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- A. Sobrero
- A. Cervantes
Introduction (ID 5910)
- A. Sobrero
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 (ID 4129)
- T. Iveson
Abstract
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.
LBA23 - FOLFOX4/XELOX in stage II–III colon cancer: Efficacy and safety results of the Italian Three Or Six Colon Adjuvant (TOSCA) trial (ID 4415)
- R. Labianca
Abstract
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
NCT00646607
Legal entity responsible for the study
GISCAD Fundation
Funding
Supported by a grant from AIFA (Agenzia Italiana del Farmaco) Grant Code FARM5RWTWZ.
Disclosure
All authors have declared no conflicts of interest.
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 (ID 4138)
- T. Yoshino
Abstract
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.
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.
473O - Three versus six months’ adjuvant oxaliplatin-based chemotherapy for patients with stage III colon cancer: Per-protocol, subgroups and long-lasting neuropathy results (ID 1584)
- J. Taieb
Abstract
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.
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) (ID 3783)
- A. Grothey
Abstract
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, 2nd 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.
Discussion by the clinician (ID 5918)
- T. Maughan
Discussion by the statistician (ID 5919)
- M. Buyse
Moderated panel discussion on clinical conditions and Q&A (ID 5921)
- A. Cervantes
- J. Meyerhardt
- A. Shields
- A. Sobrero
- I. Souglakos