Management of colorectal cancer metastases to the liver, lung or peritoneum suitable for curative intent: summary of NICE guidance

The management of metastatic colorectal cancer has undergone a strategic evolution with improvements in imaging, biomarker-based selection for systemic anticancer therapy (SACT), and innovations in surgical and local ablative techniques. Since the concept of oligometastatic disease was introduced1, the benefit of adding metastases-directed local therapy to standard-of-care systemic treatment has been unclear. Decision-making in these situations is often complex and dynamic, involving clinicians from a variety of specialties. The most common sites of metastases from colorectal cancer are the liver, lung and peritoneum. As part of the National Institute for Health and Care Excellence (NICE) guideline update for colorectal cancer2 the Guideline Committee reviewed the evidence to support treatment decisions for patients with metastases to these sites. The evidence reviews and the methods used are available on the NICE website2. Here, the key evidence behind the NICE guidance is highlighted. The most common site of colorectal metastases is the liver, occurring in 25–30 per cent of patients3. Surgical resection is considered standard treatment. Uncertainty persists around the benefits of systemic treatment in addition to liver resection, treatment other than surgical resection, and, for synchronous presentation, whether a simultaneous or staged resection of the primary tumour and liver metastases should be employed. An improvement in disease-free survival was observed among people who had chemotherapy and surgery compared with those who underwent surgery alone (hazard ratio (HR) 0.79, 95 per cent c.i. 0·66 to 0·95)4,5. The RCTs differed in terms of chemotherapy regimen (oxaliplatin/5-fluorouracil (5-FU) and 5-FU/leucovorin) and timing of chemotherapy (before and/or after resection), making pooling of the results questionable. Grade 3/4 chemotherapy-related toxicity occurred in around 25 per cent6. Local ablative techniques are an alternative to surgical resection with potentially less morbidity and mortality. The LAVA (liver resection surgery versus thermal ablation for colorectal liver metastases) randomized trial7 compared these two approaches, but was discontinued owing to poor recruitment. Only retrospective studies of local ablation with or without liver resection versus liver resection alone were available. For most patients undergoing ablation, resection was not possible because of poor performance status. The committee had concerns about comparability of groups and selection bias influencing outcomes. Evidence review showed no clinically important differences in survival, morbidity or mortality between simultaneous resection of the primary tumour and liver metastases or staged resection8. Health economic analysis was undertaken but did not allow any clear recommendations. The lung is the second most common site of colorectal metastases. Although pulmonary metastasectomy is a commonly used treatment, other less invasive approaches including stereotactic body radiation therapy (SBRT) and percutaneous ablation are used. Comparative evidence for the most effective treatment is scarce, retrospective and of low quality. Poorer lung progression-free survival at 2·5 years was observed in those receiving SBRT compared with surgery (HR 2·78, 1·67 to 4·63), but there was no difference in overall survival (HR 1·28, 0·58 to 2·83)9. Treatment-related mortality was similar in both groups. In another study10, a decrease in 5-year overall survival was observed among those who received chemotherapy or best supportive care rather than surgery (HR 2·18, 1·01 to 4·73)10. The committee acknowledged the PulMiCC (Pulmonary Metastasectomy in Colorectal Cancer) trial, an RCT of the effectiveness of pulmonary metastasectomy in patients treated previously for colorectal cancer, which was due to report, and has now been published11. Outcomes include 5-year overall survival, relapse-free survival, lung function and quality of life. The small sample size precludes a conclusive answer regarding any of these outcomes. The second most common cause of death from colorectal cancer is peritoneal metastases. Efforts to achieve long-term survival have seen the combined use of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Two RCTs12,13 of CRS and HIPEC have been carried out. The first trial12 showed an increase in 2-year overall survival in patients who received CRS and HIPEC and SACT compared with those who had conventional surgery and SACT (HR 0·55, 0·32 to 0·95). No difference in 5-year overall survival was observed in the second more recent trial (PRODIGE 7)13, which compared CRS and HIPEC using oxaliplatin with CRS alone (HR 1·00, 0·73 to 1·37). Overall survival rates for all patients were higher than expected (median survival 42 months) indicating that high-quality surgery is of value. No difference in 30-day treatment-related mortality was seen in either RCT, although PRODIGE 7 did show a greater rate of grade 3/4 morbidity with the use of high-dose oxaliplatin HIPEC, mostly due to haemorrhagic complications. An observational study14 reported increased overall survival at 50 months with SACT compared with best supportive care (HR 0·35, 0·22 to 0·56) and, despite the low quality of the evidence, the committee agreed that SACT appears to benefit patients with colorectal peritoneal metastases. Many of the studies that informed the latest NICE guideline suffer from methodological limitations affecting the risk of bias and imprecision of the effect estimates. When uncertainty exists around survival benefit, quality-of-life data are key to decision-making, but this analysis was absent. The Guideline Committee was therefore unable to make strong recommendations for treatments in this setting. Unsurprisingly, local multidisciplinary teams (MDTs) may lack the expertise necessary to make appropriate decisions. Access to specialists influences MDT decisions15 and initiatives such as IMPACT (Improving the Management for Patients with Advanced Colorectal Tumours) encourage MDTs around the country to establish networks with the knowledge to effectively manage patients with oligometastatic colorectal cancer. Based on the evidence and the Guideline Committee's expertise, the following recommendations were made. Consider resection, either simultaneous or sequential, after discussion by a MDT with expertise in resection of disease at all involved sites. Consider perioperative SACT if liver resection is a suitable treatment. Consider chemotherapy with local ablative techniques for people with colorectal liver metastases that are unsuitable for liver resection after discussion by a specialist MDT. Consider metastasectomy, ablation or SBRT for people with lung metastases that are suitable for local treatment, after discussion by a MDT that includes a thoracic surgeon and a specialist in non-surgical ablation. Consider biopsy for people with a single lung lesion to exclude primary lung cancer. Offer SACT and within a MDT, discuss referral to a nationally commissioned specialist centre to consider CRS and HIPEC. Members of the Guideline Committee are: J. Bradbury (Oxford University Hospitals NHS Foundation Trust, Oxford); M. Braun (Christie NHS Foundation Trust, Withington, Manchester); G. Burgess (University Hospitals of Leicester, Leicester); C. Chew (Hairmyres Hospital, East Kilbride); R. J. Davies (Cambridge Colorectal Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge); C. Dawson (Bowel Cancer UK, London); S. Fenwick (Liverpool University Hospitals NHS Foundation Trust, Liverpool); J. Hepburn (lay member, Newport); P. Hoskin (Mount Vernon Hospital, Northwood); D. Lennard (lay member, London); V. Misra (Christie NHS Foundation Trust, Withington, Manchester); F. Mohamed (Peritoneal Malignancy Institute and North Hampshire Hospital, Basingstoke); K. Monahan (Chelsea & Westminster Hospitals NHS Trust, London); R. Roope (The Whiteley Surgery, Whiteley, Farnham); M. Salto-Tellez (Institute for Health Sciences, Queen's University Belfast, Belfast); M. Shackcloth (Liverpool Heart and Chest Hospital, Liverpool); B. Singh (Leicester General Hospital, Leicester); and R. Verma (University Hospitals of Leicester NHS Trust, Leicester). The guideline referred to in this article was produced by the National Guideline Alliance (NGA) at the Royal College of Obstetricians and Gynaecologists (RCOG) for NICE. The views expressed in this article are those of the authors and not necessarily those of the RCOG, NGA or NICE. Disclosure: The authors declare no conflict of interest.