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completion of induction treatment were excluded, as were the probably larger group of patients with a good prognosis in whom resection of metastases was either planned or likely to be achieved. Therefore, the study population of CAIRO3 is a subset of patients with metastatic colorectal cancer and cannot be directly compared with other trials. Finally, Hegewisch-Becker and colleagues mention that CAIRO3 does not have information about censoring of patients. However, all primary and secondary endpoints are clearly described in our Article,2 in which the censoring is defined. CJAP has served on advisory boards of Roche, Amgen, Bayer, and Nordic Pharma. MK has served on advisory boards of Roche, Amgen, and Bayer. LHJS and HvT declare no competing interests.
Lieke H J Simkens, Harm van Tinteren, Cornelis J A Punt, *Miriam Koopman
[email protected] Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands (LHJS, CJAP); Department of Biostatistics, The Netherlands Cancer Institute, Amsterdam, Netherlands (HvT); and Department of Medical Oncology, University Medical Center Utrecht, Utrecht 3584CX, Netherlands (MK) 1
2
Hegewisch-Becker S, Graeven U, Lerchenmüller CA, et al. Maintenance strategies after firstline oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol 2015; 16: 1355–69. Simkens LHJ, van Tinteren H, May A, et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 2015; 385: 1843–52.
We read with great interest the Article by Susanna Hegewisch-Becker and colleagues.1 The primary endpoint of this study was time to failure of strategy, using the original definition that was subsequently validated.2,3 Although we congratulate the authors on their study, we respectfully disagree with their conclusion that “Only a few patients were exposed to reinduction treatment, thus deeming the primary endpoint time to failure of strategy non-informative and
Progression-free survival
Time to second progression
Time to failure of strategy
Event
Event
Event
First progression, no subsequent therapy Event within 1 month
Event
Event
Death
First progression followed by reinduction Event
··
··
Second progression
NA*
Event
Event
New therapeutic drug (not included in the strategy)
Censored
Censored
Event
Cessation of treatment for limiting toxicity
··
··
Censored
NA=not applicable. *Progression-free survival ends with first progression.
Table: Comparison of events included in progression-free survival, time to second progression, and time to failure of strategy
clinically irrelevant”. We believe that the validity of an alternative endpoint cannot be established according to the compliance of a treatment strategy. What is the reason behind the low frequency of oxaliplatin reinduction? Reinduction of oxaliplatin can be precluded by residual severe and cumulative sensory neuropathy that follows exposure to oxaliplatin. The duration and total dose of oxaliplatin-based induction therapy was 24 weeks and 1020–1200 mg/m² in AIO 0207 (8–12 cycles, every 2 or 3 weeks, oxaliplatin 85–130 mg/m²),1 18 weeks and 780 mg/m² in CAIRO3 (six cycles, every 2 weeks, oxaliplatin 130 mg/m²),4 and 12 weeks and 600 mg/m² in OPTIMOX2 (six cycles, every 2 weeks, oxaliplatin 100 mg/m²).5 For patients who entered a maintenance phase or therapy-free interval, the proportion of patients who underwent reinduction was 36% in AIO 0207, 54% in CAIRO3, and 83% in OPTIMOX2. Therefore, reinduction frequency might be related to the length of induction therapy and the total dose of oxaliplatin received during the induction phase. Thus, oxaliplatin-based induction therapy should be limited to 12 weeks of FOLFOX as in the OPTIMOX1 study,6 where it was shown to have no detrimental effect on survival endpoints compared with continuing therapy. What is the alternative to using progression-free survival for the assessment of treatment strategy?
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The primary endpoints of CAIRO3 and AIO 0207 were based on the occurrence of a post-reinduction event (ie, time to second progression for CAIRO3 and time to failure of strategy for AIO 0207; table). Unlike progression-free survival, alternative endpoints—eg, time to failure of strategy and duration of disease control—enable an assessment of the therapeutic effect before and after first disease progression.3 Flexibility is a key advantage of these endpoints over progression-free survival. What is the appropriate method for the validation of surrogacy? A strong association between a potential surrogate and the endpoint of interest is mandatory, both for duration (median) and treatment effect (hazard ratios); this requires meta-analyses and dedicated modelling using individual patient data from many randomised trials. Moreover, the treatment should have a similar effect on each component of the composite endpoint. Hence, time to failure of strategy should not be regarded as an irrelevant endpoint: with a low frequency of reinduction, progression-free survival and time to failure of strategy results are still very different, showing that even with a poor compliance with the treatment strategy these endpoints do not capture the same clinical or treatment effect. We believe that although progression-free survival is the preferred endpoint to assess a new e583
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maintenance treatment regimen like in the DREAM trial,7 alternative endpoints, such as duration of disease control or time to failure of strategy, should be used to assess stop-and-go treatment strategies or multi-line therapy. BC has received honoraria for consultancy and an advisory role from Roche and Sanofi. FB has received research support from Roche and Novartis and honoraria from Roche Novartis, Merck, Integragen, Nestlé, and Celgene. CT has received research support from Roche, Sanofi, Merck, Amgen, and Bayer. AdG has received honoraria for speaker activities and participation in advisory boards from Roche and Sanofi-Aventis.
Benoist Chibaudel, Franck Bonnetain, Christophe Tournigand, *Aimery de Gramont
[email protected] Department of Medical Oncology, Institut Hospitalier Franco-Britannique, 92300 LevalloisPerret, France (BC, AdG); Methodology and Quality of Life Unit, Besançon, France (FC); and Henri Mondor Hospital, Assistance Publique—Hôpitaux de Paris, Paris-Est Créteil University, Créteil, France (CT) 1
2
3
4
5
6
7
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Hegewisch-Becker S, Graeven U, Lerchenmüller CA, et al. Maintenance strategies after first-line oxaliplatin plus fluoropyrimidine plus bevacizumab for patients with metastatic colorectal cancer (AIO 0207): a randomised, non-inferiority, open-label, phase 3 trial. Lancet Oncol 2015; 16: 1355–69. Allegra C, Blanke C, Buyse M, et al. End points in advanced colon cancer clinical trials: a review and proposal. J Clin Oncol 2007; 25: 3572–75. Chibaudel B, Bonnetain F, Shi Q, et al. Alternative end points to evaluate a therapeutic strategy in advanced colorectal cancer: evaluation of progression-free survival, duration of disease control, and time to failure of strategy—an Aide et Recherche en Cancerologie Digestive Group Study. J Clin Oncol 2011; 29: 4199–204. Simkens LHJ, van Tinteren H, May A, et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 2015; 385: 1843–52. Chibaudel B, Maindrault-Goebel F, Lledo G, et al. Can a planned treatment break be given to patients with unresectable metastatic colorectal cancer? Results of the GERCOR OPTIMOX 2 study. J Clin Oncol 2009; 27: 5727–33. Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer—a GERCOR study. J Clin Oncol 2006; 24: 394–400. Tournigand C, Chibaudel B, Samson B, et al. Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial. Lancet Oncol 2015; 16: 1493–505.
Authors’ reply Since the initiation of oxaliplatincontaining combination regimens more than a decade ago, an intense debate about treatment duration and maintenance treatment of metastatic colorectal cancer has been in progress. The debate continues because progression-free survival is often longer than the dosecumulative occurrence of neuropathy in this setting. The complex and controversial discussion represents the perspectives, preferences, and treatment philosophies of physicians and patients, and the technical aspects in the assessment of this newly defined period of maintenance treatment to determine the real benefit for the right population. We agree with Benoist Chibaudel and colleagues that time to failure of strategy can remain a valuable endpoint for clinical trials. Their hypothesis that the high cumulative oxaliplatin dose as a result of a 24-week induction period could negatively affect the value of the endpoint is valid. Nevertheless, we would like to emphasise that in our study1 and in CAIRO3,2 lower rates of reinduction treatments given in the active treatment maintenance group (fluoropyrimidine plus bevacizumab) versus the observation group (47% vs 60% of patients in CAIRO3 and 19% vs 46% in AIO 0207) are seen— independent of the different duration of induction treatment in both trials (18 weeks in CAIRO3 and 24 weeks in AIO 0207)—and therefore seemingly are independent of the total dose of oxaliplatin. The probability of reinduction is thus not only driven by duration of induction therapy, but also by treatment intensity during the maintenance phase. Generally, the low frequency of immediate reinduction after first progression chosen by both physicians and patients—despite reinduction being part of the study protocol in both trials—questions the approach and therefore limits the endpoint.
With new maintenance strategies being developed, including biomarker-driven approaches, allowing enough time for a response (including an immune response) to develop might become increasingly important when measuring the extent of response as a result of induction therapy. In this regard, a 12-week induction period (as used in OPTIMOX2) 3 might not prove sufficiently effective. We believe that time to failure of strategy as an endpoint should be explored in clinical trials testing irinotecan combined with either bevacizumab or anti-EGFR antibodies, thus eliminating cumulative neuropathy as an issue. Lieke Simkens and colleagues are correct in pointing out that the CAIRO3 study population is highly selected and does not allow for direct comparisons with other maintenance trials. We agree that outcomes are affected by both patient characteristics before inclusion into induction treatment and the results of inductions treatments. CAIRO3 deliberately refrained from registering patients for the trial before starting induction therapy, since patients were excluded if they had any toxic effects during induction, and it is not stated in the CAIRO3 publication how many patients were screened for suitability to be randomly assigned. To represent treatment reality, and since we wanted to refrain from creating an artificial study population, AIO 0207 and the GERCOR-DREAM trial4 registered all patients before starting the induction treatment. 365 (44%) of 837 registered patients in AIO 0207 and 248 (35%) of 700 in GERCOR DREAM were not randomly assigned to a group. Of those, only 44 (12%; AIO 0207) and 51 (21%; GERCOR DREAM) had surgery after induction. Thus, the data from these two trials clearly do not support the assumption that the larger group of the non-randomised patients were good prognosis patients. Instead, most patients were not randomly assigned
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