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Primary surgical cytoreduction in advanced ovarian cancer: An outcome analysis within the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) Group
Gynecologic Oncology 140 (2016) 425–429
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Primary surgical cytoreduction in advanced ovarian cancer: An outcome analysis within the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) Group Stefano Greggi a,⁎, Francesca Falcone b, Raffaele Carputo a, Francesco Raspagliesi c, Cono Scaffa a, Giuseppe Laurelli a, Giorgio Giorda d, Giovanni Di Vagno e, Francesco Petruzzelli f, Gennaro Cormio g, Marco Marinaccio g, Sandro Pignata h a
Gynecologic Oncology Surgery, Istituto Nazionale Tumori “Fondazione G. Pascale” IRCCS, Naples, Italy Department of Woman, Child, and General and Specialized Surgery, Seconda Università degli Studi di Napoli, Naples, Italy c Department of Gynecologic Oncology, IRCCS National Cancer Institute, Milan, Italy d Department of Gynecological Oncology, Centro di Riferimento Oncologico (CRO) National Cancer Institute, Aviano, Italy e Department of Obstetrics and Gynecology, Umberto I Hospital, Bari, Italy f Obstetrics and Gynaecology Department, IRCCS “Casa Sollievo della Sofferenza”, Foggia, Italy g Department of Obstetrics and Gynecology, University of Bari, Bari, Italy h Department of Urology and Gynecology, Istituto Nazionale Tumori “Fondazione G. Pascale” IRCCS, Naples, Italy b
H I G H L I G H T S • Patient and tumor characteristics, quality of surgery affect surgical cytoreduction. • Quality of surgery is important to improve the outcome of advanced ovarian cancer. • Advanced ovarian cancer patient referral to high-volume centers is an urgent action.
a r t i c l e
i n f o
Article history: Received 25 November 2015 Received in revised form 18 January 2016 Accepted 25 January 2016 Available online 26 January 2016
a b s t r a c t Objective. To draw a reliable picture of the surgical management of advanced ovarian cancer (AOC) within the MITO Group, trying to correlate the disease extent at presentation, the category of center, and surgical outcome. Methods. Three tertiary referral centers for gynecologic oncology and four non-oncologic referral gynecologic surgical centers, participated in the project. A questionnaire was adopted to register perioperative data on AOCs (FIGO Stage IIIC\\IV) consecutively operated on for a period of 12 months. Results. A total of 205 patients were registered into the study: 140 and 65 were recruited in oncological referral centers and non-referral centers, respectively. Following a multivariate analysis, the Eisenkop score and the category of center resulted the most potent predictors of complete surgical cytoreduction followed by PCI, preoperative CA125, and ASA score. Complete surgical cytoreduction was associated with oncological referral centers (60% vs 24.6%, p b 0.001). The proportion of patients undergoing additional surgical procedures was significantly different comparing the two categories of centers (at least one additional procedure was performed in 81.4% vs 50.8% in oncological referral centers compared to the others, p b 0.001). Despite the more aggressive surgery performed in oncological referral centers, the perioperative outcome measures were not significantly different in the two groups. Conclusions. The chance of obtaining a complete cytoreduction mainly depends on patient characteristics, tumor spread, and quality of treatment. The latter is amenable for direct influence, and therefore, seems to be of utmost importance when considering efforts aiming at improvement in the outcome of this disease. © 2016 Elsevier Inc. All rights reserved.
1. Introduction ⁎ Corresponding author at: Gynecologic Oncology Surgery, National Cancer Institute of Naples - IRCCS “Fondazione G. Pascale”, Via M. Semmola, 80131 Naples, Italy. E-mail address: [email protected] (S. Greggi).
http://dx.doi.org/10.1016/j.ygyno.2016.01.025 0090-8258/© 2016 Elsevier Inc. All rights reserved.
Ovarian cancer (OC) is usually diagnosed at an advanced stage, with intra-abdominal tumor widespread. In these conditions, surgery is complex, very frequently involving the upper abdomen and requiring an
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extensive approach to the pelvis in most cases. The strong prognostic influence of a complete primary surgical cytoreduction has been widely proved in multiple series [1–3], and meta-analyses [4–6]. The ability to achieve a complete cytoreduction is determined by the extent of disease at diagnosis but also by the subspecialty and case volume of the surgical team involved [7–12]. For advanced OC, the International Federation of Gynecology and Obstetrics (FIGO) staging is unable to clinically select patients for whom a “standard gynecological” surgery is enough to remove all visible disease. A number of ranking systems have been proposed to more reliably quantify the disease extent [2, 13, 14]. All of them, however, are based on the intraoperative assessment, and do not allow a clinical stratification of cases according to the expected surgical complexity, and, consequently, their appropriate referral. Therefore, it seems to be crucial to act on the quality of surgery in the effort to improve the prognosis of advanced OC. The Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO) is one of the two Italian cooperative groups in gynecologic oncology. In 2012, the MITO-Group endorsed a prospective project among its surgical membership with the aim to draw a more reliable picture of the surgical management of advanced OC within the group, trying to correlate the extent of disease at presentation, the category of center, and the surgical outcome. 2. Materials and methods Tertiary referral centers for gynecologic surgical oncology, and nononcologic referral gynecologic surgical centers are part of the MITOGroup. Three of tertiary referral centers and four of non-oncological referral centers accepted to participate in this prospective survey as a sample of all centers. A questionnaire was adopted to register
Table 1 Patient and tumor characteristics. Variable
Oncological referral centers
Non oncological referral centers
Significance p – value
Patients, n (%) Age (years), median [range] WHO performance status, n (%) 0–1 2–3 ASA, n (%) 1–2 3–4 Preoperative serum CA125 levels (U/mL), median [range] Ascites (cc), median [range] Yes, n (%) No, n (%) Histologic classification, n (%) Serous Others Histologic grade, n (%) 1–2 3 FIGO stage, n (%) IIIA1(II) or IIIB IIIC or IV Bulky nodes, n (%) PCI, mean [range] “Eisenkop” score, mean [range] “Fagotti” score, mean [range]
140 (68.3) 60 [32–85]
65 (31.7) 59 [45–77]
– 0.16
114 (81.4) 26 (18.6)
52 (80) 13 (20)
0.85
85 (60.7) 55 (39.3)
42 (64.6) 23 (35.4)
0.64
792 [100–13,441]
614 [10–13,641]
0.91
2000 [50–10,000]
2000 [100–11,000]
0.88
107 (76.4) 33 (23.6)
45 (69.2) 20 (30.8)
1.00
98 (70) 42 (30)
50 (76.9) 15 (23.1)
0.32
37 (26.4) 103 (73.6)
12 (18.5) 53 (81.5)
0.29
14 (10) 126 (90) 41 (29.3) 17.2 [3−33] 8.5 [2–15]
3 (4.6) 62 (95.4) 13 (20) 15.4 [4–39] 7.8 [2−13]
0.27 0.17 0.79 0.20
7.5 [0–14]
7.3 [0–14]
0.79
ASA: American Society of Anesthesiologists; FIGO: International Federation of Gynecology and Obstetrics; PCI: peritoneal cancer index; WHO: World Health Organization.
perioperative data (primary surgery) on advanced (FIGO Stage IIIC\\IV) OC (including tubal and peritoneal epithelial cancers) patients consecutively treated for a period of 12 months. Data were collected on: patient characteristics (age; performance status according to World Health Organization (PS-WHO); American Society of Anesthesiologists (ASA) score), disease characteristics (preoperative CA125 serum level; histotype and grade; presence and quantity of ascites; detailed description of disease extent; FIGO Stage; peritoneal cancer index (PCI); “Eisenkop” score; “Fagotti” score), and surgical outcome (surgical procedures performed; completeness of cytoreduction (CC); reason(s) for the inability to achieve a complete cytoreduction; duration of surgery; estimated blood loss and blood units transfused; intra/postoperative complications/deaths; days from surgery to hospital discharge). The PCI was computed according to Sugarbaker [13], the “Eisenkop” and the “Fagotti” scores were calculated on the basis of what described by the Authors [2, 14]; scores description is available in Supplementary Table 1. In particular, participating centers were asked for fulfilling the “Fagotti” score regardless the adoption of laparoscopic evaluation of cytoreducibility. Completeness of surgical cytoreduction was categorized as proposed by Sugarbaker [13]: no macroscopic tumor (CC = 0), b 0.25 cm (CC = 1), between 0.26 and 2.5 cm (CC = 2), and more than 2.5 cm (CC = 3). Postoperative complications were registered within 30 days from hospital discharge, and graded according to the Clavien-Dindo classification [15]. FIGO Stage IIIC\\IV was originally registered according the 1988 classification. Data are now presented adopting the new FIGO classification [16]. The patient and disease characteristics are described in Table 1. Data were analyzed using the Fischer's exact test, the χ2 test, the Student t-test, and the nonparametric Mann-Whitney and Wilcoxon tests, if needed. Factors predicting completeness of surgical cytoreduction were evaluated using univariate and multivariate models. The multivariate Cox regression analysis was used to estimate odds ratios and 95% confidence intervals for the different covariables. All p-values were two-sided, and p b 0.05 was considered significant. Statistical analysis was performed with SPSS statistical software version 21.0. 3. Results A total of 205 patients were registered into the study with advanced primary OC: 140 (68%) and 65 (32%), were recruited in oncological referral centers and non-referral centers, respectively. The two subgroups were homogeneous for the main patient and disease characteristics (Table 1). At univariate analysis, the following variables were significant predictors of complete surgical cytoreduction (CC = 0): performance status, ASA score, preoperative CA125 serum level, PCI, “Eisenkop” and “Fagotti” scores, and category of center (Table 2). Following multivariate analysis, only ASA score, preoperative CA125 serum level, PCI, “Eisenkop” score, and the category of center were still independent variables. In particular, the “Eisenkop” score and the category of center resulted the most potent predictors of complete cytoreduction (Table 2). In Table 3 the completeness of cytoreduction is detailed according to the category of center. Complete (CC = 0) surgical cytoreduction was associated with oncological referral centers (60% vs 24.6%, p b 0.001). In the oncological referral centers, complete cytoreduction was achieved in 83.3% and 16.7% (p b 0.001) for PCI b 20 and ≥20, respectively, and in 79.8% and 20.2% (p b 0.001) for “Eisenkop” score b 10 and ≥10, respectively. On the contrary, no significant difference was detected for “Fagotti” score b 8 vs ≥ 8 (p = 0.39). In fact, the proportion of patients undergoing additional surgical procedures was significantly different according to the category of center, with 81.4% of patients submitted to at least one additional procedure in oncological referral centers compared to 50.8% in the others (p b 0.001) (Table 4). A critical analysis of surgical forms revealed that the causes of suboptimal outcome can be schematically considered disease-dependent or surgeon-dependent. Mainly due to tumor diffusion the former, and to
S. Greggi et al. / Gynecologic Oncology 140 (2016) 425–429 Table 2 Univariate and multivariate analyses of factors predicting complete surgical cytoreduction. Variable
Age (years) ≤60 N60 WHO performance status 0 N0 ASA 1–2 3–4 Preoperative serum CA125 ≤750 U/mL N750 U/mL Ascites No Yes Ascites ≤2000 cm3 N2000 cm3 Histologic classification Serous Others Histologic grade 1–2 3 Bulky nodes No Yes PCI b20 ≥20 “Eisenkop” score b10 ≥10 “Fagotti” score b8 ≥8 Center ORC Non-ORC
Univariate analysis
Multivariate analysis
RR [95% CI]
OR [95% CI]
1 1.54 [0.88–2.68]
pvalue 0.16
pvalue
427
Table 4 Additional surgical procedures by category of center. Additional surgical procedures/organ resections
ORC n
Non-ORC Significance n p – value
Pelvic peritonectomy Abdominal peritonectomy Diaphragmatic peritonectomy Diaphragmatic resection Pancreatic resection Partial/total gastrectomy Rectosigmoid resection and primary anastomosis Colon resection Cecum resection Ileum resection Ileostomy Colostomy Splenectomy Bladder resection Excision of pelvic masses Lymphadenectomy Total At least one procedure, n (%)
100 43 58 19 7 3 41
21 1 1 0 0 0 6
7 11 14 7 8 7 1 47 57 430 114 (81.4) 94 (67.1) 81 (57.9)
4 0 1 1 3 0 1 6 5 50 33 (50.8) b0.001
1 1.19 [0.54–2.60]
0.65
1 3.31 [1.71–6.38]
b0.001 1 1.71 [0.71–4.15]
0.22
1 2.33 [1.30–4.17]
b0.05
1 2.54 [1.08–5.96]
b 0.05
1 2.55 [1.45–4.48]
b0.05
1 2.13 [1.03–4.42]
b0.05
1 1.37 [0.73–2.58]
0.34
1 1.05 [0.38–2.85]
0.92
1 1.75 [0.52–3.34]
0.10
1 1.07 [0.46–2.51]
0.86
1 1.50 [0.81–2.78]
0.21
1 1.15 [0.50–2.65]
0.72
Non-ORC: non-oncological referral centers; ORC: oncological referral centers.
1 1.01 [0.53–1.92]
1.00
1 1.40 [0.58–3.34]
0.44
1 1.30 [0.70–2.43]
0.43
1 1.52 [0.60–3.85]
0.37
complications (including one case of death, 0.7%), however, was observed among patients operated on at oncological referral centers (Table 6).
1 5.37 [2.81–10.25]
b0.001 1 3.03 [1.16–7.94]
b0.05
1 6.00 [3.25–11.22]
b0.001 1 4.13 [1.64–10.40]
b0.001
1 3.71 [2.05–6.71]
b0.001 1 1.44 [0.55–3.73]
0.45
1 4.59 [2.37–8.16]
b0.001 1 10.44 [4.32–25.19]
Two procedures, n (%) Three or more procedures, n (%)
11 (16.9) b0.001 8 (12.3) b0.001
3.1. Discussion
b0.001
ASA: American Society of Anesthesiologists; CI: confidence interval; Non-ORC: non-oncological referral centers; OR: odds ratio; ORC: oncological referral centers; PCI: peritoneal cancer index; RR: risk ratio; WHO: World Health Organization.
incomplete or missing surgical procedures the latter (Table 5). The proportion of cases with missing or inadequate surgical procedures was significantly higher in non-oncological referral centers (p b 0.001). In particular, the lack of expertise in diaphragmatic peritonectomy and resection, and in the pelvic extraperitoneal approach were the main causes of unsuccessful surgery. Despite of the more aggressive surgery performed in oncological referral centers, the perioperative outcome measures were not significantly different in the two groups. A higher rate (8.6%) of severe Table 3 Completeness of surgical cytoreduction according to the category of center. CC score
ORC n (%)
Non-ORC n (%)
Significance p – value
0 (no visible residual tumor) 1 (residual nodules ≤0.25 cm) 2 (residual nodules N0.25 cm and ≤2.5 cm) 3 (residual nodules N2.5 cm)
84 (60) 18 (2.9) 9 (6.4) 29 (20.7)
16 (24.6) 7 (10.8) 21 (32.3) 21 (32.3)
b0.001
CC: completeness of cytoreduction; Non-ORC: non-oncological referral centers; ORC: oncological referral centers.
There is a considerable debate on which measures should be used to reflect surgical quality. In particular, the most appropriate way to assess the quality of surgical care in primary advanced OC must include the completeness of cytoreduction, which represents the most significant prognosticator. The present survey, conducted within a gynecologic oncology national cooperative group, confirms the importance of the case volume in determining surgical outcome with relevant implications in terms of quality of care, need for a centralized treatment and specific training. In fact, all the three oncological referral centers included in the present analysis treat more than 50 OC per year compared with b20 by the others. The proportion of patients achieving CC = 0–1 surgical cytoreduction is significantly higher in the oncological referral centers (62.9% vs 35.4%, p b 0.001), and, even more, the rate of complete cytoreduction (60% vs 24.6%, p b 0.001). The “Eisenkop” score and the category of center result the most potent predictors of complete Table 5 Causes of incomplete surgical cytoreduction by category of center. Causes of incomplete cytoreduction Tumor – dependent Extensive peritoneal involvement More than 3 bowel resections required Extensive involvement of mesenteric root Implants in the porta hepatis Enlargement of suprarenal LNs Total Surgeon – dependent Absent or inadequate surgery on: – Diaphragm – Diaphragm and retroperitoneal LNs – Pelvis – Pelvis and retroperitoneal LNs – Diaphragm and pelvis Total
ORC n (%)
Non-ORC n (%)
Significance p – value
24 (63.2) 1 (2.6) 3 (7.9) 1 (2.6) 3 (7.9) 32 (84.2)
7 (17.1) 0 0 0 0 7 (17.1)
b0.001
14 (34.1) 4 (9.8) 5 (12.2) 2 (4.9) 9 (22) 34 (82.9)
b0.001
3 (7.9) 0 2 (5.3) 0 1 (2.6) 6 (15.8)
LNs: lymph nodes; Non-ORC: non-oncological referral centers; ORC: oncological referral centers.
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Table 6 Intra and post-operative outcome measures by category of center. Variable
ORC
Non-ORC Significance p - value
Length of surgery (minutes), mean Blood loss (cc), mean RBC transfusion (U), mean Post-operative severe (G 3, 4, 5) complications, n (%) Hospital length of stay (days), mean
233.24 588.19 0.81 12 (8.6) 9.21
232.05 814.47 1.33 3 (4.6)
0.94 0.05 0.25 0.39
8.54
0.32
G: grade; Non-ORC: non-oncological referral centers; ORC: oncological referral centers; RBC: red blood cells.
cytoreduction at multivariate analysis, followed by ASA score, preoperative CA125 serum level, and PCI. These data confirm that disease spread and aggressiveness of surgery both have a role in determining the surgical outcome. Primary surgery must be performed to achieve complete cytoreduction as the amount of residual tumor is one of the most important prognostic factors for survival of advanced OC [1, 4, 5], and no residual tumor has been shown to be a better predictor of survival than the extent of metastatic disease present before surgery [2]. Historically, Meigs earlier and later Griffiths, suggested an inverse relationship between residual tumor diameter and survival [17, 18]. This initial observation has been confirmed by subsequent meta [4–6] and single study [1–3] analyses, and primary surgery with cytoreductive intent became the current treatment paradigm for patients with advanced OC. Bristow et al. evaluated 81 studies involving 6885 patients and demonstrated that each 10% increase in maximal cytoreduction was associated with a 5.5% increase in median survival time [4]. The results of a recent meta-analysis by the Cochrane group are consistent with the previously published meta-analysis by Bristow et al. [6]. Therefore, all attempts should be made to achieve complete cytoreduction during primary surgery for advanced stage OC. When this is not achievable, the surgical goal should be b1 cm residual disease, although, the risk of death is respectively two and three times greater if there is b1 cm and N1 cm residual disease when compared with microscopic residual disease only [6]. This concept is valid regardless of the timing of surgery and applies to the policy of neoadjuvant chemotherapy (NACT), which is not a substitute for complete resection [19]. Tumor dissemination and, consequently, the extent of surgery required, are difficult to assess preoperatively. In order to determine which patients would be less likely to benefit from primary surgery, several attempts have been made to predict cytoreductive outcome with models combining computed tomography (CT) variables, with or without clinical (PS-WHO, age, body mass index, comorbidities, smoking) and/or biochemical (CA 125, albumin, blood platelet count) parameters [20, 21]. To date, there are no models that show a good predictive performance for residual disease when extrapolated to other centers [21]. Therefore, the predictability of surgical outcome remains an area of controversy and clinical ambiguity. It is acknowledged that there is considerable variation in achieving complete cytoreduction between different surgical centers, and this can affect the development of models of prediction. To select patients who could be completely cytoreduced, and to compare patient outcomes with as little bias as possible, intraoperative scoring systems have been elaborated, based on accurate description of the disease spread. The PCI and the “Eisenkop” scores appear to give valuable information about the exact distribution of carcinomatosis, and have been considered for prediction of surgical cytoreducibility [2, 13]. Similarly, Fagotti et al. reported a laparoscopy-based score [14]. In our study, multivariate analysis showed the PCI and “Eisenkop” scores, but not the “Fagotti” score, as independent variables of complete surgical cytoreduction. The former scores allow more analytical description of intraperitoneal tumor diffusion, and this may possibly explain their better predictive value. ASA score also significantly correlated with
residual disease. This finding is consistent with that previously published by Aletti et al. [22, 23]. In this setting, a careful perioperative management in collaboration with the anaesthesiologic team is critical to improve oncological outcomes, while preventing an increase in the complication rate potentially derivable from aggressive surgical procedures. At multivariate analysis, the most potent predictor of no residual disease was the category of center (OR: 10.44 [4.32–25.19], p b 0.001), with 60% and 24.6% CC = 0 in oncological referral centers and nononcological referral centers, respectively (p b 0.001). Hospitals with ≥ 20 and b20 cases/year are usually categorized as high and lowvolume, respectively [24–26]. In our study, non-oncological referral centers treat b 20 OC per year, and showed no postsurgical residual disease in about 25% of cases. Even though such a rate is much below that is considered today the minimum required surgery for advanced OC, it has to be taken into account that the reported rates of complete cytoreduction in the EORTC (20.4%) and CHORUS (17%) trials were even lower in spite of the gynecologic oncology network settings [27, 28]. Based on some national Northern European registries, from 25 to 50% of ovarian cancer patients are operated on in high-volume hospitals [29], and this proportion is likely lower in the South of Europe. The majority of European population-based studies, have found that higher the hospital surgical volume, higher the likelihood of 0–0.25 cm residual disease, and of improved overall survival [7, 25, 26, 30, 31]. Our results confirm the previous findings, including the deep relationship between higher case-volume and more extensive surgical procedures. To achieve complete cytoreduction in the majority of OC patients, advanced surgical techniques are needed. In particular, visceral surgery is required in more than 50% of cases [32]. Bowel resections, diaphragmatic surgery, pelvic and aortic lymphadenectomy, supracolic omentectomy, splenectomy and peritonectomy should ideally be part of the skills of the surgeon, hence specialized training is needed. Several studies have shown that complete or b0.25 cm cytoreduction rates over 50% often require the incorporation of extensive upper abdominal surgical procedures [2, 33, 34]. Chi et al. reported an improvement of surgical outcome by inclusion of upper abdominal surgery, resulting in a resection rate to b1 cm residual disease from 46% to 80% within the study period, without significantly increasing perioperative morbidity and mortality [34]. Accordingly, in our study, the proportion of patients undergoing additional surgical procedures was significantly higher in oncological referral centers (81.4% vs 50.8%, p b 0.001). In particular, the lack of expertise in diaphragmatic peritonectomy and resection, and in the pelvic extraperitoneal approach were the main causes of unsuccessful surgery (Table 5). Diaphragm involvement is very common in advanced OC, and it is considered to be a major obstacle to successful cytoreductive surgery [35]. Very recently, Benedetti-Panici et al., based on the relatively low postoperative mortality rate and the ability to safely manage almost all complications, have considered the rate of morbidity to be acceptable in the light of the expected survival increase following aggressive surgical cytoreduction [36]. In our study, the frequency of severe complications was not significantly different in the two groups, although a higher rate was observed in the patients operated on at oncological referral centers, with severe complications occurring in 8.6% with only one case of postoperative mortality (0.7%). In conclusion, the chance of obtaining a complete cytoreduction mainly depends on patient characteristics, tumor spread, and quality of surgery. The first two reflect an unchangeable reality, but the latter is amenable for direct influence, and therefore, seems to be of utmost importance when considering efforts aiming at improvement in the outcome of this disease. Our study results underline the need for improving the quality of surgery in advanced OC even, or, just because within a gynecologic oncology cooperative group. Quality improvement in surgical and oncological practice has become an intense focus in medicine. Sub-specialty training in gynecologic oncology has not been established in all European countries, and this is the case for Italy. The
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European Society of Gynecologic Oncology (ESGO) has recently developed a list of quality indicators for advanced OC surgery, indicating the number of cytoreductive surgeries performed per center/surgeon per year and the rate of complete surgical cytoreduction as the main factors [37]. In our cooperative group, a program of internal training has been recently undertaken. However, the centralized referral of patients with advanced OC to high-volume expert centers seems to be the most urgent action. Furthermore, a “collaboration-net” between different institutions could allow the identification of infrastructures, types of care, best practices of the providers with better outcomes that can then be translated to institutions performing less well. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2016.01.025. Conflict of interest statement The authors declare that there are no conflicts of interest.
References [1] G.D. Aletti, S.C. Dowdy, B.S. Gostout, M.B. Jones, C.R. Stanhope, Wilson TO, et al., Aggressive surgical effort and improved survival in advanced-stage ovarian cancer, Obstet. Gynecol. 107 (1) (2006) 77–85. [2] S.M. Eisenkop, N.M. Spirtos, R.L. Friedman, W.C. Lin, A.L. Pisani, S. Perticucci, Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study, Gynecol. Oncol. 90 (2) (2003) 390–396. [3] S.M. Eisenkop, R.L. Friedman, H.J. Wang, Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study, Gynecol. Oncol. 69 (2) (1998) 103–108. [4] R.E. Bristow, R.S. Tomacruz, D.K. Armstrong, E.L. Trimble, F.J. Montz, Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis, J. Clin. Oncol. 20 (5) (2002) 1248–1259. [5] W.E. Winter 3rd, G.L. Maxwell, C. Tian, M.J. Sundborg, G.S. Rose, P.G. Rose, et al., Gynecologic Oncology Group. Tumor residual after surgical cytoreduction in prediction of clinical outcome in stage IV epithelial ovarian cancer: a Gynecologic Oncology Group Study, J. Clin. Oncol. 26 (1) (2008) 83–89. [6] A. Elattar, A. Bryant, B.A. Winter-Roach, M. Hatem, R. Naik, Optimal primary surgical treatment for advanced epithelial ovarian cancer, Cochrane Database Syst. Rev. 8 (2011), CD007565. [7] T. Paulsen, K. Kjaerheim, J. Kaern, S. Tretli, C. Tropé, Improved short-term survival for advanced ovarian, tubal, and peritoneal cancer patients operated at teaching hospitals, Int. J. Gynecol. Cancer 16 (Suppl. 1) (2006 Jan-Feb) 11–17. [8] F. Vernooij, P. Heintz, E. Witteveen, Y. van der Graaf, The outcomes of ovarian cancer treatment are better when provided by gynecologic oncologists and in specialized hospitals: a systematic review, Gynecol. Oncol. 105 (3) (2007) 801–812. [9] A. du Bois, J. Rochon, J. Pfisterer, W.J. Hoskins, Variations in institutional infrastructure, physician specialization and experience, and outcome in ovarian cancer: a systematic review, Gynecol. Oncol. 112 (2) (2009) 422–436. [10] R.E. Bristow, B.E. Palis, D.S. Chi, W.A. Cliby, The National Cancer Database report on advanced-stage epithelial ovarian cancer: impact of hospital surgical case volume on overall survival and surgical treatment paradigm, Gynecol. Oncol. 118 (3) (2010) 262–267. [11] D. Querleu, I. Ray-Coquard, J.M. Classe, J.S. Aucouturier, F. Bonnet, P. Bonnier, et al., Quality indicators in ovarian cancer surgery: report from the French Society of Gynecologic Oncology (Societe Francaise d'Oncologie Gynecologique, SFOG), Ann. Oncol. 24 (11) (2013) 2732–2739. [12] M. Fung-Kee-Fung, E.B. Kennedy, J. Biagi, T. Colgan, D. D'Souza, L.M. Elit, et al., The optimal organization of gynecologic oncology services: a systematic review, Curr. Oncol. 22 (4) (2015) e282–e293. [13] E. Halkia, J. Spiliotis, P. Sugarbaker, Diagnosis and management of peritoneal metastases from ovarian cancer, Gastroenterol. Res. Pract. 2012 (2012) 541842. [14] A. Fagotti, G. Ferrandina, F. Fanfani, A. Ercoli, D. Lorusso, M. Rossi, et al., A laparoscopy-based score to predict surgical outcome in patients with advanced ovarian carcinoma: a pilot study, Ann. Surg. Oncol. 13 (8) (2006) 1156–1161. [15] P.A. Clavien, J. Barkun, M.L. de Oliveira, J.N. Vauthey, D. Dindo, R.D. Schulick, et al., The Clavien-Dindo classification of surgical complications: five-year experience, Ann. Surg. 250 (2) (2009) 187–196.
429
[16] J. Prat, FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum, Int. J. Gynaecol. Obstet. 124 (1) (2014) 1–5. [17] J.V. Meigs, Tumors of the Female Pelvic Organs, New York, NY, Macmillan, 1934. [18] C.T. Griffiths, Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma, Natl. Cancer Inst. Monogr. 42 (1975) 101–104. [19] S. Kang, Y.H. Jong, J.H. Hwang, M.C. Lim, S.S. Seo, C.W. Yoo, et al., Is neoadjuvant chemotherapy a “waiver” of extensive upper abdominal surgery in advanced epithelial ovarian cancer? Ann. Surg. Oncol. 18 (13) (2011) 3824–3827. [20] R.S. Suidan, P.T. Ramirez, D.M. Sarasohn, J.B. Teitcher, S. Mironov, R.B. Iyer, et al., A multicenter prospective trial evaluating the ability of preoperative computed tomography scan and serum CA-125 to predict suboptimal cytoreduction at primary debulking surgery for advanced ovarian, fallopian tube, and peritoneal cancer, Gynecol. Oncol. 134 (3) (2014) 455–461. [21] M.J. Rutten, R. van de Vrie, A. Bruining, A.M. Spijkerboer, B.W. Mol, G.G. Kenter, et al., Predicting surgical outcome in patients with International Federation of Gynecology and Obstetrics stage III or IV ovarian cancer using computed tomography: a systematic review of prediction models, Int. J. Gynecol. Cancer 25 (3) (2015) 407–415. [22] G.D. Aletti, B.S. Gostout, K.C. Podratz, W.A. Cliby, Ovarian cancer surgical resectability: relative impact of disease, patient status, and surgeon, Gynecol. Oncol. 100 (1) (2006) 33–37. [23] Y. Ren, R. Jiang, S. Yin, C. You, D. Liu, X. Cheng, et al., Radical surgery versus standard surgery for primary cytoreduction of bulky stage IIIC and IV ovarian cancer: an observational study, BMC Cancer 15 (2015) 583. [24] R.E. Bristow, M.L. Zahurak, T.P. Diaz-Montes, R.L. Giuntoli, D.K. Armstrong, Impact of surgeon and hospital ovarian cancer surgical case volume on in-hospital mortality and related short-term outcomes, Gynecol. Oncol. 115 (3) (2009) 334–338. [25] C. Marth, S. Hiebl, W. Oberaigner, R. Winter, S. Leodolter, P. Sevelda, Influence of department volume on survival for ovarian cancer: results from a prospective quality assurance program of the Austrian Association for Gynecologic Oncology, Int. J. Gynecol. Cancer 19 (1) (2009) 94–102. [26] S. Kumpulainen, T. Kuoppala, A. Leminen, J. Penttinen, U. Puistola, E. Pukkala, et al., Surgical treatment of ovarian cancer in different hospital categories–a prospective nation-wide study in Finland, Eur. J. Cancer 42 (3) (2006) 388–395. [27] I. Vergote, C.G. Tropé, F. Amant, G.B. Kristensen, T. Ehlen, N. Johnson, et al., European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group; NCIC Clinical Trials Group. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer, N. Engl. J. Med. 363 (10) (2010) 943–953. [28] S. Kehoe, J. Hook, M. Nankivell, G.C. Jayson, H. Kitchener, T. Lopes, et al., Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial, Lancet 386 (9990) (2015) 249–257. [29] L. Verleye, I. Vergote, A.G. van der Zee, Patterns of care in surgery for ovarian cancer in Europe, Eur. J. Surg. Oncol. 36 (Suppl. 1) (2010) S108–S114. [30] W. Oberaigner, W. Stühlinger, Influence of department volume on cancer survival for gynaecological cancers–a population-based study in Tyrol, Austria, Gynecol. Oncol. 103 (2) (2006) 527–534. [31] C.L. Fagö-Olsen, C. Høgdall, H. Kehlet, I.J. Christensen, B. Ottesen, Centralized treatment of advanced stages of ovarian cancer improves survival: a nationwide Danish survey, Acta Obstet. Gynecol. Scand. 90 (3) (2011) 273–279. [32] M. Luyckx, E. Leblanc, T. Filleron, P. Morice, E. Darai, J.M. Classe, et al., Maximal cytoreduction in patients with FIGO stage IIIC to stage IV ovarian, fallopian, and peritoneal cancer in day-to-day practice: a Retrospective French Multicentric Study, Int. J. Gynecol. Cancer 22 (8) (2012) 1337–1343. [33] P. Harter, Z.M. Muallem, C. Buhrmann, D. Lorenz, C. Kaub, R. Hils, et al., Impact of a structured quality management program on surgical outcome in primary advanced ovarian cancer, Gynecol. Oncol. 121 (3) (2011) 615–619. [34] D.S. Chi, E.L. Eisenhauer, O. Zivanovic, Y. Sonoda, N.R. Abu-Rustum, D.A. Levine, et al., Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm, Gynecol. Oncol. 114 (1) (2009) 26–31. [35] G.D. Aletti, S.C. Dowdy, K.C. Podratz, W.A. Cliby, Surgical treatment of diaphragm disease correlates with improved survival in optimally debulked advanced stage ovarian cancer, Gynecol. Oncol. 100 (2) (2006) 283–287. [36] P. Benedetti Panici, V. Di Donato, M. Fischetti, A. Casorelli, G. Perniola, A. Musella, et al., Predictors of postoperative morbidity after cytoreduction for advanced ovarian cancer: Analysis and management of complications in upper abdominal surgery, Gynecol. Oncol. 137 (3) (2015) 406–411. [37] D. Querleu, F. Planchamp, G. Aletti, D. Barton, S. Carinelli, L. Chiva, et al., Advanced (Stage III–IV) Ovarian Cancer Surgery: Quality Indicators, 2015 Oct. (Available from: http://www.asociacionasaco.es/wp-content/uploads/2015/10/Indicators-surgery-cancer-ovario-Oct-2015.pdf).
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Primary surgical cytoreduction in advanced ovarian cancer: An outcome analysis within the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) Group Stefano Greggi a,⁎, Francesca Falcone b, Raffaele Carputo a, Francesco Raspagliesi c, Cono Scaffa a, Giuseppe Laurelli a, Giorgio Giorda d, Giovanni Di Vagno e, Francesco Petruzzelli f, Gennaro Cormio g, Marco Marinaccio g, Sandro Pignata h a
Gynecologic Oncology Surgery, Istituto Nazionale Tumori “Fondazione G. Pascale” IRCCS, Naples, Italy Department of Woman, Child, and General and Specialized Surgery, Seconda Università degli Studi di Napoli, Naples, Italy c Department of Gynecologic Oncology, IRCCS National Cancer Institute, Milan, Italy d Department of Gynecological Oncology, Centro di Riferimento Oncologico (CRO) National Cancer Institute, Aviano, Italy e Department of Obstetrics and Gynecology, Umberto I Hospital, Bari, Italy f Obstetrics and Gynaecology Department, IRCCS “Casa Sollievo della Sofferenza”, Foggia, Italy g Department of Obstetrics and Gynecology, University of Bari, Bari, Italy h Department of Urology and Gynecology, Istituto Nazionale Tumori “Fondazione G. Pascale” IRCCS, Naples, Italy b
H I G H L I G H T S • Patient and tumor characteristics, quality of surgery affect surgical cytoreduction. • Quality of surgery is important to improve the outcome of advanced ovarian cancer. • Advanced ovarian cancer patient referral to high-volume centers is an urgent action.
a r t i c l e
i n f o
Article history: Received 25 November 2015 Received in revised form 18 January 2016 Accepted 25 January 2016 Available online 26 January 2016
a b s t r a c t Objective. To draw a reliable picture of the surgical management of advanced ovarian cancer (AOC) within the MITO Group, trying to correlate the disease extent at presentation, the category of center, and surgical outcome. Methods. Three tertiary referral centers for gynecologic oncology and four non-oncologic referral gynecologic surgical centers, participated in the project. A questionnaire was adopted to register perioperative data on AOCs (FIGO Stage IIIC\\IV) consecutively operated on for a period of 12 months. Results. A total of 205 patients were registered into the study: 140 and 65 were recruited in oncological referral centers and non-referral centers, respectively. Following a multivariate analysis, the Eisenkop score and the category of center resulted the most potent predictors of complete surgical cytoreduction followed by PCI, preoperative CA125, and ASA score. Complete surgical cytoreduction was associated with oncological referral centers (60% vs 24.6%, p b 0.001). The proportion of patients undergoing additional surgical procedures was significantly different comparing the two categories of centers (at least one additional procedure was performed in 81.4% vs 50.8% in oncological referral centers compared to the others, p b 0.001). Despite the more aggressive surgery performed in oncological referral centers, the perioperative outcome measures were not significantly different in the two groups. Conclusions. The chance of obtaining a complete cytoreduction mainly depends on patient characteristics, tumor spread, and quality of treatment. The latter is amenable for direct influence, and therefore, seems to be of utmost importance when considering efforts aiming at improvement in the outcome of this disease. © 2016 Elsevier Inc. All rights reserved.
1. Introduction ⁎ Corresponding author at: Gynecologic Oncology Surgery, National Cancer Institute of Naples - IRCCS “Fondazione G. Pascale”, Via M. Semmola, 80131 Naples, Italy. E-mail address: [email protected] (S. Greggi).
http://dx.doi.org/10.1016/j.ygyno.2016.01.025 0090-8258/© 2016 Elsevier Inc. All rights reserved.
Ovarian cancer (OC) is usually diagnosed at an advanced stage, with intra-abdominal tumor widespread. In these conditions, surgery is complex, very frequently involving the upper abdomen and requiring an
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extensive approach to the pelvis in most cases. The strong prognostic influence of a complete primary surgical cytoreduction has been widely proved in multiple series [1–3], and meta-analyses [4–6]. The ability to achieve a complete cytoreduction is determined by the extent of disease at diagnosis but also by the subspecialty and case volume of the surgical team involved [7–12]. For advanced OC, the International Federation of Gynecology and Obstetrics (FIGO) staging is unable to clinically select patients for whom a “standard gynecological” surgery is enough to remove all visible disease. A number of ranking systems have been proposed to more reliably quantify the disease extent [2, 13, 14]. All of them, however, are based on the intraoperative assessment, and do not allow a clinical stratification of cases according to the expected surgical complexity, and, consequently, their appropriate referral. Therefore, it seems to be crucial to act on the quality of surgery in the effort to improve the prognosis of advanced OC. The Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO) is one of the two Italian cooperative groups in gynecologic oncology. In 2012, the MITO-Group endorsed a prospective project among its surgical membership with the aim to draw a more reliable picture of the surgical management of advanced OC within the group, trying to correlate the extent of disease at presentation, the category of center, and the surgical outcome. 2. Materials and methods Tertiary referral centers for gynecologic surgical oncology, and nononcologic referral gynecologic surgical centers are part of the MITOGroup. Three of tertiary referral centers and four of non-oncological referral centers accepted to participate in this prospective survey as a sample of all centers. A questionnaire was adopted to register
Table 1 Patient and tumor characteristics. Variable
Oncological referral centers
Non oncological referral centers
Significance p – value
Patients, n (%) Age (years), median [range] WHO performance status, n (%) 0–1 2–3 ASA, n (%) 1–2 3–4 Preoperative serum CA125 levels (U/mL), median [range] Ascites (cc), median [range] Yes, n (%) No, n (%) Histologic classification, n (%) Serous Others Histologic grade, n (%) 1–2 3 FIGO stage, n (%) IIIA1(II) or IIIB IIIC or IV Bulky nodes, n (%) PCI, mean [range] “Eisenkop” score, mean [range] “Fagotti” score, mean [range]
140 (68.3) 60 [32–85]
65 (31.7) 59 [45–77]
– 0.16
114 (81.4) 26 (18.6)
52 (80) 13 (20)
0.85
85 (60.7) 55 (39.3)
42 (64.6) 23 (35.4)
0.64
792 [100–13,441]
614 [10–13,641]
0.91
2000 [50–10,000]
2000 [100–11,000]
0.88
107 (76.4) 33 (23.6)
45 (69.2) 20 (30.8)
1.00
98 (70) 42 (30)
50 (76.9) 15 (23.1)
0.32
37 (26.4) 103 (73.6)
12 (18.5) 53 (81.5)
0.29
14 (10) 126 (90) 41 (29.3) 17.2 [3−33] 8.5 [2–15]
3 (4.6) 62 (95.4) 13 (20) 15.4 [4–39] 7.8 [2−13]
0.27 0.17 0.79 0.20
7.5 [0–14]
7.3 [0–14]
0.79
ASA: American Society of Anesthesiologists; FIGO: International Federation of Gynecology and Obstetrics; PCI: peritoneal cancer index; WHO: World Health Organization.
perioperative data (primary surgery) on advanced (FIGO Stage IIIC\\IV) OC (including tubal and peritoneal epithelial cancers) patients consecutively treated for a period of 12 months. Data were collected on: patient characteristics (age; performance status according to World Health Organization (PS-WHO); American Society of Anesthesiologists (ASA) score), disease characteristics (preoperative CA125 serum level; histotype and grade; presence and quantity of ascites; detailed description of disease extent; FIGO Stage; peritoneal cancer index (PCI); “Eisenkop” score; “Fagotti” score), and surgical outcome (surgical procedures performed; completeness of cytoreduction (CC); reason(s) for the inability to achieve a complete cytoreduction; duration of surgery; estimated blood loss and blood units transfused; intra/postoperative complications/deaths; days from surgery to hospital discharge). The PCI was computed according to Sugarbaker [13], the “Eisenkop” and the “Fagotti” scores were calculated on the basis of what described by the Authors [2, 14]; scores description is available in Supplementary Table 1. In particular, participating centers were asked for fulfilling the “Fagotti” score regardless the adoption of laparoscopic evaluation of cytoreducibility. Completeness of surgical cytoreduction was categorized as proposed by Sugarbaker [13]: no macroscopic tumor (CC = 0), b 0.25 cm (CC = 1), between 0.26 and 2.5 cm (CC = 2), and more than 2.5 cm (CC = 3). Postoperative complications were registered within 30 days from hospital discharge, and graded according to the Clavien-Dindo classification [15]. FIGO Stage IIIC\\IV was originally registered according the 1988 classification. Data are now presented adopting the new FIGO classification [16]. The patient and disease characteristics are described in Table 1. Data were analyzed using the Fischer's exact test, the χ2 test, the Student t-test, and the nonparametric Mann-Whitney and Wilcoxon tests, if needed. Factors predicting completeness of surgical cytoreduction were evaluated using univariate and multivariate models. The multivariate Cox regression analysis was used to estimate odds ratios and 95% confidence intervals for the different covariables. All p-values were two-sided, and p b 0.05 was considered significant. Statistical analysis was performed with SPSS statistical software version 21.0. 3. Results A total of 205 patients were registered into the study with advanced primary OC: 140 (68%) and 65 (32%), were recruited in oncological referral centers and non-referral centers, respectively. The two subgroups were homogeneous for the main patient and disease characteristics (Table 1). At univariate analysis, the following variables were significant predictors of complete surgical cytoreduction (CC = 0): performance status, ASA score, preoperative CA125 serum level, PCI, “Eisenkop” and “Fagotti” scores, and category of center (Table 2). Following multivariate analysis, only ASA score, preoperative CA125 serum level, PCI, “Eisenkop” score, and the category of center were still independent variables. In particular, the “Eisenkop” score and the category of center resulted the most potent predictors of complete cytoreduction (Table 2). In Table 3 the completeness of cytoreduction is detailed according to the category of center. Complete (CC = 0) surgical cytoreduction was associated with oncological referral centers (60% vs 24.6%, p b 0.001). In the oncological referral centers, complete cytoreduction was achieved in 83.3% and 16.7% (p b 0.001) for PCI b 20 and ≥20, respectively, and in 79.8% and 20.2% (p b 0.001) for “Eisenkop” score b 10 and ≥10, respectively. On the contrary, no significant difference was detected for “Fagotti” score b 8 vs ≥ 8 (p = 0.39). In fact, the proportion of patients undergoing additional surgical procedures was significantly different according to the category of center, with 81.4% of patients submitted to at least one additional procedure in oncological referral centers compared to 50.8% in the others (p b 0.001) (Table 4). A critical analysis of surgical forms revealed that the causes of suboptimal outcome can be schematically considered disease-dependent or surgeon-dependent. Mainly due to tumor diffusion the former, and to
S. Greggi et al. / Gynecologic Oncology 140 (2016) 425–429 Table 2 Univariate and multivariate analyses of factors predicting complete surgical cytoreduction. Variable
Age (years) ≤60 N60 WHO performance status 0 N0 ASA 1–2 3–4 Preoperative serum CA125 ≤750 U/mL N750 U/mL Ascites No Yes Ascites ≤2000 cm3 N2000 cm3 Histologic classification Serous Others Histologic grade 1–2 3 Bulky nodes No Yes PCI b20 ≥20 “Eisenkop” score b10 ≥10 “Fagotti” score b8 ≥8 Center ORC Non-ORC
Univariate analysis
Multivariate analysis
RR [95% CI]
OR [95% CI]
1 1.54 [0.88–2.68]
pvalue 0.16
pvalue
427
Table 4 Additional surgical procedures by category of center. Additional surgical procedures/organ resections
ORC n
Non-ORC Significance n p – value
Pelvic peritonectomy Abdominal peritonectomy Diaphragmatic peritonectomy Diaphragmatic resection Pancreatic resection Partial/total gastrectomy Rectosigmoid resection and primary anastomosis Colon resection Cecum resection Ileum resection Ileostomy Colostomy Splenectomy Bladder resection Excision of pelvic masses Lymphadenectomy Total At least one procedure, n (%)
100 43 58 19 7 3 41
21 1 1 0 0 0 6
7 11 14 7 8 7 1 47 57 430 114 (81.4) 94 (67.1) 81 (57.9)
4 0 1 1 3 0 1 6 5 50 33 (50.8) b0.001
1 1.19 [0.54–2.60]
0.65
1 3.31 [1.71–6.38]
b0.001 1 1.71 [0.71–4.15]
0.22
1 2.33 [1.30–4.17]
b0.05
1 2.54 [1.08–5.96]
b 0.05
1 2.55 [1.45–4.48]
b0.05
1 2.13 [1.03–4.42]
b0.05
1 1.37 [0.73–2.58]
0.34
1 1.05 [0.38–2.85]
0.92
1 1.75 [0.52–3.34]
0.10
1 1.07 [0.46–2.51]
0.86
1 1.50 [0.81–2.78]
0.21
1 1.15 [0.50–2.65]
0.72
Non-ORC: non-oncological referral centers; ORC: oncological referral centers.
1 1.01 [0.53–1.92]
1.00
1 1.40 [0.58–3.34]
0.44
1 1.30 [0.70–2.43]
0.43
1 1.52 [0.60–3.85]
0.37
complications (including one case of death, 0.7%), however, was observed among patients operated on at oncological referral centers (Table 6).
1 5.37 [2.81–10.25]
b0.001 1 3.03 [1.16–7.94]
b0.05
1 6.00 [3.25–11.22]
b0.001 1 4.13 [1.64–10.40]
b0.001
1 3.71 [2.05–6.71]
b0.001 1 1.44 [0.55–3.73]
0.45
1 4.59 [2.37–8.16]
b0.001 1 10.44 [4.32–25.19]
Two procedures, n (%) Three or more procedures, n (%)
11 (16.9) b0.001 8 (12.3) b0.001
3.1. Discussion
b0.001
ASA: American Society of Anesthesiologists; CI: confidence interval; Non-ORC: non-oncological referral centers; OR: odds ratio; ORC: oncological referral centers; PCI: peritoneal cancer index; RR: risk ratio; WHO: World Health Organization.
incomplete or missing surgical procedures the latter (Table 5). The proportion of cases with missing or inadequate surgical procedures was significantly higher in non-oncological referral centers (p b 0.001). In particular, the lack of expertise in diaphragmatic peritonectomy and resection, and in the pelvic extraperitoneal approach were the main causes of unsuccessful surgery. Despite of the more aggressive surgery performed in oncological referral centers, the perioperative outcome measures were not significantly different in the two groups. A higher rate (8.6%) of severe Table 3 Completeness of surgical cytoreduction according to the category of center. CC score
ORC n (%)
Non-ORC n (%)
Significance p – value
0 (no visible residual tumor) 1 (residual nodules ≤0.25 cm) 2 (residual nodules N0.25 cm and ≤2.5 cm) 3 (residual nodules N2.5 cm)
84 (60) 18 (2.9) 9 (6.4) 29 (20.7)
16 (24.6) 7 (10.8) 21 (32.3) 21 (32.3)
b0.001
CC: completeness of cytoreduction; Non-ORC: non-oncological referral centers; ORC: oncological referral centers.
There is a considerable debate on which measures should be used to reflect surgical quality. In particular, the most appropriate way to assess the quality of surgical care in primary advanced OC must include the completeness of cytoreduction, which represents the most significant prognosticator. The present survey, conducted within a gynecologic oncology national cooperative group, confirms the importance of the case volume in determining surgical outcome with relevant implications in terms of quality of care, need for a centralized treatment and specific training. In fact, all the three oncological referral centers included in the present analysis treat more than 50 OC per year compared with b20 by the others. The proportion of patients achieving CC = 0–1 surgical cytoreduction is significantly higher in the oncological referral centers (62.9% vs 35.4%, p b 0.001), and, even more, the rate of complete cytoreduction (60% vs 24.6%, p b 0.001). The “Eisenkop” score and the category of center result the most potent predictors of complete Table 5 Causes of incomplete surgical cytoreduction by category of center. Causes of incomplete cytoreduction Tumor – dependent Extensive peritoneal involvement More than 3 bowel resections required Extensive involvement of mesenteric root Implants in the porta hepatis Enlargement of suprarenal LNs Total Surgeon – dependent Absent or inadequate surgery on: – Diaphragm – Diaphragm and retroperitoneal LNs – Pelvis – Pelvis and retroperitoneal LNs – Diaphragm and pelvis Total
ORC n (%)
Non-ORC n (%)
Significance p – value
24 (63.2) 1 (2.6) 3 (7.9) 1 (2.6) 3 (7.9) 32 (84.2)
7 (17.1) 0 0 0 0 7 (17.1)
b0.001
14 (34.1) 4 (9.8) 5 (12.2) 2 (4.9) 9 (22) 34 (82.9)
b0.001
3 (7.9) 0 2 (5.3) 0 1 (2.6) 6 (15.8)
LNs: lymph nodes; Non-ORC: non-oncological referral centers; ORC: oncological referral centers.
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Table 6 Intra and post-operative outcome measures by category of center. Variable
ORC
Non-ORC Significance p - value
Length of surgery (minutes), mean Blood loss (cc), mean RBC transfusion (U), mean Post-operative severe (G 3, 4, 5) complications, n (%) Hospital length of stay (days), mean
233.24 588.19 0.81 12 (8.6) 9.21
232.05 814.47 1.33 3 (4.6)
0.94 0.05 0.25 0.39
8.54
0.32
G: grade; Non-ORC: non-oncological referral centers; ORC: oncological referral centers; RBC: red blood cells.
cytoreduction at multivariate analysis, followed by ASA score, preoperative CA125 serum level, and PCI. These data confirm that disease spread and aggressiveness of surgery both have a role in determining the surgical outcome. Primary surgery must be performed to achieve complete cytoreduction as the amount of residual tumor is one of the most important prognostic factors for survival of advanced OC [1, 4, 5], and no residual tumor has been shown to be a better predictor of survival than the extent of metastatic disease present before surgery [2]. Historically, Meigs earlier and later Griffiths, suggested an inverse relationship between residual tumor diameter and survival [17, 18]. This initial observation has been confirmed by subsequent meta [4–6] and single study [1–3] analyses, and primary surgery with cytoreductive intent became the current treatment paradigm for patients with advanced OC. Bristow et al. evaluated 81 studies involving 6885 patients and demonstrated that each 10% increase in maximal cytoreduction was associated with a 5.5% increase in median survival time [4]. The results of a recent meta-analysis by the Cochrane group are consistent with the previously published meta-analysis by Bristow et al. [6]. Therefore, all attempts should be made to achieve complete cytoreduction during primary surgery for advanced stage OC. When this is not achievable, the surgical goal should be b1 cm residual disease, although, the risk of death is respectively two and three times greater if there is b1 cm and N1 cm residual disease when compared with microscopic residual disease only [6]. This concept is valid regardless of the timing of surgery and applies to the policy of neoadjuvant chemotherapy (NACT), which is not a substitute for complete resection [19]. Tumor dissemination and, consequently, the extent of surgery required, are difficult to assess preoperatively. In order to determine which patients would be less likely to benefit from primary surgery, several attempts have been made to predict cytoreductive outcome with models combining computed tomography (CT) variables, with or without clinical (PS-WHO, age, body mass index, comorbidities, smoking) and/or biochemical (CA 125, albumin, blood platelet count) parameters [20, 21]. To date, there are no models that show a good predictive performance for residual disease when extrapolated to other centers [21]. Therefore, the predictability of surgical outcome remains an area of controversy and clinical ambiguity. It is acknowledged that there is considerable variation in achieving complete cytoreduction between different surgical centers, and this can affect the development of models of prediction. To select patients who could be completely cytoreduced, and to compare patient outcomes with as little bias as possible, intraoperative scoring systems have been elaborated, based on accurate description of the disease spread. The PCI and the “Eisenkop” scores appear to give valuable information about the exact distribution of carcinomatosis, and have been considered for prediction of surgical cytoreducibility [2, 13]. Similarly, Fagotti et al. reported a laparoscopy-based score [14]. In our study, multivariate analysis showed the PCI and “Eisenkop” scores, but not the “Fagotti” score, as independent variables of complete surgical cytoreduction. The former scores allow more analytical description of intraperitoneal tumor diffusion, and this may possibly explain their better predictive value. ASA score also significantly correlated with
residual disease. This finding is consistent with that previously published by Aletti et al. [22, 23]. In this setting, a careful perioperative management in collaboration with the anaesthesiologic team is critical to improve oncological outcomes, while preventing an increase in the complication rate potentially derivable from aggressive surgical procedures. At multivariate analysis, the most potent predictor of no residual disease was the category of center (OR: 10.44 [4.32–25.19], p b 0.001), with 60% and 24.6% CC = 0 in oncological referral centers and nononcological referral centers, respectively (p b 0.001). Hospitals with ≥ 20 and b20 cases/year are usually categorized as high and lowvolume, respectively [24–26]. In our study, non-oncological referral centers treat b 20 OC per year, and showed no postsurgical residual disease in about 25% of cases. Even though such a rate is much below that is considered today the minimum required surgery for advanced OC, it has to be taken into account that the reported rates of complete cytoreduction in the EORTC (20.4%) and CHORUS (17%) trials were even lower in spite of the gynecologic oncology network settings [27, 28]. Based on some national Northern European registries, from 25 to 50% of ovarian cancer patients are operated on in high-volume hospitals [29], and this proportion is likely lower in the South of Europe. The majority of European population-based studies, have found that higher the hospital surgical volume, higher the likelihood of 0–0.25 cm residual disease, and of improved overall survival [7, 25, 26, 30, 31]. Our results confirm the previous findings, including the deep relationship between higher case-volume and more extensive surgical procedures. To achieve complete cytoreduction in the majority of OC patients, advanced surgical techniques are needed. In particular, visceral surgery is required in more than 50% of cases [32]. Bowel resections, diaphragmatic surgery, pelvic and aortic lymphadenectomy, supracolic omentectomy, splenectomy and peritonectomy should ideally be part of the skills of the surgeon, hence specialized training is needed. Several studies have shown that complete or b0.25 cm cytoreduction rates over 50% often require the incorporation of extensive upper abdominal surgical procedures [2, 33, 34]. Chi et al. reported an improvement of surgical outcome by inclusion of upper abdominal surgery, resulting in a resection rate to b1 cm residual disease from 46% to 80% within the study period, without significantly increasing perioperative morbidity and mortality [34]. Accordingly, in our study, the proportion of patients undergoing additional surgical procedures was significantly higher in oncological referral centers (81.4% vs 50.8%, p b 0.001). In particular, the lack of expertise in diaphragmatic peritonectomy and resection, and in the pelvic extraperitoneal approach were the main causes of unsuccessful surgery (Table 5). Diaphragm involvement is very common in advanced OC, and it is considered to be a major obstacle to successful cytoreductive surgery [35]. Very recently, Benedetti-Panici et al., based on the relatively low postoperative mortality rate and the ability to safely manage almost all complications, have considered the rate of morbidity to be acceptable in the light of the expected survival increase following aggressive surgical cytoreduction [36]. In our study, the frequency of severe complications was not significantly different in the two groups, although a higher rate was observed in the patients operated on at oncological referral centers, with severe complications occurring in 8.6% with only one case of postoperative mortality (0.7%). In conclusion, the chance of obtaining a complete cytoreduction mainly depends on patient characteristics, tumor spread, and quality of surgery. The first two reflect an unchangeable reality, but the latter is amenable for direct influence, and therefore, seems to be of utmost importance when considering efforts aiming at improvement in the outcome of this disease. Our study results underline the need for improving the quality of surgery in advanced OC even, or, just because within a gynecologic oncology cooperative group. Quality improvement in surgical and oncological practice has become an intense focus in medicine. Sub-specialty training in gynecologic oncology has not been established in all European countries, and this is the case for Italy. The
S. Greggi et al. / Gynecologic Oncology 140 (2016) 425–429
European Society of Gynecologic Oncology (ESGO) has recently developed a list of quality indicators for advanced OC surgery, indicating the number of cytoreductive surgeries performed per center/surgeon per year and the rate of complete surgical cytoreduction as the main factors [37]. In our cooperative group, a program of internal training has been recently undertaken. However, the centralized referral of patients with advanced OC to high-volume expert centers seems to be the most urgent action. Furthermore, a “collaboration-net” between different institutions could allow the identification of infrastructures, types of care, best practices of the providers with better outcomes that can then be translated to institutions performing less well. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ygyno.2016.01.025. Conflict of interest statement The authors declare that there are no conflicts of interest.
References [1] G.D. Aletti, S.C. Dowdy, B.S. Gostout, M.B. Jones, C.R. Stanhope, Wilson TO, et al., Aggressive surgical effort and improved survival in advanced-stage ovarian cancer, Obstet. Gynecol. 107 (1) (2006) 77–85. [2] S.M. Eisenkop, N.M. Spirtos, R.L. Friedman, W.C. Lin, A.L. Pisani, S. Perticucci, Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study, Gynecol. Oncol. 90 (2) (2003) 390–396. [3] S.M. Eisenkop, R.L. Friedman, H.J. Wang, Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study, Gynecol. Oncol. 69 (2) (1998) 103–108. [4] R.E. Bristow, R.S. Tomacruz, D.K. Armstrong, E.L. Trimble, F.J. Montz, Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis, J. Clin. Oncol. 20 (5) (2002) 1248–1259. [5] W.E. Winter 3rd, G.L. Maxwell, C. Tian, M.J. Sundborg, G.S. Rose, P.G. Rose, et al., Gynecologic Oncology Group. Tumor residual after surgical cytoreduction in prediction of clinical outcome in stage IV epithelial ovarian cancer: a Gynecologic Oncology Group Study, J. Clin. Oncol. 26 (1) (2008) 83–89. [6] A. Elattar, A. Bryant, B.A. Winter-Roach, M. Hatem, R. Naik, Optimal primary surgical treatment for advanced epithelial ovarian cancer, Cochrane Database Syst. Rev. 8 (2011), CD007565. [7] T. Paulsen, K. Kjaerheim, J. Kaern, S. Tretli, C. Tropé, Improved short-term survival for advanced ovarian, tubal, and peritoneal cancer patients operated at teaching hospitals, Int. J. Gynecol. Cancer 16 (Suppl. 1) (2006 Jan-Feb) 11–17. [8] F. Vernooij, P. Heintz, E. Witteveen, Y. van der Graaf, The outcomes of ovarian cancer treatment are better when provided by gynecologic oncologists and in specialized hospitals: a systematic review, Gynecol. Oncol. 105 (3) (2007) 801–812. [9] A. du Bois, J. Rochon, J. Pfisterer, W.J. Hoskins, Variations in institutional infrastructure, physician specialization and experience, and outcome in ovarian cancer: a systematic review, Gynecol. Oncol. 112 (2) (2009) 422–436. [10] R.E. Bristow, B.E. Palis, D.S. Chi, W.A. Cliby, The National Cancer Database report on advanced-stage epithelial ovarian cancer: impact of hospital surgical case volume on overall survival and surgical treatment paradigm, Gynecol. Oncol. 118 (3) (2010) 262–267. [11] D. Querleu, I. Ray-Coquard, J.M. Classe, J.S. Aucouturier, F. Bonnet, P. Bonnier, et al., Quality indicators in ovarian cancer surgery: report from the French Society of Gynecologic Oncology (Societe Francaise d'Oncologie Gynecologique, SFOG), Ann. Oncol. 24 (11) (2013) 2732–2739. [12] M. Fung-Kee-Fung, E.B. Kennedy, J. Biagi, T. Colgan, D. D'Souza, L.M. Elit, et al., The optimal organization of gynecologic oncology services: a systematic review, Curr. Oncol. 22 (4) (2015) e282–e293. [13] E. Halkia, J. Spiliotis, P. Sugarbaker, Diagnosis and management of peritoneal metastases from ovarian cancer, Gastroenterol. Res. Pract. 2012 (2012) 541842. [14] A. Fagotti, G. Ferrandina, F. Fanfani, A. Ercoli, D. Lorusso, M. Rossi, et al., A laparoscopy-based score to predict surgical outcome in patients with advanced ovarian carcinoma: a pilot study, Ann. Surg. Oncol. 13 (8) (2006) 1156–1161. [15] P.A. Clavien, J. Barkun, M.L. de Oliveira, J.N. Vauthey, D. Dindo, R.D. Schulick, et al., The Clavien-Dindo classification of surgical complications: five-year experience, Ann. Surg. 250 (2) (2009) 187–196.
429
[16] J. Prat, FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum, Int. J. Gynaecol. Obstet. 124 (1) (2014) 1–5. [17] J.V. Meigs, Tumors of the Female Pelvic Organs, New York, NY, Macmillan, 1934. [18] C.T. Griffiths, Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma, Natl. Cancer Inst. Monogr. 42 (1975) 101–104. [19] S. Kang, Y.H. Jong, J.H. Hwang, M.C. Lim, S.S. Seo, C.W. Yoo, et al., Is neoadjuvant chemotherapy a “waiver” of extensive upper abdominal surgery in advanced epithelial ovarian cancer? Ann. Surg. Oncol. 18 (13) (2011) 3824–3827. [20] R.S. Suidan, P.T. Ramirez, D.M. Sarasohn, J.B. Teitcher, S. Mironov, R.B. Iyer, et al., A multicenter prospective trial evaluating the ability of preoperative computed tomography scan and serum CA-125 to predict suboptimal cytoreduction at primary debulking surgery for advanced ovarian, fallopian tube, and peritoneal cancer, Gynecol. Oncol. 134 (3) (2014) 455–461. [21] M.J. Rutten, R. van de Vrie, A. Bruining, A.M. Spijkerboer, B.W. Mol, G.G. Kenter, et al., Predicting surgical outcome in patients with International Federation of Gynecology and Obstetrics stage III or IV ovarian cancer using computed tomography: a systematic review of prediction models, Int. J. Gynecol. Cancer 25 (3) (2015) 407–415. [22] G.D. Aletti, B.S. Gostout, K.C. Podratz, W.A. Cliby, Ovarian cancer surgical resectability: relative impact of disease, patient status, and surgeon, Gynecol. Oncol. 100 (1) (2006) 33–37. [23] Y. Ren, R. Jiang, S. Yin, C. You, D. Liu, X. Cheng, et al., Radical surgery versus standard surgery for primary cytoreduction of bulky stage IIIC and IV ovarian cancer: an observational study, BMC Cancer 15 (2015) 583. [24] R.E. Bristow, M.L. Zahurak, T.P. Diaz-Montes, R.L. Giuntoli, D.K. Armstrong, Impact of surgeon and hospital ovarian cancer surgical case volume on in-hospital mortality and related short-term outcomes, Gynecol. Oncol. 115 (3) (2009) 334–338. [25] C. Marth, S. Hiebl, W. Oberaigner, R. Winter, S. Leodolter, P. Sevelda, Influence of department volume on survival for ovarian cancer: results from a prospective quality assurance program of the Austrian Association for Gynecologic Oncology, Int. J. Gynecol. Cancer 19 (1) (2009) 94–102. [26] S. Kumpulainen, T. Kuoppala, A. Leminen, J. Penttinen, U. Puistola, E. Pukkala, et al., Surgical treatment of ovarian cancer in different hospital categories–a prospective nation-wide study in Finland, Eur. J. Cancer 42 (3) (2006) 388–395. [27] I. Vergote, C.G. Tropé, F. Amant, G.B. Kristensen, T. Ehlen, N. Johnson, et al., European Organization for Research and Treatment of Cancer-Gynaecological Cancer Group; NCIC Clinical Trials Group. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer, N. Engl. J. Med. 363 (10) (2010) 943–953. [28] S. Kehoe, J. Hook, M. Nankivell, G.C. Jayson, H. Kitchener, T. Lopes, et al., Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial, Lancet 386 (9990) (2015) 249–257. [29] L. Verleye, I. Vergote, A.G. van der Zee, Patterns of care in surgery for ovarian cancer in Europe, Eur. J. Surg. Oncol. 36 (Suppl. 1) (2010) S108–S114. [30] W. Oberaigner, W. Stühlinger, Influence of department volume on cancer survival for gynaecological cancers–a population-based study in Tyrol, Austria, Gynecol. Oncol. 103 (2) (2006) 527–534. [31] C.L. Fagö-Olsen, C. Høgdall, H. Kehlet, I.J. Christensen, B. Ottesen, Centralized treatment of advanced stages of ovarian cancer improves survival: a nationwide Danish survey, Acta Obstet. Gynecol. Scand. 90 (3) (2011) 273–279. [32] M. Luyckx, E. Leblanc, T. Filleron, P. Morice, E. Darai, J.M. Classe, et al., Maximal cytoreduction in patients with FIGO stage IIIC to stage IV ovarian, fallopian, and peritoneal cancer in day-to-day practice: a Retrospective French Multicentric Study, Int. J. Gynecol. Cancer 22 (8) (2012) 1337–1343. [33] P. Harter, Z.M. Muallem, C. Buhrmann, D. Lorenz, C. Kaub, R. Hils, et al., Impact of a structured quality management program on surgical outcome in primary advanced ovarian cancer, Gynecol. Oncol. 121 (3) (2011) 615–619. [34] D.S. Chi, E.L. Eisenhauer, O. Zivanovic, Y. Sonoda, N.R. Abu-Rustum, D.A. Levine, et al., Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm, Gynecol. Oncol. 114 (1) (2009) 26–31. [35] G.D. Aletti, S.C. Dowdy, K.C. Podratz, W.A. Cliby, Surgical treatment of diaphragm disease correlates with improved survival in optimally debulked advanced stage ovarian cancer, Gynecol. Oncol. 100 (2) (2006) 283–287. [36] P. Benedetti Panici, V. Di Donato, M. Fischetti, A. Casorelli, G. Perniola, A. Musella, et al., Predictors of postoperative morbidity after cytoreduction for advanced ovarian cancer: Analysis and management of complications in upper abdominal surgery, Gynecol. Oncol. 137 (3) (2015) 406–411. [37] D. Querleu, F. Planchamp, G. Aletti, D. Barton, S. Carinelli, L. Chiva, et al., Advanced (Stage III–IV) Ovarian Cancer Surgery: Quality Indicators, 2015 Oct. (Available from: http://www.asociacionasaco.es/wp-content/uploads/2015/10/Indicators-surgery-cancer-ovario-Oct-2015.pdf).