To assess whether adding chemotherapy to standard radiation improves survival and disease-free survival in people with locoregionally advanced nasopharyngeal cancer.

MEDLARS (from 1966 to 2001), Cancerlit, Current Contents and the Cochrane Controlled Trials Register were searched; the MeSH terms used were reported. The authors also searched the bibliographies of textbooks and retrieved papers for additional studies. Papers published in any language were eligible for inclusion, whereas published abstracts were not included in the review. If a series of papers was published on a single study, the authors extracted data from the most recent report.

Study designs of evaluations included in the review

Randomised controlled trials (RCTs) were eligible for inclusion if they had a minimum of 2 years' follow-up. Non-randomised trials were excluded.

Specific interventions included in the review

Studies that compared external beam radiation therapy alone (controls) with chemotherapy plus radiotherapy were eligible for inclusion. Studies using biological or other non-cytotoxic therapy were excluded.

All studies included in the review compared standard radical external beam radiation therapy (controls) with radiation plus chemotherapy delivered either adjuvantly, neoadjuvantly, or concurrently with radiation. The exact drugs, doses and schedule varied between the studies. The regimens used in each study were tabulated in the review. Five out of 6 studies used adjuvant or neoadjuvant chemotherapy. Five out of 6 studies used a cisplatin-based chemotherapy regimen.

Participants included in the review

Studies that included adults with locoregionally advanced nasopharyngeal carcinoma (tumour stages III or IV without distant metastases) were eligible for inclusion. Although stage III to IV tumours were the focus of interest, some of the studies included in the review had a proportion of participants with stage I or undifferentiated tumours. Studies of people with recurrent disease were eligible only if those with recurrent disease were analysed separately. The authors did not report patient characteristics such as age or gender.

Outcomes assessed in the review

Studies that included data on disease-free (progression-free) survival and/or overall survival were eligible for inclusion. The primary outcomes of interest in the review were disease-free and overall survival at 2, 3 and 4 years after treatment.

How were decisions on the relevance of primary studies made?

One physician screened abstracts to exclude papers that did not meet the general inclusion criteria. The authors then retrieved and assessed the full text against more specific inclusion criteria. The authors did not report how many people made the final decision about which papers were to be included in the review.

The authors did not state that they assessed validity.

Two authors extracted the data using a form developed for recording relevant information. Any differences were resolved by consensus. Data on sample size, type of chemotherapy used, drug schedule, radiotherapy schedule and technique, and outcomes were extracted.

How were the studies combined?

The authors pooled data using a fixed-effect model (Peto method). The results were expressed as summary relative risks or odds ratios (ORs) with associated 95% confidence intervals (CIs).

How were differences between studies investigated?

The authors performed statistical tests for heterogeneity (Q test). If statistical heterogeneity was found, the authors performed sensitivity analyses to assess possible sources of differences between the studies.

Six RCTs with 1,528 participants were included.

Disease-free survival.

The addition of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma increased disease-free survival compared with radiotherapy alone by 37% at 2 years (OR 0.63, 95% CI: 0.52, 0.78, P<0.05), 40% at 3 years (OR 0.60, 95% CI: 0.49, 0.73, P<0.05), and 34% at 4 years (OR 0.66, 95% CI: 0.54, 0.80, P<0.05).

There was significant heterogeneity between the studies. For example, for 2-year disease-free survival, Q was 25.5 (P<0.005). The sensitivity analysis revealed that one study was responsible for this heterogeneity. This study contained a larger proportion of patients with WHO grade I tumours and was the only study to use concurrent chemotherapy. After removing this study from the meta-analysis, the OR for disease-free survival at 2 years was 0.73 in favour of chemoradiotherapy (95% CI: 0.59, 0.91, P<0.05). There was no remaining statistical heterogeneity (Q=6.94, P=0.14). After removing this study from the analysis, chemoradiotherapy remained associated with increased disease-free survival 2, 3, and 4 years after treatment.

Overall survival.

Four years after treatment, chemoradiotherapy increased overall survival by 21% compared with radiotherapy alone (OR 0.79, 95% CI: 0.65, 0.97, P<0.05). There was a trend towards increased overall survival at 2 and 3 years (respectively, OR 0.80, 95% CI: 0.63, 1.02 and OR 0.81, 95% CI: 0.66, 1.0), but this did not reach statistical significance (P-values not reported).

No

The addition of chemotherapy to standard radical radiotherapy in locoregionally advanced nasopharyngeal cancer increased disease-free and overall survival by 19 to 40% two to four years after treatment.

The authors specified their research questions clearly and reported inclusion and exclusion criteria. The search strategy appears to have been reasonable and there were no language restrictions. However, the authors could have provided a more detailed listing of the search terms used. It also appears that unpublished studies were excluded from the review. Given the rarity of locoregionally advanced nasopharyngeal cancer, any unpublished studies may have had small samples; however, these studies are unlikely to have been identified by the search strategy. The authors did not report any method to assess publication bias, nor did they report any special search techniques to target studies published in Southeast Asia or Southern China, where the disease is most prevalent. The methods used to assess the validity of the primary studies were also not given and details of the studies included, such as patient gender and follow-up rate, were omitted.

The authors used a meta-analysis to synthesise the data quantitatively, and conducted appropriate heterogeneity and sensitivity analyses to assess differences between the studies. They also pointed out the limitations of the techniques used.

The authors addressed their research question clearly and their report was concise and clearly written. However, some of their conclusions should be treated with caution. For example, the authors suggest that administering chemotherapy concurrently with radiotherapy has more positive outcomes in comparison with adjuvant or neoadjuvant chemotherapy. They based this conclusion on a heterogeneity analysis and the findings from one study of concurrent chemotherapy. Since none of studies included in the review compared adjuvant with concurrent chemotherapy, it may be premature to report that one regimen is likely to be more effective than another. This is especially true since the sample in the study from which this conclusion was drawn had more grade I tumours than other studies. Grade I tumours are associated with somewhat better prognosis than grade II to IV tumours.

Practice: The authors stated that adding chemotherapy to standard radiotherapy increases disease-free survival in locoregionally advanced nasopharyngeal carcinoma. Chemoradiotherapy may also increase overall survival in comparison with radiotherapy alone.

Research: The authors suggested that further trials are needed to confirm the benefits of chemoradiation and to assess the most effective regimen for combining chemotherapy and radiotherapy.

Marshfield Medical Research Foundation (WI), USA.

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.