Prof. Dr. Aydın ÖZSARAN

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1 Prof. Dr. Aydın ÖZSARAN

2 Adenocarcinomas of the endometrium Most common gynecologic malignancy in developed countries Second most common in developing countries. Adenocarcinomas, grade 1 and 2 endometrioid uterine cancers have a favorable prognosis typically present at an early stage. Other histologic types of uterine adenocarcinoma (serous, clear cell) are associated with a poorer prognosis.

3 Staging System The American Joint Committee on Cancer (AJCC) International Federation of Gynecology and Obstetrics (FIGO) Risk for recurrent or persistent disease into low, intermediate, and high risk.

5 Advanced stage endometrial cancer Advanced-stage endometrial cancer 10-15% of all newly diagnosed cases Account for over half of all uterine cancer related deaths Behbakht K, Gynecol Oncol 1994 Survival rate as low as 5 20% for stage IV disease Optimal management in women with advanced stage or recurrent endometrial cancer is not well defined Wolfson AH, Gynecol Oncol 1992

6 DEFINITION OF HIGH RISK Serous or clear cell adenocarcinoma (any stage) Pathologic stages III/IV disease Results of The Cancer Genome Atlas (TCGA) analysis suggest that a subset of grade 3 endometrioid cancers are biologically similar to serous carcinomas, but this subgroup has not been well defined using conventional clinicopathologic factors Cancer Genome Atlas Research Network, NATURE 2013

7 Uterine serous or clear cell carcinoma Surveillance, Epidemiology, and End Results (SEER) study 1998 to The five-year survival rate stratified by histologic type was respectively % 45 (serous), % 65 (clear cell), % 91 (endometrioid) adenocarcinomas. NCI, SEER Program, National Cancer Institute; Bethesda, MD 2007.

9 five year survival rate Serous Clear cell Endometrioid Stage I Stage II Stage III Stage IV NCI, SEER Program, National Cancer Institute; Bethesda, MD 2007.

10 five year survival rate Stage I Stage II Stage III Stage IV Stage III, grade 1 Stage III, grade 2 Stage III, grade (SEER) study of over 44,000 women five year survival was 97, 80, 60, and 25 percent for stage I, II, III, or IV disease NCI, SEER Program, National Cancer Institute; Bethesda, MD 2007.

11 Cytoreduction Rational Improvement of perfusion and drug delivery Decrease in adverse metabolic events to improve performance status Reduction of viable tumor cells with potential for somatic mutations that can cause drug resistance Munkarah A, Gynecol Oncol 2001

12 Surgical cytoreduction Cytoreduction Primary pelvic or intra-abdominal disease Extraabdominal disease Recurrent disease Cytoreduction appears to confer a survival advantage High quality data are lacking Limited to small, non-randomized, retrospective studies. Barlin JN,Gynecol Oncol 2010

Meta analysis of 14 retrospective case series that included 10 studies of primary disease and 4 studies of recurrent disease 1997 to 2009 andincorporated672 patients.

13 Meta analysis of 14 retrospective case series that included 10 studies of primary disease and 4 studies of recurrent disease 1997 to 2009 andincorporated672 patients. Optimal surgical cytoreduction 2 cm in three studies (140 patients or 20.8%) 1 cm in seven studies (375 patients or 55.8%) No gross evidence of disease in four studies (157 patients or 23.3%). optimal surgical cytoreduction 52% to 75%. complete surgical resection 18% to 75%. Complete cytoreduction longer median survival. Primary disease overall survival rates complete cytoreduction (30 to 51 percent) optimal cytoreduction, (15 to 51 percent). 2010

16 Patients undergoing adjuvant chemotherapy negatively impacted survival, decreasing survival by 10.4 months. GOG 122, a randomized phase III trial of whole abdominal radiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial cancer, in which chemotherapy was associated with a significantly improved progression-free and overall survival when compared to radiation Randall ME, Gynecologic Oncology Group Study. J Clin Oncol 2006

17 Pliskow et al. overall 5-year survival rate was 48% for patients who received surgery and radiation compared to surgery (8%) or radiation (25%) alone. Goff et al. median survival of 18 months in 29 women with surgically resectable disease compared to 8 months in patients who did not undergo surgery. For those patients in whom the tumor was determined to be unresectable, the median survival was 2 8 months, regardless of further treatment with radiation therapy, chemotherapy, or both Goff BA, Gynecol Oncol 1994 Chi DS, Gynecol Oncol 1997 Shih KK Gynecol Oncol 2011

The mean PFS of patients who received optimal cytoreduction was significantly better than that of the patients who received suboptimal cytoreduction (115.2 ± 16 vs. 63.6 ± 12 months, p =0.

20 The mean PFS of patients who received optimal cytoreduction was significantly better than that of the patients who received suboptimal cytoreduction (115.2 ± 16 vs ± 12 months, p =0.001) The mean OS of patients who received optimal cytoreduction was better than that of the patients who received suboptimal cytoreduction; however, no statistical significance was observed (117.2±16 vs ± 11 months, p < 0.056).

28 Treatment of recurrent or metastatic endometrial cancer Most women who relapse will do so within three years of the initial diagnosis. Bleeding (which emanates from the vagina, bladder, or rectum) Anorexia, weight loss, bone or pelvic pain Cough, shortness of breath, or lower abdominal or extremity swelling Tumors may be localized to the vagina, limited to the pelvis metastatic disease involving the abdominal cavity Extraabdominal (other organs) Survival seems to be dependent on Type of recurrence Solitary recurrence vs. carcinomatosis The ability to achieve optimal cytoreduction The time from original treatment to recurrence Campagnutta E, Cancer 2004;

29 Treatment of recurrent or metastatic endometrial cancer Historically, the role of surgery in recurrent endometrial cancer was limited to candidates for total pelvic exenteration who had recurrence limited to the vaginal apex within a previously irradiated field Postoperative morbidity were (60 80%) and mortality (10 15%) Barakat RR, Gynecol Oncol 1999 Morris M, Gynecol Oncol 2010

30 Treatment of recurrent or metastatic endometrial cancer The role of surgery for recurrent endometrial cancer has not been evaluated well. Five-year OS ranged from 40% to 66% in patients who underwent pelvic exenteration despite high rates of morbidity. Nonexenterative cytoreductive surgery Chiantera V Int J Gynecol Cancer published articles OS was 12 to 76 months for the patients in whom optimal (residual tumor <1 or <2 cm or no residual tumor) debulking surgery could be performed. Turan T, Int J Gynecol Cancer. 2015

36 Subgroup analysis found that OS was similar between patients who underwent primary chemotherapy followed by surgery and those who underwent primary surgery. Data suggest that preoperative chemotherapy may be a useful treatment choice for patients with stage IVb Endometrium Ca who are not suitable for primary surgery.

38 Vandenput et al. were unique in assessing extent of disease with laparoscopy before offering NAC. Laparoscopy has been used to triage for resectability. But, a recent Cochrane review indicated that using a laparoscopy-based prediction models for OC does not increase the sensitivity and will result in more unsuccessful debulking operations Rutten MJ, The Cochrane database of systematic reviews

39 However, only 106 cases of NAC were documented in the last two decades, majority (76) were described in retrospective case reports and case series, subject to inherent limitations and biases. Therefore, no general recommendations can be drawn from the existing data. Prospective trials can definitively determine the role of NAC in advanced EC and identify preoperative characteristics of patients that will benefit most from NAC.

40 NAC Until further progress is reached, consideration can be given to recommending NAC followed by interval debulking in a trail setting to patients with poor performance status or those patients who the surgeon believes would have suboptimal debulking if surgery was attempted.

43 The median PCI at laparotomy was 12 (mean: 11.46; extreme values 3 24). The average number of organ resections in these HIPEC procedures was 2 (range 0 4). These organ resections involved a segment of the digestive tract for three patients (resection of small intestine, right or atypical colectomy), Resection of other organs in five cases (splenectomy, hysterectomy with bilateral salpingo oophorectomy, liver segmentectomy for parenchymal metastasis, partial cystectomy, resection of the right diaphragmatic dome).

45 CC 0 = no macroscopic residual cancer, CC 1 = residual nodules <2.5 mm, CC 2 = residual nodule betweens 2.5 and 25 mm, CC 3 = residual nodule> 25 mm

47 Conclusion Optimal surgical cytoreduction (variably defined as less than or equal to 1 cm or 2 cm) has been found to improve progression-free and overall survival rates in patients with advanced-stage or recurrent endometrial cancer Five large retrospective studies have addressed the advantages of optimal cytoreductive surgery in patients with stage III and stage IV endometrial adenocarcinoma. Each study demonstrated a statistically significant progression-free and overall survival advantage when optimal cytoreduction was achieved

48 Conclusion Laparoscopy could be used to triage for estimating resectability (?) The use of NAC in the treatment of advanced endometrial cancer improves patient outcomes in selected patients. HIPEC needs more data

49 Thank You

Winship Cancer Institute of Emory University Optimizing First Line Treatment of Advanced Ovarian Cancer

Winship Cancer Institute of Emory University Optimizing First Line Treatment of Advanced Ovarian Cancer Ira R. Horowitz, MD, SM, FACOG, FACS John D. Thompson Professor and Chairman Department of Gynecology