Debate on Duration of Colon Cancer Adjuvant Chemotherapy Takes Centre Stage at ESMO 2017

LUGANO-MADRID – The debate on whether to shorten adjuvant chemotherapy for colon cancer from six to three months takes centre stage today in a special session at the ESMO 2017 Congress in Madrid. (1)

Is three months of chemotherapy enough in the adjuvant treatment of colon cancer? This is the main controversy in this debate, according to ESMO spokesperson Professor Alberto Sobrero, Head of the Medical Oncology Unit at Ospedale San Martino in Genova, Italy, co-chair of the Special Session and Scientific Co-Chair of the Congress. He said: “This debate is a practice changing one and the session will give much more clarity on how clinicians should now treat their patients.”

Six months of oxaliplatin-based chemotherapy has been the standard adjuvant therapy for stage III colon cancer since 2004. However, the neurotoxicity of oxaliplatin sparked research into whether three months of therapy provided the same benefit but with reduced side effects.

Six randomised phase III trials have been conducted worldwide comparing three versus six months of chemotherapy with FOLFOX or CAPOX. The IDEA study was a pooled analysis of the 12,834 patients enrolled in the six trials. It showed that six months gave less than 1% added benefit over three months when all patients and both types of chemotherapy were included in the analysis.

Investigators of the four most mature trials (SCOT, TOSCA, ACHIEVE, IDEA-FRANCE) will present their results during the congress session. Expert interpretation will be given by a clinician and a statistician. Gastrointestinal cancer specialist Professor Andrés Cervantes, Chair of the ESMO Educational Committee, member of the ESMO Guidelines Committee and session co-chair, will discuss how the latest data in this debate will practically impact the ESMO Clinical Practice Guidelines on Early Colon Cancer, which are set to be updated in 2018. Members of the panel will be asked to vote for three or six months of treatment in a variety of clinical scenarios.

Distinguished panel for the Special Session:

• Andrés Cervantes, session co-chair and Chair of ESMO Educational Committee. Medical Oncology Department, INCLIVA University of Valencia, Valencia, Spain.+*
• Alberto Sobrero, session and ESMO 2017 congress co-chair. Medical Oncology Unit, IRCCS San Martino, Genova, Italy.*
• Marc Buyse, Associate Professor of Biostatistics, Universiteit Hasselt, Belgium and Associate Editor, Annals of Oncology (Statistics).
• Axel Grothey, Division of Medical Oncology, Mayo Clinic, Rochester, MN, US.*
• Timothy Iveson, Department of Medical Oncology, University Hospital Southampton, Southampton, UK.
• Roberto Labianca, Cancer Centre, Ospedale Giovanni XXIII, Bergamo, Italy.+*
• Tim Maughan, Oxford Institute for Radiation Oncology, Professor of Clinical Oncology, University of Oxford, Oxford, UK.*
• Jeffrey A. Meyerhardt, Clinical Director, Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, US.
• Anthony F. Shields, Professor of Medicine and Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, US.
• Ioannis Souglakos, Assistant Professor of Medical Oncology, Medical School, University of Crete, Medical Oncologist, University Hospital of Heraklion, Greece.
• Julien Taieb, Head of the Gastroenterology and GI Oncology Department, Georges Pompidou European Hospital, Paris Descartes University, France.*
• Takayuki Yoshino, National Cancer Centre Hospital East in Chiba, Japan.*

“The common sense conclusion from the IDEA study is that it’s not worth going through the toxicity and inconvenience of six months to gain less than 1% efficacy,” said Sobrero. “Especially considering that the toxicity is cut by at least 50% with the three month regimen.”

“Statistically, three months of treatment was slightly inferior to six months in the overall study population of stage III patients,” added ESMO spokesperson Professor Eric Van Cutsem, main author of the ESMO consensus guidelines for the management of patients with metastatic colorectal cancer, Head of Digestive Oncology, University Hospitals Leuven, Belgium. “However, the clinical conclusion, given the reduction in neurotoxicity with a shorter duration of treatment, was that three months is almost identical to six months.”

Two additional analyses revealed unexpected findings. First, for high risk stage III patients (N2 or T4) the difference in efficacy widens in favour of six months. Second, the results differ according to the type of chemotherapy. CAPOX is equally effective at three or six months, independently of the patient’s level of risk. Six months of FOLFOX is more effective than three months.

Sobrero said: “While overall there are minor differences in efficacy between three and six months, high risk patients should receive six months of chemotherapy and CAPOX should be preferred over FOLFOX.”

“In low risk patients the difference was so minor that the clinical conclusion is that three months of oxaliplatin-based chemotherapy is as good as six months,” said Van Cutsem. “Although statistically the difference is small, this makes a huge clinical difference to patients with the reduction in neurotoxicity.”

Regarding the standard of care for adjuvant chemotherapy in stage III colon cancer, Van Cutsem said: “In high risk patients six months remains the standard, but in low risk patients three months should become the new standard duration of treatment.”

Van Cutsem confirmed that this is the strategy he uses with his stage III colon cancer patients. He said: “In high risk stage III patients we give six months of FOLFOX – unless the patient has neurotoxicity, in which case we stop oxaliplatin but continue with 5FU for a total duration of six months. In patients with low risk tumours, we give three months of FOLFOX.”

Sobrero said most patients prefer the three month option which gives much lower toxicity for very little loss in efficacy. He said: “Every now and then I see a patient who does not want to lose even 1% of efficacy and wants six months of chemotherapy. This is just one of the fascinating aspects of implementing the data from the IDEA study. We will thoroughly debate the issues and give clear conclusions during this session, which is set to be packed with health professionals who face patients with this serious disease everyday and desperately want better treatments.”

-END-

Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO 2017 Congress

+Co-author of ESMO Clinical Practice Guidelines on Early Colon Cancer.

*Co-author of ESMO Consensus Guidelines for the Management of Patients with Metastatic Colorectal Cancer.

References

1. The following abstracts will be presented during Special Session ‘When clinical practice demands to go beyond statistics: Adjuvant chemotherapy of colon cancer. The 3 vs 6 month story’ on Monday, 11 September 2017, 14:45 to 16:15 (CEST) in Madrid Auditorium.

• LBA21_PR ‘Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): Updated results of IDEA (International Duration Evaluation of Adjuvant chemotherapy)‘ will be presented by Axel Grothey.
• LBA22 ‘Updated results of the SCOT study: An International Phase III Randomised (1:1) Non-inferiority Trial Comparing 3 versus 6 months of oxaliplatin based adjuvant chemotherapy for colorectal cancer’ will be presented by Timothy Iveson.
• LBA23 ‘FOLFOX4/XELOX in stage II–III colon cancer: efficacy and safety results of the Italian Three Or Six Colon Adjuvant (TOSCA) trial’ will be presented by Roberto Labianca.
• LBA24 ‘Efficacy of 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy for Stage III colon cancer (CC): Results from phase III ACHIEVE trial as part of the International Duration Evaluation of Adjuvant therapy (IDEA) Collaboration’ will be presented by Takayuki Yoshino.
• 473O ‘Three versus six months adjuvant oxaliplatin-based chemotherapy for patients with stage III colon cancer: per-protocol, subgroups and long-lasting neuropathy results’ will be presented by Julien Taieb.

Disclaimer

Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct .

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Abstract LBA21_PR

Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): Updated results of IDEA (International Duration Evaluation of Adjuvant chemotherapy)

A. Grothey¹, A. Sobrero², J.A. Meyerhardt³, T. Yoshino⁴, J. Paul⁵, J. Taieb⁶, I. Souglakos⁷, R. Kerr⁸, R. Labianca⁹, A.F. Shields¹⁰, F. Bonnetain¹¹, T. Yamanaka¹², I. Boukovinas¹³, Q. Shi¹⁴, J.P. Meyers¹⁴, D. Niedzwiecki¹⁵, V. Torri¹⁶, D.J. Sargent¹⁴, T. André¹⁷, T. Iveson^18
1Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA, ²Medical Oncology Unit, IRCCS San Martino, Genova, Italy, ³Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, ⁴Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan, ⁵Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK, ⁶Gastroenterology and digestive oncology, Hôpital européen Georges-Pompidou , Sorbonne Paris Cité Université Paris Descartes, Paris, France, ⁷Dept of Medical Oncology, University Hospital of Heraklion (PAGNI), Heraklion, Greece, ⁸Dept of Oncology, Churchill Hospital University of Oxford, Oxford, UK, ⁹Dept of Oncology, Ospedale Papa Giovanni XXIII, Bergamo, Italy, ¹⁰Dept of Oncology, Karmanos Cancer Institute, Detroit, USA, ¹¹Methodological and Quality of Life Unit in Oncology (INSERM UMR 1098), University Hospital Jean Minjoz, Besançon, France, ¹²Medical Course Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan, ¹³Medical Oncology Unit, Bioclinic Thessaloniki, Thessaloniki, Greece, ¹⁴Dept of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA, ¹⁵Department of Biostatistics and Bioinformatics, Duke University,, Durham, NC, USA, ¹⁶Dept of Oncology, IRRCS Mario Negri Institute for Pharmacological Research, Milan, Italy, ¹⁷Medical Oncology, Hopital Saint Antoine, Paris, France, ¹⁸Dept of Medical Oncology, University Hospital Southampton, Southampton, UK

Background: Since 2004, 6 months (m) of oxaliplatin (oxali)-based treatment has been the standard of care as adjuv therapy for stage III CC. As oxali is associated with cumulative neurotoxicity, a shorter duration of adjuv therapy could spare pts toxicity and lead to substantial saving in health expenditures.

Methods: A prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase 3 trials (SCOT, TOSCA, Alliance/SWOG 80702, IDEA France, ACHIEVE, HORG) was performed to evaluate the non-inferiority (NI) of 3m compared with 6m (ref) of adj FOLFOX/CAPOX. The primary endpoint was disease-free survival (DFS), defined as time from enrolment to relapse, 2^nd CRC, and death (all causes). NI was to be declared if the 2-sided 95% confidence interval (CI) for DFS Hazard Ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.12. NI was examined within regimen and stage subgroups as pre-planned.

Results: The analysis included 12,834 pts from 12 countries, accrued 6/07-12/15. After 3263 (of 3390 expected) DFS events NI for the shorter duration of therapy could not be confirmed for the overall study population (HR 1.07, 95%CI 1.00-1.15). NI of 3m v 6m was seen for CAPOX (HR 0.95, 95%CI 0.85-1.06; whereas 3m of FOLFOX was inferior to 6m (HR 1.16, 95%CI 1.06-1.26). Pts treated with CAPOX (vs FOLFOX) had a higher rate of T4 CC (24.3% vs 18.6%, p<0.001), but no significant differences were seen in N-stage, gender, or number of LNs examined. Significant differences were seen in age and PS (1/2), albeit small. The overall NI results were independent of age (<70, ≥70) and gender.

Conclusions: The IDEA results provide the basis for individual adjustments of adj treatment duration based on risk of recurrence, pt preference, toxicity and the chemotherapy regimen used. Further analyses are warranted to explain the different performance of CAPOX and FOLFOX with regard to the NI question.

Clinical trial identification: NCT00749450 (SCOT); NCT00646607 (TOSCA); NCT01150045 (CALGB/SWOG 80702); NCT00958737 (IDEA France); NCT01308086 (HORG); UMIN-CTR Clinical Trial Identifier: UMIN000008543 (ACHIEVE)

Legal entity responsible for the study: Mayo Clinic

Funding: Mayo Clinic, U10CA180821, U10CA180835, U10CA180882, U10CA180888, U10CA180835, INCA, PHRC2009, EME 09/800/34, HTA 14/140/84, CRUK C1348/A15960, JFMC

Disclosure: All authors have declared no conflicts of interest.

Keywords: colon cancer, adjuvant therapy, oxaliplatin

Abstract LBA22

Updated results of the SCOT study: An International Phase III Randomised (1:1) Non-inferiority Trial Comparing 3 versus 6 months of oxaliplatin based adjuvant chemotherapy for colorectal cancer

T. Iveson¹, R. Kerr², M. Saunders³, N. Hollander⁴, J. Tabernero⁵, A. Haydon⁶, B. Glimelius⁷, A. Harkin⁸, C. Scudder⁹, K. Boyd⁸, A. Waterston¹⁰, L. Medley¹¹, C. Wilson¹², R. Ellis¹³, S. Essapen¹⁴, A. Dhadda¹⁵, M. Harrison¹⁶, S. Falk¹⁷, S. Abdel-Raouf¹⁸, J. Paul^19
1Dept of Medical Oncology, University Hospital Southampton, Southampton, UK, ²Oncology, Churchill Hospital University of Oxford, Oxford, UK, ³Oncology, The Christie NHS Foundation Trust, Manchester, UK, ⁴Oncology, Sygehus Syd Naestved, Naestved, Denmark, ⁵Medical Oncology, Vall d’Hebrón Institut d’Oncologia (VHIO), Barcelona, Spain, ⁶Medical Oncology, Alfred Health, Melbourne, Australia, ⁷Immunology, Genetics and Pathology, University Hospital, Uppsala, Sweden, ⁸CRUK CTU, University of Glasgow, Glasgow, UK, ⁹Oncology, University of Oxford, Oxford, UK, ¹⁰Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, UK, ¹¹Oncology, Dr. Louise Medley, London, UK, ¹²Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge, UK, ¹³Oncology, Royal Cornwall Hospital, Truro, UK, ¹⁴Oncology, Royal Surrey County Hospital St Luke's Cancer Centre, Guildford, UK, ¹⁵Oncology, Castle Hill Hospital, Cottingham, UK, ¹⁶Oncology, Mount Vernon Hospital, Middlesex, UK, ¹⁷Oncology, Bristol Haematology and Oncology Centre, Bristol, UK, ¹⁸Oncology, Queen's Hospital, Essex, UK, ¹⁹Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

Background: Results presented at ASCO 2017 gave conflicting results as to whether 3 months adjuvant chemotherapy was non-inferior to 6 months treatment. The effect of treatment duration on DFS appeared to depend on the chemotherapy regimen (Capox or FOLFOX) chosen and on risk group (high-risk [T4 or N2] vs low-risk [T1-3 N1]) stage lll disease.

Methods: SCOT is a non-inferiority randomised study designed to determine whether 3 months of adjuvant chemotherapy with FOLFOX or Capox (physician/patient choice) in Stage lll/high risk Stage ll colorectal cancer is as effective as 6 months treatment. Non-inferiority was determined to be a maximum 2.5% fall in 3-year disease-free survival (DFS) on the 3 month arm (from 78% on the 6 month arm). The study was designed with 90% power at the 2.5% L-sided level of statistical significance and aimed to recruit 9500 patients to observe 2,750 DFS events (relapses/deaths/new colorectal cancers).

Results: 6088 patients with Stage lll/high risk Stage ll cancers of the colon or rectum were randomised between 27th March 2008 and 29th November 2013. 1981 patients received FOLFOX and 4107 received Capox. For 3 year DFS there were 1482 events (740 in the 3 month arm and 742 in the 6 month arm). 3 year DFS was 76.7% for the 3 month arm and 77.1% for the 6 month arm (HR 1.008, for non-inferiority p=0.014). Non-inferiority was stronger for Capox than FOLFOX but the choice of regimen was not randomised. Further analysis looking at dose intensity of chemotherapy received and the effect of age and gender will be presented.

Conclusions: The updated SCOT results will allow further insight into treatment decisions for the duration of adjuvant therapy of colorectal cancer with regard to adjuvant chemotherapy regimen used and the risk of recurrence.

Clinical trial identification: Eudract Ref: 2007-003957-10; ISRCTN No: 23516549

Legal entity responsible for the study: NHS Greater Glasgow & Clyde and University of Glasgow

Funding: Medical Research Council (transferred to NETSCC - Efficacy and Mechanism Evaluation) (Grant Ref:G060170 and Cancer Research UK Core CTU Funding (Funding Ref:C6716/A9894

Disclosure: T. Iveson: Honoraria from Lilly Advisory Role for Servier, Celgene, Roche Travel and Accommodation from Servier, Roche, Bayer
 All other authors have declared no conflicts of interest.

Keywords: colon cancer, adjuvant chemotherapy

Abstract LBA23

FOLFOX4/XELOX in stage II–III colon cancer: efficacy and safety results of the Italian Three Or Six Colon Adjuvant (TOSCA) trial

R. Labianca¹, S. Lonardi², G. Rosati³, M. Di Bartolomeo⁴, M. Ronzoni⁵, N. Pella⁶, M. Scartozzi⁷, M. Banzi⁸, M.G. Zampino⁹, F. Pasini¹⁰, P. Marchetti¹¹, M. Cantore¹², A. Zaniboni¹³, L. Rimassa¹⁴, L. Ciuffreda¹⁵, S. Barni¹⁶, V. Zagonel¹⁷, E. Maiello¹⁸, E. Rulli¹⁹, A. Sobrero^20
1Medical Oncology Unit, ASST Papa Giovanni XXIII, Bergamo, Italy, ²Medical Oncology, Istituto Oncologico Veneto IRCCS, Padova, Italy, ³Medical Oncology Unit, Azienda ospedaliera Regionale S. Carlo di Potenza, Potenza, Italy, ⁴Department of Medical Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, Italy, ⁵Medical Oncology Unit, IRCCS San Raffaele, Milan, Italy, ⁶Medical Oncology Unit, AOU Santa Maria della Misericordia, Udine, Italy, ⁷Medical Oncology, University of Cagliari, University Hospital, Cagliari, Italy, ⁸Medical Oncology Unit, Azienda Ospedaliera Arcispedale Santa Maria Nuova - IRCCS, Reggio Emilia, Italy, ⁹Gastrointestinal Medical Oncology Unit, Istituto Europeo di Oncologia, Milan, Italy, ¹⁰Medical Oncology Unit, Ospedale S. Maria della Misericordia Azienda Sanitaria Local 18 Rovigo, Rovigo, Italy, ¹¹Medical Oncology, Azienda Ospedaliera St. Andrea, Roma, Italy, ¹²Medical Oncology Unit, Civic Hospital, Carrara, Italy, ¹³Oncology Unit, Fondazione Poliambulanza, Brescia, Italy, ¹⁴Medical Oncology and Hematology Unit, Istituto Clinico Humanitas, Rozzano, Italy, ¹⁵Oncology, Città della salute e della Scienza di Torino, Torino, Italy, ¹⁶Medical Oncology Unit, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio, Italy, ¹⁷Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology, Padua, Italy, ¹⁸Oncologia, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, ¹⁹Laboratory Clinical Research, IRFMN Milano, Milano, Italy, ²⁰Medical Oncology Unit, IRCCS San Martino, Genova, Italy

Background: Among the 6 randomized comparisons between 6 months and 3 months of adjuvant FOLFOX/XELOX for early stages colon cancer of the IDEA collaboration (International Duration Evaluation of Adjuvant), TOSCA was the first to start and the first to close the accrual, has already published the compliance and toxicity data (Annals of Oncology, 2016) and has now the most mature follow-up.

Methods: TOSCA is an open-label, phase III, multicenter, non-inferiority trial randomizing patients with
high-risk stage II or III radically resected colon cancer to receive 3 months versus 6 months of
FOLFOX4/XELOX (regimen at physician's choice). Primary end-point is relapse-free survival (RFS).

Results: From June 2007 to March 2013, 3759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX4 and 36% XELOX in either arm. Two thirds were stage III. At the cut-off time for analysis the median time of follow-up was 62 months and 772 relapses or deaths have been observed. At 8 years the RFS rate is 75% and OS rate 80%. This analysis was done when 82% of the planned number of events was reached, with a power of 72% instead of 80%: the decision to anticipate the analysis was based on the participation to the IDEA joint collaborative analysis of studies sharing this clinical question. The Hazard Ratio of the 3 months vs 6 months for relapse/death was 1.14 (95%CI 0.99-1.31, p for non inferiority = 0.506) and the confidence interval crossed the non inferiority limit of 1.20. Counterintuitively, while RFS curves were very similar for stage III and for XELOX treated patients, they were not for stage II and for FOLFOX treated patients (HR: 1.41 and 1.23, respectively, in favour of 6 m). The HR for OS was 1.07 (95% CI 0.89-1.29, p for non-inferiority=0.249).

Conclusions: TOSCA was not able to demonstrate that 3 months of oxaliplatin-based adjuvant treatment is as efficacious as 6 months. Nevertheless, because the absolute difference in RFS between the two treatment durations is small ( less than 2 % at 5 years ) and clinically not meaningful, the decision to complete the whole 6-month program should be individualized based on toxicity and patient attitude.

Clinical trial identification: This study is registered with ClinicalTrials.gov Registration Number: NCT00646607

Legal entity responsible for the study: GISCAD Fundation

Funding: It was supported by a grant from AIFA (Agenzia Italiana del Farmaco) Grant Code FARM5RWTWZ.

Disclosure: All authors have declared no conflicts of interest.

Keywords: Safety and efficacy, three or six months FOLFOX4/XELOX, colon cancer

Abstract LBA24

Efficacy of 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy for Stage III colon cancer (CC): Results from phase III ACHIEVE trial as part of the International Duration Evaluation of Adjuvant therapy (IDEA) Collaboration

T. Yoshino¹, T. Yamanaka², M. Kotaka³, D. MANAKA⁴, T. Eto⁵, J. Hasegawa⁶, A. Takagane⁷, M. Nakamura⁸, T. Kato⁹, Y. Munemoto¹⁰, F. Nakamura¹¹, H. Bando¹², H. Taniguchi¹³, M. Gamoh¹⁴, M. Shiozawa¹⁵, J. Sakamoto¹⁶, S. Saji¹⁷, T. Mizushima¹⁸, A. Ohtsu¹, M. Mori^18
1Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan, ²Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan, ³Gastrointestinal Cancer Center, Sano Hospital, Kobe, Japan, ⁴Department of Surgery, Gastrointestinal Center, Kyoto-Katsura Hospital, Kyoto, Japan, ⁵Department of Gastroenterology, Tsuchiura Kyodo General Hospital, Tsuchiura, Japan, ⁶Department of Surgery, Osaka Rosai Hospital, Saki, Japan, ⁷Department of Surgery, Hakodate Goryoukaku Hospital, Hakodate, Japan, ⁸Aizawa comprehensive cancer center, Aizawa Hospital, Matsumoto, Japan, ⁹Gastrointestinal Surgery, Kansai Rosai Hospital, Amagasaki, Japan, ¹⁰Department of Surgery, Fukui Saiseikai Hospital, Fukui, Japan, ¹¹Department of Surgery, Teine Keijinkai Hospital, Sapporo, Japan, ¹²Gastroenterological Surgery, Ishikawa Prefectural Central Hospital, Kanazawa, Japan, ¹³Department of Surgery, Kyoto Second Red Cross Hospital, Kyoto, Japan, ¹⁴Medical Oncology, Osaki Citizen Hospital, Osaki, Japan, ¹⁵Gastrointestinal Surgery, Kanagawa Cancer Center, Kanagawa, Japan, ¹⁶Chairperson of the Institutional Review Board, Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo, Japan, ¹⁷Chairman, Japanese Foundation for Multidisciplinary Treatment of Cancer, Tokyo, Japan, ¹⁸Department of Surgery, Osaka University Graduate School of Medicine, Suita, Japan

Background: Results of the IDEA project, a prospective preplanned pooled analysis of 6 concurrently conducted randomized phase III trials, were presented at ASCO 2017. ACHIEVE was one of the 6 trials which compared 3 months (3m) duration with 6 months (6m) duration of oxaliplatin-based adjuvant chemotherapy.

Methods: ACHIEVE was an open-label, multicenter trial randomizing patients with stage III colon cancer to receive 3m or 6m of mFOLFOX6/CAPOX after surgery. Choice of regimen was declared before randomization by a site investigator. Primary endpoint was disease-free survival (DFS).

Results: Between August 2012 and June 2014, 1313 patients from Japan were randomized and, of those, 1291 patients were analyzed for analysis. Median age was 66 years; stage distribution was 15% T1-2, 57% T3, and 28% T4 and 26% N2; the highest proportion of patients with CAPOX (75%) among the 6 IDEA trials was included. The frequency of grade 2 or higher neurotoxicity was significantly lower in arm 3m than in arm 6m (14% vs 36%, p<0.001), and the same held for that of grade 3 or higher neurotoxicity (1% vs 6%, p<0.001). As of June 2017, a total of 291 (23%) DFS events were observed with a median follow-up of 39.0m. Overall, the 3-year DFS rate was 79.5% for 3m and 77.9% for 6m, with a hazard ratio (HR) of 0.954 (95%CI, 0.758-1.201). Subgroup analyses revealed that HR was 0.811 (0.532-1.236) for low risk (T1-3 and N1) and 1.066 (0.810-1.403) for high-risk (T4 or N2), whereas HR was 1.065 (0.709-1.600) and 0.904 (0.684-1.195) in patients with FOLFOX and CAPOX, respectively.

Conclusions: ACHIEVE was the only investigation in Asia among 6 trials and the results were placed into the context of the IDEA collaboration. Short duration significantly decreased neurotoxicity. It is notable that the efficacy results of overall analysis as well as those of subgroup analyses by risk group and study regimen in ACHIEVE were consistent with the results of IDEA. (UMIN Clinical Trial Identifier: UMIN000008543)

Clinical trial identification: UMIN 000008543

Legal entity responsible for the study: Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC)

Funding: Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC) under contract with Yakult Honsha

Disclosure: T. Yoshino: Research funding from GlaxoSmithKline K.K. and Boehringer Ingelheim GmbH.
T. Yamanaka: Honoraria from Chugai Pharmaceutical and Taiho Pharmaceutical
M. Kotaka: Honoraria from Chugai, Yakult, ,Merk serono, and Takeda
T. Kato: Honoraria from CHUGAI PHARMACEUTICAL CO., LTD,Takeda Pharmaceutical Company Limited, Eli Lilly and Company, Bayer Yakuhin, Ltd., Sanofi S.A., and Yakult Honsha Company, Limited
A. Ohtsu: Research funding from BMS
All other authors have declared no conflicts of interest.

Keywords: adjuvant treatment, oxaliplatin, phase 3 study, colon cancer

Abstract 473O

Three versus six months’ adjuvant oxaliplatin-based chemotherapy for patients with stage III colon cancer: Per-protocol, subgroups and long-lasting neuropathy results

Background: The International Duration Evaluation of Adjuvant chemotherapy (IDEA) collaboration was established to combine data from 6 randomized trials to assess whether 3-month (3M) of oxaliplatin/fluoropyrimidines-based adjuvant chemotherapy is non-inferior to 6-month (6M) for 3-year disease-free survival (DFS) in stage III colon cancer (CC).

Methods: IDEA France randomized patients (pts) between 3M and 6M of chemotherapy with mFOLFOX6 or XELOX (physician choice). DFS was estimated using the Kaplan–Meier method and described using a 3-year DFS rate with 95% confidence interval (CI). Cox-proportional-hazard models were performed to estimate the hazard ratios (HRs) and 95% CIs. We present here the results in the modified ITT (mITT: pts receiving at least one dose of treatment) and modified per-protocol (mPP: pts receiving 3M in the 3M arm and >5M in the 6M arm) populations. Subgroups and long lasting neuropathy results are also reported here.

Results: From May 2009 to May 2014, 2022 pts were randomized from 129 centers and 2010 (99%) and 1757 (87%) were included in the mITT and mPP populations, respectively. With a median follow-up of 4.3 years, the 3-year DFS rate was 72% and 76% (HR = 1.24; 95% CI 1.05–1.46, p = 0.01) for the 3M and 6M mITT populations, respectively and 72% and 78% (HR = 1.36; 95% CI 1.14–1.63, p = 0.0008) for the 3M and 6 M mPP populations. In the mITT FOLFOX treated population (90% of pts), 3-year DFS was 81% (3M) and 83% (6M) for T1-3/N1 pts (N = 1106, HR = 1.15 95%CI 0.89-1.49) and 58% (3M) and 66% (6M) for T4/N2 pts (N = 702, HR = 1.44 95%CI 1.14-1.82). Grade >1 neuropathy was observed in 36% and 67% of pts (p < 0.0001) in the 3M and 6M arms, respectively. With a median follow-up of 3.6 years, final residual grade >1 neuropathy was 2.8% and 7.4% (p < 0.0001), in the 3M and 6M arms, respectively.

Conclusions: The IDEA France study, with 90% of pts treated with mFOLFOX6, shows that 6M adjuvant treatment is superior to 3M. However, this difference was not significant in the mITT and mPP T1-3N1 populations suggesting that 3M of the mFOLFOX6 regimen could be an option for these pts. Clinically relevant (grade>1) neuropathy was significantly higher in the 6M arm, with long-lasting neuropathy in 7.4% of pts.

Clinical trial identification: Registration Number (European Union Drug Regulating Authorities Clinical Trials): 2009-010384-16

Legal entity responsible for the study: GERCOR - Groupe Coopérateur Multidisciplinaire en Oncologie

Funding: French Ministry of Health and French National Cancer Institute (INCa)

Disclosure: J. Taieb: Advisory board or Board of directors: Sanofi, Baxalta, Roche, Merck, Amgen, Lilly, Celgene. F. Bonnetain: Advisory board or Board of directors: Roche, Ipsen, Amgen, Nestle, Novartis; corporate-sponsored research: Novartis, Roche. L. Mineur: Advisory board or Board of directors: Amgen, Sanofi, Bayer, Roche; corporate-sponsored research: Sanofi, Merck, Chugai. J. Bennouna: Advisory board or Board of directors and honorarium: BMS, Roche, Boehringer Ingelheim, AstraZeneca. D. Vernerey: Honorarium: Janssen, Celgene. Advisory board: HallioDx. C. Lepere: Advisory board or Board of directors: Ipsen. O. Bouche: Advisory board or Board of directors: Merck Serono, Roche, Amgen. M. Ychou: Advisory board or Board of directors: Roche, Bayer, Amgen, Lilly. T. André: Advisory board or Board of directors: BMS, Amgen, Roche; corporate-sponsored research: BMS, Roche; honoraria: Baxter, Bayer, Lilly, MSD, Sanofi, Mundipharma, Novartis. All other authors have declared no conflicts of interest.