Efficacy and toxicity of different concurrent chemoradiotherapy regimens in the treatment of advanced cervical cancer

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Introduction
Cervical cancer (CC) is the second most common female cancer worldwide. [1] In many developing countries, CC remains a major public health problem with high overall incidence and a higher frequency of advanced stage at diagnosis. [2] Lack of awareness, the low level of effective screening programs, overshadowing by other health priorities (such as acquired immune deficiency syndrome, tuberculosis, and malaria), and insufficient attention to women's health are the possible factors for the observed higher incidence rate of CC. [3] Even as a result of screening, most cervical cancers could be identified early and cured with surgery, but the lack of routine population-based screening in some parts of the word results in the majority of unscreened patients presenting with locally advanced CC. [4] Pelvic radiotherapy (RT) and intracavitary brachytherapy used to be the main treatment modality for patients with advanced CC and has played an important role in the treatment of CC. [5] The results of RT depend on disease stage, tumor volume, the presence of involved lymph nodes, delivered radiation dose, treatment duration, hemoglobin level, and the optimal use of intracavitary brachytherapy. [2] Furthermore, the major limitation to reaching a curative radiation dose in tumors is the high sensitivity to radiation and subsequent damage to the surrounding normal tissues. [6] Thus, the prognosis of patients with advanced CC is still poor, particularly for those with bulky local tumors and extensive parametrical extension. [7] Nodal involvement, particularly of paraaortic nodes, was reported to be the most important adverse prognostic factor of reduced survival rate for advanced CC. [2] Nevertheless, a series of studies has shown that the outcome of advanced CC patients can be improved by the use of concurrent chemoradiotherapy (CCRT) regimens.
CCRT is the standard organ-preservation treatment for resectable disease; it ensures optimal locoregional control and has become a cornerstone of treatment. [8] The current traditional treatment of choice for advanced CC has been CCRT. [9] CCRT can improve pelvic control and survival in advanced CC patients because it can provide active systemic cytotoxic agents against CC with the potential to enhance radiosensitivity and local tumor control and to eradicate micrometastasis. [10] A chemotherapeutic drug, Cisplatin, was reported to be one of the most effective agents and is widely used in the treatment of CC. [11] It has been demonstrated in previous randomized trials that in the last decade the results of RT are significantly improved with the addition of cisplatin-based CCRT and have become the standard of care; consequently, cisplatin-based CCRT was rapidly adopted in clinical practice for the treatment of advanced CC. [12] Although cisplatin-based CCRT was considered standard treatment for advanced CC, it could be difficult to use in aged patients or patients with comorbidities such as diabetes mellitus and hypertension. [13] However, better results have showed that gemcitabine with cisplatin-based CCRT followed by 2 cycles of adjuvant gemcitabine and cisplatin is a cost-effective treatment for locally advanced CC. [14] It is almost certain that there are many other effective CCRT regimens for the treatment of advanced CC, but which is the best one?
Network meta-analysis can provide estimates of multiple treatment regimens, even when direct comparisons are unavailable. [15] Therefore, in this article, we performed a network metaanalysis to compare the efficacy and toxicity of different CCRT regimens to investigate which is the best choice in the treatment of advanced CC.

Electronic searches
Computer-based retrieval of PubMed and the Cochrane Library databases (from inception to September 2016), combined with manual retrieval of related references, were performed. Combining the keywords and free words, the search terms were as follows: Concurrent chemoradiotherapy (CCRT), cohort study (CS), and cervical cancer.

Data collection and analysis
Studies were included in this network meta-analysis if they met the following criteria: the study design must be CSs; the study subjects should be patients with advanced CC aged 18 Studies were excluded if the following criteria were met: patients  were previously treated with pelvic radiotherapy or systemic  chemotherapy; patients were pregnant or lactating; patients had  severe or uncontrolled infection or other uncontrolled systemic  diseases; the studies contained incomplete literature data or were  non-CSs, duplications, conference reports, meta-analyses, abstracts or non-English publications. The present study is a network meta-analysis, and the eligible patients included in our study were obtained from our included studies; therefore, the ethics statement in the present study was waived based on this case.

Data extraction and quality assessment
Two researchers extracted the data of included studies independently. Additionally, a third researcher was consulted if agreement could not be reached between these 2 researchers. Two or more researchers reviewed the CSs according to Newcastle-Ottawa Scale (NOS). [16] The NOS assigns up to a maximum of 9 points for the least risk of bias in 3 domains: selection of CS (whether the exposed CSs are representative [NOS1], whether the non-exposed CSs are drawn from the same community as the exposed CSs [NOS2], whether the CSs have a secure record or structured interview [NOS3], whether the outcome of interest was present at the start of the study [NOS4]); comparability of CS (whether the CSs were selected or controlled based on the most important factor [NOS5], and whether the CSs were controlled for any additional factor [NOS6]; ascertainment of exposure and outcomes for CSs (whether the assessment of outcome was independent and blind [NOS7], whether the followup period for outcomes to occur was long enough [NOS8], whether all subjects completely followed-up or subjects lost to follow-up were unlikely to introduce bias [NOS9]). CSs with points of ≥5 were included in this network meta-analysis.

Statistical methods
Traditional pairwise meta-analyses were adopted to directly compare the different CCRT regimens. The odd ratios (ORs) or weighted mean differences (WMDs) with their 95% confidence interval (95% CI) were calculated under a fixed effects model or random effects model. The significance of the combined effect was detected by the Z test. [17] The heterogeneity of these regimens was evaluated using Cochran's Q-statistic and the I 2 test among the enrolled studies. [18,19] When P h > 0.05 or I 2 < 50%, heterogeneity was indicated, and the fixed effects model was used; if the converse was true, the random effects model was adopted. [20] A network evidence plot was drawn with the nodes indicating interventions, the node size representing sample sizes, and the thickness of lines referring to the accuracy of the effect size of the comparison between 2 studies (the inverse of variance). A surface under the cumulative ranking (SUCRA) curve was used to compare the SUCRA value of different CCRT regimens to ascertain the efficacy and toxicity of the different chemotherapy regimens; the larger the SUCRA value, the better the treatment or the lower the toxicity. [21] Cluster analyses were adopted to compare the efficacy and toxicity of different CCRT regimens in the treatment of advanced CC, according to the similarity of 2 variables to cluster the different interventions, and different intervention measures were determined to judge the merits of the effect. [21] The presence of a small-study effect was assessed using a comparison-adjusted funnel plot, which takes into account different summary effects for each set of studies (measure of precision vs. estimated treatment effect). [22] All computations were performed using Stata 13.1 (Corp, College Station, TX) software.

Pairwise meta-analysis of the efficacy and toxicity of different CCRT regimens
The results of pairwise meta-analysis showed that in terms of efficacy, the 5-year OS rates of CCRT (cisplatin) and CCRT (cisplatin + FU + hydroxyurea) were relatively higher than CCRT (hydroxyurea); however, there were no significant differences in the ORR and 5-year DFS rate among these 12 CCRT regimens ( Table 2). As for hematotoxicity, compared with CCRT (cisplatin), the incidences of anemia, neutropenia, and thrombocytopenia with CCRT (cisplatin + gemcitabine) were relatively higher; compared with CCRT (cisplatin + FU), the incidences of leukopenia with CCRT (hydroxyurea) and CCRT (cisplatin + paclitaxel) were relatively higher. As far as gastrointestinal toxicity, compared with CCRT (cisplatin), the incidence of diarrhea with CCRT (cisplatin + gemcitabine) was higher, and the incidence of nausea with CCRT (cisplatin + FU) was relatively higher; however, there was no significant difference of the incidence of vomiting among these 12 CCRT regimens (Appendix Table 1
In the case of hematotoxicity, compared with CCRT (cisplatin), the incidences of leukopenia with CCRT (hydroxyurea), CCRT Table 1 The baseline characteristics for included studies.

Cluster analysis and publication bias regarding efficacy and toxicity in the included studies
The cluster analysis based on SUCRA values indicated that the CCRT (cisplatin) regimen had lower hematotoxicity than others, wheraes CCRT (cisplatin) and CCRT (vinorelbine) had lower gastrointestinal toxicity than other CCRT regimens, and CCRT (cisplatin + FU) and CCRT (cisplatin + gemcitabine) had relatively higher gastrointestinal toxicity (Fig. 2). The comparison-adjusted funnel plot of the efficacy (ORR, 5-year OS rate, 5-year DFS rate) and toxicity (anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, nausea, and vomiting) of these 12 CCRT regimens showed that there was no publication bias among the included studies (Figs. 3 and 4).

Discussion
Our network meta-analysis included 19 cohort studies with a total of 3170 advanced CC patients, most of which were related to the comparison of RT versus CCRT (cisplatin), and the majority of these advanced CC patients were treated by CCRT (cisplatin). The main results of our study showed that the shortterm efficacy of CCRT (cisplatin + docetaxel) was better than other CCRT regimens. CCRT with low-dose cisplatin was tolerable and showed a favorable initial response as the primary therapy for advanced CC. [39] Cisplatin, as an assistant drug for chemotherapy, was often combined with other drugs to treat cancers but was also accompanied by some side effects. [40] In our study, the toxicity (both hematotoxicity and gastrointestinal toxicity) of CCRT (cisplatin) was relatively lower than the other included CCRT regimens. Additionally, FU is commonly used to treat skin cancer or damage caused by the HPV virus so that it benefitted CC caused by the HPV virus. [41] Previous studies had also confirmed that if FU was used alone, the curative rate was approximately 75%; therefore, it was better to combine it with other drugs. [42] This supported our finding that the 5-year OS rate of CCRT (cisplatin + FU + hydroxyurea) was relatively higher than the other CCRT regimens in our study. The pairwise meta-analysis of our study showed that the incidences of anemia, neutropenia, and thrombocytopenia with CCRT (cisplatin + gemcitabine) were higher than CCRT (cisplatin). However, the incidence of diarrhea with CCRT (cisplatin + gemcitabine) and the incidence of nausea with CCRT (cisplatin + FU) was higher than CCRT (cisplatin). Gemcitabine is a poly-ADP-ribose polymerase (PARP) inhibitor that could inhibit the proliferation of tumor cells by blocking PARP signaling. [43] Furthermore, gemcitabine can inhibit the growth of cancer cells by targeting particular factors. [44] A previous study indicated that FU had some toxicity and side effects that could cause body pain and endothelial tissue ulceration; at the same time, its characteristic long-term onset time makes it easier for patients to develop drug resistance. [42,45] Additionally, the SUCRA values of the efficacy and toxicity of twelve CCRT regimens demonstrated that the ORR with CCRT (cisplatin + docetaxel) was higher than other CCRT regimens. The incidence of anemia and nausea with CCRT (cisplatin + FU)   was higher than other CCRT regimens, whereas the incidence of leukopenia and thrombocytopenia with CCRT (cisplatin + paclitaxel) was higher than other CCRT regimens. A randomized phase III trial demonstrated that cisplatin + docetaxel also had superior response rates and survival in the treatment of previously untreated patients with stage IV non-small-cell lung cancer. [46] McGuire et al [47] suggested that incorporating paclitaxel into first-line therapy also can improve the duration of progression-free survival and overall survival in women with incompletely resected stage III and stage IV ovarian cancer.
In conclusion, our study demonstrated that CCRT (cisplatin + docetaxel) might be the best choice of CCRT regimens in the treatment of CC; moreover, the 5-year OS rate of CCRT (cisplatin + FU + hydroxyurea) might be the highest among these different regimens, and CCRT (cisplatin) might have the lowest toxicity among all the CCRT regimens. These findings may help clinicians in their choice of proper chemotherapy regimens for patients with CC. However, our network meta-analysis included only 19 cohort studies with 13 CCRT regimens. This showed that there was no remarkable long-term benefit for patients' survival or local disease control of the included CCRT regimens in this study. And the 19 enrolled studies both including cohort studies and randomized controlled trails, which may affect the reliability and application value of our results because of the level of evidence for these enrolled studies was different. Therefore, the incidence of late intestinal toxicity still requires further investigation, and more and more randomized controlled trails about the efficacy and toxicity of different CCRT regimens in treating advanced CC are supposed to be conducted.