ANTICANCER RESEARCH 35: 3027-3032 (2015)

Does the Diagnosis Center Influence the Prognosis of Ovarian Cancer Patients Submitted to Neoadjuvant Chemotherapy? GIUSEPPE VIZZIELLI1, FRANCESCO FANFANI1, VITO CHIANTERA2, LUCIA TORTORELLA1, ALESSANDRO LUCIDI1,2, MARCO PETRILLO1,2, BARBARA COSTANTINI1, GIOVANNI SCAMBIA1 and ANNA FAGOTTI3 1Division

of Gynecologic Oncology, Catholic University of the Sacred Heart, Rome, Italy; of Gynecologic Oncology, Foundation for Research and Care "Giovanni Paolo II”, University of Molise, Campobasso, Italy; 3Division of Minimally Invasive Gynecologic Surgery, St. Maria Hospital, University of Perugia, Terni, Italy 2Division

Abstract. Aim: To compare prognosis of advanced epithelial ovarian cancer (AEOC) patients based on where the first surgical assessment was performed. Patients and Methods: Retrospective analysis of primary AEOC patients was performed and three groups were formed based on where the decision of primary treatment was taken: Internal, if the decision was carried out at our Institution (PDS (Primary Debulking Surgery), I-IDS (Internal- Interval Debulking Surgery)) and Referred in case women were referred after neoadjuvant chemotherapy (NACT) from other Centers (R-IDS (Referred- Interval Debulking Surgery)). Results: Among 573 AEOC, 279 (48.7%) were PDS and 294 (51.3%) IDS. In particular, 134 of 294 (45.6%) were R-IDS and 160 (54.4%) were I-IDS. Median progression-free survival (PFS) was 26 months in PDS, 14 months in I-IDS and 17 months in R-IDS. The difference was statistically significant (p 1 cm Yes No Large volume ascites (500 ml) Yes No Diaphragmatic disease (infiltrating carcinosis or confluent nodules) Yes No UAD (Spleen, stomach, lesser sac)d Yes No Superficial liver metastases >2 cm and/or intraparenchymal liver metastases of any size Yes No Overall radiologic score (median) (range)

PDS N (%)

I-IDS N (%)

R-IDS N (%)

p-Valueb

p-Valuec

279

160

134

n.a.

n.a.

178 (63.8) 101 (27.6)

125 (80.6) 30 (19.4)

97 (72.4) 37 (27.6)

0.001

0.09

45 (16.1) 234 (83.9)

72 (45.0) 88 (55.0)

15 (11.2) 119 (88.8)

0.0001

0.233

38 (13.6) 241 (86.4)

30 (18.8) 130 (81.2)

10 (7.5) 124 (92.5)

0.171

0.07

36 (12.9) 243 (87.1)

37 (23.1) 123 (76.9)

20 (14.9) 114 (85.1)

0.008

0.645

37 (13.3) 242 (86.7)

35 (21.9) 125 (78.1)

26 (19.4) 108 (80.6)

0.023

0.110

187 (67.0) 92 (33.0)

135 (84.4) 25 (15.6)

100 (74.6) 34 (25.4)

0.0001

0.138

37 (13.3) 242 (86.7)

58 (36.2) 102 (63.8)

13 (9.7) 121 (90.3)

0.0001

0.337

13 (4.7) 266 (95.3)

28 (17.5) 132 (82.5)

5 (3.7) 129 (96.3)

0.0001

0.800

26 (9.3) 253 (90.7) 0 (0-4)

31 (19.4) 129 (80.6) 2 (0-6)

11 (8.2) 123 (91.8) 0 (0-4)

0.003

0.854

0.001

0.392

aAccording to Ferrandina et al. (10). PDS: Primary Debulking Surgery. I-IDS: Internal - Interval Debulking Surgery. R-IDS: Referred - Interval Debulking Surgery. bI-IDS vs. PDS. cR-IDS vs.PDS. dUAD= Upper Abdominal Disease. n.a.: Not applicable.

cycles of NACT in the referred patients with respect to the internal cases (6 cycles vs. 4 cycles; p=0.0001). However, all NACT women presented at IDS with similar percentages of radiological and serologica response independently from the Center of disease primary assessment and number of cycles. The up-front judgment of unresectability was made on both radiological and surgical evaluation in all women assessed at our tertiary-level Center, whereas 32/134 (23.9%) referred patients (R-IDS) were firstly defined as unresectable on the bases of radiological criteria only. Tumor extension at diagnosis, assessed by CT scan, is shown in Table II. As expected, women driven to NACT in our center (I-IDS) showed a much more diffused disease than those submitted to PDS, in terms of bowel and mesentery involvement, diaphragm infiltration, upper disease (i.e. spleen, lesser omentum, stomach) and liver metastases. However, as shown in Table II, similar differences were observed comparing I-IDS women with patients submitted to NACT in peripheral Centers

(R-IDS). In fact, in these latter cases, the tumor load was of the same magnitude than in PDS cases treated at the referral center. Among 279 PDS patients, 217 (77.8%) gained complete cytoreduction at the end of surgery, at the cost of major surgical procedures in 79.2% of the cases. As expected, these patients had a longer operative time and hospital stay, higher blood loss and more frequent major post-operative complications with respect to IDS women (Table III). Regarding IDS, macroscopically-absent residual tumor was achieved in comparable rates of patients, according to Centre of primary diagnosis (58.8% I-IDS vs. 66.4% R-IDS, p=0.186), but with a different rate of major surgical procedures utilized (39.4% I-IDS vs. 24.6% R-IDS; p=0.007). Regarding peri-operative parameters, the two IDS groups did not show any statistically significant difference in terms of operative time or blood loss resulting in a comparable length of stay. The overall high-grade (3 to 5) complication rate was less than 5 % in both groups (Table III).

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ANTICANCER RESEARCH 35: 3027-3032 (2015)

Figure 1. Progression-free survival (PFS) of AEOC patients submitted to surgery at CUSH. Black line, Primary Debulking Surgery (IPDS); dark grey line, Referred IDS (R-IDS); light grey line, Internal IDS (I-IDS). PFS is expressed in months.

Table III. Surgical outcome and peri-operative morbidity. Variable

All cases Absent residual tumor Yes No Surgical complexity score groupsb 1 2-3 Median blood loss (ΔHb g/dl)° (range) Median operative time (min) (range) Median length of ICU stay (days) (range) Median length of hospitalization (days) (range) Major post-operative complicationsc Grade 3 Grade 4 Grade 5

PDS N (%)

I-IDS N (%)

R-IDS N (%)

p-Valuea

279

160

134

n.a.

217 (77.8) 62 (22.2)

94 (58.8) 66 (41.2)

89 (66.4) 45 (33.6)

0.186

97 (60.6) 63 (39.4) 1.5 (0-5) 200 (60-420) 0 (0-2) 5 (2-18)

101(75.4) 33 (24.6) 2.7 (0-5) 230 (60-430) 0 (0-1) 5 (2-15)

0.007

5 (3.1) 2 (1.2) 0

2 (1.4) 1 (0.7) 0

0.880

58 (20.8) 221 (79.2) 3.7 (0-5) 320 (100-660) 1 (0-3) 7 (4 - 26) 18 (6.4) 11 (3.9) 0

0.180 0.668 0.438 0.604

PDS: Primary debulking surgery. I-IDS: Internal - Interval debulking surgery. R-IDS: Referred - Interval Debulking Surgery. ICU: Intensive Care Unit. °ΔHb g/dl: largest variation in Hb levels between pre-operative and post-operative day 1. aI-IDS vs. R-IDS. bAccording to Aletti et al. (17). cAccording to MSKCC grading system (18). n.a. Not applicable.

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Vizzielli et al: Influence of Diagnosis Center on the Prognosis of Ovarian Cancer Patients

With a median follow-up of 27 months (95% CI=8-82), median PFS was 26 months (95% CI=21.0-30.9) in PDS, 14 months (95% CI=13.0-14.9) in I-IDS and 17 months (95% CI=14.5-19.4) in R-IDS (Figure 1). The difference was statistically significant between all the groups (PDS vs. I-IDS p=0.0001; PDS vs. R-IDS p=0.0001; I-IDS vs. R-IDS p=0.004).

Discussion In the present study, we report on the outcome of women submitted to surgery at our tertiary referral medical center depending on the hospital in which they received their primary disease assessment. The main result of this retrospective analysis is that women primarily assessed for NACT at a peripheral Center (R-IDS) have the same tumor burden at diagnosis than cases submitted to PDS in a referral Center. Moreover, when selected in a referral centre (I-IDS), they show a lower tumor load than patients receiving the same approach (NACT+IDS). This finding clearly supports the idea that if R-IDS patients received their primary assessment in a tertiary referral center, they were offered optimal PDS. Indeed, only about 20% of patients in the R-IDS group have extensive tumor in the upper quadrants and only about 10% have mesenteral retraction at pre-operative CT scan. In other words, based on imaging data and the high rate of ECOG PS