Clinical impact of anti-epidermal growth factor receptor monoclonal antibodies in first-line treatment of metastatic colorectal cancer: meta-analytical estimation and implications for therapeutic strategies

CRD summary

The authors concluded that adding an anti-epidermal growth factor receptor monoclonal antibodies treatment to first-line chemotherapy improved response and slightly improved progression-free survival in Kirsten rat sarcoma viral oncogene homologue (KRAS) wild-type patients with metastatic colorectal cancer. The quality of trials was unclear, they varied and were poorly described; the reliability of the evidence is unclear.

Authors' objectives

To evaluate the impact of adding an anti-epidermal growth factor receptor (EGFR) monoclonal antibodies treatment to first-line chemotherapy for patients with metastatic colorectal cancer. The impact of Kirsten rat sarcoma viral oncogene homologue (KRAS) status on treatment outcome was investigated.

Searching

MEDLINE and the websites of the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) were searched up to November 2010. Search terms were reported. The lectures of major meetings of the ASCO , the ASCO Gastrointestinal Symposium, the ESMO, and the European Cancer Organisation (ECCO) were searched. The references of reviews and selected papers were handsearched.

Study selection

Randomised controlled trials (RCTs) comparing anti-EGFR monoclonal antibodies treatment plus chemotherapy versus chemotherapy alone in previously untreated participants with metastatic colorectal cancer were eligible for inclusion. The primary outcome was progression-free survival and the secondary outcomes were overall survival and overall response rate.

In the included trials, the anti-EGFR monoclonal antibodies treatments were cetuximab, panitumumab and bevacizumab. Chemotherapy treatments included folinic acid (leucovorin) plus 5-fluorouracil plus irinotecan (FOLFIRI), folinic acid plus 5-fluorouracil plus oxaliplatin (FOLFOX), and capecitabine plus oxaliplatin (CAPOX or XELOX). Most of the trials included participants with or without KRAS mutation. Some trials reported secondary outcomes, such as safety, resection rate, duration of response, disease control rate, time to response, quality of life, time to treatment failure, and time to progression. These findings were not reported in the review.

The authors did not state how many reviewers selected the trials.

Assessment of study quality

The authors did not state that trial quality was assessed.

Data extraction

For progression-free and overall survival, hazard ratios and their corresponding 95% confidence intervals were extracted. For overall response rate, the event-based relative risks and cumulative ratios, with corresponding 95% confidence intervals, were extracted. Three reviewers extracted the data for participants unselected for KRAS status, for those without KRAS mutation (KRAS wild-type), and for those with KRAS mutation. Where more than one time-point of data was reported for a trial, the most recent data were extracted.

Methods of synthesis

For progression-free and overall survival, the pooled hazard ratios with 95% confidence intervals were calculated. For overall response rate, the pooled relative risks with 95% confidence intervals were calculated. Meta-analyses were performed using both random-effects (DerSimonian and Laird) and fixed-effect models. Statistical heterogeneity was assessed using Χ². The number needed to treat to achieve a given benefit was calculated. Sensitivity analyses were performed by oxaliplatin- versus irinotecan-containing chemotherapy. A meta-regression was performed for outcomes.

Four reviewers independently performed the statistical analyses.

Results of the review

Eight RCTs, with 6,609 participants, were included in the review. There were 3,257 participants without KRAS mutation, and 2,220 with KRAS mutation.

Progression-free survival: In a fixed-effect analysis, the addition of anti-EGFR monoclonal antibodies treatments to chemotherapy significantly improved progression-free survival in KRAS wild-type patients, compared with chemotherapy alone (HR 0.91, 95% CI 0.84 to 0.99). There was evidence of significant statistical heterogeneity (p<0.001) and the improvement disappeared when a random-effects model was used. In KRAS mutant patients, the addition of an anti-EGFR monoclonal antibodies treatment significantly decreased progression-free survival using a fixed-effect model (HR 1.13, 95% CI 1.03 to 1.25). There was borderline evidence of statistical heterogeneity (p=0.056) and the effect disappeared when a random-effects model was used. For patients not selected by KRAS, the addition of anti-EGFR monoclonal antibodies treatment to chemotherapy did not significantly increase progression-free survival compared with chemotherapy alone.

Sensitivity analyses revealed that irinotecan chemotherapy significantly improved progression-free survival for KRAS unselected patients compared with other chemotherapy treatments (p=0.011), but adding an anti-EGFR monoclonal antibodies treatment did not significantly alter progression-free survival.

Overall survival: The addition of anti-EGFR monoclonal antibodies treatment to chemotherapy did not increase overall survival for KRAS unselected, wild-type, or mutant patients. Irinotecan significantly improved overall survival compared with other chemotherapy regimens in KRAS unselected patients (p=0.023).

Overall response rate: The addition of an anti-EGFR monoclonal antibodies treatment to chemotherapy significantly improved the overall response rate in KRAS wild-type patients (RR 1.17, 95% CI 1.04 to 1.33; seven trials) and KRAS unselected populations (RR 1.10, 95% CI 1.01 to 1.21; seven trials). There was evidence of significant statistical heterogeneity for both these analyses (p=0.003 wild-type and p=0.059 unselected). There was a significant benefit in the overall response rate with irinotecan in KRAS wild-type populations (p=0.01). The addition of an anti-EGFR monoclonal antibodies treatment did not significantly improve the overall response rate in KRAS mutant populations. The number needed to treat for KRAS wild-type populations was 11 patients treated for one to benefit. The number needed to treat for KRAS unselected populations was 23.

The meta-regression found that for KRAS wild-type and KRAS unselected populations the benefit in overall response rate was significantly associated with improvements in progression-free survival (p=0.00001 wild-type and p=0.0001 unselected) and overall survival (p=0.0019 wild-type and p=0.0027 unselected).

Authors' conclusions

Adding an anti-EGFR monoclonal antibodies treatment to first-line chemotherapy clearly improved the response rate and had a small benefit in progression-free survival for KRAS wild-type patients with metastatic colorectal cancer.

CRD commentary

The review addressed a clear question with well-defined inclusion criteria. Several relevant databases were searched, but it was unclear whether language restrictions were applied and language bias cannot be ruled out. Attempts were made to identify unpublished data. Appropriate steps were taken in the data extraction process to minimise reviewer error and bias. It was unclear whether similar steps were taken in the study selection process. Limited information was reported on the individual trials, making it unclear to what extent the findings can be applied or generalised and whether the presence of any confounding factors might influence the results.

A quality assessment was not reported and the quality of the trials and reliability of their findings is unclear. Suitable methods were used to combine the trials, but significant statistical heterogeneity was found for some outcomes and this could undermine the reliability of the results. The magnitude of the effect was small and there were some inconsistencies in the direction of the effect for some outcomes.

Given the unclear quality of the included trials, the limited information on them, and the presence of statistical heterogeneity, the reliability of the evidence is unclear and the conclusions should be interpreted with caution.

Implications of the review for practice and research

Practice: The authors stated that the addition of an anti-EGFR monoclonal antibodies treatment should be determined by the KRAS status of patients with metastatic colorectal cancer. They stated that irinotecan-based regimens should be used.

Research: The authors stated that future research, using individual patient data, was needed. This research should collect biologic data from participants to investigate the role of molecular predictors in the response to anti-EGFR monoclonal antibodies treatments. It should evaluate the efficacy of anti-EGFR monoclonal antibodies treatments in the initial induction phase, followed by anti-vascular endothelial growth factor monoclonal antibodies treatments in the maintenance phase for metastatic colorectal cancer.

Funding

Not reported.

Bibliographic details

Loupakis F, Cremolini C, Salvatore L, Schirripa M, Lonardi S, Vaccaro V, Cuppone F, Giannarelli D, Zagonel V, Cognetti F, Tortora G, Falcone A, Bria E. Clinical impact of anti-epidermal growth factor receptor monoclonal antibodies in first-line treatment of metastatic colorectal cancer: meta-analytical estimation and implications for therapeutic strategies. Cancer 2012; 118(6): 1523-1532. [PubMed: 22009364]

Original Paper URL

http://onlinelibrary.wiley.com/doi/10.1002/cncr.26460/abstract

Indexing Status

Subject indexing assigned by NLM

MeSH

Antibodies, Monoclonal /therapeutic use; Colorectal Neoplasms /drug therapy /genetics /mortality /pathology; Disease-Free Survival; Humans; Neoplasm Metastasis; Proto-Oncogene Proteins /genetics; Randomized Controlled Trials as Topic; Receptor, Epidermal Growth Factor /antagonists & inhibitors; Regression Analysis; ras Proteins /genetics

AccessionNumber

12012016956

Database entry date

25/10/2012

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.