Study On Individualized Optimal Treatment Of Endometrial Carcinoma Based On

Part Ⅰ A Prospective Study of Fertility-Sparing Treatment with Megestrol Acetate Following Hysteroscopic Curettage for Well-differentiated Endometrioid Carcinoma and Atypical Hyperplasia in Young WomenObjective:To investigate the feasibility and efficacy of curettage with hysteroscopy followed by megestrol acetate (MA) for well-differentiated endometrioid carcinoma (EC) confined to endometrium and atypical hyperplasia (AH) in young women. Patients and Methods:Fourteen patients with EC and12patients with AH prospectively enrolled onto this study. All patients received at least12weeks oral MA (160mg/day) following thorough curettage with hysteroscopy. Response was assessed histologically every12weeks. The primary endpoint was the complete response rate. Adverse event, pregnancy rate and recurrence rate were secondary end points. Results: Twenty-one (80.8%) patients responded to treatment. The median time to response was12weeks. After a median follow-up of32months,6patients recurred. Significantly more patients with infertility or PCOS experienced recurrence (P=0.040, P=0.015). Eight patients attempted to conceive after complete response,5conceive and4normal deliveries were achieved. No disease-related or treatment-related death was observed. Conclusions:Fertility-sparing treatment with MA following entirely hysteroscopic curettage is effective with the least toxicities for rigorously selected young women with well-differentiated EC confined to endometrium or AH, however, close follow-up is needed for potential consequences of improper patient selection and substantial rate of recurrence. Part II Role of systematic lymphadenectomy in the treatment strategy of endometrial cancer and feasibility study for carrying out the surgeryPurpose:The role of lymphadenectomy for endometrial cancer is still controversial. Few Gynecologists in China carry out para-aortic lymphadenectomy for patients with endometrial cancer. The aim of the current study was to investigate the role of systematic lymphadenectomy in the treatment strategy of endometrial cancer and the feasibility in carrying out the surgery. Patients and Methods:The status of lymphadenectomy and the complications associated with the procedure of the128patients of endometrial cancer undergoing surgical pathological staging from January2005to July2008in Cancer Hospital, Fudan University were analyzed retrospectively. Results:Nineteen (14.8%) of128patients undergoing systematic lymphadenectomy had lymph node metastases:both pelvic and para-aortic in7patients, only pelvic in8patients, and exclusively isolated to the para-aortic area in4patients. Therefore, more than half of patients with lymphatic dissemination had para-aortic lymph node metastases. Adjuvant chemotherapy and/or tumor-directed radiotherapy were needed for15patients who were upstaged due to lymph-nodal invasion. Furthermore, adjuvant therapy could eliminate for early stage endometrial cancer patients with negative lymph nodes and no extrauterine spread. Complications were found in8patients:3pelvic infection,2residual vaginal bleeding, and1pero-bowel obstruction, deep venous thrombosis accompanied with lymphocyst and lacunar infarction. The median time of the procedure was150minutes, median blood loss was300ml, and27patients received blood transfusion. Conclusions:The findings of the current study suggest that it is safe and feasible to carry out systematic lymphadenectomy in women with endometrial cancer. Surgical pathological staging surgery can assess the status of lymph nodes, provide accurate prognostic information, and help to formulate adjuvant therapy after surgery. Part III Clinicopathological factors associated with para-aortic lymph node metastasis in endometrioid endometrial adenocarcinoma:a consecutive study of689patientsObjective:To evaluate the correlations between various clinicopathological findings and para-aortic lymph node metastasis (PALNM) in endometrioid endometrial adenocarcinoma (EEA). Patients and methods:We prospectively followed689consecutive patients with EEA who were surgically staged from Jan2006to Dec2011at Fudan University Shanghai Cancer Center for incident cases of lymph node metastasis. Correlations between various clinicopathological factors and PALNM were assessed by univariate and multivariate analyses. Results:Among the689eligible patients,61(8.9%) had lymph node metastases. Of these,30(49.2%) had only pelvic lymph node metastasis (PLNM) and21(34.4%) had metastases that involved both pelvic and para-aortic lymph nodes. The other10(16.4%) patients had PALNM without PLNM (defined as isolated PALNM). The incidence of PALNM and isolated PALNM in the study cohort were4.5%and1.5%, respectively. Univariate analysis showed that poor differentiation, tumor diameter (TD)≥2cm, deep. myometrial invasion (DMI), cervical invasion, corneal or fundus-localized tumors, adnexal invasion, lymph-vascular space invasion (LVSI), serum CA125≥35IU/ml, positive peritoneal washings and PLNM were significant factors for PALNM. Multivariate analysis revealed that only adnexal invasion, serum CA125≥35IU/ml and PLNM were independent factors for PALNM. Regarding isolated PALNM, DMI, cervical invasion, adnexal invasion, LVSI, serum CA125≥35IU/ml and positive peritoneal washings were significantly involved in PALNM, but only adnexal involvement and LVSI were identified as significant independent factors by multivariate analysis. Conclusions:Adnexal invasion, elevated serum levels of CA125and PLNM are significant independent factors for PALNM, but only adnexal involvement and LVSI are significant independent factors for isolated PALNM. Owning to the lack of preoperative and intraoperative methods to correctly assess these parameters, PLA is still necessary for patients, except for those with well differentiated EEA without DMI. Multicenter, prospective studies are required to confirm the observations. Further studies to identify who can safely omit comprehensive PLA are urgently warranted. Part IV Para-aortic lymphadenectomy should be carried out in patients with clinically early-stage non-endometrioid carcinoma:a study of56consecutive patientsObjective:To evaluate the rate of para-aortic lymph node metastasis (LNM) among patients with comprehensive pelvic and para-aortic lymphadenectomy with clinically early-stage non-endometrioid carcinoma, and the correlation between para-aortic LNM and various clinical-pathological findings. Patients and methods:We prospectively collected the medical records and pathological findings of56consecutive patients with non-endometrioid carcinoma who were surgically staged at Fudan University Shanghai Cancer Center from Jan2006to Dec2011. Para-aortic lymphadenectomy was extended to the inferior mesenteric artery before Jan2010, after which the procedure was modified to extend up to the renal vessels. Results: The median number of lymph nodes harvested was21(range,10-39) and6(range,4-29) for pelvic nodes and para-aortic nodes, respectively. LNM was identified in19patients, pelvic LNM alone was identified in2(10.5%) patients, both pelvic LNM and para-aortic LNM were identified in10(52.6%) patients, and para-aortic LNM alone was identified in7(36.8%) patients. Univariate analysis showed that deep myometrial invasion, adnexal invasion, lymph-vascular space invasion, positive peritoneal washings, a corneal or fundus-localized tumor, and pelvic LNM were significantly associated with para-aortic LNM and/or isolated para-aortic LNM, but only pelvic LNM and a corneal or fundus-localized tumor were significant independent factors for para-aortic LNM and isolated para-aortic LNM, respectively. Conclusions:Due to the lack of preoperative and intraoperative methods to correctly assess the clinical-pathological factors associated with para-aortic LNM and the high risk for para-aortic LNM in patients with non-endometrioid carcinoma, para-aortic lymphadenectomy is necessary for such patients. PART V Sentinel lymph nodes mapping and micrometastases detection in patients with early-stage endometrial cancerObjective:We did a prospective, randomized study to assess the rate and diagnostic accuracy of the sentinel lymph node (SLN) procedure in predicting the pathological retroperitoneal lymph node status in patients with early-stage endometrial cancer via pericervical injection, subserosal injection and peritumor injection. Patients and Methods:All patients were randomly allocated to pericervical injection group, subserosal injection group and peritumor injection group. For patients in cervical injection group,24hours before surgery2mCi(74MBq) of (99m)Tc-nanocolloid (2mL) was injected into four spots in cervical myometrium. SLN was localized preoperatively by lymphoscintigraphy and intraoperatively with gamma probe. Four millimeter patent blue was injected into four spots in cervical myometrium at surgery. For patients in subserosal injection group,4ml patent blue was injected into4subserosal spots near the fundus and2pericevical spots from isthmus. Four millimeter patent blue was injected into four spots around the tumor for patients at peritumor injection group. After SLN biopsy the patients underwent a complete pelvic and paraaortic lymphadenectomy. All lymph nodes were histopathologically examined and SLNs were serial sectioned and examined by immunochemistry in patients with negative SLN and non-SLN by HE. Results:One hundred and sixty patients with early-stage endometrial cancer enrolled between Sep2010and Mar2013:57patients in cervical group,53patients in subserosal group, and50patients in peritumor group. At least one SLN was detected in100%,96.2%,80%patients of the3group, respectively. Significantly less SLN was detected in peritumor group(P<0.05). Considering the hemipelvis as the unit of analysis, the detection rate was77.1%,72.6%, and68.0%, respectively. Significantly more SLN was detected among patients in cervical group, but more less para-aortic SLN was detected in this cohort. The median harvest SLN was4for all3group, and the false negative rate was2.0%,2.3%and0for patients in cervical group, subserosal group and peritumor group. Eighteen patients had micrometastases in SLN. No allergic reactions was recorded. Conclusions:Although SLN biopsy has shown good diagnostic performance in endometrial cancer, such performance should be interpreted with caution because of false negative rate. SLN biopsy with cervical dual labelling could be a trade-off between systematic lymphadenectomy and no dissection at all in patients with endometrial cancer of low risk. For patients with intermediate or high risk endometrial cancer, peritumor injection or subserosal injection may be the appropriate selection. Current evidence is not yet sufficient to establish the true performance of SLN biopsy in endometrial cancer. Further study was needed to assess the feasibility and safety of omitting systematic lymphadenectomy in patients with SLN biopsy in patients with early-stage endometrial cancer. Part VI A phase II study of paclitaxel plus carboplatin in patients with advanced or recurrent endometrial cancerObjective:A phase Ⅱ trial of combination paclitaxel and carboplatin (TC) was performed in patients with advanced or recurrent endometrial cancer in Fudan University Shanghai Cancer Center to estimate the efficacy and toxicity. Patients and Methods:Eligible patients with measurable disease were enrolled between Jan2009and Sep2012. Six courses of paclitaxel (135mg/m2) and carboplatinum (AUC5) on day1every3weeks were administered in outpatients. Response rates were evaluated according to the response evaluation criteria in solid tumors. Results:Forty patients with assessable disease enrolled,16with residual disease after primary or second cyto-reductive surgery (group A),24with unresectable recurrent or metastatic disease (group B). In the complete series,12CR (30%) and16(40%) PR were recorded, with an ORR (overall response rate) of70%(95%CI53%-83%). Significantly more patients in group A experienced CR than group B (56.2%VS16.67%, P=0.009), but the difference of ORR was not statistically significant (P=0.205). In unvariate analysis, residual disease≤2cm and chemotherapy-naive were associated with increased CR(P <0.001, P=0.011). In multivariate analysis, only chemotherapy-naive was associated with increased response rate (P=0.041). The2-year OS and DFS were71.8%and77.6%, respectively. Hematological toxicities (G3/G4) were neutropenia (35.0%/7.5%), anemia (10%/2.5%) and thrombocytopenia (2.5%/2.5%). Reversible G3hypersensitivity (4.8%), G2vomiting (2.5%) and G2cardiotoxicity (2.5%) was uncommon. Conclusions:TC regimen has an acceptable toxicity profile and appears to have activity in advanced or recurrent endometrial cancer, especially in chemotherapy-naive patients. Further studies are urgently warranted to confirm the efficacy of TC regimen and to explore new agents for TC-refractory patients.