CHEMORADIOTHERAPY FOR CERVICAL CANCER

January 26, 2010 — Adding chemotherapy to radiotherapy adds a modest but significant benefit in women with cervical cancer, according to a meta-analysis reported in the first 2010 issue of the Cochrane Database of Systematic Reviews. The results also suggest that adjuvant chemotherapy is beneficial, although more data are needed.

Data from 13 trials showed that patients treated with chemoradiotherapy had a 6% improvement in 5-year survival, compared with those treated with radiotherapy alone (hazard ratio (HR), 0.81; P < .001).

The researchers noted that in 2 other trials, a larger survival benefit was seen when chemotherapy was administered after chemoradiotherapy. The HR for these 2 trials was 0.46 (95% confidence interval [CI], 0.32 - 0.66; P < .001), which represents a 54% reduction in the risk for mortality and an absolute survival benefit of 19% at 5 years (range, 60% to 79%).

A third finding was that a significant survival benefit was observed for both platinum-based (HR, 0.83; P = .017) and nonplatinum-based (HR, 0.77; P = .009) chemoradiotherapy.

"The type of study that we did — a systematic review and meta-analysis using individual patient data — is often said to be the gold standard or yardstick of systematic reviews," said lead author Claire Vale, PhD, from the Meta-Analysis Group, MRC Clinical Trials Unit in London, United Kingdom. "Therefore, I think that what we have provided in doing this review is strong evidence about the use of chemoradiotherapy, and probably the best evidence available to date."

Even so, she told Medscape Oncology, the treatment of any individual woman with cervical cancer is based on many factors, including tumor stage, general health, and personal preference. "There are some women for whom chemoradiotherapy will not suitable, so for them, other treatments, such as radiotherapy alone, will necessarily be considered," she said.

The use of adjuvant chemotherapy might need to be further assessed in randomized controlled trials, Dr. Vale added. "As far as I am aware, there is considerable interest about this question in the research community."

Meta-Analysis Needed to Clarify Data

Following the publication of 5 clinical trials, the National Cancer Institute (NCI) issued a clinical alert in 1999 recommending that "concomitant chemoradiotherapy should be considered instead of radiotherapy alone in women with cervical cancer," the authors note. These recommendations led to a subsequent change in therapeutic regimens for many women diagnosed with cervical cancer.

Although 2 subsequent reviews reported improvements in several outcome measures, including overall survival, progression-free survival, and recurrence rates with chemoradiotherapy, the interpretation of results was complicated and left unanswered questions, write the authors. There was heterogeneity in trial results, inconsistency in the definition of outcomes between trials, and different control-group treatments in the studies included in these analyses.

Therefore, the Cochrane researchers conducted a meta-analysis that included updated individual patient data from all randomized controlled trials to better evaluate the effectiveness of chemoradiotherapy for all outcomes.

A total of 15 studies (3452 participants) met the eligibility criteria for inclusion in the analysis. The studies all looked at women with high-risk early-stage or locally advanced cervical cancer.

The median follow-up time for living patients across all 15 trials was 5.2 years, and data on overall survival, disease-free survival, locoregional disease-free survival, and metastases-free survival were available for all trials included in the analysis.

Benefit Seen Across All Outcomes

In addition to improving overall survival, chemoradiotherapy also reduced local and distant recurrence and progression, and improved disease-free survival. The HR of 0.78 (95% CI, 0.70 - 0.87; P < .001) for disease-free survival translated to an absolute benefit of 8% at 5 years (from 50% to 58%), and similar and significant absolute benefits for chemoradiotherapy were seen for 5-year locoregional disease-free survival (9%; P < .001), time to locoregional recurrence/progression (6%; P = .00009), and metastases-free survival (7%; P < .001).

The authors note that for time to metastases at 5 years, the improvement was smaller and "less convincing" (4%; P = .04).

A suggestion of a difference in the size of the survival benefit was observed with tumor stage, but not with other patient subgroups, note the authors.

The incidence of acute hematologic and gastrointestinal toxicity was higher with chemoradiotherapy, but only a few of the trials measured late toxicity. Thus, the data were insufficient to evaluate whether serious late toxicity is affected by the type of treatment, although available data suggest that only about 1% to 3% of women experience serious late toxicities.

"These results endorse the recommendations of the NCI alert, but also demonstrate their applicability to all women and a benefit of nonplatinum-based chemoradiotherapy," the authors conclude.

Cochrane Database Syst Rev. 2010;1:CD008285. Abstract