients with a CRM>1mm, we selected patients with more favourable outcomes because non-responders to CRT were effectively excluded. This factor might explain the paucity of relevant events such as low local recurrence rate.
The evidence-base for postoperative adjuvant chemotherapy in LARC is scanty. A phase III Japanese trial of oral UFT15 in 274 patients, suggests an advantage to postoperative adjuvant chemotherapy in rectal cancer although no NCRT was given and surgery involved bilateral lateral pelvic lymph node dissection. A recent metaanalysis16 of 21 randomised controlled trials in 9221 patients, examined postoperative chemotherapy and showed a significant benefit in terms of DFS (HR=0.75,CI: 0.680.83) and OS (HR=0.83, CI: 0.76-0.91) for patients with rectal cancer administered postoperative fluoropyrimidine-based chemotherapy (without oxaliplatin) as compared to observation alone. However, only 3 studies11,17,18 included patients who had received preoperative radiotherapy. In the largest EORTC 22921 study11,19 in 1011 patients with T3/T4 resectable there was no significant benefit in terms of DFS or OS from the addition of postoperative FUFA.
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The Chronicle trial benefits from high levels of complete data, pathologic verification,
9
A Korean study randomised 320 patients (161 to 5FU, 159 to FOLFOX) with ypstage II and III rectal cancer following CRT20. After a median follow-up of 22.5 months, estimated 2-year DFS rate was 82.0% in FOLFOX and 69.4% in the 5FU arm (HR=0.46; 95% CI, 0.28-0.76, p=0.002).
There is a well-recognised problem of delivery and compliance to chemotherapy following preoperative CRT and surgery, because of slow recovery and healing, poor patients10,11,21. The Chronicle trial demonstrates only 48% of patients allocated chemotherapy completed 6 cycles. In contrast, compliance to chemotherapy in the preoperative setting is high22 and delivered more easily than postoperative23, enabling full systemic doses of chemotherapy to be delivered at an early stage rather than a delay of up to 18 weeks associated with CRT.
Unpublished studies The Eastern Cooperative Oncology Group (E3201) trial closed after 225 patients of the planned 3150 had been enrolled, when the GI Intergroup developed an alternative trial with bevacizumab (E5204). An updated analysis24 showed no difference in OS between patients who received 5FU alone, oxaliplatin-based or irinotecan-based adjuvant therapy. The follow-on E5204 trial aimed to randomise 2100 patients between modified FOLFOX 6 with or without bevacizumab but closed in 2009. The PETACC 6 (1094 patients)25 and the German ARO/CAO/AIO-04 trials (1259 patients)26 may provide further evidence regarding the role of postoperative FOLFOX (ARO/CAO/AIO-04) or XELOX (PETACC 6) versus adjuvant 5FU/capecitabine alone.
The Dutch CKTO/2003-16/PROCTOR/SCRIPT study initially randomised patients after short course preoperative radiotherapy (5x5Gy) to capecitabine or control, but was amended to include preoperative chemoradiation. Preliminary results in 470 of the 840 originally intended patients, show the 3-year DFS was 67.4% for chemotherapy versus 66.1% for observation (HR 0.835, 95% CI: 0.61-1.13 p=0.24)27.
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tolerance, marked dose reductions and patient reluctance – affecting at least 40% of
10
In Chronicle there were sufficient centres open, but the high rate of refusals to take part reflects lack of equipoise on the part of oncologists and strong preferences by patients for no further treatment following CRT. This is a well-recognised problem in non-blinded randomised trials and is unlikely to be due to a specific feature of rectal cancer.
The Chronicle trial did not detect a significant difference in DFS or OS for adjuvant XELOX. No definitive conclusion can be drawn from a trial with inadequate numbers, poor compliance and insufficient statistical power. We remain unsure of the advantage of additional adjuvant chemotherapy following CRT, either in terms of 5FU alone or combined with oxaliplatin, and of specific subgroups who might benefit most/least. Although unable to provide a definitive result, this trial in terms of the hazard ratio of 0.80 for DFS (95% CI: 0.38-1.69), can contribute to future reviews and meta-analyses.
The poor compliance to oxaliplatin containing chemotherapy in the postoperative setting following chemoradiation therefore supports the hypothesis that neoadjuvant chemotherapy – as piloted in the UK BACCHUS Study (NCT01650428) and the US NCCTG N1048 PROSPECT trial (NCT01515787) - might prove a more effective strategy.
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Conclusion
11
Acknowledgements The Chronicle trial was conducted across the National Cancer Research Network, and funded by Cancer Research UK - grant award no C10568/A4148. We would like to acknowledge Wendy Wood and Patricia Henley for trial coordination. Capecitabine and Oxaliplatin were supplied free of charge by Roche and Sanofi-Aventis respectively.
Sothi, Alexandra Hospital (Redditch); Dr McDonald, Beatson Oncology Centre; Dr Geh, Birmingham Heartlands Hospital; Dr Susnerwala, Blackpool Victoria Hospital; Dr Falk, Bristol Royal Infirmary; Dr Lowdell, Charing Cross Hospital; Dr Myint, Clatterbridge Hospital; Dr Sebag-Montefiore, Cookridge Hospital; Dr Wadsley, Doncaster Royal Infirmary; Dr Sizer, Essex County Hospital; Dr Biswas, Furness General Hospital; Dr Glaholm, Good Hope Hospital; Dr Soomal, Ipswich Hospital; Dr Churn, Kidderminster Hospital; Dr Hartley, Manor Hospital; Dr Glynne-Jones, Mount Vernon Hospital; Dr Osborne, North Devon District Hospital; Dr Bridgewater, Princess Alexandra Hospital; Dr Maraveyas, Princess Royal Hospital; Dr Geh, Queen Elizabeth Hospital (Birmingham); Dr Dobrowsky, Queen Elizabeth Hospital (Gateshead); Dr Kulkarni, Queen's Hospital; Dr Whillis, Raigmore Hospital; Dr Wilson, Royal Albert Edward Infirmary; Dr Osborne, Royal Devon and Exeter Hospital; Dr Biswas, Royal Lancaster Infirmary; Dr Awwad, Royal Shrewsbury Hospital; Dr Hamilton, Scarborough Hospital; Dr Hamid, Scunthorpe General Hospital; Dr Bateman, Southampton General Hospital; Dr Tsang, Southend Hospital; Dr Myint, Southport and Formby DGH; Dr Cottrill, St Bartholomew's Hospital; Dr O'Callaghan, St Mary's Hospital (Portsmouth); Dr Pedley, Sunderland Royal Hospital;
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Recruiting hospitals and investigators: Dr Samuel, Aberdeen Royal Infirmary; Dr
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Dr Ledermann, UCLH (Middlesex Hospital); Prof Maughan, Velindre Hospital; Dr Riddle, West Middlesex University Hospital; Dr Wadsley, Weston Park Hospital; Dr Hochhauser, Whittington Hospital; Dr Weaver, Wycombe Hospital; Dr Falk, Yeovil Hospital.
RGJ has received honoraria and research funding from Roche, Sanofi-Aventis and
All remaining authors have declared no conflicts of interest.
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Merck KgaA. DSM has received research funding from Roche and Sanofi-Aventis.
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References 1. Moertel CG, Fleming TR, Macdonald JS et al., Levamisole and fluorouracil for adjuvant chemotherapy of resected colon carcinoma. New Engl J Med. 1990;322: 352-358 2. Kuebler JP, Wieand HS, O’Connell MJ et al., Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol 2007;25(16):2198204
4 NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA. 1990;264(11):1444-50. 5. Minsky BD, Röedel C, Valentini V. Combined modality therapy for rectal cancer. Cancer J. 2010;16(3):253-61. 6. Glimelius B. Adjuvant chemotherapy in rectal cancer—an issue or a nonissue? Ann Oncol. 2010;21(9):1739-41 7. Schmoll H, Van Cutsem E, Stein A et al., ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol. 2012;23(10):2479-516 8. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Rectal Cancer Version 4.2013 ncrn.org . (last accessed 15/2/2013) 9. Benson AB 3rd, Bekaii-Saab T, Chan E,et al., Rectal cancer. J Natl Compr Canc Netw. 2012 Dec 1;10(12):1528-64 10. Bujko K, Glynne-Jones R, Bujko M. Does adjuvant fluoropyrimidine-based chemotherapy provide a benefit for patients with resected rectal cancer who have already received neoadjuvant radiochemotherapy? A systematic review of randomised trials. Ann Oncol 2010;21(9):1743-50. 11. Bosset JF, Collette L, Calais G et al. Chemotherapy with pre-operative radiotherapy in rectal cancer. NEJM, 2006;355:1114-23 12. Cionini L, Sainato A, De Paoli A et al. Final results of randomized trial on adjuvant chemotherapy after preoperative chemoradiation in rectal cancer. Radiother Oncol. 2010;96 (Suppl 1):S113–S114 (Abstr) 13. Bosset JF, Calais G, Mineur L, et al., Preoperative radiotherapy (preop RT) in rectal cancer: Impact of chemotherapy on the outcome—Long-term results of the randomized 22921 phase III trial of EORTC. J Clin Oncol 2013;31: (suppl;abstr 3560)
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3. André T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27:3109–3116.
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14. Biagi JJ, Raphael MJ, Mackillop WJ, et al., Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic review and meta-analysis. JAMA 2011;305:2335–2342. 15. Akasu T, Moriya Y, Ohashi Y,et al., Adjuvant chemotherapy with uraciltegafur for pathological stage III rectal cancer after mesorectal excision with selective pelvic lymphadenectomy: A multicentre randomised controlled trial. Jpn J Clin Onc 2006;36(4)237-244
17. Quasar Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 2007;370(9604):2020-29 18. Glimelius B, Dahl O, Cedermark B, et al., Adjuvant Chemotherapy in colorectal cancer: a joint analysis by the Nordic Gastrointectinal Tumour Adjuvant Therapy Group. Acta Oncol 2005;44(8):904-12 19. Bosset JF, Calais G, Mineur L,et al., EORTC Radiation Oncology Group. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014;15(2):184-90 20. Hong Y, Nam B, Jung K et al., Adjuvant chemotherapy with oxaliplatin/5fluorouracil/leucovorin (FOLFOX) versus 5-fluorouracil/leucovorin (FL) in patients with locally advanced rectal cancer after preoperative chemoradiotherapy followed by surgery: A randomized phase II study (The ADORE). J Clin Oncol 2013;31: (suppl;abstr 3570) 21. Sauer R, Becker H, Hohenberger W et al.; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351:1731–1740. 22. Chau I, Brown G, Cunningham D et al., Neoadjuvant Capecitabine and Oxaliplatin Followed by Synchronous Chemoradiation and Total Mesorectal Excision in Magnetic Resonance Imaging –Defined Poor-Risk Rectal Cancer. J Clin Oncol 2006;24:668-674 23. Fernández-Martos C, Pericay C, Aparicio J, et al., Phase II, Randomized Study of Concomitant Chemoradiation Followed by Surgery and Adjuvant Capecitabine Plus Oxaliplatin (CAPOX) Compared With Induction CAPOX Followed by Concomitant Chemoradiation and Surgery in Magnetic Resonance Imaging-Defined, Locally Advanced Rectal Cancer: Grupo Cancer de Recto 3 Study. J Clin Oncol. 2010;28(5):859-65. 24. Nimeiri HS, Feng Y, Catalano PJ et al, Intergroup randomized phase III study of postoperative irinotecan, 5-fluorouracil, and leucovorin versus oxaliplatin, 5-
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16. Petersen SH, Harling H, Kirkeby LT, Wille-Jørgensen P, Mocellin S. Postoperative adjuvant chemotherapy in rectal cancer operated for cure. Cochrane Database Syst Rev. 2012 Mar 14;3:CD004078.
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fluorouracil, and leucovorin versus 5-fluorouracil and leucovorin for patients with stage II or III rectal cancer receiving either preoperative radiation and 5-fluorouracil or postoperative radiation and 5-fluorouracil: ECOG E3201—An updated survival analysis. J Clin Oncol 2013; 31:(suppl; Abstract e14711) 25. Schmoll H-J, Haustermans K, Price TJ, et al., Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: First results of the PETACC-6 randomized phase III trial. J Clin Oncol 2013;31:(suppl;abstr 3531)
27. Breugom AJ, van den Broek CBM, van Gijn W et al., The value of adjuvant chemotherapy for rectal cancer patients after preoperative radiotherapy or chemoradiation and TME-surgery. Results of the PROCTOR/SCRIPT study. Eur J Cancer 2013;49(S3) The European Cancer Congress 2013, Amsterdam LBA.
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26. Rödel C, Liersch T, Becker H,et al., German Rectal Cancer Study Group. Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol. 2012 Jul;13(7):679-87.
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CONSORT diagram
Figure 2.
(A) Disease-free and (B) overall survival curves according to treatment arms in all patients – ITT Population
Table 1.
Baseline Characteristics – ITT Population
Table 2.
Compliance to Chemotherapy – ITT Population
Table 3.
Reported Grade 3 or 4 Toxicities – Safety Population
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Figure 1.
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19
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Table 1.
Baseline Characteristics – ITT Population
Variable
Capecitabine + Oxaliplatin
median (IQR)
median (IQR)
58.0 (52.0 – 65.0) 9.2 (7.4 – 11.4) 8.9 (7.1 – 10.6) 8.7 (7.3 – 10.6)
59.0 (55.0 – 66.0) 8.7 (7.1 – 11.7) 8.5 (7.1 – 11.9) 8.9 (7.0 – 10.6)
No. Gender Female Male WHO performance status 0 1 Tumour site Lower (0 – 4.9cm) Middle (5 – 9.9cm Upper (10 – 15cm) Tumour stage (ypT) T0 T1 T2 T3 T4 Nodal status (ypN) N0 N1 N2 Surgical technique Abdomino-perineal resection Anterior resection Low Hartmann's Other Missing
(%)
(n = 54)
No.
(%)
20 39
(33.9) (66.1)
10 44
(18.5) (81.5)
37 22
(62.7) (37.3)
33 21
(61.1) (38.9)
30 16 13
(50.9) (27.1) (22.0)
25 17 12
(46.3) (31.5) (22.2)
1 2 14 38 4
(1.7) (3.4) (23.7) (64.4) (6.8)
8 2 15 27 2
(14.8) (3.7) (27.8) (50.0) (3.7)
31 23 5
(52.4) (39.0) (8.5)
44 7 3
(81.5) (13.0) (5.6)
21 31 3 3 1
(36.2) (53.4) (5.2) (5.2)
25 27 0 1 1
(47.2) (50.9) (0.0) (1.9)
NB: the apparent imbalance for some of the baseline characteristics (e.g. gender) is due to chance: patients were randomly assigned by blocked stratification using nodal status and surgeon, but with 82 surgeons there were many randomisation ‘cells’, and with only 113 recruited patients out of the target of 800, this method of randomisation can produce chance imbalances.
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Age at random assignment, years Time from chemotherapy to surgery, weeks Time from radiotherapy to surgery, weeks Time from surgery to randomisation, weeks
Follow-up only (n = 59)
Table 2.
Compliance to Chemotherapy – ITT Population
Variable
Capecitabine + Oxaliplatin
Cycle
(n = 54) No.
(%)
0 1 2 3 4 5 6 missing
3 12 3 2 5 2 26 1
(5.6) (22.2) (5.6) (3.7) (9.3) (3.7) (48.1) (1.9)
Dose delay
1 2 3 4 5 6
6 1 6 9 9 4 21
(11.1) (1.9) (11.1) (16.7) (16.7) (7.4) (38.9)
1 2 3 4 5 6
8 3 2 6 4 1 21
(14.8) (5.6) (3.7) (11.1) (7.4) (1.9) (38.9)
Any dose delay
Dose reduction
Any dose reduction
median (IQR) Total dose Capecitabine given, mg/m2 Total dose Oxaliplatin given, mg/m2
96923 (28290, 160000) 601 (130, 769)
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Number of cycles received
Table 3.
Reported Grade 3 or 4 Toxicities – Safety Population
Variable
(n = 50) No.
(%)
20*
(40.0) (16.0) (12.0) (8.0) (8.0) (6.0) (6.0) (2.0) (2.0) (2.0) (2.0) (2.0) (2.0)
8 6 4 4 3 3 1 1 1 1 1 1
* Grade 4 = 3 patients (6.0%): Diarrhoea (n=1), Neuropathy:sensory (n=2)
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Any toxicity (each patient counted once) Diarrhoea Fatigue Nausea Neuropathy:sensory Hand-Foot reaction Vomiting Anorexia Clumsiness Febrile neutropenia Granulocytes Pain - abdomen Paraesthesiae/dyaesthesiae
Capecitabine + Oxaliplatin