This review concluded that cetuximab-based therapy for treating cancer was associated with an increased risk of hypokalaemia. It was possible that other confounding factors may have affected results and, because of the types of studies included, the authors were unable to address this. Therefore the conclusion should be treated with some caution.

To evaluate the risks of hypokalaemia in patients undergoing treatment with cetuximab-based therapy.

PubMed, EMBASE, the Cochrane Library and Web of Science were searched to December 2008. No language restrictions were applied. Search terms were reported. Meeting abstracts from the American Society of Clinical Oncology (2000 to 2008) and references of identified studies and reviews were checked.

Phase II or III prospective clinical trials on patients with cancer receiving cetuximab, and reporting on incidence of hypokalaemia, were eligible for inclusion. Cetuximab dosage had to be 400mg/m² intravenously on day one, followed by 250 mg/m² weekly. Trials assessing variations in dosage or timing were excluded.

The primary outcome of interest was the incidence of any grade of hypokalaemia. Incidence of higher grade (3 or 4) hypokalaemia was also reported. Grading was defined according to the US National Cancer Institute common terminology criteria for adverse events.

The included trials included more men than women; median ages ranged from 54 to 65 years. Cancers consisted of head and neck, colorectal, non-small cell lung, ovarian, gastric and oesophagogastric. Treatment was first line, except in the largest trial where it was second line. Therapy was cetuximab combined variously with capecitabine, carboplatin, cisplatin, docetaxel, fluorouracil, irinotecan, paclitaxel and radiotherapy. In the RCTs, the comparator groups received combination therapy minus cetuximab.

The reviewers did not state how papers were selected for the review.

The quality of RCTs was assessed using the Jadad score, which scored items on methods of randomisation, blinding and completion of follow-up. The maximum score was 5 points.

The authors did not state how many reviewers performed the assessment.

The proportion, and 95% confidence intervals (CI), of patients with hypokalaemia were calculated. For RCTs odds ratio (OR) and 95% confidence intervals were calculated.

Two reviewers extracted data independently; disagreements were resolved by consensus.

Event rates and 95% confidence intervals from single arm trials and treatment arms of RCTs were pooled using a fixed-effect model. Heterogeneity was assessed using the Q test and I² statistic. If heterogeneity was present, a random-effects model was used. For RCTs pooled odds ratios and 95% confidence intervals were calculated. Heterogeneity was investigated using subgroup analysis (details not presented) and sensitivity analysis excluding trials which potentially biased results.

Eleven trials were included in the review (2,254 participants; 1,324 assigned to cetuximab). Of these, three were RCTs (1,857 participants) and eight were single arm trials (397 participants). Most participants came from two large RCTs. One small RCT scored 5 points for quality; two others scored 3 points.

The pooled incidence of grade 3 or 4 hypokalaemia was 6.2% (95% CI 4.9 to 7.7; I²=49.81%; fixed-effect; 1,306 participants). The pooled incidence of any grade hypokalaemia was 8.0% (95% CI 4.5 to 13.9; I²=84.78%; random-effects;1,306 participants).

An increase in grades 3 and 4 hypokalaemia was associated with cetuximab-based therapy compared with non-cetuximab therapy (OR 1.81, 95% CI 1.12 to 2.93, I²=0%; three RCTs).

Cetuximab-based therapy was associated with a significant risk of hypokalaemia.

The inclusion criteria of this review were clearly stated in terms of participants, treatments, outcomes and study design. The search covered a number of relevant sources, including unpublished studies, and was not restricted by language. This was likely to have reduced the possibility of language or publication bias. The methods of data extraction were those likely to have reduced the possibility of reviewer error or bias, although those for study selection and validity assessment were not described.

The quality of RCTs was assessed using an established checklist, although only the composite score was reported, which made it difficult to independently comment on the reliability of evidence presented. Non-RCTs did not appear to have been assessed for quality. The method of synthesis would appear appropriate. However, there was evidence of significant heterogeneity, which the authors said that they investigated but could not account for. Although the results for any grade hypokalaemia were pooled, only two trials appeared to have reported on grades other than 3 or 4. Full details of included participants were not given, but the general characteristics of participants and treatments in the included trials varied and, as the authors acknowledged, it was possible that other confounding factors may have affected the results. There appeared to be some discrepancies in numbers between some tables and figures.

The authors' conclusion should be treated with some caution.

Practice: The authors stated that early monitoring and effective management of hypokalaemia is important in people receiving cetuximab-based therapy.

Research: The authors did not state any implications for research.

None stated.

Cao Y, Liao C, Tan A, Liu L, Gao F. Meta-analysis of incidence and risk of hypomagnesemia with cetuximab for advanced cancer. Chemotherapy 2010; 56(6): 459-465.

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.