REVIEW ARTICLE Weekly Versus Triweekly Cisplatin-Based Chemotherapy Concurrent With Radiotherapy in the Treatment of Cervical Cancer A Meta-Analysis Xingxing Chen, MD,* Haizhou Zou, MD,Þ Huifang Li, MD,* Ruifang Lin, MD,* Meng Su, MD,* Wenyi Zhang, MD,* Yongqiang Zhou, MD,* Ping Zhang, MD,* Meng Hou, PhD,* Xia Deng, MD,* and Changlin Zou, MD* Background: The aim of this study was to evaluate toxicity, compliance, recurrence and the survival of weekly and triweekly cisplatin-based concomitant chemoradiation in treatment of cervical cancer. Materials and Methods: The databases were searched from 1995 until 2015 to identify eligible studies on weekly versus triweekly cisplatin chemoradiotherapy. The data were analyzed by RevMan 5.3 software. Results: A total of 5 randomized controlled trials were included in this review. Weekly cisplatin regimen significantly reduced the incidence of Hematologic toxicity. However, there was no significantly different between the 2 arms in compliance, recurrence and the survival rate (all P 90.05). Conclusions: Weekly cisplatin regimen had the similar therapeutic effect as the triweekly cisplatin regimen but with less hematologic toxicity. Therefore, we recommend the weekly cisplatin 30 to 40 mg/m 2 chemoradiotherapy as the strong candidate for the optimal cisplatin dose and dosing schedule in the treatment of locally advanced cervical cancer. Key Words: Cervical cancer, Chemoradiotherapy, Cisplatin, Weekly, Triweekly Received July 29, 2016, and in revised form September 14, 2016. Accepted for publication October 5, 2016. (Int J Gynecol Cancer 2017;27: 344Y349) ervical carcinoma is one of the most common gynecologic malignancies worldwide, and advanced disease carries C a poor prognosis. 1 On the basis of the consistent results of 5 large *Department of Chemoradiation Oncology, The First Affiliated Hospital of Wenzhou Medical University; Department of Oncology, Wenzhou Hospital of Traditional Chinese Medicine, Wenzhou, Zhejiang, P.R. China. Address correspondence and reprint requests to Changlin Zou, MD, Department of Chemoradiation Oncology, the First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue Street, Wenzhou, 325000, Zhejiang, P.R. China. E-mail: zcl19670115@163.com. X.C. and H.Z. contributed equally to this work. The authors declare no conflicts of interest. Copyright * 2016 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0000000000000883 randomized trials, which demonstrated improvements in survival rate, cisplatin-based concomitant chemoradiation has become the standard treatment for locally advanced cervical cancer. 2Y6 The 2 trials adopted weekly cisplatin 40 mg/m 2 among the previous 5 randomized clinical trials, while the other 3 trials used triweekly cisplatin at a dose range of 50 to 75 mg/m 2 combined with 5-fluorouracil (5-FU). 2Y6 Despite the variety in cisplatin dose and dosing schedules, the optimal chemotherapy regimen is still undetermined. The study performed by the Gynecologic Oncology Group found that intravenous infusion of 5-FU in combination with pelvic radiotherapy was not likely to achieve a better outcome over weekly cisplatin, the role of 5-FU, which previously popularly included in clinical trials, as a radiosensitizer became subject to debate. 7 Weekly cisplatin concurrent with radiation is widely accepted as the standard regimen of chemoradiation by reason 344 International Journal of Gynecological Cancer & Volume 27, Number 2, February 2017
International Journal of Gynecological Cancer & Volume 27, Number 2, February 2017 Weekly vs Triweekly Cisplatin Chemoradiotherapy of its convenience, favorable toxicity, and equal effectiveness. A previous study demonstrated that the regimen of chemoradiation using weekly cisplatin significantly improves compliance with treatment and reduces acute hematologic toxicity, whereas not affecting response and survival rates. 8 However, a randomized trial observed a tendency of superiority in triweekly cisplatin 75 mg/m 2 chemotherapy concurrent with radiotherapy as far as overall survival (OS) and disease-free survival were concerned. 9 In addition, Ryu et al 10 reported that triweekly cisplatin regimen was more effective than the conventional weekly cisplatin regimen and may be a strong candidate for the optimal cisplatin dose and dosing schedule in the treatment of locally advanced cervical cancer. In light of the results of the previous clinical trial that indicated 5-FU may not be an active radiosensitizer, weekly cisplatin 40 mg/m 2 and triweekly cisplatin 75 mg/m 2 remain the most popular cisplatin doses and dosing schedules. In order to analyze systematically which regimen is better, a meta-analysis has been conducted to compare differences between weekly and triweekly cisplatin arms. 11 Nevertheless, the studies evaluated in the research are not all randomized controlled trials (RCTs), along with 2 of the articles from different stages of the same study, which impairs validity and credibility of the result. Consequently, the aim of this study was to evaluate adverse effect and survival of 2 regimens more fully and precisely. MATERIALS AND METHODS Search Strategy The electronic databases of PubMed, EMBASE, the Cochrane Library of Controlled Trials, and Web of Science were searched from May 1995 until December 2015 to identify studies on weekly versus triweekly cisplatin-based chemotherapy concurrent with radiotherapy in the treatment of cervical cancer. The core search consisted of terms related to cancer sites (cervical OR uterine cervical OR cervix uteri) and descriptions of cancer (cancer OR neoplasm OR carcinoma OR tumor). These were combined with specific terms for treatments (chemoradiotherapy OR chemoradiation OR radiochemotherapy OR chemotherapy OR radiotherapy OR radiation) and cycle of treatments (weekly OR Triweekly). Only studies in English were considered. An additional search was carried out by manually reviewing the references of topical papers and checked for potentially relevant studies. Inclusion and Exclusion Criteria Studies were included in the analysis if: (1) publication in English; (2) RCT design, and conducted on the treatment of cervical cancer with weekly versus triweekly chemotherapy arms concurrent with radiotherapy; (3) no evidence of para-aortic lymph node or distant metastasis on pretreatment imaging (stage I to IVA); and (4) the long-term OS and progression-free survival (PFS) were assessed as outcomes to measure the effect of the treatment. If studies were duplicates, the study with the most up-to-date results was included. Studies were excluded if patients had previous histories of chemotherapy or radiotherapy, histories of rare tumor, such as melanoma and metastatic cancers, serious medical disease or pregnant state. Data Collection and Extraction To identify studies for inclusion in the analysis, we reviewed all resulting article titles and abstracts, and then obtained the full text for the determination of eligibility. Two independent investigators retrieved and evaluated all eligible studies. Any discrepancies were resolved by an independent investigator. Toxicity, compliance, recurrence, the OS and PFS were the outcomes of interest. Data were extracted and entered into the Excel database that included first author, title of trial and country, year of publication and study design, number of participants, and their basic characteristics data. Methodological Quality According to the Cochrane Handbook for Systematic Reviews of Interventions, 12 all RCTs should be assessed on the following domains: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other possible bias. This assessment was performed independently by 2 reviewers. If any disagreements arise, a consensus should be reached by discussion. Statistical Analysis The data were analyzed by RevMan 5.3 software in this meta-analysis, and statistical heterogeneity between studies was examined using the W 2 test and the I 2 statistic. P G 0.05 indicating heterogeneity and I 2 values of 25%, 50%, and 75% corresponded to minimal, moderate and substantial degrees of heterogeneity, respectively. 13 When statistically significant heterogeneity was observed, the random-effect model was used for meta-analysis. Alternatively, the fixed-effect model was used. If the grade of heterogeneity was too large, descriptive analysis was used. The toxic effects, rates of compliance and recurrence and the survival rates were estimated using the odds ratios with the corresponding 95% confidence intervals (CI) and P values. P less than 0.05 was considered statistically significant. The Begg funnel plot was used to detect potential publication bias. RESULTS Study Selection The search strategy initially provided 4756 potentially relevant articles. Among these studies, 385 of the studies published in English involved randomized controlled trials. After excluding irrelevant papers by reviewing the titles and abstracts, 11 reports remained. Among them, the following 6 articles were excluded from the final assessment: full text not available (n = 2), duplicate study (n = 2), studies had fewer than 50 samples (n = 1), outcomes did not include complete data (n = 1). Eventually, a total of 5 trials 8Y10,14,15 were included in this review for further analysis. Characteristics of Eligible Studies Five randomized trials in the United States, Korea and Romania were published between 2007 and 2014, with the number of the included patients reaching 1313. Of these, * 2016 IGCS and ESGO 345
Chen et al International Journal of Gynecological Cancer & Volume 27, Number 2, February 2017 TABLE 1. Characteristics of the included studies Author Year Country Method Stage N (QW/Q3W) Treatment DiSilvestro 2014 USA RCT IB2YIVA 194/185 QW: CIS 40 mg/m 2, 6 cycles Q2W:CIS 75 mg/m 2, 3 cycles Combined TPZ Viorica 2012 Romania RCT IIBYIIIB 162/164 QW: CIS 40 mg/m 2, 6 cycles Q3W:CIS 20 mg/m 2 per day, 5 d, 3 cycles Ryu 2011 Korea RCT IIBYIVA 51/53 QW: CIS 40 mg/m 2, 6 cycles Q3W:CIS 75 mg/m 2, 3 cycles Kim 2007 Korea RCT IIBYIVA 77/78 QW: CIS 30 mg/m 2, 6 cycles Q4W: CIS 20 mg/m 2 /d, 5 d, 3 cycles combined FU 1 mg/m 2 per day, 5 d Rose 2007 USA RCT IIBYIVA 176/173 QW: CIS 40 mg/m 2, 6 cycles Q4W: CIS 50 mg/m 2 per day, 2 cycles combined FU 4 mg/m 2 per 96 h, Hydroyurea 2 mg/m 2, twice per week CIS, cisplatin; QW/Q3W, weekly/triweekly; TPZ, tirapazamine. 660 patients received weekly cisplatin-based chemotherapy arm concurrent with radiotherapy and the remaining 653 patients received triweekly arm. All studies included in our meta-analysis were randomized and controlled. However, none of them was a double-blinded study due to the nature of the trials. Only one study 10 had mentioned that all the investigators were masked to the assignment of treatment group. And information on selective reporting was not mentioned in any of the studies. Thus, the studies have a moderate risk of bias. The characteristics of the trials and the risk of bias summary are presented in Table 1 and Figure 1, respectively. Toxic Effects The main chemotherapy related adverse events were hematologic toxicity, gastrointestinal toxicity and so on. Hematologic toxicity was reported in 3 trials and 2 of them reported the event number of grade 3 and 4 leukopenia and thrombocytopenia. Weekly cisplatin regimen significantly reduced the incidence of hematotoxicity (odds ratio, 0.62; 95% CI, 0.46Y0.83, P = 0.001, Fig. 2) compared with triweekly regimen. Gastrointestinal complications (reported in 3 trials) including grade 3 or 4 nausea, vomiting or diarrhea. There was no different between the 2 arms in the risk of gastrointestinal toxicity (odds ratio, 0.72; 95% CI, 0.37Y1.43, P = 0.35, Fig. 3). Compliance and Recurrence The rate of compliance was extracted from 3 of the 5 included studies. The analysis found that weekly cisplatin FIGURE 1. Risk of bias summary. 346 * 2016 IGCS and ESGO
International Journal of Gynecological Cancer & Volume 27, Number 2, February 2017 Weekly vs Triweekly Cisplatin Chemoradiotherapy FIGURE 2. Forest plot of hematologic toxicity. chemotherapy concurrent with radiotherapy was not significantly superior to the triweekly cisplatin arm (odds ratio, 0.62; 95% CI, 0.21Y1.79, P = 0.38). And the rate of recurrence, which was reported in all 5 trials, was similar between the weekly and triweekly chemotherapy regimens (odds ratio, 1.19; 95% CI, 0.93-1.53, P =0.17). Survival Rates The OS was mentioned in all of the 5 studies. Three trials reported the 5-year OS, Kim2008evaluated the 4-year OS and DiSilvestro 2014 showed the 3-year OS. The analysis for the OS of the 2 cisplatin schedules did not find significantly statistical difference (odds ratio, 0.83; 95% CI, 0.66Y1.06, P =0.13). Data on PFS were extracted from 3 publications, which reporting the 5-year PFS, 4-year PFS and 3-year PFS, respectively. There was no difference between weekly cisplatin and triweekly cisplatin regimens (odds ratio, 1.03; 95% CI, 0.78Y1.35, P =0.84). Figure 4 and Figure 5 showed the forest plot of OS and PFS. Risk of Publication Bias Publication bias was assessed using Begg s funnel plot, and no obvious asymmetry was presented. This suggests that there was no evidence of publication bias. DISCUSSION Previous studies demonstrated that locally advanced cancer had high recurrence rate after completion of radiation therapy in spite of improving the radiation equipment and techniques. 16 With the development of a series of large randomized trials (2Y6), the advantage of cisplatin-based concurrent chemoradiation was widely realized. Rose et al 5 found higher rates of survival and PFS among patients who were treated with radiotherapy and cisplatin-based chemotherapy. The reason is that cisplatin could enhance the effects of FIGURE 3. Forest plot of gastrointestinal toxicity. * 2016 IGCS and ESGO 347
Chen et al International Journal of Gynecological Cancer & Volume 27, Number 2, February 2017 FIGURE 4. Forest plot of the OS. radiation by restraining the repair of radiation-induced sublethal damage and sensitizing hypoxic cells to radiation. Although the most popular regimens are weekly cisplatin chemotherapy concurrent with radiotherapy, the optimal dose and regimen have not yet been defined. Thus, we performed this metaanalysis to evaluate the effectiveness of weekly and triweekly cisplatin concurrent chemoradiation, with 5 randomized controlled clinical trials included eventually. Nevertheless, the incidence of adverse reactions has been reported to be significantly higher in patients treated with concurrent chemoradiotherapy using cisplatin than that observed in the control group. 17 Hematologic toxicity is a severe problem in patients receiving concurrent chemoradiotherapy for treatment of cervical cancer, which often resulting in delayed or missed chemotherapy treatments and even impacting the prognosis. 18 The degree of hematologic toxicities, especially leucopenia, is one of the major dose-limiting factors in cisplatin administration. 17,19 Our analysis demonstrated that there was lower hematologic toxicity in weekly cisplatin 30 to 40 mg/m 2 than triweekly cisplatin 50 to 100 mg/m 2 chemotherapy concurrent with radiotherapy. This could be interpreted by the lower cisplatin dose and shorter duration of treatment. However for gastrointestinal complications, there was no discrepancy between the 2 chemoradiotherapy groups. Although the previous trials showed the superiority of compliance 8 and recurrence 9,15 in weekly cisplatin chemotherapy concurrent with radiotherapy, our study did not discover the obvious differentiation comparing weekly versus triweekly cisplatin arm. Weekly cisplatin regimen was considerable and feasible, though it was not superior in the OS and PFS than triweekly cisplatin. Kim et al 14 reported that weekly cisplatin group had the same treatment outcomes as the triweekly cisplatin group but with less toxicity. Furthermore, the arm of weekly cisplatin has the advantage of not requiring hospitalization. 8 Therefore, we recommend the weekly cisplatin 30 FIGURE 5. Forest plot of the PFS. 348 * 2016 IGCS and ESGO
International Journal of Gynecological Cancer & Volume 27, Number 2, February 2017 Weekly vs Triweekly Cisplatin Chemoradiotherapy to 40 mg/m 2 chemoradiotherapy as the strong candidate for the optimal cisplatin dose and dosing schedule in the treatment of locally advanced cervical cancer. REFERENCES 1. Garcia AA, Blessing JA, Darcy KM, et al. Phase II clinical trial of capecitabine in the treatment of advanced, persistent or recurrent squamous cell carcinoma of the cervix with translational research: a gynecologic oncology group study. Gynecol Oncol. 2007;104:572Y579. 2. Keys HM, Bundy BN, Stehman FB, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 1999;340:1154Y1161. 3. Morris M, Eifel PJ, Lu J, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 1999;340: 1137Y1143. 4. Peters WA 3rd, Liu PY, Barrett RJ 2nd, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol. 2000;18:1606Y1613. 5. Rose PG, Bundy BN, Watkins EB, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999;340:1144Y1153. 6. Whitney CW, Sause W, Bundy BN, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group Study. J Clin Oncol. 1999;17:1339Y1349. 7. Lanciano R, Calkins A, Bundy BN, et al. Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in combination with pelvic radiation in advanced cervix cancer: a gynecologic oncology group study. J Clin Oncol. 2005;23:8289Y8295. 8. Kim YS, Shin SS, Nam JH, et al. Prospective randomized comparison of monthly fluorouracil and cisplatin versus weekly cisplatin concurrent with pelvic radiotherapy and high-dose rate brachytherapy for locally advanced cervical cancer. Gynecol Oncol. 2008;108:195Y200. 9. Nagy VM, Ordeanu C, Coza O, et al. Randomized phase 3 trial comparing 2 cisplatin dose schedules in 326 patients with locally advanced squamous cell cervical carcinoma: long-term follow-up. Int J Gynecol Cancer. 2012;22:1538Y1544. 10. Ryu SY, Lee WM, Kim K, et al. Randomized clinical trial of weekly vs. triweekly cisplatin-based chemotherapy concurrent with radiotherapy in the treatment of locally advanced cervical cancer. Int J Radiat Oncol Biol Phys. 2011;81:e577Ye581. 11. Hu Y, Cai ZQ, Su XY. Concurrent weekly cisplatin versus triweekly cisplatin with radiotherapy in the treatment of cervical cancer: a meta-analysis result. Asian Pac J Cancer Prev. 2012;13:4301Y4304. 12. das Nair R, Martin KJ, Lincoln NB. Memory rehabilitation for people with multiple sclerosis. Cochrane Database Syst Rev. 2016;3:CD008754. 13. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557Y560. 14. Rose PG, Ali S, Watkins E, et al. Long-term follow-up of a randomized trial comparing concurrent single agent cisplatin, cisplatin-based combination chemotherapy, or hydroxyurea during pelvic irradiation for locally advanced cervical cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25:2804Y2810. 15. DiSilvestro PA, Ali S, Craighead PS, et al. Phase III randomized trial of weekly cisplatin and irradiation versus cisplatin and tirapazamine and irradiation in stages IB2, IIA, IIB, IIIB, and IVA cervical carcinoma limited to the pelvis: a Gynecologic Oncology Group study. J Clin Oncol. 2014;32:458Y464. 16. Lanciano RM, Won M, Coia LR, et al. Pretreatment and treatment factors associated with improved outcome in squamous cell carcinoma of the uterine cervix: a final report of the 1973 and 1978 patterns of care studies. Int J Radiat Oncol Biol Phys. 1991;20:667Y676. 17. Kirwan JM, Symonds P, Green JA, et al. A systematic review of acute and late toxicity of concomitant chemoradiation for cervical cancer. Radiother Oncol. 2003;68:217Y226. 18. Green JA, Kirwan JM, Tierney JF, et al. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis. Lancet. 2001;358:781Y786. 19. Ohno T, Kato S, Wakatsuki M, et al. Incidence and temporal pattern of anorexia, diarrhea, weight loss, and leukopenia in patients with cervical cancer treated with concurrent radiation therapy and weekly cisplatin: comparison with radiation therapy alone. Gynecol Oncol. 2006;103:94Y99. * 2016 IGCS and ESGO 349