Systemic cytotoxic and biologic therapies for colorectal cancer liver metastases: expert consensus statement

The past 10 to 15 years have seen a great deal of excitement in the field of metastatic colorectal cancer and, in particular, in the management of hepatic metastases. In addition to ongoing improvements in perioperative management, ablative therapies and imaging techniques, the introduction of new cytotoxic and targeted systemic therapies has created wider treatment opportunities. With the improved outcomes of systemic chemotherapy come additional complexities that are yet to be fully resolved (and probably will not be as the field continues to evolve). The most relevant questions in the current environment refer to the value and appropriate timing of adjunctive systemic therapies in conjunction with hepatectomy, and to strategies to optimize the outcomes of systemic therapies in patients with advanced unresectable disease. The potential impact of these therapies on the histology and function of the liver in patients who may be candidates for partial hepatectomy should be carefully considered and understood. The nature and complexities of these issues require close collaboration among hepatic surgeons and medical oncologists, as well as other members of the global treatment team, including radiation oncologists and general and colorectal surgeons. In this issue of HPB, Schwarz et al.1 present readers with an important summary of a consensus conference session that aimed to clarify the roles of systemic therapies in patients with, respectively, unresectable and resectable hepatic metastases. Specific questions addressed by the panel referred to the value of adjuvant peri-hepatectomy therapy, the optimization of cytotoxic therapies, the roles of targeted therapies, and the potential hepatotoxicities of these therapies. This session appropriately brought together surgeons, medical oncologists and pathologists, all of whom contributed to the construction of the consensus statement. Prior to discussing specific scenarios, it should be emphasized that one of the most fundamental principles in selecting the optimal type and sequence of therapies is that the goals of treatment must be clearly established. For example, it should be determined beforehand whether the disease in the liver is considered resectable or may be rendered so by successful therapy, or whether it is never going to be operable for possible cure. The terminology used should also be clarified because the terms ‘preoperative’, ‘perioperative’ and ‘postoperative’ all mean different things and should not be used interchangeably. For patients with resectable disease, the authors of the consensus statement declare that perioperative FOLFOX [folinic acid (leucovorin), fluorouracil (5-FU), oxaliplatin] (i.e. delivered pre- and post-hepatectomy) should be regarded as the reference treatment as findings in previous adjuvant trials of postoperative chemotherapy did not show differences in outcomes of statistical significance. For many within the field, this is likely to be contentious because the European Organization for Research and Treatment of Cancer (EORTC) 40983 trial, reported by Nordlinger and colleagues,2 showed negative outcomes from an intent-to-treat perspective (in enrolled patients) in that it demonstrated an increase in post-hepatectomy morbidity in patients receiving pre-hepatectomy chemotherapy. At the consensus conference, Dr Nordlinger presented data from a more recent analysis of EORTC 40983, demonstrating significance from an intent-to-treat perspective. It should be noted that this trial does not resolve the issue of whether peri- or postoperative chemotherapy is more effective, but only compares perioperative treatment with none. Therefore, even if this updated experience is disseminated in a peer-reviewed manner, some individuals will continue to regard post-hepatectomy systemic approaches as generally equivalent in easily resectable patients in whom tumour shrinkage is not deemed beneficial. In recognition of these issues, the consensus statement is supportive of postoperative systemic therapy when pre-hepatectomy chemotherapy has been omitted, but recognizes that Level I evidence for this approach does not exist. As prognostic factors for early recurrence and progression, the prior administration of adjuvant chemotherapy following initial tumour resection and a short lead time to the development of metachronous colorectal liver metastasis will need to be weighed in this decision. Based on outcomes of using FOLFIRI [folinic acid (leucovorin), 5-FU, irinotecan] as an adjuvant for primary colorectal cancer3 and in the context of a randomized trial comparing the use of adjuvant FOLFIRI with that of 5-FU in post-hepatectomy patients with metastatic disease who failed to demonstrate a benefit,4 the authors of the consensus statement do not recommend FOLFIRI. The proper role of targeted therapies in the adjuvant treatment of these patients is unclear, although it is common practice for medical oncologists to include bevacizumab with preoperative FOLFOX (omitting it in the cycle immediately prior to hepatectomy). Published data suggesting that the hepatotoxicity of FOLFOX is ameliorated by the inclusion of bevacizumab, together with evidence of its benefits in unresectable patients with metastatic disease, make it difficult to argue against its inclusion.5 Finally, response criteria certainly need to be clarified and standardized, as radiologic response and pathologic response may not be concordant and their incorrect interpretation may lead to suboptimal decisions regarding subsequent therapy. In addressing the role of systemic agents, including targeted therapies, in unresectable patients, the consensus team importantly focuses on the need to establish the goals of therapy prior to selecting a treatment regimen. Specifically, is treatment aimed at downsizing the tumour to provide a reasonable possibility of resection or is it intended to provide a non-curative or even palliative approach? In recognition of the current literature, the consensus statement allows for significant flexibility in the choice of systemic regimens. For patients in whom there is a reasonable possibility of downsizing to a point at which resection is feasible, the consideration of hepatic and general toxicity is paramount. This should be weighed against response rate expectations and according to the minimum number of treatment cycles necessary to achieve the intended treatment goals. Specifically, the use of FOLFIRI and FOLFOXIRI, which may have more significant toxicity profiles, should be carefully considered in these potentially resectable patients, especially in those in whom an extended duration of therapy (>4 months) may be required.6 The addition of anti-vascular endothelial growth factor (anti-VEGF) or anti-epidermal growth factor receptor (anti-EGFR) targeted agents to first- and second-line cytotoxic backbones is highly encouraged by the consensus group and is generally supported by improvements in survival and response rates reported in the literature,7,8 whereas anti-EGF targeted therapy alone may be reasonable within third-line treatment. Conversely, data from the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE)9 and CAIRO-210 studies indicate that a combination of current anti-VEGF and anti-EGF agents should not be used. The authors of the consensus statement also address the limitations of capecitibine, both in combination with irinotecan and alone, in patients in whom prior regimens containing 5-FU have failed. This drug remains a reasonable alternative in combination with oxaliplatin11 or as a single agent when 5-FU has not previously failed. The consensus group has appropriately laid foundations for the acceptable utilization of systemic therapies in patients with hepatic colorectal metastases. It is clear from these guidelines that significant questions relating to the optimization of systemic regimens and the appropriate timing of multimodal therapy in resectable patients persist. There has been a general plateau in the evolution of cytotoxic therapies and targeted pathways (VEGF and EGF) such that the past decade has accommodated the study of how the delivery of these existing strategies might be optimized and their roles in primary and metastatic disease better understood. Further meaningful improvements depend on the identification and development of new targets or agents that are more effective against current targets. In this regard, regorafenib12 and aflibercept13 are of definite interest. In addition, it is hoped that as the biology of these tumours is further elucidated, and molecular abnormalities are identified, a much more rational and targeted approach to the choice and sequencing of therapy will become possible. Finally, the consensus statement does not specifically address the integration of alternative strategies, such as liver-directed therapy with intra-arterial chemotherapy, chemoembolization, yttrium-90 or radiofrequency ablation, with systemic therapies. The optimal use of these modalities is undefined and requires further study.