Author's response to reviews Title:Randomized Phase III Trial of Radiotherapy or Chemoradiotherapy With Topotecan and Cisplatin in Intermediate-Risk Cervical Cancer Patients After Radical Hysterectomy Authors: Wenze Sun (swz032021511986@163.com) Tao Wang (wangtaoxjtu@126.com) Fan Shi (shifanxjtu@1126.com) Jiquan Wang (wangjiquanxjtu@126.com) Juan Wang (wangjuanxjtu@126.com) Beina Hui (huibeinaxjtu@126.com) Yingbing Zhang (zhangyingbingxjtu@126.com) Jinli Lu (lujinlixjtu@126.com) Hongwei Chen (chenhongweixjtu@163.com) Zi Liu (liuzmail@163.com) Version:4Date:31 March 2015 Author's response to reviews: see over
Author's response to reviews Title: Randomized Phase III Trial of Radiotherapy or Chemoradiotherapy With Topotecan and Cisplatin in Intermediate-Risk Cervical Cancer Patients After Radical Hysterectomy Authors: Wenze Sun (swz032021511986@163.com) Tao Wang (wangtaoxjtu@126.com) Fan Shi (shifanxjtu@1126.com) Jiquan Wang (wangjiquanxjtu@126.com) Juan Wang (wangjuanxjtu@126.com) Beina Hui (huibeinaxjtu@126.com) Yingbing Zhang (zhangyingbingxjtu@126.com) Jinli Lu (lujinlixjtu@126.com) Hongwei Chen (chenhongweixjtu@163.com) Zi Liu (liuzmail@163.com) Version: 2 Date: 31 March 2015 Author's response to reviews: see over
Dear Editor: Thank you for the feedback. I am very grateful for your advice and reviewers comments about our manuscript (Randomized Phase III Trial of Radiotherapy or Chemoradiotherapy With Topotecan and Cisplatin in Intermediate-Risk Cervical Cancer Patients After Radical Hysterectomy. MS: 1822812462147239). In response to the comments and advices, we have revised our manuscript. Here are the point-to-point responses to the reviewers comments: Reviewer # 1 ( Dr Giulia Amadio): We first thank for the positive comments 1-5, 8 and10 of Giulia Amadio. 6 The discussion and conclusions are well balanced and adequately supported by the data but the limitations of the work are not clearly stated in the paper; a longer follow up period could be useful to report survival data. Revision: We have stated the limitations of the study in the discussion part of revised paper. It could be seen in lines 268 to 275 on page 7: Although our study showed severe hematologic toxicity of concurrent chemoradiation with topotecan and cisplatin in safe dose to radiation in patients with intermediate-risk factors, the efficacy and toxicity are still unclear. As we mentioned in the results, the number of patients in the different group is small (14 in group A, 15 in group B and 10 in group C) because the study closed ahead of schedule and the media follow-up time is only 16 months. In spite of these limitations, due to topotecan has been identificated as an antineoplastic agent with cisplatin in cervival cancer, a trial with optimal dose,sufficient size and long term follow-up would be necessary to demonstrate the advantage of concurrent chemoradiation in patients with intermediate-risk factors. 7 authors may report : Postoperative pelvic intensity-modulated radiotherapy and concurrent chemotherapy in intermediate- and high-risk cervical cancer. Folkert MR, Shih KK, Abu-Rustum NR, Jewell E, Kollmeier MA, Makker V, Barakat RR, Alektiar KM. Gynecol Oncol. 2013 Feb;128(2):288-93. doi: 10.1016/j.ygyno.2012.11.012.Epub 2012 Nov 15. Impact of the addition of concurrent chemotherapy to pelvic radiotherapy in surgically treated stage IB1-IIB cervical cancer patients with intermediate-risk or high-risk factors: a 13-year experience. Okazawa M, Mabuchi S, Isohashi F, Suzuki O, Yoshioka Y, Sasano T, Ohta Y,Kamiura S, Ogawa K, Kimura T. Int J Gynecol Cancer. 2013 Mar;23(3):567-75. Role of adjuvant radiotherapy after radical hysterectomy in node-negative stage IB-IIA cervical cancer with intermediate risk factors.tuipae S, Yanaranop M, Oniem N.J Med Assoc Thai. 2012 Mar;95 Suppl 3:S117-24. Revision: We have reported the studies in our revised discussion in lines 196 to 197 and lines 205 to 210 on page 6. Lines 196-197: In addition, in the study of Tuipae S et al, distant recurrence was still the major pattern of treatment failure after adjuvant radiotherapy in cervical cancer with intermediate risk factors[12]. Lines 205-210: Okazawa M et al reviewed the medical records of 316 patients with stage
IB1-IIB cervical cancer who had been treated with adjuvant radiotherapy (RT) (n = 124, RT group) or adjuvant CCRT (n = 192, CCRT group) after radical hysterectomy and found that CCRT was superior to RT with regard to recurrence rate and PFS in patents with 2 or more intermediate risk factors, while the patients with only 1 intermediate risk factor showed no survival benefit of CCRT over RT[20]. Reviewer # 2 (Dr Giacomo Corrado): We also first thank for the comments of Giacomo Corrado. 1 The number of patients in the different group is very small in order to express any conclusion. Revision: We aimed to report that, although topotecan with cisplatin has been shown acceptable toxicity and good response rates in recurrent or metastatic cervical cancer, topotecan plus cisplatin chemotherapy in safe dose with RT in present study showed severe hematologic toxicity and the study was closed ahead of schedule. Therefore, the number of enrolled patients was small which may have resulted in study data bias. Trials with optimal dose,sufficient size and long term follow-up would be carried out to demonstrate the advantage of concurrent chemoradiation with topotecan and cisplatin in patients with intermediate-risk factors in the following time. 2 Authors should explain what kind of radical surgery performed in these patients. Revision: We have explained what kind of radical surgery performed in these patients in lines 99 to 101 on page 3: Radical hysterectomy and pelvic lymphadenectomy, with or without para-aortic lymphadenectomy was performed either via laparotomy or laparoscopy, according to the Gynecologic Procedures Manual of the GOG, which outlined minimum surgical requirements for study entry[15]. 3 Authors should explain the scientific basis on which they wanted to create the group C. Authors report 20 IB2 and 10 IIA in their study. Why these patients have not been treated with RTCT neoadjuvant or exclusive? In fact, these treatments are considered the first choice in these patients. Revision: We have explained the scientific basis on which we wanted to create the group C in our revised discussion on pages 6-7. Recently, cisplatin-based consolidation chemotherapy after CCRT has been reported to enhance local control and promote eradication of possible distant micro-metastases in locally advanced cervical cancer by phase II studies [1-3]. These promising results suggested that consolidation chemotherapy after primary CCRT may play a role independent of the radiotherapy in locally advanced cervical carcinoma. Furthermore, for high-risk patients after radical surgery, whether consolidation chemotherapy after CCRT could improve PFS and OS as compared to CCRT-only is controversial [4-5]. However, to date, no study has looked at the role of consolidation chemotherapy following CCRT in intermediate-risk cervical cancer patients? We designed arm C (CCRT+CT) to examine whether the addition of consolidation chemotherapy to CCRT could improve the PFS and OS in patients with intermediate-risk factors after radical surgery.
References: 1. Vrdoljak E, Prskalo T, Omrcen T, Situm K, Boraska T, Frleta Ilić N, Janković S, Hamm W:Concomitant chemobrachyradiotherapy with ifosfamide and cisplatin followed by consolidation chemotherapy in locally advanced squamous cell carcinoma of the uterine cervix: results of a phase II study. Int J Radiat Oncol Biol Phys. 2005, 61:824-9. 2. Zhang MQ, Liu SP, Wang XE: Concurrent chemoradiotherapy with paclitaxel and nedaplatin followed by consolidation chemotherapy in locally advanced squamous cell carcinoma of the uterine cervix: preliminary results of a phase II study. Int J Radiat Oncol Biol Phys. 2010, 78:821-7. 3. Choi CH, Lee YY, Kim MK, Kim TJ, Lee JW, Nam HR, Huh SJ, Lee JH, Bae DS, Kim BG: A matched-case comparison to explore the role of consolidation chemotherapy after concurrent chemoradiation in cervical cancer. Int J Radiat Oncol Biol Phys. 2011, 81:1252-7. 4. Peters 3rd WA, Liu PY, Barrett 2nd RJ, Stock RJ, Monk BJ, Berek JS, Souhami L, Grigsby P, Gordon W Jr, Alberts DS: 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: 1606-13. 5. Kim HS, Kim MK, Kim HJ, Han SS, Kim JW: Phase II Study of Consolidation Chemotherapy after Adjuvant or Primary Concurrent Chemoradiation Using Paclitaxel and Carboplatin to Treat High-Risk Early-Stage or Locally Advanced Cervical Cancer. Cancer Res Treat. 2012, 44:97-103. According to NCCN guideline, definitive concurrent chemoradiotherapy is considered to be the first choice for stage IB2 and IIA2 cervical cancer (category 1). But at the same time, radical surgery followed by adjuvant therapy has also been accepted as the treatment in patients with stage IB2 and IIA2 cervical cancer (category 2B). In China, not every medical institution could perform definitive radiotherapy. Therefore, they may first choose the radical surgery for stage IB2 and IIA2 cervical cancer according to their own ability. 4 To improve the quality of the study, the authors should perform a review of published works on the subject with careful attention to the impact on the survival of the different treatments performed. Revision: In our revised discussion on page 6(lines 199 to 210),some retrospective studies in recent years have showed adjuvant CCRT was superior to RT with regard to RFS (recurrence-free survival) or PFS in patients with intermediate-risk factors[1-5]. However, due to the lack of randomized trials,whether adjuvant CCRT or adjuvant CCRT followed by consolidation chemotherapy could improve PFS and OS in patients with intermediate-risk factors is still unclear. On account of the scientific basis, we wanted to carry out the present study. We will perform a review of studies on the subject with careful attention to the impact on the survival of the different treatments performed in the following time. References: 1. Soisson AP, Soper JT, Clarke-Pearson DL, Berchuck A, Montana G, Creasman WT: Adjuvant radiotherapy following radical hysterectomy for patients with stage IB and IIA cervical cancer. Gynecol Oncol 1990, 37: 390-5. 2. Kim K, Kang SB, Chung HH, Kim JW, Park NH, Song YS: Comparison of chemoradiation with radiation as postoperative adjuvant therapy in cervical cancer patients with intermediate-risk factors. Eur J Surg Oncol 2009, 35: 192-6. 3. Ryu SY, Park SI, Nam BH, Cho CK, Kim K, Kim BJ, Kim MH, Choi SC, Lee ED, Lee KH: Is adjuvant chemoradiotherapy overtreatment in cervical cancer patients with intermediate risk factors? Int J Radiat Oncol Biol Phys 2011, 79: 794-9. 4. Lee TY, Jeung YJ, Lee CJ, Kim HY, Kim SH, Kim WG: Promising treatment results of adjuvant chemotherapy following
radical hysterectomy for intermediate risk stage 1B cervical cancer. Obstet Gynecol Sci 2013, 56:15-21. 5. Okazawa M, Mabuchi S, Isohashi F, Suzuki O, Yoshioka Y, Sasano T, Ohta Y, Kamiura S, Ogawa K, Kimura T: Impact of the addition of concurrent chemotherapy to pelvic radiotherapy in surgically treated stage IB1-IIB cervical cancer patients with intermediate-risk or high-risk factors: a 13-year experience. Int J Gynecol Cancer. 2013, 23:567-75. All changes made when revising the manuscript have been highlighted with red colored letters. Yours sincerely, Wenze Sun, Zi Liu