Tertiary cytoreductive surgery in recurrent epithelial ovarian cancer: a multicentre MITO retrospective study. Falcone F., Scambia G., Benedetti Panici P., Signorelli M., Cormio G., Giorda G., Bogliolo S., Marinaccio M., Ghezzi F., Rabaiotti E., Breda E., Casella G., Fanfani F., Di Donato V., Leone Roberti Maggiore U., Greggi S. Submitted to Gynecologic Oncology on June 16, 2017

Background The role of secondary/tertiary cytoreductive surgery has not been yet clearly defined. In particular, data on tertiary cytoreductive surgery (TCS) are even more limited than those in the secondary setting Whether the complete cytoreduction is the primary objective of TCS must be still confirmed, and the factors predicting no postoperative residual tumor identified Given the high technical difficulty associated with repetitive surgery, accurate patient selection is mandatory The MITO Group endorsed a project among its surgical membership with the aim to retrospectively evaluate EOC patients undergoing TCS.

Methods Exclusion criteria The primary endpoints for this study were to evaluate the impact of TCS on the overall survival and to determine predictors of complete surgical cytoreduction The secondary endpoint was to assess the value of a potential score predicting a complete cytoreduction. A total of 103 recurrent EOC patients, undergoing TCS within a 5-year observation period, were included in the present analysis Aged >75 years PS according to ECOG >1 Serological recurrence only Non-epithelial or borderline tumors TFI <6 months after completion of 1st-/2nd-/3rd-line therapy Patients operated on for strictly palliative purposes Patients with second malignancies Exclusion criteria

BEFORE Results tertiary cytoreduction Variable   Age, median [range], years 55 [20 – 71] Origin of disease, n (%) Ovary Fallopian tube Peritoneum 98 (95.1) 1 (1.0) 4 (3.9) FIGO stage at initial diagnosis, n (%) I II III IV Missing 12 (11.7) 2 (1.9) 80 (77.7) 3 (2.9) 6 (5.8) Tumor grade, n (%) 1 2 3 8 (7.8) 86 (83.5) Histology, n (%) Adenoca, NOS Clear cell Endometrioid Mixed Mucinous Serous Undifferentiated 83 (80.6) Clinico-pathologic characteristics BEFORE tertiary cytoreduction Completeness of primary cytoreduction, n (%) 0 (no visible residual tumor) 1 (residual nodules ≤0.25 cm) 2 (residual nodules >0.25 cm and ≤2.5 cm) 3 (residual nodules >2.5 cm) Missing   67 (65.0) 12 (11.7) 11 (10.7) 6 (5.8) 7 (6.8) Completeness of secondary cytoreduction, n (%) 83 (80.6) 9 (8.7) 3 (2.9) 1 (1.0) Time from the end of initial treatment to first relapse (months), median [range] 21.5 [6 – 115]

Results AT THE TIME OF tertiary cytoreduction Variable   Age, median [range], years 60 [23 – 75] Years after primary diagnosis, n (%) <2 ≥2 and <3 ≥3 5 (4.8) 13 (12.6) 85 (82.5) Last TFI, n (%) 6 – 12 months ≥12 months 65 (63.1) 38 (36.9) ECOG performance status, n (%) 1 76 (73.8) 27 (26.2) ASA, n (%) 1 – 2 3 – 4 90 (87.4) CA 125 (U/mL) serum levels, n (%) <35 35 – 500 >500 43 (41.7) 52 (50.5) 8 (7.8) Intraoperative ascites, n (%) ≤500 mL >500 mL 101 (98) 2 (2) Sites of recurrence, n (%) Abdominal Distant Both 86 (83.5) 9 (8.7) Abdominal tumor involvement, n (%) Intraperitoneal Retroperitoneal 55 (58.5) 21 (22.3) 18 (19.1) Clinico-pathologic characteristics AT THE TIME OF tertiary cytoreduction Lesion number, n (%) Single Multiple   45 (43.7) 58 (56.3) Size (mm) of largest recurrence, median [range] 25 [5 – 120] Completeness of tertiary cytoreduction, n (%) 0 (no visible residual tumor) 1 (residual nodules ≤0.25 cm) 2 (residual nodules >0.25 cm and ≤2.5 cm) 3 (residual nodules >2.5 cm) 71 (68.9) 13 (12.6) 4 (3.9) 15 (14.6) Post-operative complications, n (%) G 1 – 2 G 3 – 4 G 5 3 (2.9) 10 (9.7) 0 (0) Adjuvant therapy after tertiary cytoreduction, n (%) Platinum-based Non-platinum based 54 (52.4) 36 (34.9) Follow-up (months) after TCS, median [range] 39.5 [1 – 138] Status at last follow-up, n (%) NED AWD DOD DID Missing 26 (25.2) 25 (24.3) 40 (38.8) 5 (4.9) 7 (6.8)

Results Significant predictors of mortality and complete tumor resection Significant predictors of mortality Complete tertiary cytoreduction (yes* vs no) FIGO stage at initial diagnosis (I-II* vs III-IV) Site of abdominal recurrence (retroperitoneal only* vs other) Interval from primary diagnosis (>3* vs <3yrs) Hazard ratio 10.7 4.5 4 3.5 95% CI 4.3 – 26.2 1.3 – 15.6 1.1 – 14.5 1 – 12.8 p-value <0.001 0.01 0.03 0.04 Significant predictors of complete tumor resection Single lesion ECOG performance status 0 Odds ratio 14.2 4.6 4 – 50.6 1.4 – 14.9 0.009 *Protective

prognostic factors for survival Results Kaplan–Meier curves according to significant prognostic factors for survival

Results … in our study Single lesion + PS ECOG 0 PPV =94.6% NPV =45.5% AGO score PPV =75.8% NPV =43.2% The observed PPV was very consistent with that recently reported in secondary cytoreduction (72.5%) DESKTOP III

Conclusions Our study demonstrates the achievement of postoperative no residual disease as the primary objective of TCS, confirming the prognostic impact of complete surgical cytoreduction even in a tertiary setting. Accurate patient selection is of utmost importance to have the best chance of complete cytoreduction although the value of the clinical scores could be affected by the intrinsic nature of a tumor usually seen in long surviving patients. In this perspective, TCS could be offered to all patients with good clinical conditions for whom a complete surgical cytoreduction is judged reasonably feasible in a high volume gynecologic oncology referral centre.