Ann Surg Oncol DOI 10.1245/s10434-014-4329-7

ORIGINAL ARTICLE – GYNECOLOGIC ONCOLOGY

Prognostic and Predictive Value of the Peritoneal Cancer Index in Primary Advanced Epithelial Ovarian Cancer Patients After Complete Cytoreductive Surgery: Study of Tumor Bank Ovarian Cancer Khayal Gasimli, MD2,1, Elena Ioana Braicu, MD1,2, Rolf Richter, MPH1,2, Radoslav Chekerov, MD1,2, and Jalid Sehouli, MD, PhD1,2 1

Department of Gynecology, Virchow Campus Clinic, Charite´ Medical University Berlin, Berlin, Germany; 2Tumor Bank Ovarian Cancer Network (TOC), European Comprehensive Center for Ovarian Cancer, Charite´ Comprehensive Cancer Center (CCCC), Berlin, Germany

ABSTRACT Purpose. The peritoneal cancer index (PCI) is used to refer gastrointestinal malignancy patients to either palliative or curative management of their peritoneal carcinomatosis. The aim of this retrospective study was to evaluate the prognostic value of the PCI in patients with primary advanced epithelial ovarian cancer (EOC) after complete cytoreductive surgery. Methods. PCI quantitatively assesses cancer distribution on the peritoneum by calculating tumor sizes in each of 13 abdominopelvic regions. Correlation between PCI score and clinical factors were analyzed using Kendall’s tau b. Univariate and multivariate survival analyses were performed with the Kaplan–Meier method and Cox regression model, respectively. Results. We retrospectively enrolled 80 consecutive patients with primary EOC treated in our gynecology department. All patients underwent complete cytoreductive surgery. Patients whose history included interval tumor debulking and completion cytoreductive surgery were excluded. Most tumors were of a serous histological subtype (96.3 %). Median age at diagnosis was 58.0 years. Their median PCI score was 12.0 (range 3–32). We found statistical correlations between PCI and ascites (p = 0.001), surgery duration (p \ 0.001), T status of TNM staging (p = 0.036), and preoperative CA 125 (p = 0.025). In the

Ó Society of Surgical Oncology 2015 First Received: 21 April 2014 K. Gasimli, MD e-mail: [email protected]

univariate analysis, higher PCI scores were related to poor overall (OS) and progression-free (PFS) survival rates (p = 0.036 and p \ 0.001, respectively). Multivariate analysis showed that the association remained significant only for PFS (p = 0.005), not for OS (p = 0.162). Conclusions. PCI did not portend OS in patients with primary ovarian cancer. Further prospective and multicenter studies are needed to validate these results.

Ovarian cancer is the third most common cancer in women and the second most common cause of cancer-related deaths from gynecologic malignancies worldwide.1 Incidences are higher in developed countries and among postmenopausal women.1,2 Symptoms for ovarian cancer are nonspecific, causing to it being diagnosed when it has already developed into an advanced International Federation of Gynecology and Obstetrics (FIGO) stage and tumor cells have already disseminated into the peritoneal cavity and to other organs.3,4 Intraperitoneal spread of ovarian cancer is the most typical, earliest distribution pathway.5 To determine objectively and quantify the extent of peritoneal metastasis, there are currently two main groups of established assessment tools in surgical oncology. One group, for gastrointestinal malignancies, includes the Lyon classification,6 assessment of the P factor proposed by the Japanese Research Society for Gastric Cancer,7 the Peritoneal Cancer Index (PCI),8 and a Simplified Peritoneal Cancer Index (SPCI).9 The other group, for ovarian cancer, includes methods proposed by Eisenkop et al.10 Sehouli et al.11,12 Fagotti et al.13 Zivanovic et al.14 and Aletti et al.15. These assessment tools are based on tumor size and/or their localization within the peritoneal cavity.

K. Gasimli et al.

The mainstay for staging and treating epithelial ovarian cancer (EOC) is surgery.16 When disease has spread throughout the peritoneal cavity, optimal debulking with no macroscopic evidence of residual tumor is associated with better overall survival rates.17,18 Ideally, surgery can accomplish complete staging and removal of all macroscopically identified tumor with minimal harm to the patient.16 Primary debulking with the aim of removing as much tumor as possible followed by platinum-based chemotherapy is currently the standard treatment for advanced EOC. In high-volume centers, optimal tumor debulking can be achieved in 70–90 % of cases.19–21 The outcome of debulking surgery depends not only on the surgeon’s skills and the patient’s co-morbidities but also on the tumor’s pattern and biology.22 Several groups have tried to define quality indicators for surgical debulking. It is extremely important for the operating room staff to record the degree of tumor spread at the beginning of the surgery and the residual tumor mass afterward so there is prospective documentation on which to base identification of quality indicators. It seems that a small cohort of patients would not benefit from cytoreductive surgery, which calls for a discussion on the role of neoadjuvant chemotherapy. To date, no indicators have been identified that could distinguish situations in which there is a need for debulking surgery alone from those in which neoadjuvant therapy with interval debulking would benefit the patient. The highly investigated PCI was first proposed by Sugarbaker et al.8,23 in 1995 for colon cancer that had metastasized to the peritoneum. The PCI is frequently applied for referring gastrointestinal malignancies with peritoneal spread to either palliative or curative management.24,25 In contrast to gastrointestinal malignancies, there is still only superficial knowledge about the role of the PCI in ovarian cancer patients. The aim of our current study was to analyze retrospectively the clinical impact and prognostic value of the PCI in patients with primary advanced EOC. To the best of our knowledge, this is the first study that has analyzed the role of the PCI in EOC patients after complete cytoreductive surgery (CRS).

PATIENTS AND METHODS

TABLE 1 Patients’ characteristics Parameter

80 patients (in total) n (%)

Age at diagnosis (years)a

58.0 (32–86)

PCI

a

Preoperative serum CA 125 (U/ml)a

12.0 (3–32) 877 (14–18,400)

ECOG status 0

12 (15.0 %)

1

60 (75.0 %)

2 3

5 (6.2 %) 3 (3.8 %)

FIGO stage IIIB

8 (10.0 %)

IIIC

57 (1.2 %)

IV

15 (18.8 %)

Histology Serous

77 (96.3 %)

Clear cell

2 (2.5 %)

Endometrioid

1 (1.2 %)

Grade I

5 (6.2 %)

II

17 (21.3 %)

III

58 (72.5 %)

Lymph node involvement N0 N1

18 (22.5 %) 54 (67.5 %)

Nxb

8 (10.0 %)

Ascites \500 ml

33 (41.2 %)

[500 ml

32 (40.0 %)

None

15 (18.8 %)

Other malignancies Breast cancer

4 (5.0 %)

Cervix cancer

1 (1.3 %)

Nonsolid cancer

2 (2.5 %)

Family history of ovarian and/or breast cancer

13 (16.2 %)

Hormonal status Premenopausal

11 (13.8 %)

Postmenopausal

69 (86.3 %)

PCI peritoneal cancer index, ECOG Eastern Cooperative Oncology Group—Performance Status, FIGO Fe´de´ration Internationale de Gyne´cologie et d’Obste´trique 1987 a

Median values

b

Eighty consecutive patients with primary advanced EOC who underwent optimal tumor debulking surgery at our institution were selected for our retrospective analysis. The patients’ characteristics are detailed in Table 1. All clinical data were obtained from the Tumor Bank Ovarian Cancer (www.toc-network.de). The patients were included prospectively in the TOC. Tumor spread, presence of ascites and peritoneal carcinomatosis, and the

Patients were included in the control arm of the ongoing AGO– LION study: lymphadenectomy in ovarian neoplasms [Arbeitsgemeinschaft Gynaekologische Onkologie]; www.clinicaltrials.gov/. No.: NCT00712218

residual mass and its localization were documented prospectively during debulking surgery via an interview with the surgeon. All data were documented in a validated data bank.11

Peritoneal Cancer Index in Patients with Ovarian Cancer

Patients were enrolled in the TOC between January 2007 and December 2012. All patients underwent surgery in the Gynecology Department of Charite´ University Berlin at the European Competence Center for Ovarian Cancer. During this period, 563 women with primary ovarian cancer underwent surgery. Each surgery was aimed to accomplish maximum tumor debulking and was performed via median laparotomy that included systematic pelvic and paraaortic lymphadenectomy as a standard procedure. The surgical techniques applied are listed in Table 2. Patients’ data related to survival and the disease courses were regularly updated after the primary therapy. The local ethics commission granted approval (No. EK207/2003), and all participating patients were well informed and signed the consent form. Maximum tumor debulking—resulting in no macroscopically identified residual tumor—was achieved in 376 of the 563 patients (67 %). We excluded from the study 54 patients who underwent neoadjuvant chemotherapy followed by interval debulking surgery and 159 patients who

TABLE 2 Overview of primary therapy management (complete cytoreductive surgery and adjuvant platinum-based chemotherapy) Parameter

No.

Surgery duration (min), median

277.5 (150–529)

Surgical procedures Hysterectomy

62 (77.5 %)

Adenectomy (unilateral or bilateral)

80 (100 %)

Omentectomy

80 (100 %)

Peritonectomy

80 (100 %)

Pelvic lymphadenectomy Paraaortic lymphadenectomy

72 (93.6 %) 72 (93.6 %)

Intestinal resection

47 (58.8 %)

Small bowel

8 (10.0 %)

Large bowel

44 (55.0 %)

Ileostomy

2 (2.5 %)

Appendectomy

41 (51.3 %)

Partial liver resection

2 (2.5 %)

Liver capsule resection

14 (17.5 %)

Partial gastrectomy

1 (1.3 %)

Cholecystectomy

8 (10.0 %)

Splenectomy

21 (26.3 %)

Partial diaphragm resection

35 (43.8 %)

Partial urinary bladder resection

1 (1.3 %)

Postoperative complications Intestinal genesis (ileus, anastomotic insufficiency, bowel perforation)

9 (11.3 %)

Infection

8 (10.0 %)

Thromboembolism

6 (7.5 %)

Death within 30 days

1 (1.3 %)

Each surgery aimed to maximum tumor debulking and was performed per median laparotomy

underwent completion surgery. Among the 376 patients, 151 had peritoneal tumor burdens, which classified the patients as being at FIGO stage IIIB–IV. Another 71 patients whose medical reports contained ambiguous descriptions of the tumor size and the involved regions were excluded from this study. The PCI score was determined retrospectively based on the histopathological and surgical reports. Because of the retrospective nature of our study, we were obliged to involve only patients with maximum tumor debulking so the PCI could be accurately determined based on histopathological reports. All resected tissues were analyzed separately, and we were confident that the diameters of the lesions had been reported accurately. The histopathological assessment was performed at the Charite´ Institute. Two experienced pathologists independently assessed each tumor. All surgeries were performed by one of three gynecological oncological surgeons. Staging was defined according to the 1987 FIGO classification. Following primary adjuvant chemotherapy, the patients were examined every 3 months. Gynecological and ultrasonographic examinations, together with the serum CA 125 biomarker concentration, were performed at each visit. Computed tomography (CT) and magnetic resonance imaging (MRI) scans were obtained when clinical examination or elevated CA125 serum levels indicated the possibility of disease progression or recurrence. Isolated CA125 serum elevation was not considered to indicate relapse. The last follow-up data for each patient included in the study were obtained in September 2013. The occurrence of relapse and the response to first-line platinum-based chemotherapy were detected according to response evaluation criteria in solid tumors (RECIST)26 and the CA 125 biomarker concentration in serum. Response to platinum-based chemotherapy was defined as the absence of relapse or progression of disease during the first 6 months after completion of the first-line chemotherapy. Patients who relapsed within the first 6 months were classified as nonresponders. First-line chemotherapy was applied in 76 of the 80 enrolled patients. In all, 71 patients received six cycles of carboplatin and paclitaxel. The response could not be evaluated five patients because they were lost of follow-up prior to 6 months after chemotherapy completion. Four patients never received platinum-based chemotherapy due do sudden death in three cases and chemotherapy refusal in one case. Calculation of the PCI The PCI is used to assess cancer distribution on the peritoneum quantitatively. It is based on calculating the

K. Gasimli et al.

Statistical Analysis Associations between the PCI and clinical factors were analyzed using the v2 test, Kendall’s tau b, Mann–Whitney U test, Kruskal–Wallis H test, or Spearman’s rho, where appropriate. Univariate and multivariate survival analyses were performed using the Kaplan–Meier method and Cox regression models, respectively. The PCI cutoff values for overall survival (OS) and progression-free survival (PFS) were evaluated with the log-rank test. The predictive value of the PCI for response to chemotherapy was determined on the basis of a receiver operator characteristic (ROC) curve. The statistical analysis for platinum response was repeated separately on patients who received the six cycles chemotherapy. Statistical analysis was performed using IBM SPSS Statistics (Version 21.0; IBM, Armonk, NY, USA). For all tests, a probability value of p \ 0.05 was considered statistically significant.

IIIC (71.2 %) and as having a serous EOC (96.3 %). Altogether, 75 (93.8 %) patients presented with high-grade tumors (grades II and III). Positive lymph nodes were diagnosed in 54 cases (67.5 %), with either the pelvic or paraaortic system (or both) being affected. Among the whole cohort, seven patients (8.8 %) did not respond to platinum chemotherapy. The median duration of the surgical procedures to achieve optimum tumor debulking was 277.5 min (range 150–529 min). The main postoperative complications were of intestinal genesis (11.3 %), such as ileus, anastomotic insufficiency and bowel perforation followed by infection (10.0 %), and thromboembolism (7.5 %). The details about treatment procedures are presented in Table 2. Correlation of PCI Scores with Clinicopathological Factors The PCI score was significantly associated with the presence of ascites (p = 0.001), T status of TNM staging (p = 0.036), preoperative CA 125 concentration (p = 0.025), and prolonged duration of surgery (p \ 0.001). No associations between the PCI and other clinicopathological factors, such as age (p = 0.876), FIGO stage (p = 0.248), grading (p = 0.264), lymph node involvement (p = 0.330), distant metastasis (p = 0.386), histology (p = 0.514), and ECOG status (p = 0.865) were found. High PCI scores were related to the rate of nonresponders to first-line adjuvant platinum-based chemotherapy (p = 0.050), but it did not reach statistical significance in the ROC curve analysis (p = 0.063, 95 % CI = 0.53–0.89) (Fig. 1). We analyzed the correlation between the PCI and IMO scoring systems with ROC Curve

1.0

0.8

Sensitivity

lesion size in each of 13 abdominopelvic regions (numbered from 0 to 12 in a clockwise direction). After complete adhesiolysis, the lesion size (in centimeters) is determined for each region through inspection of both the parietal and visceral peritoneal surfaces. The size is then converted to nominal numbers from 0 to 3 for scoring. Lesion size score (LSS) 0 defines no visible tumor burden on the peritoneum. LSSs 1, 2, and 3 describe the greatest diameter of tumor nodes up to 0.5, 5.0, and [5 cm (confluence), respectively. After summarizing the LLSs from all regions, the PCI can be calculated for each patient. The highest PCI that could be reached is 39 (13 9 3).8 The PCIs in our study were calculated with the help of the surgical and histopathological reports. In addition to the last two reports, we used a validated tool, intraoperative mapping of ovarian cancer (IMO), to compare all data regarding tumor dissemination on the peritoneal surface to obtain a more objective, precise calculation of the PCI. Sehouli et al.11 were the first to describe the IMO as a tumor-documentation tool for ovarian cancer patients. It includes detailed facts about the tumor dissemination pattern, residual tumor mass, surgical procedures, and tumor histopathology. Tumor spread is documented prospectively during surgery. The abdominal cavity is divided into nine areas. Then, the areas to which the tumor has spread, the maximum tumor load, and the residual tumor mass are recorded.11,12

0.6

0.4

0.2

0.0

RESULTS

0.0

0.2

0.4

0.6

0.8

1.0

1 - Specificity

The patients’ median age at diagnosis was 58 years (range 32–86 years). The median PCI was 12 (range 3–32). The majority of the patients were diagnosed as FIGO stage

FIG. 1 Receiver operator characteristic–area under the curve (ROC– AUC) analysis of the peritoneal cancer index (PCI) to predict resistance to chemotherapy

Peritoneal Cancer Index in Patients with Ovarian Cancer

regard to the tumor spread pattern. IMO correlated with the PCI (tau b = 0.54, p \ 0.001) (increased number of IMO fields involved correlated with a high PCI score). Concordance of systems regarding peritoneal tumor distribution in the lower and upper abdomen was observed (p = 0.001 and p \ 0.001, respectively). Analysis of the role of PCI in predicting perioperative complications for a 30-day period showed no statistically significant differences (median PCI = 13 in patients with complications versus PCI = 11 for patients without complications; p = 0.295). Survival Analysis The median follow-up time was 29.1 months (range 0.4–71.8 months). Overall, 26 patients (32.5 %) died during the course of their disease, and 39 patients (48.8 %) experienced a relapse after their primary treatment. Higher PCI scores were related to poor OS and PFS in the univariate analysis (p = 0.036 and p \ 0.001, respectively). The best PCI cutoff values for OS and PFS determined by log-rank test were 18 (p = 0.013) and 13 (p = 0.001), respectively. In patients with PCI \18 the median OS was

71.1 months and the 3-year survival rate was 76 % (95 % CI 63.8–88.2), whereas in patients with PCI C18 the corresponding figures were, respectively, 39 months and 51 % (95 % CI 14.4–87.8). In patients with PCI\13 versus those with PCI C13, the median PFSs were 29 versus 16 months. The 2-year PFS rates were 60 % (95 % CI 44.2–75.3) vs. 27 % (95 % CI 8.0–45.9), respectively. The high risk of an elevated PCI score regarding OS did not remain statistically significant (p = 0.162) in the multivariate analysis after adjusting for age, FIGO stage, T status, grading, histology, distant metastasis, and lymph node involvement, as shown in Table 3 and Fig. 2. Age and lymph node involvement remained independent factors for OS (p = 0.005 and p = 0.034, respectively). In contrast, an elevated PCI showed a statistically significant (p = 0.005) decrease in PFS (Fig. 2). The following data were obtained in the univariate analysis when the OS and PFS were analyzed only on the 71 patients who received all six cycles of platinum-based chemotherapy: Higher PCIs were related to PFS (p = 0.002), presence of ascites (p = 0.003), duration of

TABLE 3 R Cox regression analysis of tumor-free operated patients with advanced primary ovarian cancer Variable

OS HR

PFS 95 % CI

p value

Variable

HR

95 % CI

p value

The results of multivariate analysis of 80 patients PCI (C18 vs. \18)

2.21

0.73–6.74

0.162

PCI (C13 vs. \13)

2.43

1.30–4.54

0.005

Age

1.07

1.02–1.12

0.005

Age

1.03

1.00–1.06

0.110

FIGO (IV vs. III)

0.09

0.01–1.20

0.069

FIGO (IV vs. III)

1.60

0.18–14.17

0.674

Grade (I/II vs. III)

1.15

0.42–3.13

0.783

Grade (I/II vs. III)

1.12

0.56–2.23

0.749

pT (3c vs. 3b)

2.26

0.44–11.59

0.329

pT (3c vs. 3b)

1.75

0.71–4.31

0.226

cMx versus cM0

0.81

0.30–2.17

0.673

cM (x vs. 0)

1.37

0.66–2.82

0.397

cM1 versus cM0

7.29

0.57–94.03

0.128

cM (1 vs. 0)

1.01

0.11–9.04

0.997

pNx versus pN0

2.19

0.45–10.61

0.328

pN (x vs. 0)

2.00

0.69–5.79

0.202

pN1 versus pN0

3.39

1.09–10.52

0.034

pN (1 vs.0)

2.13

0.95–4.75

0.067

The results of multivariate analysis of chemotherapy-performed 71 patients PCI (C18 vs. \18)

1.36

0.33–5.50

0.663

PCI (C13 vs. \13)

2.52

1.16–5.46

0.019

Age

1.09

1.02–1.16

0.004

Age

1.02

0.98–1.05

0.209

FIGO (IV vs. III)

0.02

0.01–0.54

0.018

FIGO (IV vs. III)

2.28

0.24–21.36

0.470

Grade (I/II vs. III) pT (3c vs. 3b)

1.54 1.70

0.36–6.51 0.27–10.50

0.556 0.568

Grade (I/II vs. III) pT (3c vs. 3b)

1.49 1.71

0.67–3.31 0.69–4.19

0.326 0.240

cMx versus cM0

0.63

0.20–2.02

0.446

cM (x vs. 0)

1.43

0.68–3.00

0.342

cM1 versus cM0

6.05

0.40–89.90

0.191

cM (1 vs. 0)

0.71

0.07–6.60

0.764

pNx versus pN0

2.58

0.38–17.47

0.331

pN (x vs. 0)

2.61

0.82–8.26

0.102

pN1 versus pN0

8.06

1.61–40.29

0.011

pN (1 vs.0)

2.34

0.89–6.10

0.082

Ascites versus no ascites

1168163

0.01–2, 385E?275

0.965

Ascites versus no ascites

2.51

0.85–7.36

0.093

Non-responder versus responder

7.67

2.02–29.17

0.003

HR hazard ratio, CI confidence interval Bold values indicate significance

K. Gasimli et al.

1.0

0.6 0.4 0.2 0.0

PCI Score < 13 ≥ 13

0.8

Cum Survival

0.8

Cum Survival

1.0

PCI Score < 18 ≥ 18

0.6 0.4 0.2

p=0.162 0

0.0

6 12 18 24 30 36 42 48 54 60 66 72

Overall survival (months)

p=0.005 0

6

12

18

24

30

36

42

48

Progression free survival (months)

FIG. 2 Multivariate analysis of the PCI using the Cox regression model

surgery (p \ 0.001), and preoperative CA 125 concentration (p = 0.019). In comparison, the PCI was not associated with OS (p = 0.077), FIGO stage (p = 0.546), grading (p = 0.482), age (p = 0.727), T status (p = 0.105), lymph node involvement (p = 0.525), distant metastasis (p = 0.520), histology (p = 0.635), Eastern Cooperative Oncology Group status (p = 0.421), or the response to chemotherapy (p = 0.062). The PCI was established as an independent factor only for PFS (p = 0.019) in the multivariate analysis. The association between a higher PCI score and OS could not statistically be reached in Cox’s regression analysis (p = 0.663). Details of the multivariate analysis are shown in Table 3. DISCUSSION The main goal of our study was to identify the impact of the PCI on clinical outcome in patients with primary advanced EOC who underwent complete cytoreduction. Our aim was to determine if the extent of tumor dissemination, in terms of peritoneal carcinomatosis, negatively affects the OS and PFS rates in patients with maximum debulked primary EOC. We also wanted to determine whether patients with higher PCI scores would be better candidates for neoadjuvant chemotherapy or palliative treatment if there was no survival benefit after aggressive CRS. This practice might set new standards in decision-making for appropriate therapy management of EOC—the current standard therapy consisting of CRS followed by adjuvant platinumbased chemotherapy.27 The predictive and prognostic value of the PCI was previously investigated in studies of colon cancer patients.9,23,28–30 It was concluded that a high PCI score is associated with a low survival rate for patients whose colorectal cancer has metastasized to the peritoneum. In a prospective study of 100 patients with colorectal cancer, Sugarbaker demonstrated that a poor prognosis for survival was significantly correlated with a high PCI score.24 He

revealed that patients with PCI scores\10, 10–20, and[20 showed 50, 20, and 0 % 5-year survival rates, respectively. He advised that a PCI[20 is a relative contraindication for CRS ? hyperthermic intraperitoneal chemotherapy (HIPEC). Rather, the aim in such situations should be palliative because there are almost no differences in the median survival rates of patients who undergo CRS ? HIPEC and those who are not subjected to this aggressive approach.31 Tentes et al.32 first evaluated the prognostic relevance of the PCI in 60 ovarian cancer patients. They found significant differences in 5-year survival rates (65 vs. 29 %) between patients with PCI B10 and PCI [10, respectively. Nearly half of the patients in their study, however, had residual tumor after surgery. Residual tumor mass is a strong, independent, crucial factor for survival.17,33–37 Patients with a residual tumor load after surgery were not included in our study so we could judge the power of the PCI alone as a prognostic factor for survival. Also, our study was based on retrospective analysis, where only patients with maximum tumor debulking (i.e., no residual tumor mass) could be evaluated. Although the PCI was correlated with OS in the univariate analysis, it did not retain its significance according to the Cox regression analysis after adjusting for clinicopathological factors. The same results were obtained when the analysis was performed on only the 71 patients in our study who received all six cycles of platinum-based chemotherapy. In the light of these results, we concluded that complete CRS in EOC patients has more impact on survival than the extent of the tumor burden on the peritoneal surface—reflected in a high PCI—at the initial surgical exploration. Similar results were reported in several other gynecological and nongynecological studies.10,38–40 Eisenkop et al.10 evaluated the role of preoperative tumor extent and complete cytoreduction in 408 EOC patients with FIGO stage IIIC disease. They concluded that

Peritoneal Cancer Index in Patients with Ovarian Cancer

cytoreductive surgery has more impact on survival than the extent of the tumor burden in the peritoneal cavity. Although the tumor extent does not affect survival directly, it precludes the success of complete cytoreduction. In the context of a multi-center prospective phase III trial in ovarian cancer patients, Wimberger et al.39 reported that the presence of peritoneal carcinomatosis is associated with low rates of maximum tumor debulking in high-volume centers, but peritoneal carcinomatosis was not an independent prognostic factor for OS. The use of the PCI has limitations (in terms of feasibility and utility) in regard to rapidly metastasizing peritoneal tumors as validated by a number of authors.25,31,41,42 PCI also has no prognostic value when evaluating noninvasive tumors (e.g., pseudomyxoma peritonei, peritoneal mesothelioma).31 Despite extensive distribution of tumor burdens throughout the abdominal cavity and high PCI scores for these tumors, complete cytoreduction is simply achievable, and the after-treatment prognosis is favorable.31,41 In contrast, with invasive cases, the disease acts as if it were widespread when crucial sites of the upper abdomen (e.g. biliary tract, porta hepatis) are affected. This is true even though only a few areas with tumor burden are present, as indicated by low PCI scores.31 Although there are no variations in PCI scores, regardless of whether they were recorded by junior or senior surgeons,25 the score might be under- or overestimated because of the subjective determination of transitional zones in the small bowel. For instance, resectable tumor implants in regions 9–12 would add at least four extra points to the PCI, although they can be completely resected without damaging bowel function.42 Several PCI cutoff values have been reported. They have varied considerably among studies with different entities and even in studies where peritoneal carcinomatosis of the same entities was investigated.25,29,31,32,42 These differences make it difficult to apply the PCI as an objective tool in daily practice. Another limitation of the PCI is the fact that it describes only the tumor distribution pattern and lesion size, with no reference to the patient’s performance status, co-morbidities, or tumor biology. The role of radiological techniques in determining the PCI score preoperatively was evaluated in several studies.43–47 Experts concluded that CT and MRI present low sensitivity when tumor nodes are [1 cm and are located between the bowel loops. Moreover, reactive nodes are often difficult to differentiate from tumor nodes. Because of these considerations, the accuracy of the PCI determined by imaging methods remains restricted. A limitation of this study is the retrospective nature of PCI documentation, which led us to focus only on macroscopically residual-free, advanced-stage EOC patients. The results obtained from histopathological reviews

might be different from the results obtained during surgery. Therefore, differences in PCI status might be expected. It will be of clinical interest to analyze the role of PCI in predicting the residual tumor mass in EOC patients. This point can be addressed only in a prospective study. Nevertheless, this study was the first to analyze the role of the PCI in a uniform collective of primary EOC patients. The strengths of our study consist in its prospective documentation of macroscopically identified residual masses, applied surgical techniques, and macroscopically apparent tumor patterns in a high-volume center with wellhoned expertise in ovarian cancer. CONCLUSIONS The PCI score provides descriptive information regarding the extent of tumor distribution and tumor load on the peritoneal surface. Our results suggest that the residual tumor mass after CRS remains the major prognostic factor, independent of the tumor pattern. Tumor biology, the patient’s health status, and clinical experience with ovarian cancer should be taken into account and applied to each patient individually when establishing treatment of indications. ACKNOWLEDGMENT This project was supported by a research grant form Berliner Krebsgesellschaft e. V.

REFERENCES 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. 2. Holschneider CH, Berek JS. Ovarian cancer: epidemiology, biology, and prognostic factors. Semin Surg Oncol. 2000;19(1):3– 10. 3. Heintz AP, Odicino F, Maisonneuve P, et al. Carcinoma of the ovary. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006;95(Suppl 1):S161–92. 4. Engel J, Eckel R, Schubert-Fritschle G, et al. Moderate progress for ovarian cancer in the last 20 years: prolongation of survival, but no improvement in the cure rate. Eur J Cancer. 2002;38(18):2435–45. 5. Meyers MA. Distribution of intra-abdominal malignant seeding: dependency on dynamics of flow of ascitic fluid. AJR Am J Roentgenol. 1973;119(1):198–206. 6. Gilly FN, Carry PY, Sayag AC, et al. Regional chemotherapy (with mitomycin C) and intra-operative hyperthermia for digestive cancers with peritoneal carcinomatosis. Hepatogastroenterology. 1994;41(2):124–9. 7. Kajitani T. The general rules for the gastric cancer study in surgery and pathology. Part I. Clinical classification. Jpn J Surg. 1981;11(2):127–39. 8. Sugarbaker PH, Jablonski KA. Prognostic features of 51 colorectal and 130 appendiceal cancer patients with peritoneal carcinomatosis treated by cytoreductive surgery and intraperitoneal chemotherapy. Ann Surg. 1995;221(2):124–32. 9. Verwaal VJ, van Tinteren H, van Ruth S, Zoetmulder FA. Predicting the survival of patients with peritoneal carcinomatosis of colorectal

K. Gasimli et al.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

origin treated by aggressive cytoreduction and hyperthermic intraperitoneal chemotherapy. Br J Surg. 2004;91(6):739–46. Eisenkop SM, Spirtos NM, Friedman RL, Lin WC, Pisani AL, Perticucci S. Relative influences of tumor volume before surgery and the cytoreductive outcome on survival for patients with advanced ovarian cancer: a prospective study. Gynecol Oncol. 2003;90(2):390–6. Sehouli J, Konsgen D, Mustea A, et al. [‘‘IMO’’–intraoperative mapping of ovarian cancer]. Zentralbl Gynakol. 2003;125(3– 4):129–35. Sehouli J, Senyuva F, Fotopoulou C, et al. Intra-abdominal tumor dissemination pattern and surgical outcome in 214 patients with primary ovarian cancer. J Surg Oncol. 2009;99(7):424–7. Fagotti A, Ferrandina G, Fanfani F, et al. A laparoscopy-based score to predict surgical outcome in patients with advanced ovarian carcinoma: a pilot study. Ann Surg Oncol. 2006;13(8):1156–61. Zivanovic O, Sima CS, Iasonos A, et al. The effect of primary cytoreduction on outcomes of patients with FIGO stage IIIC ovarian cancer stratified by the initial tumor burden in the upper abdomen cephalad to the greater omentum. Gynecol Oncol. 2010;116(3):351–7. Aletti GD, Eisenhauer EL, Santillan A, et al. Identification of patient groups at highest risk from traditional approach to ovarian cancer treatment. Gynecol Oncol. 2011;120(1):23–8. Verleye L, Ottevanger PB, van der Graaf W, et al. EORTC-GCG process quality indicators for ovarian cancer surgery. Eur J Cancer. 2009;45(4):517–26. Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a metaanalysis. J Clin Oncol. 2002;20(5):1248–59. Panici PB, Maggioni A, Hacker N, et al. Systematic aortic and pelvic lymphadenectomy versus resection of bulky nodes only in optimally debulked advanced ovarian cancer: a randomized clinical trial. J Natl Cancer Inst. 2005;97(8):560–6. Sehouli J, Savvatis K, Braicu EI, Schmidt SC, Lichtenegger W, Fotopoulou C. Primary versus interval debulking surgery in advanced ovarian cancer: results from a systematic single-center analysis. Int J Gynecol Cancer. 2010;20(8):1331–40. Cornelis S, Van Calster B, Amant F, Leunen K, van der Zee AG, Vergote I. Role of neoadjuvant chemotherapy in the management of stage IIIC-IV ovarian cancer: survey results from the members of the European Society of Gynecological Oncology. Int J Gynecol Cancer. 2012;22(3):407–16. Grabowski JP, Harter P, Hils R, et al. Outcome of immediate reoperation or interval debulking after chemotherapy at a gynecologic oncology center after initially incomplete cytoreduction of advanced ovarian cancer. Gynecol Oncol. 2012;126(1):54–7. Gagliardi AR, Fung MF, Langer B, Stern H, Brown AD. Development of ovarian cancer surgery quality indicators using a modified Delphi approach. Gynecol Oncol. 2005;97(2):446–56. Jacquet P, Sugarbaker PH. Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. Cancer Treat Res. 1996;82:359–74. Sugarbaker PH. Successful management of microscopic residual disease in large bowel cancer. Cancer Chemother Pharmacol. 1999;43(Suppl):S15–25. Elias D, Souadka A, Fayard F, et al. Variation in the peritoneal cancer index scores between surgeons and according to when they are determined (before or after cytoreductive surgery). Eur J Surg Oncol. 2012;38(6):503–8. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47. Morgan RJ Jr., Alvarez RD, Armstrong DK, et al. Ovarian cancer: clinical practice guidelines in oncology. J Natl Compr Cancer Netw 2008;6(8):766–94.

28. Portilla AG, Sugarbaker PH, Chang D. Second-look surgery after cytoreduction and intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal cancer: analysis of prognostic features. World J Surg. 1999;23(1):23–9. 29. Elias D, Blot F, El Otmany A, et al. Curative treatment of peritoneal carcinomatosis arising from colorectal cancer by complete resection and intraperitoneal chemotherapy. Cancer. 2001;92(1): 71–6. 30. Glehen O, Gilly FN, Boutitie F, et al. Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy: a multi-institutional study of 1,290 patients. Cancer. 2010;116(24):5608–18. 31. Harmon RL, Sugarbaker PH. Prognostic indicators in peritoneal carcinomatosis from gastrointestinal cancer. Int Semin Surg Oncol. 2005;2(1):3. 32. Tentes AA, Tripsiannis G, Markakidis SK, et al. Peritoneal cancer index: a prognostic indicator of survival in advanced ovarian cancer. Eur J Surg Oncol. 2003;29(1):69–73. 33. Makar AP, Baekelandt M, Trope CG, Kristensen GB. The prognostic significance of residual disease, FIGO substage, tumor histology, and grade in patients with FIGO stage III ovarian cancer. Gynecol Oncol. 1995;56(2):175–80. 34. Eisenkop SM, Friedman RL, Wang HJ. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol. 1998;69(2):103–8. 35. Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr. 1975;42:101–4. 36. Hacker NF, Berek JS, Lagasse LD, Nieberg RK, Elashoff RM. Primary cytoreductive surgery for epithelial ovarian cancer. Obstet Gynecol. 1983;61(4):413–20. 37. Allen DG, Heintz AP, Touw FW. A meta-analysis of residual disease and survival in stage III and IV carcinoma of the ovary. Eur J Gynaecol Oncol. 1995;16(5):349–56. 38. Le T, Krepart GV, Lotocki RJ, Heywood MS. Does debulking surgery improve survival in biologically aggressive ovarian carcinoma? Gynecol Oncol. 1997;67(2):208–14. 39. Wimberger P, Lehmann N, Kimmig R, et al. Prognostic factors for complete debulking in advanced ovarian cancer and its impact on survival: an exploratory analysis of a prospectively randomized phase III study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR). Gynecol Oncol. 2007;106(1):69–74. 40. Konigsrainer I, Zieker D, Glatzle J, et al. Experience after 100 patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. World J Gastroenterol 2012;18(17):2061–6. 41. Sugarbaker PH. Management of peritoneal-surface malignancy: the surgeon’s role. Langenbecks Arch Surg. 1999;384(6):576–87. 42. Swellengrebel HA, Zoetmulder FA, Smeenk RM, Antonini N, Verwaal VJ. Quantitative intra-operative assessment of peritoneal carcinomatosis: a comparison of three prognostic tools. Eur J Surg Oncol. 2009;35(10):1078–84. 43. Koh JL, Yan TD, Glenn D, Morris DL. Evaluation of preoperative computed tomography in estimating peritoneal cancer index in colorectal peritoneal carcinomatosis. Ann Surg Oncol. 2009;16(2):327–33. 44. De Bree E, Koops W, Kroger R, van Ruth S, Witkamp AJ, Zoetmulder FA. Peritoneal carcinomatosis from colorectal or appendiceal origin: correlation of preoperative CT with intraoperative findings and evaluation of interobserver agreement. J Surg Oncol. 2004;86(2):64–73. 45. Dromain C, Leboulleux S, Auperin A, et al. Staging of peritoneal carcinomatosis: enhanced CT vs. PET/CT. Abdom Imaging. 2008;33(1):87–93.

Peritoneal Cancer Index in Patients with Ovarian Cancer 46. Esquivel J, Chua TC, Stojadinovic A, et al. Accuracy and clinical relevance of computed tomography scan interpretation of peritoneal cancer index in colorectal cancer peritoneal carcinomatosis: a multi-institutional study. J Surg Oncol. 2010;102(6):565–70.

47. Pfannenberg C, Konigsrainer I, Aschoff P, et al. (18)F-FDG-PET/ CT to select patients with peritoneal carcinomatosis for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Ann Surg Oncol. 2009;16(5):1295–303.