Selective internal radiotherapy in advanced colorectal cancer: only for right-sided tumours?
Authors: Hans-Joachim Schmoll
Journal: The Lancet Oncology (2017)

Colorectal cancer is a biologically unique tumour entity; in 30–40% of patients, metastases are confined exclusively to the liver, lung, or both, with or without minor additional lymph node involvement. Different from all other tumour types, R0-resection of these lesions is not always followed by systemic relapse in other regions, therefore this local approach is—despite systemic spread of the disease—leads to a potentially curative resection in up to 61% of patients.1Folprecht G Gruenberger T Bechstein W et al.Survival of patients with initially unresectable colorectal liver metastases treated with FOLFOX/cetuximab or FOLFIRI/cetuximab in a multidisciplinary concept (CELIM study).Ann Oncol. 2014; 25: 1018-1025Summary Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 2Gruenberger T Bridgewater J Chau I et al.Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial.Ann Oncol. 2015; 26: 702-708Summary Full Text Full Text PDF PubMed Scopus (231) Google Scholar Therefore, locoregional treatment of metastases is of key importance. If surgery alone is not appropriate, other locoregional modalities can be given,3Nosher JL Ahmed I Patel AN et al.Non-operative therapies for colorectal liver metastases.J Gastrointestinal Oncol. 2015; 6: 224-240PubMed Google Scholar such as hepatic arterial infusion of floxuridine, mitomycin, and oxaliplatin; addition of starch microspheres or application of drug-coated glass beads (eg, irinotecan beads) for prolonged arterial drug exposure; chemoembolisation (transarterial chemoembolization; TACE); ablation-techniques (eg, radiofrequency, ultrasound, laser-ablation, heat-ablation, or cryoablation, radiosurgery, and brachytherapy [yttrium-90 resin microspheres; selective internal radiotherapy; SIRT]). However, randomised trials testing the individual value of any one treatment are rare; only radiofrequency ablation with or without surgical resection plus chemotherapy has been prospectively proven effective for superior overall survival versus chemotherapy alone (phase 3 CLOCC trial4Ruers T vanCoevorden F Punt C et al.Local treatment in unresectable liver metastases: results of a randomized phase II trial.J Natl Cancer Inst. 2017; 109: djx015Crossref Scopus (255) Google Scholar). Beyond this, SIRT also showed clinically relevant efficacy on liver metastases in three small randomised trials in patients refractory to standard systemic chemotherapy; therefore, a broad investigation in first-line therapy was justified. In The Lancet Oncology, Harpreet Wasan and colleagues5Wasan HS Gibbs P Sharma NK et al.First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trials.Lancet Oncol. 2017; (published Aug 3.)http://dx.doi.org/10.1016/S1470-2045(17)30457-6Summary Full Text Full Text PDF PubMed Scopus (205) Google Scholar report the results of a combined analysis of three trials of first-line FOLFOX (leucovorin, fluorouracil, and oxaliplatin) chemotherapy with or without SIRT. Eligibility criteria used in the three trials were more or less comparable, including patients with unresectable, but limited, liver metastases, with or without lung metastases, and with or without lymph node metastases.6Wirdee PS Moschandreas J Gebski V et al.Protocol for combined analysis of FOXFIRE, SIRFLOX, and FOXFIRE-Global randomized phase III trials of chemotherapy +/- selective internal radiation therapy as first-line treatment for patients with metastatic colorectal cancer.JMIR Res Protoc. 2017; 6: e43Crossref PubMed Scopus (14) Google Scholar As expected, the local effect of SIRT is clear, with an improved proportion of patients achieving an overall response and liver-only progression. However, this locoregional effect did not translate into improved overall progression-free survival or overall survival, even in those patients with metastases restricted to the liver (one third of the patients). This result suggests that the biology of the disease is only transiently changed by the locoregional SIRT treatment. Why does this proven effective locoregional approach not alter the overall course of disease, even in liver-only disease? Several potential contributing factors that caused imbalance between the groups might have been involved, including different eligibility criteria in each of the three trials, different oxaliplatin dose between treatment groups (29% less in the FOLFOX plus SIRT group in cycles 1–3 than in the FOLFOX alone group), lower dose of bevacizumab starting 2–3 months later in the FOLFOX plus SIRT group, fewer patients who had bevacizumab in the FOLFOX plus SIRT group compared with the FOLFOX alone group (197 [36%] vs 256 [47%]), less salvage treatment in the FOLFOX plus SIRT group, and heterogeneity of the SIRT dose between patients, centres, and treatment times. However, these factors alone cannot explain the absence of overall benefit from SIRT. More relevant factors might be the fact 47 (8%) of 554 patients randomly assigned to SIRT did not receive SIRT, that 41 (7%) patients only had unilobar application, and 18 (3%) patients crossed over from FOLFOX alone to FOLFOX plus SIRT. However, even if those patients are eliminated from the analysis, the overall outcome would not change substantially. Another relevant factor might be the short overall survival of patients in all three trials, which was shorter than that of other trials with comparable patient populations but that included treatment with one or two targeted drugs (bevacizumab and EGFR inhibitors).7Schmoll HJ Meinert FM Cygon F et al."CHARTA": FOLFOX/bevacizumab vs. FOLFOXIRI/bevacizumab in advanced colorectal cancer—final results, prognostic and potentially predictive factors from the randomized phase II trial of the AIO.Proc Am Soc Clin Oncol. 2017; 35 (abstr).: 3533Crossref Google Scholar In the FOXFIRE trials, EGFR inhibitors were not used and VEGF inhibitors were used in only one third of patients. Additionally, fewer secondary metastases resections were done in the FOXFIRE trials. This difference is mainly due to the enrolment and treatment era of the largest trial included in the analysis, SIRFLOX (2006–13) and also the fact that patients were treated in countries without routine access to the targeted drugs. However, if systemic treatment is weak as in this case, shouldn't SIRT have a bigger effect on overall survival? This is obviously not the case, because, beyond the local treatment only, complete metastases resection after optimal and highly active chemotherapy can improve the long term outcome.4Ruers T vanCoevorden F Punt C et al.Local treatment in unresectable liver metastases: results of a randomized phase II trial.J Natl Cancer Inst. 2017; 109: djx015Crossref Scopus (255) Google Scholar Furthermore, although the local SIRT approach improved frequency of resection, it only marginally increased the depth of response, the most important prerequisite for complete secondary resection. Therefore, the frequency of secondary resection of liver (and lung) metastases was not sufficiently increased to improve survival. However, in an important subgroup analysis,8Van Hazel G Heinemann V Sarma N et al.Impact of primary tumour location on survival in patients with metastatic colorectal cancer receiving selective internal radiation therapy and chemotherapy as first-line therapy.Ann Oncol. 2017; 28 (mdx302.005 (abstr).)Google Scholar SIRT was shown to significantly improve overall survival (p=0·007) and progression-free survival (p=0·053) in one third of patients with right-sided primary tumours, known to be much less sensitive to all types of systemic treatment versus left sided tumours, but had no effect in patients with left-sided primary tumours. SIRT, which is not affected by chemoresistance in the same way, appears to overcome the intrinsic chemoresistance of liver metastases of right-sided primary tumours. This is an important message from Wasan and colleagues' study, the HR for overall survival in patients with right-sided tumours was 0·67 (0·48–0·92) versus non-significant for left-sided tumours, which could have an impact on further clinical research, to improve the poor outcome of patients who have right-sided tumours. Further research into SIRT and also other locoregional approaches, together with optimal systemic chemotherapy in this patient group, is now more than justified. For patients with left-sided primary tumours, SIRT is not an option in first-line treatment. However, the potential indication for salvage treatment with SIRT in non-first-line treatment is not affected by these findings. I have received compensation from Sirtex for chairing a satellite symposium at ESMO World Congress on Gastrointestinal Cancer 2012. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX, and FOXFIRE-Global): a combined analysis of three multicentre, randomised, phase 3 trialsAddition of SIRT to first-line FOLFOX chemotherapy for patients with liver-only and liver-dominant metastatic colorectal cancer did not improve overall survival compared with that for FOLFOX alone. Therefore, early use of SIRT in combination with chemotherapy in unselected patients with metastatic colorectal cancer cannot be recommended. To further define the role of SIRT in metastatic colorectal cancer, careful patient selection and studies investigating the role of SIRT as consolidation therapy after chemotherapy are needed. Full-Text PDF Open Access