Primary surgical treatment for early epithelial ovarian cancer Francesco Fanfani Department of Medicine and Aging Sciences University "G. d'Annunzio” Chieti-Pescara, Italy francesco.fanfani@unich.it

Agenda Epidemiology and Prognosis in EOC Type of approach in EOC Role of lymphadenectomy in EOC SLN in EOC Importance of restaging Tumor rupture during LPS The role of dedicated pathologist Fertility Sparing Surgery

Early Stage Ovarian Cancer Some considerations.. 5Y Relative-survival Early stage EOC have good prognosis (around 90%) Ovarian cancer may appear during their reproductive age (around 15% of cases) MAIN ISSUES Minimally Invasive Approach Fertility sparing surgery 3

NCCN-GL recommend appropriate surgical staging, followed by adjuvant CT. Comprehensive surgical staging is recommended and includes WC, peritoneal biopsies, BSO, TH, omentectomy, Pe and Ao LFN. In selected patients who want to preserve fertility, USO can be considered. There is no mention of the type to approach to use. Adjuvant CT is based on the pathologic findings of the surgical specimen. The current NCCN guidelines recommend adjuvant CT in patients with Stage IA G3, IB G3, or any grade of IC.

No survival benefit from Lymphadenectomy Furthermore, the only available RCT , although affected by underpowered bias, did not demonstrate a survival benefit in the group of pts receiving lymphadenectomy. (SI POTREBBE ELIMINARE) No survival benefit from Lymphadenectomy

Positive LNs according with tumor histotype: Serous≈25% Mucinous=<1% Endometrioid/Clear cell≈10% Surgical staging could be tailored according to clinico-pathological risk factors Positive LNs according with tumor grade: G1/2s≈2% G3≈23% One of the major open question regarding surgical staging of appreantly Stage I-II ovarian cancer is the role of lymphadenectomy. As we present here, the percentage of metastatic lymph nodes is highly variable according with the clinico-pathological variables suggesting that SURGICAL STAGING needs to be personalized… Positive LNs according with CA125: <35UI/ml<1% >35 UI/ml≈22%

Recurrence free survival Disease specific survival

MINIMALLY INVASIVE SURGERY IN GYO ....and where we are now ESMO NCCN 2015 Endometrial cancer MIS is superior to standard laparotomy in early stage disease MIS recommended in early stage disease Level Evidence=1 Cervical cancer - MIS or laparotomy can both used in early stage disease Level Evidence=III Ovarian cancer MIS can be used for surgical staging in early stage disease Level Evidence=IIB MIS can be used to decide upfront treatment in advanced stage …but the current and last decades have been the golden age of MIS in GYO. In fact, as we can see in this slide, MIS is now considered, even if with still low level of evidence, the standard surgical approach in several clinical setting…

It is retrospective study includes a large number of homologous patients with the same histology who underwent a similar surgical procedure and received platinum-based CT. This study revealed no significant difference in clinical outcomes between groups with early and late start of CT within 6 weeks.

2005 The first, and to date the only, case control study comparing the surgical outcome of MI vs LPT approach for surgical staging was performed by MSKCC in 2005. In this study, MI approach was able to ensure a suprimposable radicality in the two groups, but with surgical outcomes and complciations rate in favor of the LPS group. No differences were observed in term of harvested lymph nodes, and omental size between the two groups Surgical outcomes and complication rate were in favour of the LPS group

2009 LPS staging appears to be feasible and comprehensive without compromising survival when performed by GYO experienced with advanced LPS

This study is the largest series of laparoscopic staging of EOC reported to date Operative time was statistically significantly higher in hospital A compared to both hospitals B and C (325 ± 74 min vs. 209 ± 13 min vs. 237 ± 52 min, P<0.0001). Operating time in one institution compared with the others may be partly explained by the longer turnaround time of frozen sections because the pathology service is located outside the institution, and the messenger staff members must transport specimens across the city Lymph node yield No difference was found among the three oncologic service in terms of (total pelvic plus aortic: 34 ± 9 vs. 38 ± 6 vs. 38 ± 11, P = 0.16) Estimated blood loss The proportion of patients with an of>500 ml was 8 (18.6%) of 43, 0 (0%) of 26, and 2 (18.2%) of 11 in hospitals A, B, and C, respectively (P = 0.06).

This study is the largest series of laparoscopic staging of EOC reported to date Operative time was statistically significantly higher in hospital A compared to both hospitals B and C (325 ± 74 min vs. 209 ± 13 min vs. 237 ± 52 min, P<0.0001). Operating time in one institution compared with the others may be partly explained by the longer turnaround time of frozen sections because the pathology service is located outside the institution, and the messenger staff members must transport specimens across the city Lymph node yield No difference was found among the three oncologic service in terms of (total pelvic plus aortic: 34 ± 9 vs. 38 ± 6 vs. 38 ± 11, P = 0.16) Estimated blood loss The proportion of patients with an of>500 ml was 8 (18.6%) of 43, 0 (0%) of 26, and 2 (18.2%) of 11 in hospitals A, B, and C, respectively (P = 0.06).

300 pts 75% of patients underwent Pe/Ao LFN Multi-istitutional cohort study. 300 apparently early EOC staged by LPS from 2000 to 2014:Group 1: Primary treatment; Group2I: restaging Median FU 22 months 75% of patients underwent Pe/Ao LFN Si mostra solo l’aspetto chirurgico per dimostrare l’adeguatezza e la riproducibilità di procedure LPS complesse Conversions rate was higher in Group 1 versus Group 2

UPSTAGED PATIENTS: Group 1: 24.9% Group 2: 7.4% (lnf 10%, peritonal 14.8%) Group 2: 7.4% (lnf 4.7%, peritoneal 2.7%) In conclusion, thanks to the successful cooperative efforts of multiple referral Gynecologic Oncology Units across the country, we confirmed in a very large series that laparoscopic staging of ESOM is feasible and safe, and provides survival outcomes comparable to those obtained with open surgical approach The 3-year DFS and OS rates were 85.1%, and 93.6%, respectively in the whole series and were comparable to those reported in the literature

Apparent early EOC can be safely managed with LPS in referral Centers The 3-yr DFS and OS were 85% and 94% in the whole series 16

2015 Int J Gynecol Cancer 406 SGO members responded to the survey Endometrial cancer Adnexal masses SOB Others commonly performed Procedure most Minimally invasive surgery, including traditional laparoscopy and robotic-assisted laparoscopy, is becoming increasingly common in the surgical management of gynecologic malignancies. Numerous studies have shown that laparoscopic surgery is safe and feasible in most patients with endometrial, cervical, or early-stage ovarian cancer. Objective of the study: To evaluate the current patterns of use of minimally invasive surgical procedures, including traditional, robotic-assisted, and single-port laparoscopy, by Society ofGynecologic Oncology (SGO) members and to compare the results to those of our 2004and 2007 surveys. 2012 Between 2007 and 2012, there were significant increases in the proportions of respondents who thought MIS was appropriate for staging of EC, OC and CC

Perspectives and key-issues SLN in EOC Importance of restaging Tumor rupture during LPS The role of dedicated pathologist Fertility Sparing Surgery

PERSONALIZING SURGICAL STAGING: Tailoring radicality with SNB Sentinel Node in ovarian cancer (SONAR) (NCT01734746) Maastricht University Medical Centre, Maastrich, The Netherlands Phase I, single-arm, feasibility/safety study/20 pts LPS probes available!!! Women with highly suspicious ovarian malignancy receiving laparotomy Injection of both blu-dye and technetium in the ligamentum ovarii proprium (median side) and the ligamentum infundibulo-pelvicum (lateral side). After 15 minutes the ovarian mass is removed, retroperitonal space is opened , SN is detected and removed In this context, a potential strategy to tail or surgical staging avoiding unnecessary procedures and comorbidities in EOC could be SNB. This Phase I trial has been designed in the context of standard LPT approach, but laparoscopic probes to detect radioactive isotope (tecnezio) are currently available, opening the way for an LPS-SNB Primary end-point: accuracy of SNB technique Secondary end-poin: anatomical distribution of metastatic lymph nodes

SELLY UCSC RANDOMIZED PROTOCOL Suspected pelvic mass planned for surgery SELLY UCSC RANDOMIZED PROTOCOL CT scan or MRI Pelvic US Ca125 SENTINEL LYMPH NODE detection and removal ISB IC-G Removal of the pelvic mass and sending to frozen section Frozen section: benign Frozen section: malignant Surgical Staging (radical1 or conservative2) Stop surgery Excluded from the study Included in the study 1 Total histeroctomy, salpingoopherectomy bilateral, lomboaortic lymphadenectomy, total omentectomy, peritoneal biopsies, peritoneal washing 2 Monolateral adnexectomy, controlater ovarian biopsy, lomboaortic lymphadenectomy, total omentectomy, peritoneal, biopsies, peritoneal washing

RESTAGING EOC Radiological staging Revision of histological samples (dualistic model) COUNSELLING Restaging ip/lfn SOM vs. Conventional surgery MIS

MIS re-staging of apparent early EOC should be performed when possible Advantages Early discharge and more rapid onset of CT Less adhesions that can impair fertility Disadvantages Longer operative time Does not allow thorough inspection of posterior diaphragm behind the liver or the high part of left hemidiaphragm Risk of spillage Port site mts* * (1.96% according to Zivanivic et al Gynecol Oncol 2008)

Time delay influences the stage of disease and survival time. Strict preoperative protocols should be in place to ensure that an absolute minimum number of patients with OC have a first preliminary and then a second definitive surgery

DFS OS p<0.05 p=0.2

An accurate frozen section for ovarian tumors is of great value in preventing under- and over-treatments

Relevance of the problem Fertility-sparing: Relevance of the problem OC: 10-20 cases per 100,000 women/y Nearly 80% are advanced stage 14% of women with EOC are < 40 years old

 The recent increase in early gynecologic checkups using ultrasonography has increased the frequency of EOC diagnoses at early stages  Vital statistics reports from Europe state a strong tendency of continued first birth postponement  diagnosis of EOC during reproductive years is increasing  Answer of fertility-sparing surgery (preservation of at least a part of 1 ovary and the uterus).

Available Guidelines for conservative management of Ovarian cancer

FSS is safe in low risk eEOC FSS is safe in low risk eEOC. Young patients with high risk eEOC, who wish to preserve their childbearing potential may benefit from FSS approach. Pts with high risk disease experienced worse survival outcomes, these survival results are not influenced by type of surgical approach (FSS vs. RSC). The opportunity to extend the indication to conservative surgery to women with more advanced disease is highly controversial and needs further investigations.

Thanks for your attention