RE: Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial

JNCI: Journal of the National Cancer Institute, Oct 2017

Macbeth, Fergus, Farewell, Vern, Treasure, Tom

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RE: Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial

JNCI J Natl Cancer Inst ( RE: Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial Fergus Macbeth 0 1 Vern Farewell 0 1 Tom Treasure 0 1 0 The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions , please 1 Affiliations of authors: The Centre for Trials Research, Cardiff University , Cardiff , UK ( FM); MRC Biostatistics Unit, University of Cambridge , Cambridge , UK ( VF); Clinical Operational Research Unit, University College London , London, UK, TT - The CLOCC trial analysis reports a statistically significant overall survival benefit from radiofrequency ablation (RFA) treatment of liver metastases from colorectal cancer ( 1 ). There was no difference in overall survival at five years, and at nearly 10 years the conclusion relies on 11 patients at risk. We noted the asymmetry of the CONSORT diagram and were unable to reconcile it with the log-rank and Kaplan-Meier analyses. In the combined arm (CONSORT diagram left), nine patients were excluded as either “ineligible” or not receiving adjuvant chemotherapy, leaving 51 patients and 39 deaths. In the systemic treatment–alone arm, no patients were excluded, despite 10 patients being deemed “ineligible,” resected, or having a “major protocol violation,” giving 53 deaths out of a population of 59 patients (right). The Kaplan-Meier plot for overall survival is based on denominators of 60 and 59 (combined arm and systemic alone, respectively), suggesting an intention-to-treat analysis. However, if the deaths among the nine excluded patients were omitted, with the denominator of 60 retained, the two arms of the trial have been treated differently in the survival analysis, potentially creating a false impression of a survival benefit. The authors report a clear difference in the number of liver metastases, a major determinant of survival ( 2 ), in the two randomized arms. Nevertheless, their Supplementary Material reports identical estimated treatment effects (hazard ratio [HR] ¼ 0.62, 95% confidence interval [CI] ¼ 0.34 to 1.15 and 0.35 to 1.12) in the four or fewer and more than four metastases groups. In contrast, a simple analysis of survival proportions from data provided in Supplementary Figure 1 of the article ( 1 ) generates very different estimated odds ratio effects of 0.41 (95% CI ¼ 0.13 to 1.32; 63% vs 81% survival) and 0.07 (95% CI ¼ 0.008 to 0.59; 68% vs 97% survival) in the two groups, the latter being statistically significant at the 5% level. This suggests that the hazard ratios are not constant over time, and investigation of the time-varying effect of RFA is of interest. This would help to quantify the authors’ implicit claim that overall survival benefit is only apparent with long-term follow-up. The CLOCC trial report opens with, “Surgery is the gold standard of treatment in patients with resectable colorectal liver metastases” ( 1 ), but the authors of a recent systematic review and meta-analysis of treatment of advanced colorectal cancer praise oncologists for doing randomized trials of systemic treatments, but contrast this with the absence of controlled trials of metastasectomy ( 3 ). They also suggest that the longer survival due to randomized controlled trial–proven systemic treatments presents more opportunities for metastasectomy to be performed ( 3 ). It may be an example of reverse causation: the association between increased numbers of metastasectomies is the result, not the cause, of more long-term surviving patients. Policies of more intensive monitoring after primary resection have consistently brought forward the identification of metastases suitable for metastasectomy, but no survival benefit is seen in randomized controlled trials ( 4 ). CLOCC is a small randomized phase II trial that is already being taken as definitive evidence that treating colorectal cancer metastases confers survival benefit ( 5–7 ). This makes clarification of discrepancies in the arms of the trial, and a more detailed examination of the reported overall survival effect, urgently needed. 1. Ruers T , van Coevorden F , Punt CJ , et al. Local treatment of unresectable colorectal liver metastases: Results of a randomized phase II trial . J Natl Cancer Inst . 2017 ; 109 ( 9 ): djx015 . 2. Roberts KJ , White A , Cockbain A , et al. Performance of prognostic scores in predicting long-term outcome following resection of colorectal liver metastases . Br J Surg . 2014 ; 101 ( 7 ): 856 - 866 . 3. Jawed I , Wilkerson J , Prasad V , Duffy AG , Fojo T. Colorectal cancer survival gains and novel treatment regimens: A systematic review and analysis . JAMA Oncol . 2015 ; 1 ( 6 ): 787 - 795 . 4. Mokhles S , Macbeth F , Farewell V , et al. Meta-analysis of colorectal cancer follow-up after potentially curative resection . Br J Surg . 2016 ; 103 ( 10 ): 1259 - 1268 . 5. Helwick C . Thumbs up for radiofrequency ablation, jury still out for selective internal radiotherapy . The ASCO Post . 2017 . tember-10 -2015/colorectal-liver-metastases-thumbs-up-for-radiofrequency-ab lation-jury-still-out-for-selective-internal-radiotherapy/ . Accessed May 23 , 2017 . 6. Gilhams A . Colorectal cancer patient the challenge - local ablation in oligometastatic disease . European Conference on Interventional Oncology . 2017 . Accessed May 23, 2017 . 7. van Delden O. Colorectal cancer and IO: Where is the evidence? CLOCC trial in detail . European Conference on Interventional Oncology . 2017 . https://cirse. Accessed May 23, 2017 .

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Macbeth, Fergus, Farewell, Vern, Treasure, Tom. RE: Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial, JNCI: Journal of the National Cancer Institute, 2017, DOI: 10.1093/jnci/djx149