Does the Chemotherapy Backbone Impact on the Efficacy of Targeted Agents in Metastatic Colorectal Cancer? A Systematic Review and Meta-Analysis of the Literature.
OBJECTIVE
The EGFR inhibitors (EGFR-I) cetuximab and panitumumab and the angiogenesis inhibitors (AIs) bevacizumab and aflibercept have demonstrated varying efficacy in mCRC.


OBJECTIVE
To document the overall impact of specific chemotherapy regimens on the efficacy of targeted agents in treating patients with mCRC.


METHODS
MEDLINE, EMBASE and Cochrane databases were searched to 2014, supplemented by hand-searching ASCO/ESMO conference abstracts.


METHODS
Published RCTs of patients with histologically confirmed mCRC were included if they investigated either 1) chemotherapy with or without a biological agent or 2) different chemotherapy regimens with the same biological agent. EGFR-I trials were restricted to KRAS exon 2 wild-type (WT) populations.


METHODS
Data were independently abstracted by two authors and trial quality assessed according to Cochrane criteria. The primary outcome was overall survival with secondary endpoints progression free survival (PFS), overall response rate (ORR) and toxicity.


RESULTS
EGFR-I added to irinotecan-based chemotherapy modestly improved OS with HR 0.90 (95% CI 0.81-1.00, p = 0.04), but more so PFS with HR 0.77 (95% CI 0.69-0.86, p<0.00001). No benefit was evident for EGFR-I added to oxaliplatin-based chemotherapy (OS HR 0.97 (95% CI 0.87-1.09) and PFS HR 0.92 (95% CI 0.83-1.02)). Significant oxaliplatin-irinotecan subgroup interactions were present for PFS with I2 = 82%, p = 0.02. Further analyses of oxaliplatin+EGFR-I trials showed greater efficacy with infusional 5FU regimens (PFS HR 0.82, 95% CI 0.72-0.94) compared to capecitabine (HR 1.09; 95% CI 0.91-1.30) and bolus 5FU (HR 1.07; 95% CI 0.79-1.45); subgroup interaction was present with I2 = 72%, p = 0.03. The oxaliplatin-irinotecan interaction was not evident for infusional 5FU regimens. For AIs, OS benefit was observed with both oxaliplatin-based (HR 0.83) and irinotecan-based (HR 0.77) regimens without significant subgroup interactions. Oxaliplatin+AI trials showed no subgroup interactions by type of FP, whilst an interaction was present for irinotecan+AI trials although aflibercept was only used with infusional FP (I2 = 89.7%, p = 0.002).


CONCLUSIONS
The addition of EGFR-I to irinotecan-based chemotherapy has consistent efficacy, regardless of FP regimen, whereas EGFR-I and oxaliplatin-based regimens were most active with infusional 5FU. No such differential activity was observed with the varying chemotherapy schedules when combined with AIs.
Royal North Shore Hospital, Northern Clinical School, University of Sydney, St Leonards, New South Wales, Australia.
David L
DL
Chan
Royal North Shore Hospital, Northern Clinical School, University of Sydney, St Leonards, New South Wales, Australia.
Nick
N
Pavlakis
Department of Medical Oncology, Monash University, Victoria, Australia.
Jeremy
J
Shapiro
The Queen Elizabeth Hospital and University of Adelaide, South Australia, Australia.
Timothy J
TJ
Price
Flinders University and Flinders Medical Centre, Flinders Centre for Innovation in Cancer, Bedford Park, South Australia, Australia.
Christos S
CS
Karapetis
Austin Health, Victoria, Australia.
Niall C
NC
Tebbutt
St Vincent's Clinical School, University of New South Wales, NSW, Australia.
Eva
E
Segelov
D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069287:Capecitabine / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000627:therapeutic use; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000627:therapeutic use; D000077150:Oxaliplatin; D000077544:Panitumumab; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D015996:Survival Rate; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D000077150:Oxaliplatin; C533178:aflibercept; D000068258:Bevacizumab; D000069287:Capecitabine; D000077544:Panitumumab; D000077146:Irinotecan; C512478:EGFR protein, human; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; D016283:Proto-Oncogene Proteins p21(ras); D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin