Author s response to reviews Title: Case Report of an uncommon response to metronomic therapy in a heavily pre treated patient with Metastatic Carcinosarcoma Authors: Debora Gagliato (dgagliato@gmail.com) Rudinei Diogo Marques Linck (rudineilinck@hotmail.com) Regis Otaviano Bezerra (regisfranca@gmail.com) Mirela Souto (msouto_med@hotmail.com) Gabriel Lima Lopes (gablopes_87@hotmail.com) Glauco Baiocchi (glbaiocchi@yahoo.com.br) Max Mano (max.mano@gmail.com) Version: 1 Date: 20 Jan 2016 Author s response to reviews: Rebuttal Letter Reviewer # 1 Uterine carcinosarcoma (UCS) is an aggressive malignancy with poor survival. Considering that there is no standard chemotherapy regimen, clinical physicians are exploring the proper and effective management. In this case, we found the patient with UCS that had already been treated with both cytoreductive surgery and multiple lines of conventional chemotherapy, whereas with little response. When she was treated with oral metronomic cyclophosphamide at a 50 mg per day dose, a thrilling clinical and imaging response occurred. This case may have great values in the management of UCS patients with recurrences. There still lie some questions: 1. In the Case Presentation, the author only showed the histopathology examination with not enough information, what about the pathology of LVSI, myometrial invasive depth, the status of lymph node and so on. Answer to the Reviewer: Thank you for your observation. We included details regarding the histopathology. Refer to Page 3.
2. During the treatment of oral cyclophosphamide, was there any side effects occurring such as fatigue, nausea? Was it possible that the liver abscess was correlated with the metronomic chemotherapy? Answer to the Reviewer: Patient tolerated cyclophosphamide quite well, and she didn t report any side effect from the medication. Being a cytotoxic agent, cyclophosphamide has a significant ability to suppress the immune system and can predispose patients to infections, such as the liver abscess found in this particular patient. Nevertheless, patient was regularly monitored with complete blood cells, and no leucopenia was observed during therapy. 3. Since the author analyzed the potential mechanism of the treatment of metronomic chemotherapy and VEGF protein expression was considered to be a critical activator and was associated with increased tumoral angiogenesis. Is it possible the author can use the pathological sample to do additional immunohistological staining? The positive expression of VEGF and other protein correlated with tumoral angiogenesis may bring strong evidence for the mechanism. Answer to the Reviewer: Thank you for bringing such an import observation. Angiogenesis is a complex and highly adaptive biologic process. Although VEGF is an import component of angiogenesis, multiple other factors can play an essential role during angiogenesis. We believe that a single biomarker, such as VEGF immunohistochemistry staining, may not reliably predict treatment benefit with the metronomic chemotherapy regimen. VEGF expression on tumor cells was previously studied by using immunohistochemistry, but few positive correlations were observed in patients treated with bevacizumab, a monoclonal antibody anti VEGF. In contrast, levels of VEGF-A would be more accurate in predicting response to an anti angiogenic therapy, as previous trials demonstrated that levels of VEGF-A correlated to bevacizumab response. 4. In the conclusion part, the author claimed that "exploring an anti angiogenic strategy in a heavily pre treated metastatic patient", which was not expressed properly. Because the patient did have several cytoreductive operation and conventional scheduled chemotherapy, it is not appropriate to use the phrase "pre treated". Reviewer # 2 Answer to the Reviewer: Thank you for your observation. We modified the sentence at the Conclusion part. Refer to page 6. In this clinical report, de Melo Gagliato present the case of a woman with uterine carcinosarcoma who underwent several surgical and chemotherapeutic procedures with multiple relapse and
progressive disease eventually. Switch to metronomic cyclophosphamide achieved partial response. The case is interesting, however the authors are requested to fix the following issues: 1. English need serious editing throughout the MS. For instance: Abstract P1L14: "with very little response" should be replaced by "patient (...) with multiple relapse and progressive disease despite several lines of chemotherapy". 2. Intoduction P1L40 "at initial diagnosis" rather than "at the initial diagnosis" 3. P1L52 ".. compared ifosfamide used either alone or combined with paclitaxel", rather than "ifosfamide VS the same chemotherapy combined with paclitaxel" 4. P1L43 "histo-pathological staging", 5. P2L15 "The rationale (...) will be further discussed." rather than "will be provided at the discussion.", 6. Results P4L12 "great detoriation of PS" rather than "great performance status deterioration", 7. L15 "to initiate" rather than "to start her on..." 8. Conclusion P6L13 "entity" should be replaced by "disease" and so on.
9. please rephrase the first sentence of the P2 which is far too long. Answer to the Reviewer: Thank you for your observation. We rephrased the sentence. 10. Metronomics is all about dosing and scheduling. Consequently, the switch to metronomic cyclophosphamide should be better presented if you provide full details on the dosing and scheduling of the previous chemotherapeutic cycles (i.e., CBDCA + paclitaxel, ifosfamide + epirubucin (please note that it is epirubicin, not "epirrubicin"), docetaxel, topotecan, vinorelbine), as well as duration of metronomic cyclophosphamide administration. As far as we can read abdominal pain showed 3 months after starting metronomics - was the patient undergoing continuous dosing? Answer to the Reviewer: Thank you for your observations. We provided at the Manuscript the dosing of each chemotherapy regimen. We gave cyclophosphamide continuously. 11. Please provide a new figure with a time-line encapsulating all the surgical and chemotherapeutic steps this patient underwent, including switch to metronomic schedule. This will be more than helpful to picture the whole case. Answer to the Reviewer: We do not have imaging evaluation following each procedure or chemotherapy line this patient underwent, because not every procedure and chemotherapy was performed at our institution. 12. oral vinorelbine is a good candidate as well for metronomic schedule - when switching from cyclophosphamide to this later one, was it following a metronomic strategy or a standard dosing? Answer to the Reviewer: We gave the standard vinorelbine dosing at 25 mg/m2 D1 and D8 every 21 days. 13. Grade and exact nature of the treatment-induced toxicities should be provided (P2L52). Answer to the Reviewer: Thank you for your observation. We included the toxicities description. Refer to page 3. 14. Determining the optimal dosing and scheduling of metronomic administration remain a challenging issue. Here, how dosing, frequency and duration of the administration were chosen? This should be discussed. In adults, 50 mg is often used indeed with metronomic cyclophosphamide, sometimes 50 mg/m² has been tested instead, and in some cases dosing has been increased or decreased. To date, little rationale seems to support the choice of 50 mg but previously published data regarding its tolerance. This is fine with
me, but the empirical approach of current metronomic strategies should be underlined in the MS. Answer to the Reviewer: Thank you for your observation. We included the toxicities description. Refer to page 4 and 5. 15. Overall duration of the PR should be indicated. Answer to the Reviewer: We included the response duration and PR length.