EJSO (2004) 30, 976–981
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Prognosis of stage III or IV primary peritoneal serous papillary carcinoma G. Dubernard, P. Morice*, A. Rey, S. Camatte, V. Fourchotte, A. Thoury, ´, P. Duvillard, D. Castaigne C. Pomel, P. Pautier, C. Lhomme Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France Accepted for publication 9 August 2004 Available online 15 September 2004
KEYWORDS Peritoneal carcinoma; Debulking surgery; Neoadjuvant chemotherapy
Abstract Aims. To study the prognosis of patients with stage IIIC/IV primary peritoneal serous papillary carcinoma (PSPC) (study group) compared with that of patients with epithelial ovarian carcinoma (EOC) (control group). Methods. A retrospective case-control study including a study group of 37 patients who were matched with a control group of 37 patients. Patients were matched for the histologic subtype (serous tumor), tumor stage, tumor grade, residual disease at the end of debulking surgery (initial or interval) and age (G5 years). Results. Debulking surgery was performed initially or at interval surgery in respectively, 10 and 27 patients in the study group and 17 and 20 in the control group. All patients were treated with platinum-based chemotherapy (combined with paclitaxel in 33) in both groups. The overall survival rate at 3 years in the study and control groups was, respectively, 60% versus 55% (NS). However, event-free survival rates at 3 years (CI 95%) were statistically different (respectively, 29% in the study group versus 16% in the control group: pZ0.008). Conclusions. Peritoneal disease is more bulky in patients with PSPC. Neoadjuvant chemotherapy is more often required to achieve optimal debulking surgery in PSPC. Overall survival of patients with PSPC is similar to that of their EOC counterparts. Thus, the management of PSPC should not be different from that of advanced stage EOC. q 2004 Elsevier Ltd. All rights reserved.
Introduction Primary peritoneal serous papillary carcinoma (PSPC) was first described 45 years ago by Swerdlow. Peritoneal carcinomatosis is present in this * Corresponding author. Tel.: C33-142-11-44-39; fax: C33142-11-52-13. E-mail address:
[email protected] (P. Morice).
entity and is similar to that observed in serous Epithelial Ovarian Cancer (EOC) but there is no deep-seated tumor in the ovarian stroma.1 There are numerous case reports of very small series of patients with this disease but larger series are rare. The paper concerning the largest series (74 patients) was published 14 years ago.2 This important study unveiled the characteristics of patients with PSPC. Other retrospective studies compared
0748-7983/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejso.2004.08.005
Primary peritoneal serous palillary carcinoma the prognosis of PSPC to that of EOC.3–6 In order to give more weight to the relevance of these retrospective studies, a few teams reported case-control studies evaluating the prognosis of PSPC in order to determine whether the management of this tumor should be different from that of EOC.7–10 A recent paper suggested molecular similarities between PSPC and EOC.11 Several questions concerning the management of EOC remain unclear. In order to study the prognosis in patients with PSPC, we decided to conduct a retrospective analysis of cases treated in our institution and to match them with a control group of patients with EOC. The aim of this study was two-fold: (1) to evaluate the characteristics of patients with PSPC; and (2) to analyze the survival of these patients.
Methods Patients From 1996 to January 2003, 37 women were treated in our institution for a stage III/IV PSPC with debulking surgery combined with adjuvant chemotherapy. These patients constituted the ‘study group’ and data concerning them were reviewed. All histologic slides of the ovarian tumor and peritoneal disease were reviewed by the same pathologist. PSPC was defined according to the recommendation of the Gynecologic Oncology Group (GOG), which stipulated the presence of two macroscopic and two microscopic features: (1) diffuse involvement of the extra-ovarian peritoneum; (2) greater involvement of the peritoneum than of the ovary measuring !4 cm. During the microscopic examination: (1) absence of deepseated invasive ovarian carcinoma or invasive disease in the ovarian cortical stroma with a tumor measuring less than 5!5 mm2 and (2) histological characteristics of the tumor and peritoneal disease similar to that observed in ovarian serous papillary adenocarcinoma (whatever the grade).7,12 Patients with non-epithelial or borderline ovarian or tubal carcinoma were excluded from this study. The disease stage was defined as IIIC when patients had peritoneal disease O2 cm and as IV when peritoneal disease was associated with pleural effusion, according to the 1987 FIGO classification.
Treatments The initial surgical procedure should be performed before adjuvant chemotherapy for patients in
977 whom peritoneal disease is considered ‘resectable’. The criteria used to select patients with resectable or ‘unresectable’ disease in our institution have previously been reported.13,14 Patients were considered as resectable if an optimal cytoreductive surgery (intra-abdominal residual disease !2 cm) could be achieved using a standard surgery (including: total hysterectomy with bilateral salpingo-oophorectomyCtotal omentectomyGlymphadenectomyGisolated resection of the spleen if necessaryGresection of the rectosigmoid if necessary). A pelvic and para-aortic lymphadenectomy was included in the standard surgery for patients with good medical status at the end of the debulking surgery and with a complete macroscopic resection (absence of residual disease) or a very small residual disease (!1 cm). In patients with a larger residual disease and/or poor medical condition at the end of the debulking surgery, lymphadenectomies were omitted at the time of debulking surgery. Patients were classified as unresectable if an optimal cytoreduction is not possible using a standard surgery (involvement of: hepatic pedicle, and/or mesentery, and/or para-aortic involvement above the level of the left renal vessels, and/or involvement of the diaphragmatic muscle) or feasible but with an extensive surgery (resection of least two segments of the digestive tract, and/or spleno-pancreatectomy associated with bowel resection). In these patients with unresectable intra-abdominal spread, debulking surgery (termed ‘interval debulking surgery’) follows neoadjuvant chemotherapy (in absence of progressive disease at the end of adjuvant chemotherapy). All patients received platinum-based chemotherapy. Some of them received a platinum-based regimen including paclitaxel. Patients were monitored during each course of chemotherapy: they underwent a clinical examination, CA125 determination and a computed tomography (CT) scan just before surgery (for patients who underwent interval debulking surgery). This study group was matched with a ‘control group’ constituted from a series of 86 patients treated in our institution during the same period by the same team of surgeons or oncologists for an advanced-stage EOC. This group of patients has previously been reported.14 Study patients were matched to controls for: (1) histologic subtype (serous EOC); (2) FIGO stage (1987 classification); (3) tumor grade; (4) size of the residuum at the time of debulking surgery (none; between 0 and 2 cm and O2 cm) and age at diagnosis (G5 years) (Table 1). Characteristics of debulking surgery (residual disease), surgical procedures (bowel resection and
978 Table 1
G. Dubernard et al. Patient characteristics in matched groups Study group (PSPC) (nZ37)
Age (median-years) 60 (43–73) Stage IIIC 29 IV 8 Tumor grade Grade 1 2 Grade 2 11 Grade 3 13 Not determined 2 Histologic subtypes Serous 37 (100%) Size of residuum at the end of debulking surgery (None (complete macro24 scopic resection) R%2 cm 9 R O2 cm 4 Timing of debulking surgery Initial 10 Interval 27 Chemotherapy Platinum-based 37 PaclitaxelCplatinum based 33 8 (3–9) Median number of courses of first-line chemotherapy (range)
Control group (EOC) (nZ37)
p value
58 (40–75)
NS
29 8
NS NS
1 16 13 1
NS NS NS
37 (100%)
NS
22 12 3
NS
17 20
NS
37 33 6 (2–9)
NS NS
PSPC, peritoneal serous papillary carcinoma; EOC, epithelial ovarian cancer.
enterostomy), morbidity rates and the survival of patients were compared between the two groups. The Wilcoxon Rank test was used to compare continuous variables. The c2 test was used to compare proportions and a p value of !0.05 was considered significant. Survival curves were compared using the Log-rank test.
Results Characteristics of patients The characteristics of the two groups are detailed in Table 1. In the study group (PSPC), two patients had a previous history of hysterectomy and unilateral oophorectomy for benign disease. Twenty-two patients complained of abundant ascites and 14 had abdominal pains and/or bowel obstruction. The initial median CA125 level (available for 31 patients) was 833 IU/ml (range, 40–7300). A CT scan was performed before surgery in 33 patients. CT findings in 22 patients were reviewed. They all had normal sized ovaries (less than 4 cm) with massive involvement of the peritoneum in 19.
Treatments and morbidity Debulking surgery was performed in 10 patients initially and after neoadjuvant chemotherapy in 27 patients. In the 27 patients treated with neoadjuvant chemotherapy, the median number of chemotherapy courses was 3. All patients received a platinumCpaclitaxel regimen. One patient received two courses of neoadjuvant chemotherapy and four were referred for debulking surgery after six courses of chemotherapy administered outside our institution. For these patients chemotherapy was continued after the interval debulking surgery. The surgical procedures performed at the time of debulking surgery in the 37 patients were: hysterectomy (32 patients), salpingo-oophorectomy (37 patients), complete omentectomy (30 patients), appendectomy (10 patients), bowel resection (7 patients), resection of the peritoneum of Douglas’ pouch (16 patients), extensive resection of the peritoneum of the para-colic gutters (five patients) and resection of the peritoneum of the diaphragm (five patients). Twenty-two patients underwent a lymphadenectomy (19 pelvic and para-aortic and
Primary peritoneal serous palillary carcinoma two, underwent a pelvic picking alone). All these procedures were performed via a large midline incision. No patient died of complications after debulking surgery. Postoperative complications were observed in 12 patients: a symptomatic lymphocyst in seven patients (four of which required percutaneous drainage), an anastomotic leakage in one (treated by colostomy), postoperative peritonitis (1), postoperative bleeding requiring a blood transfusion (1), one bowel obstruction and one postoperative pneumothorax (after resection of the peritoneum of the diaphragm). After debulking surgery, 24 patients had no residual disease, the residuum was optimal (less than 2 cm) in 9 patients and sub-optimal (more than 2 cm) in 4 patients. Interval debulking surgery was performed via a midline incision. Histological examination of the surgical specimens revealed nodal involvement in 14 patients (respectively, 13 and 11 positive pelvic and para-aortic nodes). The median number of first-line chemotherapy courses was 8 (range, 3–9). The regimens administered are detailed in Table 1. Fourteen patients relapsed (abdominal peritoneum in 13 and axillary nodes in 1). Overall and disease-free survival rates are reported in Fig. 1. Overall survival according to the size of the residuum (absence versus presence of residual disease) was significantly different. In the control (EOC) group, 19 patients complained of abundant ascites and 15 had abdominal pains and/or bowel obstruction. Debulking surgery was performed in 17 patients initially and after neoadjuvant chemotherapy in 20 patients. Surgical procedures included a hysterectomy, a bilateral salpingo-oophorectomy and an omentectomy in all patients, a bowel resection in 18 patients, an appendectomy in 17 patients, resection of the
Figure 1 Overall and event-free survival curves in 37 patients with peritoneal serous papillary carcinoma.
979 peritoneum of Douglas’ pouch in 22 patients, extensive resection of the peritoneum of the para-colic gutters in 11 patients, resection of the peritoneum of the diaphragm in nine patients and lymphadenectomies in 30 patients (six pelvic alone and 24 pelvic and para-aortic). None of the patients died of complications after debulking surgery. Fourteen patients experienced major perioperative complications (anastomotic leakage [nZ5], major infection with shock [nZ1], lymphocyst [nZ 3], ureteral stenosis [nZ1], bladder lesion [nZ1], postoperative bleeding requiring transfusion [nZ2] and a wound abscess [nZ1]). After debulking surgery, 22 patients had no residual disease; it was optimal (less than 2 cm) in 12 patients and suboptimal (more than 2 cm) in 3 patients. Twentyfour patients had nodal involvement (12 in the paraaortic area and 12 in the pelvic area). The median number of first-line chemotherapy courses was 6 (range, 2–9). The type of regimens are detailed in Table 1.
Survival The median duration of follow-up was 23 months (range, 6–83). The median duration of survival could not be evaluated for the study group as more than half of the population is alive today. The overall survival rate at 3 years (CI 95%) in the study and control groups is, respectively, 60% (40%–76%) vs. 55% (35%–74%) (NS) (Fig. 2). However, the eventfree survival rates at 3 years (CI 95%) were statistically different (respectively 29% (15%–48%) in study group vs. 16% (6%–36%) in the control group) (pZ.008). The overall survival rate at 5 years (CI 95%) in the study and control groups is respectively 54% (35%–72%) vs. 29% (10%–60%).
Figure 2 Overall survival in the study (peritoneal serous papillary carcinoma) and control (epithelial ovarian cancer) groups.
980
Discussion The prognosis of PSPC compared to EOC continues to be a subject of debate in the literature. Several comparative or case-control studies seem to suggest that these two tumors have a similar prognosis3–5,7 whereas other series suggest poorer survival in PSPC.6,8,9 The analysis in our series is important because it adds interesting results and it is one of the largest to date (ranking second after the largest matched case-control study by Kowalski et al.10). One of the interesting findings in the present study is the high rate of extensive peritoneal spread at the time of initial surgery. This has been reported by several authors.2,9,15 In the series of 18 patients reported by Taus et al., the rate of massive involvement in the upper abdomen was high and explained why 38% of patients underwent exploratory laparotomy alone.15 In the series reported by Fromm et al., the rate of successful debulking surgery was only 41%.2 We obtained a similar rate in our series. The percentage of patients who underwent debulking surgery after neoadjuvant chemotherapy (because of massive unresectable disease during initial surgery) was higher in our study group than in the control group (63% vs. 54%). This indicates that peritoneal spread is more extensive (particularly in the upper abdomen) in PSPC than in EOC. However, complete cytoreductive surgery (during the initial or interval debulking procedure) was achieved in 65% of PSPC and residual disease measuring !2 cm was obtained in 89%. These results are similar to those obtained after debulking surgery in advanced-stage ovarian carcinoma reported in the literature. Thus, although optimal debulking surgery is not initially feasible in PSPC, it can be achieved more easily at the time of interval debulking surgery. Can a difference in the rates of initial or interval procedures between the two groups modify our analysis of survival? We recently published our results on interval debulking surgery in advanced-stage ovarian cancer and found that the survival of patients without residual disease was similar whatever the timing of surgery (initial or interval surgery).14 Another recent paper suggest that the completion of debulking surgery is more important that the extent of initial spread in stage IIIC disease.16 So, the prognostic value of the size of the residuum would appear to be similar in patients, whether debulking is obtained at initial surgery or after neoadjuvant chemotherapy. Treatment of patients with PSPC should include debulking
G. Dubernard et al. surgery (initial or interval if the peritoneal spread is too extensive) so that a maximum effort is deployed to obtain complete resection of all macroscopic disease, as in EOC. If debulking surgery is to be included in the management of PSPC, what kind of chemotherapy should we administer? The regimen used should be similar to that used in EOC. Platinum-based regimens improved the survival of patients.2 Long-term survival could be achieved with platinum-based chemotherapy.17,18 The use of paclitaxelCplatinum-based chemotherapy in PSPC was evaluated by Kennedy et al. in 38 patients.19 CA 125 levels declined by O50% in 92% of patients and by 55% in O90%. Median overall survival was 40 months.19 One of the major results of the present study is that it confirms that the prognosis in PSPC is similar to that of EOC. We even found a statistical difference in event-free survival in favor of patients with PSPC. Piura et al. recently reported a similar observation with a higher 5-year overall survival rate in PSPC than in EOC (52% versus 20%).5 One of the potential biases of the present study that could influence the survival analysis, is that the median number of chemotherapy courses given in the study group is slightly higher than in the control group (8 versus 6, a difference which was not significant). But a Danish prospective randomized study investigating 6 versus 12 cycles of the CAP regimen (cyclophosphamide, adriamycin and cisplatin) in advanced-stage ovarian cancer demonstrated similar results for both treatment schedules in optimally debulked patients.20 Thus, the difference in the median number of cycles of chemotherapy between the two groups had a limited or no effect on survival. This retrospective case-matched comparison confirms that peritoneal disease spreads more extensively in patients with PSPC. Neoadjuvant chemotherapy is required more frequently to achieve optimally debulked disease. Optimal debulking surgery (residual disease !2 cm) can be achieved in 89% of patients with PSPC (with complete resection in 65%). Overall survival of patients with PSPC is similar to that of their EOC counterparts (provided the size of the residuum at the end of debulking surgery is similar). Thus, the management of PSPC should not be different from that of advanced-stage EOC.
Acknowledgements The authors acknowledge Lorna Saint Ange for editing.
Primary peritoneal serous palillary carcinoma
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