Highlights
- •Randomised trials for adjuvant therapy in colon cancer (CC) use multiple time-to-event (TTE) end-points that lack standardised definitions.
- •Recommendations for the definition of TTE end-point in adjuvant CC randomised trials were established.
- •These guidelines should become standard practice because they would facilitate data interpretation and across-trial comparisons.
Abstract
Background
The variability of definitions for time-to-event (TTE) end-points impacts the conclusions
of randomised clinical trials (RCTs). The Definition for the Assessment of Time-to-event
Endpoints in CANcer (DATECAN) initiative aims to provide consensus definitions for
TTE end-points used in RCTs. Here, we formulate guidelines for adjuvant colon cancer
RCTs.
Methods
We performed a literature review to identify TTE end-points and events included in
their definition in RCT publications. Then, a consensus was reached among a panel
of international experts, using a formal modified Delphi method, with 2 rounds of
questionnaires and an in-person meeting.
Results
Twenty-four experts scored 72 events involved in 6 TTE end-points. Consensus was reached
for 24%, 57% and 100% events after the first round, second round and in-person meeting.
For RCTs not using overall survival as their primary end-point, the experts recommend
using disease-free survival (DFS) rather than recurrence-free survival (RFS) or time
to recurrence (TTR) as the primary end-point. The consensus definition of DFS includes
all causes of death, second primary colorectal cancers (CRCs), anastomotic relapse
and metastatic relapse as an event, but not second primary non-CRCs. Events included
in the RFS definition are the same as for DFS with the exception of second primary
CRCs. The consensus definition of TTR includes anastomotic or metastatic relapse,
death with evidence of recurrence and death from CC cause.
Conclusion
Standardised definitions of TTE end-points ensure the reproducibility of the end-points
between RCTs and facilitate cross-trial comparisons. These definitions should be integrated
in standard practice for the design, reporting and interpretation of adjuvant CC RCTs.
Keywords
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References
- Survival endpoints in colorectal cancer and the effect of second primary other cancer on disease free survival.BMC Canc. 2011; 11: 438https://doi.org/10.1186/1471-2407-11-438
- Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3.J Clin Oncol. 2009; 27: 3117-3125https://doi.org/10.1200/JCO.2008.21.6663
- International conference on harmonisation; guidance on statistical principles for clinical trials; availability-FDA. Notice.Fed Regist. 1998; 63: 49583-49598
- CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials.Ann Intern Med. 2010; 152: 726-732https://doi.org/10.7326/0003-4819-152-11-201006010-00232
- Endpoints in adjuvant treatment trials: a systematic review of the literature in colon cancer and proposed definitions for future trials.J Natl Cancer Inst. 2007; 99: 998-1003https://doi.org/10.1093/jnci/djm024
- Protocol of the Definition for the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN) project: formal consensus method for the development of guidelines for standardised time-to-event endpoints' definitions in cancer clinical trials.Eur J Canc. 2013; 49: 769-781https://doi.org/10.1016/j.ejca.2012.09.035
- Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.Ann Oncol. 2015; 26: 2392-2398https://doi.org/10.1093/annonc/mdv380
- Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials).Ann Oncol. 2015; 26: 873-879https://doi.org/10.1093/annonc/mdv106
- Guidelines for time-to-event end point definitions in sarcomas and gastrointestinal stromal tumors (GIST) trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials).Ann Oncol. 2015; 26: 865-872https://doi.org/10.1093/annonc/mdu360
- Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials).Eur J Canc. 2014; 50: 2983-2993https://doi.org/10.1016/j.ejca.2014.07.011
- Censoring issues in survival analysis.Annu Rev Publ Health. 1997; 18: 83-104https://doi.org/10.1146/annurev.publhealth.18.1.83
- Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial.J Am Med Assoc. 2012; 307: 1383-1393https://doi.org/10.1001/jama.2012.385
- Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803.J Clin Oncol. 2007; 25: 3456-3461https://doi.org/10.1200/JCO.2007.11.2144
- Documenting the natural history of patients with resected stage II adenocarcinoma of the colon after random assignment to adjuvant treatment with edrecolomab or observation: results from CALGB 9581.J Clin Oncol. 2011; 29: 3146-3152https://doi.org/10.1200/JCO.2010.32.5357
- Final results of a randomised phase III study on adjuvant chemotherapy with 5 FU and levamisol in colon and rectum cancer stage II and III by the Norwegian Gastrointestinal Cancer Group.Acta Oncol. 2009; 48: 368-376https://doi.org/10.1080/02841860902755244
- Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1.J Clin Oncol. 2007; 25: 3732-3738https://doi.org/10.1200/JCO.2007.12.2234
- Bevacizumab in stage II-III colon cancer: 5-year update of the national surgical adjuvant breast and Bowel project C-08 trial.J Clin Oncol. 2013; 31: 359-364https://doi.org/10.1200/JCO.2012.44.4711
- 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: 3109-3116https://doi.org/10.1200/JCO.2008.20.6771
- Prodige 34-FFCD 1402-ADAGE: adjuvant chemotherapy in elderly patients with resected stage III colon cancer: a randomized phase 3 trial.Dig Liver Dis. 2016; 48: 206-207https://doi.org/10.1016/j.dld.2015.11.023
- Randomized controlled trial of intraportal chemotherapy combined with adjuvant chemotherapy (mFOLFOX6) for stage II and III colon cancer.Ann Surg. 2016; 263: 434-439https://doi.org/10.1097/SLA.0000000000001374
- Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial.Lancet Oncol. 2012; 13: 1225-1233https://doi.org/10.1016/S1470-2045(12)70509-0
- Duration of adjuvant chemotherapy for stage III colon cancer.N Engl J Med. 2018; 378: 1177-1188https://doi.org/10.1056/NEJMoa1713709
- Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer.J Clin Oncol. 2011; 29: 1465-1471https://doi.org/10.1200/JCO.2010.33.6297
- Capecitabine versus S-1 as adjuvant chemotherapy for patients with stage III colorectal cancer (JCOG0910): an open-label, non-inferiority, randomised, phase 3, multicentre trial.The Lancet Gastroenterology & Hepatology. 2018; 3: 47-56https://doi.org/10.1016/S2468-1253(17)30297-2
- Final results of randomized trials by the national surgical adjuvant study of colorectal cancer (NSAS-CC).Canc Chemother Pharmacol. 2011; 67: 587-596https://doi.org/10.1007/s00280-010-1358-1
- Perioperative and adjuvant chemotherapy in colon cancer: results of SAKK trial 40/93.Int J Colorectal Dis. 2009; 24: 351-352https://doi.org/10.1007/s00384-008-0577-y
- 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial.Lancet Oncol. 2018; 19: 562-578https://doi.org/10.1016/S1470-2045(18)30093-7
- Neoadjuvant FOLFOX 4 versus FOLFOX 4 with Cetuximab versus immediate surgery for high-risk stage II and III colon cancers: a multicentre randomised controlled phase II trial – the PRODIGE 22 - ECKINOXE trial.BMC Canc. 2015; 15https://doi.org/10.1186/s12885-015-1507-3
- A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: the Pan-European Trial in Adjuvant Colon Cancer 2 study.Eur J Canc. 2013; 49: 1868-1875https://doi.org/10.1016/j.ejca.2013.01.030
- 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 Orthod. 2007; 25: 2198-2204https://doi.org/10.1200/JCO.2006.08.2974
- A randomised-controlled trial of 1-year adjuvant chemotherapy with oral tegafur–uracil versus surgery alone in stage II colon cancer: SACURA trial.Eur J Canc. 2018; 96: 54-63https://doi.org/10.1016/j.ejca.2018.03.009
- A randomized phase III trial of adjuvant chemotherapy with irinotecan, leucovorin and fluorouracil versus leucovorin and fluorouracil for stage II and III colon cancer: a Hellenic Cooperative Oncology Group study.BMC Med. 2011; 9: 10https://doi.org/10.1186/1741-7015-9-10
- Raltitrexed (tomudex) versus standard leucovorin-modulated bolus 5-fluorouracil: results from the randomised phase III pan-European trial in adjuvant colon cancer 01 (PETACC-1).Eur J Canc. 2008; 44: 2204-2211https://doi.org/10.1016/j.ejca.2008.07.002
- Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502.Ann Oncol. 2015; 26: 2274-2280https://doi.org/10.1093/annonc/mdv358
- Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: final results of JCOG0205.Eur J Canc. 2014; 50: 2231-2240https://doi.org/10.1016/j.ejca.2014.05.025
- A prospective randomised phase III trial of adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer.Br J Canc. 2007; 97: 1021-1027https://doi.org/10.1038/sj.bjc.6604011
- Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial.Lancet Oncol. 2014; 15: 862-873https://doi.org/10.1016/S1470-2045(14)70227-X
- Capecitabine versus 5-fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results from the X-ACT trial with analysis by age and preliminary evidence of a pharmacodynamic marker of efficacy.Ann Oncol. 2012; 23: 1190-1197https://doi.org/10.1093/annonc/mdr366
- A phase III randomised trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802).Ann Oncol. 2009; 20: 674-680https://doi.org/10.1093/annonc/mdn680
- S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial).Ann Oncol. 2014; 25: 1743-1749https://doi.org/10.1093/annonc/mdu232
- Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses.J Clin Oncol. 2011; 29: 3768-3774https://doi.org/10.1200/JCO.2011.36.4539
Article info
Publication history
Published online: March 12, 2020
Accepted:
February 8,
2020
Received in revised form:
February 5,
2020
Received:
November 26,
2019
Identification
Copyright
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