Adjuvant Systemic Therapy after Chemoradiation and Brachytherapy for Locally Advanced Cervical Cancer: A Systematic Review and Meta-Analysis

Abstract

Background: Standard of care for locally advanced cervical cancer is chemoradiation and brachytherapy. The addition of adjuvant systemic treatment may improve overall survival. A systematic review and meta-analysis was conducted to summarize evidence on survival outcomes, treatment completion and toxicity.

Methods: PubMed, EMBASE and Web of Science were systematically searched for relevant prospective and retrospective studies. Two authors independently selected studies, extracted data and assessed study quality. Pooled hazard ratios for survival endpoints were estimated using random effect models. Weighted averages of treatment completion and toxicity rates were calculated and compared by the Fisher exact test.

Results: The search returned 612 articles; 35 articles reporting on 29 different studies on adjuvant chemotherapy or immunotherapy were selected for systematic review. Twelve studies on an adjuvant platinum-pyrimidine antagonist or platinum-taxane were included for meta-analysis. The pooled hazard ratios for overall survival were 0.76 (99%CI: 0.43-1.34, p = 0.22) and 0.47 (99%CI: 0.12-1.86, p = 0.16) for the addition of, respectively, a platinum-pyrimidine antagonist or platinum-taxane to chemoradiation and brachytherapy. Completion rates were 82% (95%CI: 76-87%) for platinum-pyrimidine antagonist and 74% (95%CI: 63-85%) for platinum-taxane. Severe acute hematological and gastro-intestinal toxicities were significantly increased by adding adjuvant chemotherapy to chemoradiation and brachytherapy.

Conclusions: The addition of adjuvant platinum-pyrimidine antagonist or platinum-taxane after chemoradiation and brachytherapy does not significantly improve overall survival, while acute toxicity is significantly increased. These adjuvant treatment strategies can therefore not be recommended for unselected patients with locally advanced cervical cancer.

Keywords: adjuvant therapy; cervical cancer; chemotherapy; immunotherapy; meta-analysis; overall survival.

Figure 1

Systematic search and article selection process.

Figure 2

Risk of bias assessment of included studies. Definition of abbreviations: CRT = chemoradiotherapy; AdjTx = adjuvant systemic therapy; RCT = randomized controlled trial; Pros = prospective study; Retro = retrospective study; HR = high risk; LR = low risk; SC = some concerns; ? = unclear risk. ^a The number of patients reported in this table are the numbers of patients that could be included in the current study as either a control group (CRT) or experimental group (CRT + AdjTx); patients who were treated with other regimens (e.g., radiotherapy only) are not included in the current study and not represented here. ^b Conflicts of interest of one or more authors; relations with or employees of pharmaceutical companies. ^c Concerns about correctness of reported survival outcomes; discrepancies between reported estimates and survival curves.

Figure 3

Impact on the overall survival of the addition of adjuvant chemotherapy to chemoradiation and brachytherapy. Each study in the forest plot is represented by a black square which represents the study’s hazard ratio and a whisker on each side that represents the study’s 99% confidence interval. The size of the black square represents the weight of the study in the meta-analysis. The pooled hazard ratios are shown as diamond shapes; the light blue diamond represents the pooled hazard ratio based on only randomized controlled trials, the dark blue diamond represents the pooled hazard ratio based on only non-randomized studies, and the black diamond is the pooled hazard ratio of all studies combined. (A) Meta-analysis of overall survival after concurrent chemoradiation and brachytherapy with adjuvant platinum derivate and pyrimidine antagonist vs. concurrent chemoradiation and brachytherapy only. I² = 62%, Q-test p = 0.02. (B) Meta-analysis of overall survival after concurrent chemoradiation and brachytherapy with adjuvant platinum derivate and taxane vs. concurrent chemoradiation and brachytherapy only. I² = 74%, Q-test p = 0.002. Definition of abbreviations: CRT = chemoradiation and brachytherapy; AdjTx = adjuvant therapy; HR = hazard ratio; CI = confidence interval. * Imputed values; methods described in Supplementary Materials I.

Figure 4

The assessment of the publication bias of studies included in the meta-analysis. Each circle represents a study included in the meta-analysis on overall survival; light blue circles are randomized controlled trials; dark blue circles are non-randomized controlled trials. The grey contours indicate the 95 and 99% confidence intervals of the hazard ratio for the impact of the addition of adjuvant systemic therapy to chemoradiation on the overall survival in the individual studies. The black vertical line is placed at the pooled estimate for the hazard ratio for overall survival based on the studies included in the meta-analysis. The black diagonal lines indicate the 99% confidence interval of the pooled estimate. Lack of symmetry in the presence of studies across the area defined by the black lines may indicate publication bias. Panel (A): Funnel plot of the studies on the addition of adjuvant platinum–pyrimidine antagonist after chemoradiation and brachytherapy. Panel (B): Funnel plot of the studies on the addition of adjuvant platinum–taxane after chemoradiation and brachytherapy.