Chemotherapy plus targeted drugs in conversion therapy for potentially resectable colorectal liver metastases: a meta-analysis

Objectives To evaluate the safety and efficiency of the conversion therapy : chemotherapy plus anti-epidermal growth factor Receptor (EGFR) or anti-vascular endothelial growth factor receptor (VEGFR) monoclonal antibodies (MoAbs) with different rat sarcoma (RAS) status in patients with potentially resectable colorectal liver metastases (CRLM). Methods Randomized controlled trials (RCTs) were identified and the association between RAS mutation and clinical outcome in CRLM patients treated with anti-EGFR or anti-VEGFR MoAbs was investigated. Searches were performed for data recorded between January 2005 and August 2015 in the Cochrane Library, MEDLINE, PubMed, and EMBASE. Objective response rates (ORR), conversion resection rates (CRR), R0 resection rates (R0R) and rate ratios (RR) were used to assess the strength of the association between different RAS status, MoAbs and conversion efficiency. Results In the conversion therapy, ORR and RR were associated with patients with wild type RAS and different MoAbs. Patients treated with MoAbs: anti-VEGFR or anti-EGFR drugs, resulted in higher ORR, (RR=1.53, 95% confidence interval [CI]: 1.27-1.84, P < 0.05). Furthermore, anti-EGFR regimens displayed higher ORR compared with anti-VEGFR regimens in CRLM patients, (RR=1.15, 95%CI: 1.04-1.26, P < 0.05). However, CRLM patients with mutant type RAS did not benefit from anti-EGFR therapy, (RR=0.91, 95%CI: 0.76-1.08, P<0.05) and wild type RAS patients displayed higher ORR with anti-EGFR therapy, (RR=1.56, 95%CI: 1.16-2.01, P <0.05). In addition, the patients achieved higher resection rates (RR=1.67, 95%CI: 1.00-2.81, P ≤ 0.05) and R0 resection (RR=1.85, 95%CI: 1.04-3.27, P < 0.05). Conclusion We noted that the addition of MoAbs (anti-EGFR or anti-VEGFR) to standard chemotherapy could improve conversion efficiency for patients with potentially resectable CRLM patients, and anti-EGFR therapies maybe more effective than anti-VEGFR therapies. RAS status is a potential predictive marker of the clinical benefit resulting from treatment with anti-EGFR MoAbs therapy in CRLM patients and anti-EGFR MoAbs therapy could displayed greater efficiency only in patients with wild type RAS.

[1]  S. Curley,et al.  Extended Preoperative Chemotherapy Does Not Improve Pathologic Response and Increases Postoperative Liver Insufficiency After Hepatic Resection for Colorectal Liver Metastases , 2010, Annals of Surgical Oncology.

[2]  G. Folprecht,et al.  Defined criteria for resectability improves rates of secondary resection after systemic therapy for liver limited metastatic colorectal cancer. , 2014, European journal of cancer.

[3]  R. Schilsky,et al.  CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  I. Chau,et al.  Colorectal cancer with liver metastases: neoadjuvant chemotherapy, surgical resection first or palliation alone? , 2014, World journal of gastroenterology.

[5]  G. Fontanini,et al.  Folfoxiri plus Bevacizumab as first-line treatment of BRAF mutant metastatic colorectal cancer patients. , 2012 .

[6]  Hartmut Link,et al.  FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. , 2014, The Lancet. Oncology.

[7]  Josep Tabernero,et al.  Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  D. Sargent,et al.  Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial , 2013, The Lancet.

[9]  Lihua Huang,et al.  Mechanisms of resistance to EGFR tyrosine kinase inhibitors , 2015, Acta pharmaceutica Sinica. B.

[10]  E. Van Cutsem,et al.  Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. , 2015, The Lancet. Oncology.

[11]  E. Van Cutsem,et al.  Advanced colorectal cancer: ESMO Clinical Practice Guidelines for treatment. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[12]  E. Van Cutsem,et al.  Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. , 2009, The New England journal of medicine.

[13]  Yuguo Liu,et al.  A randomized Phase II clinical study of combining panitumumab and bevacizumab, plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) compared with FOLFIRI alone as second-line treatment for patients with metastatic colorectal cancer and KRAS mutation , 2015, OncoTargets and therapy.

[14]  E. Van Cutsem,et al.  Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  M. Tez,et al.  Role of surgery in colorectal cancer liver metastases. , 2014, World journal of gastroenterology.

[16]  H. Kindler,et al.  Metastatic colorectal cancer , 2001, Current treatment options in oncology.

[17]  N. Kemeny.  Presurgical chemotherapy in patients being considered for liver resection. , 2007, The oncologist.

[18]  G. Fontanini,et al.  FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer. , 2014, European journal of cancer.

[19]  R. Goldberg,et al.  TREATMENT OF METASTATIC COLORECTAL CANCER Review of recent advances , 2005 .

[20]  J. Hecht,et al.  PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  Jianming Xu,et al.  Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  K. Sugihara,et al.  Therapeutic strategies for hepatic metastasis of colorectal cancer: overview , 2012, Journal of hepato-biliary-pancreatic sciences.

[23]  B. Clary,et al.  Colorectal Cancer with Potentially Resectable Hepatic Metastases: Optimizing Treatment , 2014, Current Oncology Reports.

[24]  E. Van Cutsem,et al.  Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  E. Van Cutsem,et al.  Pooled analysis of the surgical treatment for colorectal cancer liver metastases. , 2015, Critical reviews in oncology/hematology.

[26]  Likuan Hu,et al.  A multi-center randomized phase II clinical study of bevacizumab plus irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) compared with FOLFIRI alone as second-line treatment for Chinese patients with metastatic colorectal cancer , 2014, Medical Oncology.

[27]  A. Venook.  Critical evaluation of current treatments in metastatic colorectal cancer. , 2005, The oncologist.

[28]  C. Bokemeyer,et al.  Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  M. Choti,et al.  Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors , 2012, Clinical epidemiology.

[30]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[31]  P. A. Futreal,et al.  Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2012, The New England journal of medicine.

[32]  D. Ribero,et al.  Potentially resectable metastatic colorectal cancer: an individualized approach to conversion therapy. , 2014, Critical reviews in oncology/hematology.

[33]  A R Jadad,et al.  Assessing the quality of reports of randomized clinical trials: is blinding necessary? , 1996, Controlled clinical trials.

[34]  Daniel Azoulay,et al.  Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[36]  B. Li,et al.  Preoperative administration of bevacizumab is safe for patients with colorectal liver metastases. , 2013, World journal of gastroenterology.

[37]  A. Carrato,et al.  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. , 2007, European journal of cancer.

[38]  W. Hawkins,et al.  Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. , 2005, Journal of the American College of Surgeons.

[39]  A. Jemal,et al.  Global cancer statistics, 2012 , 2015, CA: a cancer journal for clinicians.

[40]  D. Lambrechts,et al.  Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial , 2011, The Lancet.