Secondary technical resectability of colorectal cancer liver metastases after chemotherapy with or without selective internal radiotherapy in the randomized SIRFLOX trial

B Garlipp, P Gibbs, G A Van Hazel, R Jeyarajah, R C G Martin, C J Bruns, H Lang, D M Manas, G M Ettorre, F Pardo, V Donckier, C Benckert, T M van Gulik, D Goéré, M Schoen, J Pratschke, W O Bechstein, A M de la Cuesta, S Adeyemi, J Ricke, M Seidensticker, B Garlipp, P Gibbs, G A Van Hazel, R Jeyarajah, R C G Martin, C J Bruns, H Lang, D M Manas, G M Ettorre, F Pardo, V Donckier, C Benckert, T M van Gulik, D Goéré, M Schoen, J Pratschke, W O Bechstein, A M de la Cuesta, S Adeyemi, J Ricke, M Seidensticker

Abstract

Background: Secondary resection of initially unresectable colorectal cancer liver metastases (CRLM) can prolong survival. The added value of selective internal radiotherapy (SIRT) to downsize lesions for resection is not known. This study evaluated the change in technical resectability of CRLM with the addition of SIRT to FOLFOX-based chemotherapy.

Methods: Baseline and follow-up hepatic imaging of patients who received modified FOLFOX (mFOLFOX6: fluorouracil, leucovorin, oxaliplatin) chemotherapy with or without bevacizumab (control arm) versus mFOLFOX6 (with or without bevacizumab) plus SIRT using yttrium-90 resin microspheres (SIRT arm) in the phase III SIRFLOX trial were reviewed by three or five (of 14) expert hepatopancreatobiliary surgeons for resectability. Reviewers were blinded to one another, treatment assignment, extrahepatic disease status, and information on clinical and scanning time points. Technical resectability was defined as at least 60 per cent of reviewers (3 of 5, or 2 of 3) assessing a patient's liver metastases as surgically removable.

Results: Some 472 patients were evaluable (SIRT, 244; control, 228). There was no significant baseline difference in the proportion of technically resectable liver metastases between SIRT (29, 11·9 per cent) and control (25, 11·0 per cent) arms (P = 0·775). At follow-up, significantly more patients in both arms were deemed technically resectable compared with baseline: 159 of 472 (33·7 per cent) versus 54 of 472 (11·4 per cent) respectively (P = 0·001). More patients were resectable in the SIRT than in the control arm: 93 of 244 (38·1 per cent) versus 66 of 228 (28·9 per cent) respectively (P < 0·001).

Conclusion: Adding SIRT to chemotherapy may improve the resectability of unresectable CRLM.

© 2019 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.

Figures

Figure 1
Figure 1
CONSORT diagram for the study
Figure 2
Figure 2
Blinded surgical review panel agreement on resectability at baseline and follow‐up for each patient Percentage agreement on resectability or unresectability in a,b control and c,d selective internal radiotherapy (SIRT) arms at a,c baseline and b,d follow‐up. The dotted lines denote the 60 per cent threshold of agreement by the surgical review panel on resectability or unresectability.
Figure 3
Figure 3
Resectability of colorectal liver metastases Baseline and follow‐up resectability rates in a the whole cohort; b patients deemed unresectable at baseline; c patients with a hepatic tumour burden of 25 per cent or less; d patients with a hepatic tumour burden greater than 25 per cent; e patients without hepatic miliary disease; f patients with hepatic miliary disease.

References

    1. Berber E, Pelley R, Siperstein AE. Predictors of survival after radiofrequency thermal ablation of colorectal cancer metastases to the liver: a prospective study. J Clin Oncol 2005; 23: 1358–1364.
    1. Navarra G, Ayav A, Weber JC, Jensen SL, Smadga C, Nicholls JP et al Short‐ and long‐term results of intraoperative radiofrequency ablation of liver metastases. Int J Colorectal Dis 2005; 20: 521–528.
    1. Rothbarth J, van de Velde CJ. Treatment of liver metastases of colorectal cancer. Ann Oncol 2005; 16(Suppl 2): ii144–ii149.
    1. Van Cutsem E, Nordlinger B, Adam R, Kohne CH, Pozzo C, Poston G et al Towards a pan‐European consensus on the treatment of patients with colorectal liver metastases. Eur J Cancer 2006; 42: 2212–2221.
    1. Abbas S, Lam V, Hollands M. Ten‐year survival after liver resection for colorectal metastases: systematic review and meta‐analysis. ISRN Oncol 2011; 2011: 763245.
    1. Adam R, Avisar E, Ariche A, Giachetti S, Azoulay D, Castaing D et al Five‐year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol 2001; 8: 347–353.
    1. Welch JP, Donaldson GA. The clinical correlation of an autopsy study of recurrent colorectal cancer. Ann Surg 1979; 189: 496–502.
    1. Helling TS, Martin M. Cause of death from liver metastases in colorectal cancer. Ann Surg Oncol 2014; 21: 501–506.
    1. Adam R, Delvart V, Pascal G, Valeanu A, Castaing D, Azoulay D et al Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long‐term survival. Ann Surg 2004; 240: 644–657.
    1. Nordlinger B, Van Cutsem E, Rougier P, Köhne CH, Ychou M, Sobrero A et al; European Colorectal Metastases Treatment Group . Does chemotherapy prior to liver resection increase the potential for cure in patients with metastatic colorectal cancer? A report from the European Colorectal Metastases Treatment Group. Eur J Cancer 2007; 43: 2037–2045.
    1. Adam R, Bhangui P, Poston G, Mirza D, Nuzzo G, Barroso E et al Is perioperative chemotherapy useful for solitary, metachronous, colorectal liver metastases? Ann Surg 2010; 252: 774–787.
    1. Nordlinger B, Van Cutsem E, Gruenberger T, Glimelius B, Poston G, Rougier P et al; European Colorectal Metastases Treatment Group; Sixth International Colorectal Liver Metastases Workshop . Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel. Ann Oncol 2009; 20: 985–992.
    1. Folprecht G, Grothey A, Alberts S, Raab HR, Köhne CH. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 2005; 16: 1311–1319.
    1. Jones RP, Hamann S, Malik HZ, Fenwick SW, Poston GJ, Folprecht G. Defined criteria for resectability improves rates of secondary resection after systemic therapy for liver limited metastatic colorectal cancer. Eur J Cancer 2014; 50: 1590–1601.
    1. Adam R, Wicherts DA, de Haas RJ, Ciacio O, Lévi F, Paule B et al Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol 2009; 27: 1829–1835.
    1. Basso M, Dadduzio V, Ardito F, Lombardi P, Strippoli A, Vellone M et al Conversion chemotherapy for technically unresectable colorectal liver metastases: a retrospective, STROBE‐compliant, single‐center study comparing chemotherapy alone and combination chemotherapy with cetuximab or bevacizumab. Medicine (Baltimore) 2016; 95: e3722.
    1. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D et al ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016; 27: 1386–1422.
    1. Malik H, Khan AZ, Berry DP, Cameron IC, Pope I, Sherlock D et al Liver resection rate following downsizing chemotherapy with cetuximab in metastatic colorectal cancer: UK retrospective observational study. Eur J Surg Oncol 2015; 41: 499–505.
    1. Devaud N, Kanji ZS, Dhani N, Grant RC, Shoushtari H, Serrano PE et al Liver resection after chemotherapy and tumour downsizing in patients with initially unresectable colorectal cancer liver metastases. HPB (Oxford) 2014; 16: 475–480.
    1. Henry LR, Hostetter RB, Ressler B, Bowser I, Yan M, Vaghefi H et al Liver resection for metastatic disease after Y90 radioembolization: a case series with long‐term follow‐up. Ann Surg Oncol 2015; 22: 467–474.
    1. van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M et al SIRFLOX: Randomized phase III trial comparing first‐line mFOLFOX6 (plus or minus bevacizumab) versus mFOLFOX6 (plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol 2016; 34: 1723–1731.
    1. Sangro B, Gil‐Alzugaray B, Rodriguez J, Sola I, Martinez‐Cuesta A, Viudez A et al Liver disease induced by radioembolization of liver tumors: description and possible risk factors. Cancer 2008; 112: 1538–1546.
    1. Van Hazel G, Blackwell A, Anderson J, Price D, Moroz P, Bower G et al Randomised phase 2 trial of SIR‐Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer. J Surg Oncol 2004; 88: 78–85.
    1. Folprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JT et al Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 2010; 11: 38–47.
    1. Gibbs P, Gebski V, Van Buskirk M, Thurston K, Cade DN, Van Hazel GA; SIRFLOX Study Group . Selective internal radiation therapy (SIRT) with yttrium‐90 resin microspheres plus standard systemic chemotherapy regimen of FOLFOX versus FOLFOX alone as first‐line treatment of non‐resectable liver metastases from colorectal cancer: the SIRFLOX study. BMC Cancer 2014; 14: 897.
    1. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A et al Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009; 360: 1408–1417.
    1. Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L et al Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med 2014; 371: 1609–1618.
    1. Tabernero J, Salazar R. Gastrointestinal cancer: light and shade of intrahepatic arterial radiotherapy in mCRC. Nat Rev Clin Oncol 2016; 13: 467–468.
    1. Modest DP, Denecke T, Pratschke J, Ricard I, Lang H, Bemelmans M et al Surgical treatment options following chemotherapy plus cetuximab or bevacizumab in metastatic colorectal cancer – central evaluation of FIRE‐3. Eur J Cancer 2018; 88: 77–86.
    1. Pardo F, Sangro B, Lee RC, Manas D, Jeyarajah R, Donckier V et al The Post‐SIR‐Spheres Surgery Study (P4S): retrospective analysis of safety following hepatic resection or transplantation in patients previously treated with selective internal radiation therapy with yttrium‐90 resin microspheres. Ann Surg Oncol 2017; 24: 2465–2473.
    1. Aubin JM, Bressan AK, Grondin SC, Dixon E, MacLean AR, Gregg S et al Assessing resectability of colorectal liver metastases: how do different subspecialties interpret the same data? Can J Surg 2018; 61: 251–256.
    1. Homayounfar K, Bleckmann A, Helms HJ, Lordick F, Ruschoff J, Conradi LC et al Discrepancies between medical oncologists and surgeons in assessment of resectability and indication for chemotherapy in patients with colorectal liver metastases. Br J Surg 2014; 101: 550–557.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe