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Primary peritoneal serous carcinoma treated by cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. A multi-institutional study of 36 patients
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EJSO 39 (2013) 742e747
www.ejso.com
Primary peritoneal serous carcinoma treated by cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. A multi-institutional study of 36 patients N. Bakrin a,*, F.N. Gilly a, D. Baratti b, J.M. Bereder c, F. Quenet d, G. Lorimier e, F. Mohamed f, D. Elias g, O. Glehen a Association Franc¸aise de Chirurgie a
Surgical Oncology Department, Lyon Civil Hospices, South Lyon University Hospital Center, 165 chemin du grand Revoyet, 69365 Pierre Benite, France b Istituto Nazionale per la Cura e lo Studio dei Tumori, Milano, Italy c Surgical Oncology Department, l’Archet Hospital, Nice University Hospital Center, Nice, France d Surgical Oncology Department, Val d’Aurelle Center, Montpellier, France e Surgical Oncology Department, Paul Papin Center, Angers, France f School of Surgical and Reproductive Sciences, Newcastle upon Tyne, United Kingdom g Surgical Oncology Department, Institut Gustave Roussy, Villejuif, France Accepted 20 February 2013 Available online 16 March 2013
Abstract Aim: Primary peritoneal serous carcinoma (PPSC) is a rare condition, histologically identical to ovarian serous carcinoma and often diagnosed at late stage. There is not any standardized treatment for PPSC. A retrospective multicentric study was performed in French speaking centers to evaluate cytoreduction surgery and Hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal carcinomatosis from different origins. The manuscript’s aim was to study the particular population with PPSC. Methods: Between September 1997 and July 2007, 36 patients with PPSC from 9 institutions underwent 39 procedures. Results: Mortality and morbidity rates were 5.6% and 20.6% respectively. The overall survival at 1, 3 and 5 years are respectively 93.6, 71.5 and 57.4%. The median overall survival was not reached. By univariate analysis, the only factor that had prognostic value was PCI (p ¼ 0.03). Conclusions: The therapeutic approach combining cytoreductive surgery with HIPEC may achieve long-term survival in patients with PPSC. Ó 2013 Elsevier Ltd. All rights reserved. Keywords: Hyperthermia; HIPEC; Ovarian carcinoma; Peritoneal neoplasm
Introduction Primary peritoneal serous carcinoma (PPSC) is a rare condition that was first described by Swerdlow in 1959. It is an extra-ovarian primary peritoneal malignancy,
Abbreviation: CC-R, completeness of the cancer resection; CRS, cytoreductive surgery; HIPEC, hyperthermic intraperitoneal chemotherapy; PC, peritoneal carcinomatosis; PCI, peritoneal cancer index; PPSC, primary peritoneal serous carcinoma. * Corresponding author. Tel.: þ33 478865644. E-mail address: [email protected] (N. Bakrin). 0748-7983/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2013.02.018
histologically identical and clinically similar to advanced stage serous ovarian carcinoma. PPSC can occur in women many years after oophorectomy performed for benign diseases or prophylactic oophorectomy.1 In advanced cases of pelvic adenocarcinoma the diagnosis of ovarian carcinoma is usually made because the ovaries cannot be distinguished from the extensive disease within the pelvis. The incidence of PPSC is unclear but estimated to be ten percent the rate of epithelial ovarian carcinoma.1 As the clinical features, staging, treatment and pathology of primary peritoneal serous carcinoma are considered
N. Bakrin et al. / EJSO 39 (2013) 742e747
identical to advanced stage ovarian serous carcinoma, these groups are usually combined in data analysis. Most reported series of PPSC are small with only a few large reports in the literature.2,3 Epidemiological, clinical and molecular differences exist and raise the question of what therapeutic approach should be taken for patients with PPSC.1,4 Over the past two decades a new therapeutic strategy to treat peritoneal carcinomatosis (PC) has developed, combining optimal cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). Its efficacy in carcinomatosis of non-gynaecological origin has been widely reported.5e7 Despite studies suggesting survival benefit, the oncology community remains sceptical of this combined therapeutic approach because of high reported toxicity. To obtain further data, a collaborative effort of 25 centres involved in the treatment of peritoneal surface malignancies provided information on a large number of patients with peritoneal carcinomatosis. Patients with PPSC were selected from this group to study outcomes following CRS with HIPEC and to identify prognostic factor.5 Patients and methods Patient population Between September 1997 and July 2007, 36 patients with PPSC underwent 39 procedures combining cytoreductive surgery with HIPEC in 8 French speaking centres and an Italian centre. Pathologic diagnoses were made according to the Gynecologic Oncology Group recommendations8:
743
intraoperative exploration. Centres used two different tools: Gilly’s classification9 and Sugarbaker’s Peritoneal Cancer Index (PCI)10 to assess the extent of PC. By Gilly’s classification, carcinomatosis is classified into five stages: stage 0, positive peritoneal cytology, stage I, malignant tumour nodules less than 5 mm in diameter localized to one part of the abdomen; stage II, malignant tumour nodules diffuse over the whole abdomen; stage III, tumour nodules 5 mm to 2 cm in diameter; stage IV, large (>2 cm in diameter) tumour deposits. The PCI is described in Fig. 1. For analysis, four subgroups of PCI were created: 1e6, 7e12, 13e19, and >19. Information recorded about the combined procedure included the date, the completeness of cytoreductive surgery, the presence or absence of lymph node metastases, the modalities of HIPEC (duration, drugs, “closed” or “open” HIPEC, temperatures), and treatment with adjuvant systemic chemotherapy. The assessment of the completeness of the cancer resection (CCR) by cytoreductive surgery was performed by the surgeon at the end of the procedure and classified into three categories4,11: CCR-0 indicated no macroscopic residual cancer remained, CCR-1 indicated no residual nodule greater than 2.5 mm, and CCR-2 indicated that the diameter of residual nodules was greater than 2.5 mm. The centres were classified according to their experience at the time of the procedure (0e3 years, 3e7 years, 7e11 years and more than 11 years). Analysis was also performed on the chronological period in which surgery was undertaken (between 1997 and 1999, between 2000 and 2002, between 2003 and 2004 and after 2005). Information was obtained regarding postoperative course, including postoperative death (within
1. Ovaries of normal size or enlarged by a benign process. 2. Absent ovarian involvement or limited to the surface and/or superficial cortex with no tumour nodule within the ovarian cortex exceeding 5*5 mm 3. Serous histology 4. Volume of extra-ovarian disease which significantly exceeds that of ovarian disease. The exclusion criteria were the presence of extraabdominal metastases. Standardized clinical data were received and entered into a central data-base. The same author reviewed all data sheets before their entry into the database in an effort to make this a uniform interpretation of retrospective data. Data forms A standard data form was created to retrieve information on the status of the patient before undergoing the combined procedure, including the sex, the age, the extent of peritoneal carcinomatosis and the previous treatment with systemic chemotherapy. The extent of PC was assessed by
Figure 1. Peritoneal Cancer Index (PCI). The abdomen and the pelvis are divided into 12 regions. The lesion sizes of the largest implants are scored (0 through 3) in each abdominopelvic region. The PCI can be expressed as a numerical score, ranging from 1 to 39.
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30 days of surgery), major complications (grade 3 and 4 complications according to the National Cancer Institute’s Common Toxity Criteria), and reoperations. Follow-up data recorded included last date of follow up and status of the patient.12 Statistical analysis All procedures were included in the analyses of postoperative morbidity and mortality (death or major complications occurring within 30 days of surgery). The influence of patient, disease and treatment characteristics were related to the risk of postoperative morbidity and mortality using univariate logistic regression models. To study relationships between variables, standard tests were used: chi2 with two qualitative variables, Pearson’s correlation if quantitative. Survival analysis was performed using the KaplaneMeier method, and comparisons of curves were made using the log-rank test. The cut-off date for survival analysis was fixed at December 2006, because an active enquiry was performed in all institutions to collect the status (dead/alive) of the patients at that date. Standard probability cut-off, p < 0.05, was chosen as the significance level. SASÒ software was used to perform calculations. Disease-free survival was defined as time until recurrence or last follow up date if no disease recurrence occurred. For patients who died of disease, if the date of recurrence was unknown, the date of death was used to calculate disease-free survival. Patients treated by CCR-2 resections with residual tumour nodules greater than 2.5 mm were considered as having immediate relapse. Postoperative deaths were not excluded from the survival analysis. Results Patients characteristics Nine centres included 36 patients with a median age of 60.5 years (range 40e75) who underwent 39 procedures. Two patients underwent iterative procedures (respectively 2 and 3). There were 35 female patients (97.1%) and one male patient. All patients but one received a previous platin-based chemotherapy and the median number of neoadjuvant chemotherapy course was 6 (Table 1). Preoperative radiological examinations were undertaken for diagnosis and staging (CT for 27 patients, PET for 7 patients, MRI for 3 patients). Surgery was performed with the intent of achieving complete cytoreduction in all patients.
Table 1 Patients characteristics. No of patients Sex Male Female Age (yr) Median Range Preoperative chemotherapy (cycles) Median Range Procedures 1 2 3 Carcinomatosis extent (Sugarbaker index) Median Range CCR CCR-0 CCR-1 CCR-2
1 35 60.5 40e75 6 1e14 34 1 1 10 1e26 27 5 4
Gilly stage and PCI were 3 (range 1e4) and 10 (range 1e26), respectively. At the completion of a best surgical effort at cytoreductive surgery, 27 CCR-0 resections (75%), 5 CCR-1 resections (13.9%), and 4 CCR-2 resection (11.1%) were recorded. The median hospital stay was 18 days (range: 10e69). The drugs and regimens used for HIPEC are reported in Table 2. All HIPEC procedures were performed intraoperatively after cytoreductive surgery, but with many variations in exposure techniques (open abdomen in 22 procedures (56.4%) and closed abdomen in 17 procedures (43.5%)), drugs, duration, intraperitoneal temperatures, type of perfusate, and flow rates. A total of 7 patients received at least one course of adjuvant systemic chemotherapy: paclitaxel and platinum (n ¼ 4), paclitaxel and platinum and epirubicin (n ¼ 1), topotecan (n ¼ 1), platinum and pegylated doxorubicin (n ¼ 1).
Table 2 Drugs and regimen chemotherapy. Variable
Data
Open wall Closed wall Length
22 17 9 3 1 19 1 33
Treatment The assessment of carcinomatosis extent was performed using Gilly’s classification in 21 procedures and Sugarbaker’s PCI in 33 procedures. The median preoperative
36
Chemotherapy agent Mitomycin þ platinum Oxaliplatin Mitomycin monotherapy
30 min 60 min 75 min 90 min 120 min Platinum based 9 8 3
N. Bakrin et al. / EJSO 39 (2013) 742e747
745
Morbidity and mortality Two patients (5.6%) died from treatment-related complications within thirty days of surgery and before discharge from hospital. A 55-year-old woman presented with an extensive peritoneal carcinomatosis (PCI ¼ 29) and underwent a complete cytoreductive surgery and HIPEC. She experienced a grade 3 neutropenia. The cause of death was septic shock on the 29th postoperative day. A 65year-old-woman underwent incomplete cytoreduction (CCR-2) and HIPEC. She experienced a grade 3 neutropenia and died on the 16th postoperative day from Adult Respiratory Distress Syndrome. Of 39 procedures, 7 were followed by at least one grade III/IV complication: 1 heamoperitoneum, 1 pancreatitis, 1 gastroparesis, 1 gastrointestinal fistula and 4 grade III/IV haematological toxicities. The morbidity rate was 20.6%. Survival Survival analyses were performed in 32 patients. One, three and five year survival were 93.6, 71.5 and 57.4% respectively (Fig. 2). Median disease-free survival was 16.7 months and disease-free survival at 1, 3 and 5 years were 59.5, 40 and 24% respectively (Fig. 3). By univariate analysis, the only factor that had prognostic value was PCI ( p ¼ 0.03). Discussion The clinical characteristics, pathology, staging and treatment of PPSC are often considered identical to advanced stage ovarian serous carcinoma (OC) with PPSC having a similar3,13,14 or worse prognosis.15,16 These two groups are usually combined in data analysis.17,18 There are numerous case reports and small series of patients with PPSC but publications with large numbers are rare2,3 making our study one of the largest reported. PPSC and OC are histologically indistinguishable, in as much as it is often impossible to determine the organ of
Figure 2. Overall survival.
Figure 3. Disease-free survival.
origin when the ovaries, abdominal cavity and fallopian tubes are all involved. That is the reason why at advanced stage, there may be numerous misclassifications. The exact incidence of PPSC is unclear but estimated at about 10 percent the rate of epithelial ovarian carcinoma.3 Over the last decade, the incidence of PPSC has risen more than 13% per year in the United States. Whether this trend is attributable to better diagnosis of PPSC remains unknown. If this represents a true increase then it is important that an effective treatment strategy is established. PPSC and OC cells display many similarities in their biochemical properties, chemosensitivity and metastatic behaviour,19,20 and remain confined to the peritoneal cavity for much of their natural history. At diagnosis, patients with PPSC produce more malignant cells in ascitic fluid than those with serous OC, which suggests a greater tendency to desquamation.15,21 We can assume that comprehensive cytoreductive surgery followed by HIPEC would be an appropriate therapeutic option in patients with PPSC. After a complete cytoreduction, intraperitoneal chemotherapy targets microscopic residual disease that surgery cannot treat. Intraperitoneal administration of chemotherapy agents provides high local concentrations and low systemic toxicity.22 HIPEC combines the direct cytotoxicity of hyperthermia with the thermal enhancement of anticancer drugs such as cisplatin.23 Its efficacy in the treatment of intraperitoneal malignancies such as ovarian cancer has been widely demonstrated.22,24,25 The peritoneum is the first line of defence against malignant cells within the abdomen. The raw surfaces created by an extensive dissection of peritoneal carcinomatosis provide the perfect milieu for deep implantation of cancer cells.26 Utilizing HIPEC minimizes the potential risk that peritonectomy procedures used in isolation presents. Patients who undergo extensive surgery without perioperative intraperitoneal chemotherapy have been shown to have a poor prognosis.17 In our study, we reported an optimal cytoreduction in 32 procedures (89%) (27 CCR-0 and 5 CCR-1), which is
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higher than previously reported.2,3 This is probably due to strict patient selection allowing only those patients with disease amenable to complete cytoreduction to undergo this comprehensive treatment strategy. In patients with carcinomatosis of non-gynaecological origin treated by CRS with HIPEC a complete resection has been shown to be a prerequisite for long-time survival. In a retrospective study by Fromm and colleagues,3 residual disease was not a prognostic indicator of survival in papillary serous carcinoma of the peritoneum. In our study, residual disease did not appear to be a prognostic factor, but only four patients underwent incomplete cytoreduction, so this result has to be interpreted with care. We believe that complete cytoreduction combined with HIPEC is essential in achieving any hope of long term survival in patients with peritoneal carcinomatosis from primary appendiceal neoplasms, colorectal carcinomatosis and peritoneal mesothelioma. Further evidence is required to confirm this hypothesis in PPSC. The median preoperative Gilly stage and PCI were 3 (range 1e4) and 10 (range 1e26), respectively which indicates a moderate carcinomatosis extent at time of debulking surgery. Although the diagnosis of PPSC is often late, the majority of patients in this series received preoperative chemotherapy (96%) which may have successfully downstaged disease. The reported rate of optimal cytoreduction at time of initial surgery is traditionally low in patients with PPSC, because of more extensive carcinomatosis and a greater involvement of the upper abdomen.2,27 However, after systemic chemotherapy and downstaging of the carcinomatosis, the rate of successful debulking is similar in patients with PPSC and OC.2 The combination of the two procedures exposes patients to an increased risk of complications, but most morbidity is due to surgery.22 For procedures with high morbidity and mortality it is imperative that patients are subjected to rigorous selection criteria to ensure their length and quality of life are improved. We reported two postoperative deaths, four grade III/IV surgical-related complications and four grade III/IV haematological toxicities related to chemotherapy use in 7 patients. The overall morbidity rate of this study (20.6%) is lower than that previously reported22,28 and the surgical morbidity rate (12.1%) is the lowest reported for PPSC. Modifications in the dose of antineoplastic drug in the HIPEC perfusate may decrease haematological toxicity and this needs further investigation. Median survival projected to be longer than 5 years which is better than that previously reported.8,16,29,30 Survival analyses were performed from the date of surgery and not from initial diagnosis and so may well underestimate survival. This study demonstrates that CRS and HIPEC can achieve long-term survival with acceptable morbidity in patients with PPSC. Carefull patient selection is essential to ensure morbidity and mortality is minimized so that optimal benefit from CRS and HIPEC can be obtained.
Acknowledgements The authors would like to thank Nadine Bossard and Florent Boutitie from the Biostatistic Department, Centre Hospitalo-Universitaire, Lyon Sud for their help with the preparation of this manuscript. Conflict of interest statement The authors declare they have no conflict of interest. References 1. Jordan SJ, Green AC, Whiteman DC, et al. Serous ovarian, fallopian tube and primary peritoneal cancers: a comparative epidemiological analysis. Int J Cancer 2008 Apr 1;122(7):1598–603. 2. Dubernard G, Morice P, Rey A, et al. Prognosis of stage III or IV primary peritoneal serous papillary carcinoma. Eur J Surg Oncol 2004 Nov;30(9):976–81. 3. Fromm GL, Gershenson DM, Silva EG. Papillary serous carcinoma of the peritoneum. Obstet Gynecol 1990 Jan;75(1):89–95. 4. Iavazzo C, Vorgias G, Katsoulis M, et al. Primary peritoneal serous papillary carcinoma: clinical and laboratory characteristics. Arch Gynecol Obstet 2008 Jul;278(1):53–6. 5. 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 Dec 15; 116(24):5608–18. 6. Glehen O, Mohamed F, Gilly FN. Peritoneal carcinomatosis from digestive tract cancer: new management by cytoreductive surgery and intraperitoneal chemohyperthermia. Lancet Oncol 2004 Apr;5(4):219–28. 7. Verwaal VJ, Kusamura S, Baratti D, et al. The eligibility for localregional treatment of peritoneal surface malignancy. J Surg Oncol 2008 Sep 15;98(4):220–3. 8. Bloss JD, Liao SY, Buller RE, et al. Extraovarian peritoneal serous papillary carcinoma: a case-control retrospective comparison to papillary adenocarcinoma of the ovary. Gynecol Oncol 1993 Sep;50(3):347–51. 9. 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 Apr;41(2): 124–9. 10. Jacquet P, Sugarbaker PH. Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis. Cancer Treat Res 1996;82:359–74. 11. Yan TD, Morris DL. Cytoreductive surgery and perioperative intraperitoneal chemotherapy for isolated colorectal peritoneal carcinomatosis: experimental therapy or standard of care? Ann Surg 2008 Nov; 248(5):829–35. 12. Common terminology criteria for adverse events (CTCAE). Version 4.0 2009. 13. Ben-Baruch G, Sivan E, Moran O, et al. Primary peritoneal serous papillary carcinoma: a study of 25 cases and comparison with stage III-IVovarian papillary serous carcinoma. Gynecol Oncol 1996 Mar;60(3):393–6. 14. Dalrymple JC, Bannatyne P, Russell P, et al. Extraovarian peritoneal serous papillary carcinoma. A clinicopathologic study of 31 cases. Cancer 1989 Jul 1;64(1):110–5. 15. Halperin R, Zehavi S, Langer R, et al. Primary peritoneal serous papillary carcinoma: a new epidemiologic trend? A matched-case comparison with ovarian serous papillary cancer. Int J Gynecol Cancer 2001 SepeOct;11(5):403–8. 16. Killackey MA, Davis AR. Papillary serous carcinoma of the peritoneal surface: matched-case comparison with papillary serous ovarian carcinoma. Gynecol Oncol 1993 Nov;51(2):171–4.
N. Bakrin et al. / EJSO 39 (2013) 742e747 17. Look M, Chang D, Sugarbaker PH. Long-term results of cytoreductive surgery for advanced and recurrent epithelial ovarian cancers and papillary serous carcinoma of the peritoneum. Int J Gynecol Cancer 2004 JaneFeb;14(1):35–41. 18. Ramirez PT, Schmeler KM, Milam MR, et al. Efficacy of letrozole in the treatment of recurrent platinum- and taxane-resistant high-grade cancer of the ovary or peritoneum. Gynecol Oncol 2008 Jul;110(1):56–9. 19. Fishman DA, Chilukuri K, Stack MS. Biochemical characterization of primary peritoneal carcinoma cell adhesion, migration, and proteinase activity. Gynecol Oncol 1997 Nov;67(2):193–9. 20. Kowalski LD, Kanbour AI, Price FV, et al. A case-matched molecular comparison of extraovarian versus primary ovarian adenocarcinoma. Cancer 1997 Apr 15;79(8):1587–94. 21. Barda G, Menczer J, Chetrit A, et al. Comparison between primary peritoneal and epithelial ovarian carcinoma: a population-based study. Am J Obstet Gynecol 2004 Apr;190(4):1039–45. 22. Glehen O, Osinsky D, Cotte E, et al. Intraperitoneal chemohyperthermia using a closed abdominal procedure and cytoreductive surgery for the treatment of peritoneal carcinomatosis: morbidity and mortality analysis of 216 consecutive procedures. Ann Surg Oncol 2003 Oct; 10(8):863–9. 23. Mohamed F, Marchettini P, Stuart OA, et al. Thermal enhancement of new chemotherapeutic agents at moderate hyperthermia. Ann Surg Oncol 2003 May;10(4):463–8.
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24. Sugarbaker PH, Welch LS, Mohamed F, et al. A review of peritoneal mesothelioma at the Washington Cancer Institute. Surg Oncol Clin N Am 2003 Jul;12(3):605–21. xi. 25. van de Vaart PJ, van der Vange N, Zoetmulder FA, et al. Intraperitoneal cisplatin with regional hyperthermia in advanced ovarian cancer: pharmacokinetics and cisplatin-DNA adduct formation in patients and ovarian cancer cell lines. Eur J Cancer 1998 Jan;34(1):148–54. 26. Sugarbaker PH. Peritoneum as the first-line of defense in carcinomatosis. J Surg Oncol 2007 Feb 1;95(2):93–6. 27. Taus P, Petru E, Gucer F, et al. Primary serous papillary carcinoma of the peritoneum: a report of 18 patients. Eur J Gynaecol Oncol 1997;18(3): 171–2. 28. Stephens AD, Alderman R, Chang D, et al. Morbidity and mortality analysis of 200 treatments with cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy using the coliseum technique. Ann Surg Oncol 1999 Dec;6(8):790–6. 29. Bertelsen K, Jakobsen A, Stroyer J, et al. A prospective randomized comparison of 6 and 12 cycles of cyclophosphamide, adriamycin, and cisplatin in advanced epithelial ovarian cancer: a Danish Ovarian Study Group trial (DACOVA). Gynecol Oncol 1993 Apr;49(1): 30–6. 30. Ransom DT, Patel SR, Keeney GL, et al. Papillary serous carcinoma of the peritoneum. A review of 33 cases treated with platin-based chemotherapy. Cancer 1990 Sep 15;66(6):1091–4.
EJSO 39 (2013) 742e747
www.ejso.com
Primary peritoneal serous carcinoma treated by cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. A multi-institutional study of 36 patients N. Bakrin a,*, F.N. Gilly a, D. Baratti b, J.M. Bereder c, F. Quenet d, G. Lorimier e, F. Mohamed f, D. Elias g, O. Glehen a Association Franc¸aise de Chirurgie a
Surgical Oncology Department, Lyon Civil Hospices, South Lyon University Hospital Center, 165 chemin du grand Revoyet, 69365 Pierre Benite, France b Istituto Nazionale per la Cura e lo Studio dei Tumori, Milano, Italy c Surgical Oncology Department, l’Archet Hospital, Nice University Hospital Center, Nice, France d Surgical Oncology Department, Val d’Aurelle Center, Montpellier, France e Surgical Oncology Department, Paul Papin Center, Angers, France f School of Surgical and Reproductive Sciences, Newcastle upon Tyne, United Kingdom g Surgical Oncology Department, Institut Gustave Roussy, Villejuif, France Accepted 20 February 2013 Available online 16 March 2013
Abstract Aim: Primary peritoneal serous carcinoma (PPSC) is a rare condition, histologically identical to ovarian serous carcinoma and often diagnosed at late stage. There is not any standardized treatment for PPSC. A retrospective multicentric study was performed in French speaking centers to evaluate cytoreduction surgery and Hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal carcinomatosis from different origins. The manuscript’s aim was to study the particular population with PPSC. Methods: Between September 1997 and July 2007, 36 patients with PPSC from 9 institutions underwent 39 procedures. Results: Mortality and morbidity rates were 5.6% and 20.6% respectively. The overall survival at 1, 3 and 5 years are respectively 93.6, 71.5 and 57.4%. The median overall survival was not reached. By univariate analysis, the only factor that had prognostic value was PCI (p ¼ 0.03). Conclusions: The therapeutic approach combining cytoreductive surgery with HIPEC may achieve long-term survival in patients with PPSC. Ó 2013 Elsevier Ltd. All rights reserved. Keywords: Hyperthermia; HIPEC; Ovarian carcinoma; Peritoneal neoplasm
Introduction Primary peritoneal serous carcinoma (PPSC) is a rare condition that was first described by Swerdlow in 1959. It is an extra-ovarian primary peritoneal malignancy,
Abbreviation: CC-R, completeness of the cancer resection; CRS, cytoreductive surgery; HIPEC, hyperthermic intraperitoneal chemotherapy; PC, peritoneal carcinomatosis; PCI, peritoneal cancer index; PPSC, primary peritoneal serous carcinoma. * Corresponding author. Tel.: þ33 478865644. E-mail address: [email protected] (N. Bakrin). 0748-7983/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2013.02.018
histologically identical and clinically similar to advanced stage serous ovarian carcinoma. PPSC can occur in women many years after oophorectomy performed for benign diseases or prophylactic oophorectomy.1 In advanced cases of pelvic adenocarcinoma the diagnosis of ovarian carcinoma is usually made because the ovaries cannot be distinguished from the extensive disease within the pelvis. The incidence of PPSC is unclear but estimated to be ten percent the rate of epithelial ovarian carcinoma.1 As the clinical features, staging, treatment and pathology of primary peritoneal serous carcinoma are considered
N. Bakrin et al. / EJSO 39 (2013) 742e747
identical to advanced stage ovarian serous carcinoma, these groups are usually combined in data analysis. Most reported series of PPSC are small with only a few large reports in the literature.2,3 Epidemiological, clinical and molecular differences exist and raise the question of what therapeutic approach should be taken for patients with PPSC.1,4 Over the past two decades a new therapeutic strategy to treat peritoneal carcinomatosis (PC) has developed, combining optimal cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). Its efficacy in carcinomatosis of non-gynaecological origin has been widely reported.5e7 Despite studies suggesting survival benefit, the oncology community remains sceptical of this combined therapeutic approach because of high reported toxicity. To obtain further data, a collaborative effort of 25 centres involved in the treatment of peritoneal surface malignancies provided information on a large number of patients with peritoneal carcinomatosis. Patients with PPSC were selected from this group to study outcomes following CRS with HIPEC and to identify prognostic factor.5 Patients and methods Patient population Between September 1997 and July 2007, 36 patients with PPSC underwent 39 procedures combining cytoreductive surgery with HIPEC in 8 French speaking centres and an Italian centre. Pathologic diagnoses were made according to the Gynecologic Oncology Group recommendations8:
743
intraoperative exploration. Centres used two different tools: Gilly’s classification9 and Sugarbaker’s Peritoneal Cancer Index (PCI)10 to assess the extent of PC. By Gilly’s classification, carcinomatosis is classified into five stages: stage 0, positive peritoneal cytology, stage I, malignant tumour nodules less than 5 mm in diameter localized to one part of the abdomen; stage II, malignant tumour nodules diffuse over the whole abdomen; stage III, tumour nodules 5 mm to 2 cm in diameter; stage IV, large (>2 cm in diameter) tumour deposits. The PCI is described in Fig. 1. For analysis, four subgroups of PCI were created: 1e6, 7e12, 13e19, and >19. Information recorded about the combined procedure included the date, the completeness of cytoreductive surgery, the presence or absence of lymph node metastases, the modalities of HIPEC (duration, drugs, “closed” or “open” HIPEC, temperatures), and treatment with adjuvant systemic chemotherapy. The assessment of the completeness of the cancer resection (CCR) by cytoreductive surgery was performed by the surgeon at the end of the procedure and classified into three categories4,11: CCR-0 indicated no macroscopic residual cancer remained, CCR-1 indicated no residual nodule greater than 2.5 mm, and CCR-2 indicated that the diameter of residual nodules was greater than 2.5 mm. The centres were classified according to their experience at the time of the procedure (0e3 years, 3e7 years, 7e11 years and more than 11 years). Analysis was also performed on the chronological period in which surgery was undertaken (between 1997 and 1999, between 2000 and 2002, between 2003 and 2004 and after 2005). Information was obtained regarding postoperative course, including postoperative death (within
1. Ovaries of normal size or enlarged by a benign process. 2. Absent ovarian involvement or limited to the surface and/or superficial cortex with no tumour nodule within the ovarian cortex exceeding 5*5 mm 3. Serous histology 4. Volume of extra-ovarian disease which significantly exceeds that of ovarian disease. The exclusion criteria were the presence of extraabdominal metastases. Standardized clinical data were received and entered into a central data-base. The same author reviewed all data sheets before their entry into the database in an effort to make this a uniform interpretation of retrospective data. Data forms A standard data form was created to retrieve information on the status of the patient before undergoing the combined procedure, including the sex, the age, the extent of peritoneal carcinomatosis and the previous treatment with systemic chemotherapy. The extent of PC was assessed by
Figure 1. Peritoneal Cancer Index (PCI). The abdomen and the pelvis are divided into 12 regions. The lesion sizes of the largest implants are scored (0 through 3) in each abdominopelvic region. The PCI can be expressed as a numerical score, ranging from 1 to 39.
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N. Bakrin et al. / EJSO 39 (2013) 742e747
30 days of surgery), major complications (grade 3 and 4 complications according to the National Cancer Institute’s Common Toxity Criteria), and reoperations. Follow-up data recorded included last date of follow up and status of the patient.12 Statistical analysis All procedures were included in the analyses of postoperative morbidity and mortality (death or major complications occurring within 30 days of surgery). The influence of patient, disease and treatment characteristics were related to the risk of postoperative morbidity and mortality using univariate logistic regression models. To study relationships between variables, standard tests were used: chi2 with two qualitative variables, Pearson’s correlation if quantitative. Survival analysis was performed using the KaplaneMeier method, and comparisons of curves were made using the log-rank test. The cut-off date for survival analysis was fixed at December 2006, because an active enquiry was performed in all institutions to collect the status (dead/alive) of the patients at that date. Standard probability cut-off, p < 0.05, was chosen as the significance level. SASÒ software was used to perform calculations. Disease-free survival was defined as time until recurrence or last follow up date if no disease recurrence occurred. For patients who died of disease, if the date of recurrence was unknown, the date of death was used to calculate disease-free survival. Patients treated by CCR-2 resections with residual tumour nodules greater than 2.5 mm were considered as having immediate relapse. Postoperative deaths were not excluded from the survival analysis. Results Patients characteristics Nine centres included 36 patients with a median age of 60.5 years (range 40e75) who underwent 39 procedures. Two patients underwent iterative procedures (respectively 2 and 3). There were 35 female patients (97.1%) and one male patient. All patients but one received a previous platin-based chemotherapy and the median number of neoadjuvant chemotherapy course was 6 (Table 1). Preoperative radiological examinations were undertaken for diagnosis and staging (CT for 27 patients, PET for 7 patients, MRI for 3 patients). Surgery was performed with the intent of achieving complete cytoreduction in all patients.
Table 1 Patients characteristics. No of patients Sex Male Female Age (yr) Median Range Preoperative chemotherapy (cycles) Median Range Procedures 1 2 3 Carcinomatosis extent (Sugarbaker index) Median Range CCR CCR-0 CCR-1 CCR-2
1 35 60.5 40e75 6 1e14 34 1 1 10 1e26 27 5 4
Gilly stage and PCI were 3 (range 1e4) and 10 (range 1e26), respectively. At the completion of a best surgical effort at cytoreductive surgery, 27 CCR-0 resections (75%), 5 CCR-1 resections (13.9%), and 4 CCR-2 resection (11.1%) were recorded. The median hospital stay was 18 days (range: 10e69). The drugs and regimens used for HIPEC are reported in Table 2. All HIPEC procedures were performed intraoperatively after cytoreductive surgery, but with many variations in exposure techniques (open abdomen in 22 procedures (56.4%) and closed abdomen in 17 procedures (43.5%)), drugs, duration, intraperitoneal temperatures, type of perfusate, and flow rates. A total of 7 patients received at least one course of adjuvant systemic chemotherapy: paclitaxel and platinum (n ¼ 4), paclitaxel and platinum and epirubicin (n ¼ 1), topotecan (n ¼ 1), platinum and pegylated doxorubicin (n ¼ 1).
Table 2 Drugs and regimen chemotherapy. Variable
Data
Open wall Closed wall Length
22 17 9 3 1 19 1 33
Treatment The assessment of carcinomatosis extent was performed using Gilly’s classification in 21 procedures and Sugarbaker’s PCI in 33 procedures. The median preoperative
36
Chemotherapy agent Mitomycin þ platinum Oxaliplatin Mitomycin monotherapy
30 min 60 min 75 min 90 min 120 min Platinum based 9 8 3
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Morbidity and mortality Two patients (5.6%) died from treatment-related complications within thirty days of surgery and before discharge from hospital. A 55-year-old woman presented with an extensive peritoneal carcinomatosis (PCI ¼ 29) and underwent a complete cytoreductive surgery and HIPEC. She experienced a grade 3 neutropenia. The cause of death was septic shock on the 29th postoperative day. A 65year-old-woman underwent incomplete cytoreduction (CCR-2) and HIPEC. She experienced a grade 3 neutropenia and died on the 16th postoperative day from Adult Respiratory Distress Syndrome. Of 39 procedures, 7 were followed by at least one grade III/IV complication: 1 heamoperitoneum, 1 pancreatitis, 1 gastroparesis, 1 gastrointestinal fistula and 4 grade III/IV haematological toxicities. The morbidity rate was 20.6%. Survival Survival analyses were performed in 32 patients. One, three and five year survival were 93.6, 71.5 and 57.4% respectively (Fig. 2). Median disease-free survival was 16.7 months and disease-free survival at 1, 3 and 5 years were 59.5, 40 and 24% respectively (Fig. 3). By univariate analysis, the only factor that had prognostic value was PCI ( p ¼ 0.03). Discussion The clinical characteristics, pathology, staging and treatment of PPSC are often considered identical to advanced stage ovarian serous carcinoma (OC) with PPSC having a similar3,13,14 or worse prognosis.15,16 These two groups are usually combined in data analysis.17,18 There are numerous case reports and small series of patients with PPSC but publications with large numbers are rare2,3 making our study one of the largest reported. PPSC and OC are histologically indistinguishable, in as much as it is often impossible to determine the organ of
Figure 2. Overall survival.
Figure 3. Disease-free survival.
origin when the ovaries, abdominal cavity and fallopian tubes are all involved. That is the reason why at advanced stage, there may be numerous misclassifications. The exact incidence of PPSC is unclear but estimated at about 10 percent the rate of epithelial ovarian carcinoma.3 Over the last decade, the incidence of PPSC has risen more than 13% per year in the United States. Whether this trend is attributable to better diagnosis of PPSC remains unknown. If this represents a true increase then it is important that an effective treatment strategy is established. PPSC and OC cells display many similarities in their biochemical properties, chemosensitivity and metastatic behaviour,19,20 and remain confined to the peritoneal cavity for much of their natural history. At diagnosis, patients with PPSC produce more malignant cells in ascitic fluid than those with serous OC, which suggests a greater tendency to desquamation.15,21 We can assume that comprehensive cytoreductive surgery followed by HIPEC would be an appropriate therapeutic option in patients with PPSC. After a complete cytoreduction, intraperitoneal chemotherapy targets microscopic residual disease that surgery cannot treat. Intraperitoneal administration of chemotherapy agents provides high local concentrations and low systemic toxicity.22 HIPEC combines the direct cytotoxicity of hyperthermia with the thermal enhancement of anticancer drugs such as cisplatin.23 Its efficacy in the treatment of intraperitoneal malignancies such as ovarian cancer has been widely demonstrated.22,24,25 The peritoneum is the first line of defence against malignant cells within the abdomen. The raw surfaces created by an extensive dissection of peritoneal carcinomatosis provide the perfect milieu for deep implantation of cancer cells.26 Utilizing HIPEC minimizes the potential risk that peritonectomy procedures used in isolation presents. Patients who undergo extensive surgery without perioperative intraperitoneal chemotherapy have been shown to have a poor prognosis.17 In our study, we reported an optimal cytoreduction in 32 procedures (89%) (27 CCR-0 and 5 CCR-1), which is
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higher than previously reported.2,3 This is probably due to strict patient selection allowing only those patients with disease amenable to complete cytoreduction to undergo this comprehensive treatment strategy. In patients with carcinomatosis of non-gynaecological origin treated by CRS with HIPEC a complete resection has been shown to be a prerequisite for long-time survival. In a retrospective study by Fromm and colleagues,3 residual disease was not a prognostic indicator of survival in papillary serous carcinoma of the peritoneum. In our study, residual disease did not appear to be a prognostic factor, but only four patients underwent incomplete cytoreduction, so this result has to be interpreted with care. We believe that complete cytoreduction combined with HIPEC is essential in achieving any hope of long term survival in patients with peritoneal carcinomatosis from primary appendiceal neoplasms, colorectal carcinomatosis and peritoneal mesothelioma. Further evidence is required to confirm this hypothesis in PPSC. The median preoperative Gilly stage and PCI were 3 (range 1e4) and 10 (range 1e26), respectively which indicates a moderate carcinomatosis extent at time of debulking surgery. Although the diagnosis of PPSC is often late, the majority of patients in this series received preoperative chemotherapy (96%) which may have successfully downstaged disease. The reported rate of optimal cytoreduction at time of initial surgery is traditionally low in patients with PPSC, because of more extensive carcinomatosis and a greater involvement of the upper abdomen.2,27 However, after systemic chemotherapy and downstaging of the carcinomatosis, the rate of successful debulking is similar in patients with PPSC and OC.2 The combination of the two procedures exposes patients to an increased risk of complications, but most morbidity is due to surgery.22 For procedures with high morbidity and mortality it is imperative that patients are subjected to rigorous selection criteria to ensure their length and quality of life are improved. We reported two postoperative deaths, four grade III/IV surgical-related complications and four grade III/IV haematological toxicities related to chemotherapy use in 7 patients. The overall morbidity rate of this study (20.6%) is lower than that previously reported22,28 and the surgical morbidity rate (12.1%) is the lowest reported for PPSC. Modifications in the dose of antineoplastic drug in the HIPEC perfusate may decrease haematological toxicity and this needs further investigation. Median survival projected to be longer than 5 years which is better than that previously reported.8,16,29,30 Survival analyses were performed from the date of surgery and not from initial diagnosis and so may well underestimate survival. This study demonstrates that CRS and HIPEC can achieve long-term survival with acceptable morbidity in patients with PPSC. Carefull patient selection is essential to ensure morbidity and mortality is minimized so that optimal benefit from CRS and HIPEC can be obtained.
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