Author's response to reviews

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1 Author's response to reviews Title: Paclitaxel and concomitant radiotherapy in high-risk endometrial cancer patients: preliminary findings. Authors: Giorgia Mangili Patrizia De Marzi Saverio Beatrice Emanuela Rabaiotti Riccardo Vigano Luigi Frigerio Cinzia Gentile Ferruccio Fazio Version: 4 Date: 12 April 2006 Author's response to reviews: Milan, 12/04/2006 To BioMed Central Editorial Team Object: MS : "Paclitaxel and concomitant radiotherapy in high-risk endometriale cancer patients: preliminary findings". Thank you for consideration of our manuscript for publication in your journal. We have reviewed the manuscript according to your reviewer's comments. Reviewer 1: Patricia J. Eifel MAJOR COMPULSORY REVISIONS:. The status of the PANs must be described more clearly, particularly in view of the fact that at least 2 of the 4 recurrences involved the PANs. Of pts who had lymphadenectomy, how many had PAN dissection? How many had PAN involvement? If pts with PAN+ were excluded, this should be stated in eligibility criteria. If they were included, why were the pts treated with only pelvic RT? The status of the PANs has been described in Materials and Methods' section: "In the other cases lymph node status was unknown because these patients were either referred to our Institution after primary surgery or randomized between pelvic lymphadenectomy and nodes sampling only if grossly involved. No systematic periaortic dissection was performed in these cases. Patients with macroscopic periaortic positive nodes were excluded".. Survival rates should be calculated according to intent to treat. If the authors want to quote a second value for the pts who completed tx, it should be secondary. In the revised version of the paper survival rates have been calculated according to intent to treat. Secondly we have analyzed survival rates in patients who completed at least five cycles of chemotherapy and all the RT: "Overall and disease-free survival were evaluated from the time of surgery. Survival rates was calculated according to intent to treat. Secondly we studied survival rates in the patients who completed at least five cycles of chemotherapy and all the RT in assessing the efficacy of this treatment". Results' section has also been modified: "Relapses occurred in five patients (21.7%). Median time to recurrence was 18.6 months (range 3-28). None of the five stage IIIC patients with metastatic pelvic nodes developed periaortic recurrences (Table 3). Final event, defined according to date of death or last contact,

2 showed 17 patients (73.9%) still alive and free from disease, one alive with tumor, four dead for disease. Another patient died from another primary tumor. Overall survival of the patients who completed chemo-radiation was 81%. In this group median time to recurrence was 19.2 months. All recurrences were outside the radiation field".. In some respects, the toxicity is the most interesting part of this study as there are as yet only a few published experiences with combined weekly taxol and pelvic RT in Gyn patients. A bit more detail is justified. In particular, the authors should state what scoring system was used to measure acute and late effects in the Methods section. Did any patients require hospitalization or ER visits for acute toxicity? Acute and late toxicity data have been reported more precisely, using the WHO scale. No life-threatening toxicity was present. No patients required hospitalization or ER visits for acute toxicity. Dose reduction was not required. Eight cycles were delayed one week, in four cases for grade 3 neutropenia, in three for severe diarrhea and one for increased liver enzymes. No patients presented emesis. Hematological toxicity was mild in other cases without reduction of doses or delay of treatment. Blood transfusions and hematological support were not administered to these patients. One patient developed anaphylactic clinical reaction and suspended the chemotherapy. No patients developed alopecia. Late toxicity included one subocclusive status 8 weeks after the end of the treatment with medical resolution. Three patients reported mild recurrent intestinal dysfunctions (stipsis and/or diarrhea). One patient presented recurrent cystitis related to the treatment. MINOR ESSENTIAL REVISIONS:. The authors should add a short description of eligibility criteria in the abstract since the definitions of "high-risk" can vary widely between investigators. The description in the M&M also remains a bit ambiguous. For example, would a patient with stage IIIA disease (washings only) who had cervical stroma involved have been eligible? We add the definition of "high-risk endometrial cancer" in the abstract section. In Materials and Methods we have specified that stage IIIA did not include patients with positive washing as single unfavorable prognostic factor.. The authors refer to a "median time to recurrence." Most investigators understand this term to represent the median time to event for all patients (not reached in this series) unless otherwise stated. The authors could ammend this to "median time to recurrence for the 4 patients who relapsed" to avoid ambiguity. However, with only 4 events, it makes more sense to just list the time to rec. for each of the four (presumably 3,19.2, 28 mos and one other). Relapses occurred in five patients (21.7%). Median time to recurrence was 18.6 months (range 3-28). In the manuscript patients who relapsed have been described in detail.. M&M: "All were surgically staged..." Today, this statement would usually imply that the patients did have lymphadenectomy. It would be more accurate to state, e.g., "Patients were classified according to the FIGO surgical staging system based on findings from TAH-BSO... etc. and, in 13/23 patients, lymphadenectomy." We have changed "surgically staged" with "surgically treated" as suggested.

3 Reviewer 2: Krystyna Serkies. The manuscript focused on efficacy of chemoradiotherapy regimen. The study population is too small and heterogenous to draw the firm conclusion. Indeed, no data about therapy tolerance were included in Abstract. Thus, the alternative conclusion may be that "This small series demonstrates pelvic radiotherapy in combination with weekly paclitaxel followed by three consolidation chemotherapy cycles as an effective combined approach in HREC patients".. The authors include into this analysis only patients who received at least full 5 planned cycles of paclitaxel?. I suggest all patients enrolled into this institutional protocol should be analyzed (as intent-to-treat analysis).. Does the study group include patients analyzed in the previous manuscript?. How many patients were administered extended field irradiation?. This might influence treatment toxicity. We analyzed also the patients included in the previous manuscript. Extended field irradiation was administered to two patients.. Were the patients with cancer relapse treated?. How? The patients with relapsed cancer have been treated in four cases with chemotherapy (Cysplatin and Doxorubicine) and in one case with hormonal treatment.. The combined treatment strategy is accompanied by enhanced toxic effects. In some cases the addition of chemotherapy to RT may results in increased acute toxicity necessitating an unplanned gap of RT. It will be interesting to report in details the treatment compliance. It should be clearly described how many CHT cycles- during and after RT completion, were administered in patients who relapsed. This may be of great importance as only cancer recurrence outside of the irradiated field was observed. All the patients who presented a relapse of the disease completed 8 cycles of chemotherapy in combination with radiotherapy.. Except treatment outcome this manuscript includes information about acute toxicity which should be clearly stated in the text and in the title of Tab. 2. Toxicity scale used should be added.. I recommend that the authors include evaluation of late toxicity, as the median follow-up is nearly 3 years. Long-term complications of combined therapy in pelvic malignancies is still not fully determined. Late toxicity included one subocclusive status 8 weeks after the end of the treatment with medical resolution. Three patients reported mild recurrent intestinal dysfunctions (stipsis and/or diarrhea). One patient presented recurrent cystitis related to the treatment.. High-risk EC patients may be treated using various methods including whole abdomen RT. I recommend that the authors discuss their results in relation to study population and therapy used byother authors in more details. In the Discussion section we have been reported literature data about the use of whole abdominal radiotherapy in the treatment of endometrial cancer patients: "Sutton et al found 29% recurrence free survival in patients with endometrial adenocarcinomas stage III-IV with gross residual disease, gross extrauterine spread with all disease resected or microscopic extrauterine disease while Martinez et al obtained 59% disease free survival rate in stage I-III endometriale carcinoma at high risk for intra-abdominopelvic recurrence. The comparison between whole abdominal radiation therapy and

4 Doxorubicin plus Cisplatin chemotherapy in a randomized phase III trial on advanced endometrial carcinoma showed a significantly improved progression-free and overall survival in patients treated with chemotherapy". SOME MINOR REMARKS:. The authors stated that "A total of the 157 cycles of paclitaxel were administered concomitantly with RT". This is not true - 23 pts x 5 cycles administered during RT = 115 cycles. Similarly in the sentence "Brachytherapy was used in IIIB patients". According to data from Tab. 1 there was only one patient (no. 18) with stage IIIB EC. Total number of cycles of Paclitaxel was 157 and included both the cycles administered during radiotherapy and the consolidation chemotherapy. We correct the sentence as "Brachiterapy was used in IIIB patient". The units should be used in unique manner (SI scale) in all the study. Reviewer 3: David G. Mutch GENERAL:. The paper must be approved by a human studies committee. I saw no such approval. This study has been approved by the Ethic Committee of our Institute. MAJOR COMPULSORY REVISIONS:. The numbers are quite small to asses response of efficacy; more patients would be helpful. There is essentially no toxicity data. Just a small number of high risk endometrial cancer patients are commonly admitted to each institute, that's why it is difficult to obtain studies on a larger series of cases. A multicentric study would be required to verify the efficacy of this treatment. Our paper represents an analysis on toxicity and preliminary data of efficacy of concomitant chemotherapy and radiation therapy. Toxicity data have been reported in details in the revised version of the manuscript.

5 . This would be better tested on a recurrent population and then tried in a primary setting group. Since recurrences normally occur in high risk patients previously submitted to postoperative radiation therapy it is rather difficult to perform this kind of treatment in case of relapse. Best regards, Giorgia Mangili

Case Scenario 1. History

Case Scenario 1. History History Case Scenario 1 A 53 year old white female presented to her primary care physician with post-menopausal vaginal bleeding. The patient is not a smoker and does not use alcohol. She has no family