On 2015 Feb 05, Serge Evrard commented:

We have followed with interest the publication of interim results from the New EPOC trial Primrose J, 2014 and the controversies emerging around its conclusions (e.g. Nordlinger B, 2015 Primrose JN, 2014 and Hasegawa K, 2014). The unexpected result indicating shorter PFS with cetuximab, despite a higher rate of complete or partial response (70% versus 62% in the control arm) is so peculiar that a clear explanation needs to be found. The absence of residual tumor in 15% of the retrieved specimens in both arms also raises questions.

Based on findings regarding the efficacy of Cetuximab in the palliative setting, the add-on value of Cetuximab as a peri-operative adjunct to surgical treatment of colorectal liver metastases (CRLM) could be expected to be low when translated into PFS. In this context, it is clear that a small imbalance in the severity of disease across groups or in the modalities of the surgery may cancel or even inverse such a small expected improvement. A historical example of an adjuvant randomized trial that was biased by the surgery was the McDonald trial in gastric cancer where postoperative chemoradiotherapy was established as an adjuvant treatment to surgery when actually it was just necessary to make up for inadequate surgical choices. There are some possible concerns with the surgery in the New EPOC trial regarding the number of R1 resections and the use of ablation. R1 hepatectomy or use of ablation could result either from suboptimal practice in liver surgery or from lesions that are more difficult to treat. Especially intra-operative use of ablation is often used when resection cannot be done easily. Therefore, patients with more R1 margin resections and more ablation procedures might have suffered more advanced disease, which was the case for the cetuximab group.

For these reasons, we would like to call for an external audit of the patient-level data, following the increasingly-accepted principles of data transparency promoted by journals such as Plos One. Launched on an online platform initially by GlaxoSmithKline, public access to patient-level data from clinical trials is now a standard offered by many industry sponsors. As an academic trial funded by Cancer research UK, the new EPOC trial has no obligation to make patient-level data available for external audit. However, making this data available would allow validation, reanalysis and reinterpretation of these important results that potentially have a direct impact on patient care. Well-designed phase III trials are sufficiently rare in surgical oncology; the efforts of the study design committee should be lauded for their rigorous planning and carrying out of this large trial. It would be a pity for both the clinicians involved in this trial and the patients who participated, for the results to be discarded due to unsolved controversies during analysis and reporting.

Serge Evrard, Institut Bergonié, Bordeaux

René Adam, APHP Hôpital Paul Brousse, Villejuif

On 2015 Feb 05, Serge Evrard commented:

We have followed with interest the publication of interim results from the New EPOC trial Primrose J, 2014 and the controversies emerging around its conclusions (e.g. Nordlinger B, 2015 Primrose JN, 2014 and Hasegawa K, 2014). The unexpected result indicating shorter PFS with cetuximab, despite a higher rate of complete or partial response (70% versus 62% in the control arm) is so peculiar that a clear explanation needs to be found. The absence of residual tumor in 15% of the retrieved specimens in both arms also raises questions.

Based on findings regarding the efficacy of Cetuximab in the palliative setting, the add-on value of Cetuximab as a peri-operative adjunct to surgical treatment of colorectal liver metastases (CRLM) could be expected to be low when translated into PFS. In this context, it is clear that a small imbalance in the severity of disease across groups or in the modalities of the surgery may cancel or even inverse such a small expected improvement. A historical example of an adjuvant randomized trial that was biased by the surgery was the McDonald trial in gastric cancer where postoperative chemoradiotherapy was established as an adjuvant treatment to surgery when actually it was just necessary to make up for inadequate surgical choices. There are some possible concerns with the surgery in the New EPOC trial regarding the number of R1 resections and the use of ablation. R1 hepatectomy or use of ablation could result either from suboptimal practice in liver surgery or from lesions that are more difficult to treat. Especially intra-operative use of ablation is often used when resection cannot be done easily. Therefore, patients with more R1 margin resections and more ablation procedures might have suffered more advanced disease, which was the case for the cetuximab group.

For these reasons, we would like to call for an external audit of the patient-level data, following the increasingly-accepted principles of data transparency promoted by journals such as Plos One. Launched on an online platform initially by GlaxoSmithKline, public access to patient-level data from clinical trials is now a standard offered by many industry sponsors. As an academic trial funded by Cancer research UK, the new EPOC trial has no obligation to make patient-level data available for external audit. However, making this data available would allow validation, reanalysis and reinterpretation of these important results that potentially have a direct impact on patient care. Well-designed phase III trials are sufficiently rare in surgical oncology; the efforts of the study design committee should be lauded for their rigorous planning and carrying out of this large trial. It would be a pity for both the clinicians involved in this trial and the patients who participated, for the results to be discarded due to unsolved controversies during analysis and reporting.

Serge Evrard, Institut Bergonié, Bordeaux

René Adam, APHP Hôpital Paul Brousse, Villejuif