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International Journal of Gynecological Cancer IS CYTOREDUCTIVE SURGERY WITH PERIOPERATIVE INTRAPERITONEAL CHEMOTHERAPY JUSTIFIED AS UPFRONT TREATMENT IN LOCALLY ADVANCED EPITHELIAL OVARIAN CANCER? --Manuscript Draft-Manuscript Number: Full Title: IS CYTOREDUCTIVE SURGERY WITH PERIOPERATIVE INTRAPERITONEAL CHEMOTHERAPY JUSTIFIED AS UPFRONT TREATMENT IN LOCALLY ADVANCED EPITHELIAL OVARIAN CANCER? Short Title: INTRAPERITONEAL CHEMOTHERAPY IN OVARIAN CANCER Article Type: Original Study Keywords: Cytoreductive surgery; peritoneal carcinomatosis; Ovarian cancer; HIPEC Corresponding Author: Antonios-Apostolos K Tentes, M. D. Didimotichon General Hospital Didimotichon, Evros GREECE Corresponding Author Secondary Information: Corresponding Author's Institution: Didimotichon General Hospital Corresponding Author's Secondary Institution: First Author: Antonios-Apostolos K Tentes, M. D. First Author Secondary Information: Order of Authors: Antonios-Apostolos K Tentes, M. D. Theodosios B Palaskas, Professor Konstantinos M Stamou, MD, PhD Chrysostomos E Stoforos, Assistant Professor Nicolaos Pallas, MD Christina Karamveri, MD Dimitrios Kyziridis, MD Christos Hristakis, MD Order of Authors Secondary Information: Manuscript Region of Origin: GREECE Abstract: Objective: Perioperative intraperitoneal chemotherapy after maximal cytoreductive surgery has been used in the treatment of recurrent or persistent epithelial ovarian cancer. The purpose of the study is the evaluation of the effect of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) as upfront treatment in advanced ovarian cancer. Material/Methods: This is a prospective observational study of 166 women that underwent 189 cytoreductive surgical operations for locally advanced epithelial ovarian cancer. HIPEC was used in 135 cases (71.4%), and in 55 cases (29.1%) as upfront treatment. Clinical indicators were correlated to four qualitative variables; morbidity, hospital mortality, survival, and recurrences. Results: HIPEC as upfront treatment in ovarian cancer was found to be related to recurrence (p=0.001) but not to overall survival. The prognostic variables of survival were the performance status, the completeness of cytoreduction, and the use of HIPEC (p<0.001). The prognostic variables of recurrence were the degree of differentiation, and the use of systemic chemotherapy (p=0.05). Conclusion: HIPEC combined with maximal cytoreductive surgery may be used with Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation promising results as upfront treatment in patients with advanced epithelial ovarian cancer. Prospective randomized trials are required. Suggested Reviewers: Paul H Sugarbaker Director, Medstar Washington Hospital Center [email protected] Specialist on cytoreductive surgery and intraperitoneal chemotherapy Jesus Esquivel Director, Cancer Treatment Centers of America [email protected] Specialist on cytoreductive surgery and intraperitoneal chemotherapy Opposed Reviewers: Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation Cover Letter Antonios-Apostolos K. Tentes, MD Director, Surgical Oncology Metropolitan Hospital Venizelou 1 New Faliro, 18547 Greece Tel: +302104807177 Fax: +302104809293 Mobile: +306974703016 To the Editor International Journal of Gynecological Cancer Dear Sir, It would be very kind of you to accept the manuscript “IS CYTOREDUCTIVE SURGERY WITH PERIOPERATIVE INTRAPERITONEAL CHEMOTHERAPY JUSTIFIED AS UPFRONT TREATMENT IN LOCALLY ADVANCED EPITHELIAL OVARIAN CANCER?” for consideration and possible publication in your journal. The manuscript has not been under consideration in any other journal and has not been presented elsewhere. All the authors have equally contributed to the preparation of the manuscript and agree with the results. Sincerely yours Antonios-Apostolos K. Tentes, MD Figure Figure 1 Figure 2 LEGENDS Figure 1: Overall survival in patients receiving HIPEC as upfront treatment. Blue line=patients with HIPEC as upfront treatment. Green line=remaining patients with HIPEC. Figure 2: Survival of patients in relation with PSS. Green line=patients with PPS-0. Yellow line=patients with PSS-1, Blue line=patients with PSS-2, and Red line=patients with PSS-3. Table Table 1: Patients’ general characteristics No of patients % 90-100% 156 82.5 70-80% 30 15.9 50-60% 3 1.6 Large volume 163 86.2 Small volume 26 13.8 CC-0 114 55 CC-1 59 31.2 CC-2 11 5.8 CC-3 15 7.9 PSS-0 85 45 PSS-1 17 9 PSS-2 63 33.3 PSS-3 24 12.7 1-13 89 47.1 14-20 47 24.9 21-39 53 28 HIPEC 135 71.4 Performance status Tumor volume CC-score PSS PCI Table 2: Peritonectomy procedures Type of procedure No Pelvic peritonectomy 121 Greater omentectomy 119 Right subdiaphragmatic 86 Lesser omentectomy 87 Epigastric peritonectomy 73 Splenectomy 59 Right parietal peritonectomy 54 Cholecystectomy+resection of the omental bursa 51 Left parietal peritonectomy 43 Left subdiaphragmatic peritonectomy 40 Table 3: Postoperative complications in 63 patients (33.3%) complication No of pts % Anastomotic failure 17 26.9 Wound infection 11 17.5 Respiratory 8 12.7 Postoperative bleeding 2 3.2 Ileus 1 1.5 Urinary infection 2 3.2 Cardiac 2 3.2 Renal failure 1 1.5 Hepatic failure 1 1.5 Enterocutaneous fistula 2 3.2 Purulent peritonitis 8 12.7 Intra-abdominal abscess 3 4.7 Pancreatitis 1 1.5 Central line infection 4 6.4 Table 4: univariate and multivariate analysis for recurrence Univariate Multivariate variable P value P value Systemic chemotherapy <0.001 0.05 HIPEC 0.01 HIPEC as upfront treatment <0.001 G 0.02 Tumor volume 0.04 PSS 0.05 CC-score 0.01 Metastatic lymph nodes 0.01 Table 5: univariate and multivariate analysis of survival univariate multivariate P value P value Performance status 0.001 <0.001 HIPEC 0.04 <0.001 variable PCI <0.001 PSS <0.001 CC <0.001 Ascites 0.02 <0.001 0.05 Title Page IS CYTOREDUCTIVE SURGERY WITH PERIOPERATIVE INTRAPERITONEAL CHEMOTHERAPY JUSTIFIED AS UPFRONT TREATMENT IN LOCALLY ADVANCED EPITHELIAL OVARIAN CANCER? AUTHORS AND AFFILIATIONS Antonios-Apostolos K. Tentes, Director, Surgical Oncology, Peritoneal Surface Malignancy Program, Metropolitan Hospital, Venizelou 1, 18547, N. Faliro, Greece, [email protected] Theodosios B. Palaskas, Professor, Department of Economics and Regional Development, Panteion University, 136 Singrou Av, 17576, Athens, Greece, [email protected] Konstantinos Stamou, General Surgeon, Surgical Oncology, Peritoneal Surface Malignancy Program, Metropolitan Hospital, Venizelou 1, 18547, N. Faliro, Greece, [email protected] Chrysostomos E. Stoforos, Assistant Professor, Department of Economics and Regional Development, Panteion University, 136 Singrou Av, 17576, Athens, Greece, [email protected] Nicolaos Pallas, General Surgeon, Surgical Oncology, Peritoneal Surface Malignancy Program, Metropolitan Hospital, Venizelou 1, 18547, N. Faliro, Greece, [email protected] Christina Karamveri, General Surgeon, Surgical Oncology, Peritoneal Surface Malignancy Program, Metropolitan Hospital, Venizelou 1, 18547, N. Faliro, Greece, [email protected] Dimitrios Kyziridis, General Surgeon, Euromedica Kyanous Stavros, Viziis 1, 54636, Thessaloniki, Greece, [email protected] Christos Hristakis, Director, Surgical Oncology, Euromedica Kyanous Stavros, Viziis 1, 54636, Thessaloniki, Greece, [email protected] Vasilios Kyriakopoulos. Anesthesiologist, Metropolitan Hospital, Venizelou 1, 18547, N. Faliro, Greece, [email protected] ADDRESS FOR CORRESPENDENCE Antonios-Apostolos K. Tentes Director, Surgical Oncology, Peritoneal Surface Malignancy Program, Metropolitan Hospital, New Faliro, Greece, 18547 Tel: +302104807177, fax: +302104809293 e-mail: [email protected] Manuscript (All Manuscript Text Pages in MS Word format, including References and Figure Legends) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 IS CYTOREDUCTIVE SURGERY WITH PERIOPERATIVE INTRAPERITONEAL CHEMOTHERAPY JUSTIFIED AS UPFRONT TREATMENT IN LOCALLY ADVANCED EPITHELIAL OVARIAN CANCER? ABSTRACT Objective: Perioperative intraperitoneal chemotherapy after maximal cytoreductive surgery has been used in the treatment of recurrent or persistent epithelial ovarian cancer. The purpose of the study is the evaluation of the effect of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) as upfront treatment in advanced ovarian cancer. Methods/Materials: This is a prospective observational study of 166 women that underwent 189 cytoreductive surgical operations for locally advanced epithelial ovarian cancer. HIPEC was used in 135 cases (71.4%), and in 55 cases (29.1%) as upfront treatment. Clinical indicators were correlated to four qualitative variables; morbidity, hospital mortality, survival, and recurrences. Results: HIPEC as upfront treatment in ovarian cancer was found to be related to recurrence (p=0.001) but not to overall survival. The prognostic variables of survival were the performance status, the completeness of cytoreduction, and the use of HIPEC (p<0.001). The prognostic variables of recurrence were the degree of differentiation, and the use of systemic chemotherapy (p=0.05). Conclusion: HIPEC combined with maximal cytoreductive surgery may be used with promising results as upfront treatment in patients with advanced epithelial ovarian cancer. Prospective randomized trials are required. KEY-WORDS Cytoreductive surgery, peritoneal carcinomatosis, ovarian cancer, HIPEC INTRODUCTION 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Cytoreductive surgery followed by systemic adjuvant chemotherapy is considered the standard treatment for advanced epithelial ovarian cancer [1]. Despite a favorable initial response, the majority of patients eventually develop local-regional recurrence leading to poor overall outcome with 5-year survival rate not exceeding 30% and the disease free survival not exceeding 18 months [2-3]. Perioperative intraperitoneal chemotherapy, after maximal cytoreductive surgery, has been shown to be effective in the treatment of pseudomyxoma peritonei [4], diffuse malignant peritoneal mesothelioma [5], and gastrointestinal cancer with peritoneal carcinomatosis [6]. This treatment strategy has been used as an alternative in recurrent and persistent ovarian cancer [7-10] and as upfront treatment in ovarian cancer with its role not yet clear [8, 11]. Ovarian cancer is a disease that almost until the end remains confined to the peritoneal surfaces. Under such circumstances the use of intraperitoneally administered chemotherapy may be effective in eradicating the microscopic residual tumor load. So far, the proper timing for the use of intraperitoneal chemotherapy has not been clarified. The purpose of the study is to evaluate the effect of HIPEC after extensive cytoreductive surgery as upfront treatment in locally advanced epithelial ovarian cancer. MATERIALS AND METHODS This is a prospective observational study designed in 2002 for women with locally advanced epithelial ovarian cancer. The medical records of the patients that underwent treatment until 2013 were included in the analysis. All patients were treated by the same surgical team. The protocol was approved by the Ethical Committee of the Hospital and all patients gave written informed consent. Patient selection Women with FIGO stage III ovarian cancer with good performance status (Karnofsky performance scale ≥ 50%) capable to undergo major surgery were included in the study. The patients were diagnosed either at the time of initial diagnosis, or at recurrence, or even when found to be treatment-refractory. The adopted exclusion criteria were evidence of unresectable disease at preoperative evaluation, white blood cell count <4000/mm3, platelets <100 000, blood urea level > 50mg/dl, creatinine level > 1.5 mg/dl, abnormal liver function other than bile duct obstruction, patient unable to undergo major surgery according to anesthesiological assessment. Disease was considered “unresectable” if gross small bowel infiltration was evident or distant metastases were present. Preoperative assessment included physical examination, hematological-biochemical examinations, tumor markers (CEA, CA-125), and abdominal and thoracic CT-scan. Treatments A midline incision from the xiphoid process to the pubic symphysis was always used for maximal exposure of the abdomen. The extent and distribution of peritoneal carcinomatosis was assessed after complete lysis of the adhesions and the Peritoneal Carcinomatosis Index (PCI) was calculated [12-3]. Prior surgical score (PSS) was 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 always assessed according to available previous surgical reports. Patients that did not undergo previous surgery were assessed as PSS-0. Patients that underwent biopsy or surgery in one abdominopelvic region were assessed as PSS-1. Patients with previous history of surgery in 2-5 abdominopelvic regions were assessed as PSS-2, and those with history of surgery in > 5 regions as PSS-3 [13]. Standard peritonectomy procedures were used with the intent of resecting the entire macroscopically visible tumor load [14]. The completeness of cytoreductive surgery was assessed after the completion of surgery using Sugarbaker’s criteria as CC-0, CC1, CC-2, and CC-3 [13-4]. Large volume disease was considered as peritoneal deposits with lesion size greater than 0.5cm or confluence of lesions. HIPEC with the Coliseum technique was always administered after tumor resection and before the reconstruction of the alimentary tract. HIPEC was possible with a continuous closed circuit of four drains (two inlet and two outlet), one heat exchanger, and two roller pumps connected to the inlet and outlet drains (Sun-Chip, Gamida Tech, France). The cytostatic drugs were diluted in 2-3 liters of Ringer’s Lactate solution and the intraabdominal temperature was maintained at 42.5-430C during perfusion. Cis-platin (50 mg/m2) in combination with doxorubicin (15 mg/m2) were used in chemotherapy naïve patients, or in platinum sensitive patients for 90 min. Platinum resistant patients received melphalan (70 mg/m2) or gemcitabine (1000 mg/m2) for 60 minutes. Early postoperative intraperitoneal chemotherapy (EPIC) was given through a Tenckhoff catheter during the first 5 postoperative days. The chemotherapy regimen was 5-fluorouracil (400 mg/m2) diluted in 1.5lit of D1.5W. HIPEC and EPIC was used in CC-1 patients, while CC-2 and CC-3 patients did not receive intraperitoneal chemotherapy. Adjuvant systemic chemotherapy was recommended to all patients and was left to the discretion of the attending medical oncologist or the multidisciplinary team. All patients remained for a minimum of 24 hours in the ICU after surgery. Patients treated with EPIC remained in the ICU for 5 additional days postoperatively until the completion of treatment. Postoperative complications were recorded and assessed according to the following criteria. The uncomplicated patients were assessed as Grade 0. Complications that required minor intervention, oral antibiotics, bowel rest or monitoring were assessed as Grade 1. Complications that required IV antibiotics or bowel rest or chest tube draining were assessed as Grade 2, those that required hospital re-admission or surgical or radiological intervention as Grade 3, those that produced chronic disability or organ resection or bowel diversion as Grade 4, and those that resulted to death as Grade 5. Grade 1 and 2 were assessed as minor complications and Grade 3-5 as major complications. Advanced age was regarded as age over 65 years. Survival was estimated from the time of surgery until the last follow-up or the time of death. Follow-up All patients were followed-up every four months for the first year and every six months for the next 4 years with physical, hematological-biochemical examinations, tumor markers (CEA, CA-125), abdominal and thoracic CT-scan. Recurrences and the sites of recurrence were recorded. No patient was lost during follow-up. Statistical analysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Statistical analysis was possible using the SPSS (Statistical Package for Social Sciences), version 17. Pearson, Kendall's Tau_b and Spearman's rho were applied to test for the existence of correlation between the variables of interest depending on whether they were dichotomous or continuous. Mean comparison was made possible using ANOVA, Kruskal-Wallis, Mann-Whitney and the Pearson’s chi-square tests depending on the nature of the data set. Multivariate analysis of survival was possible with the Cox proportional hazard model for the identification of the prognostic variables of survival. Cut off points were set at clinically important values or after examining different possible points. Logistic regression analysis was applied to identify the prognostic variables of recurrence, hospital mortality, and morbidity. A two-tailed p value < 0.05 was considered statistically significant. RESULTS From 2003 until 2012, 166 women with locally advanced epithelial ovarian cancer underwent 189 cytoreductive operations. The mean age of the patients was 58.3+12 (16-86) years. The patients’ general characteristics are listed in Table1. The mean PCI was 14.8. Complete or near complete cytoreduction (CC-0 and CC-1) was possible in 163 patients (86.2%). HIPEC was used in 135 cases (71.4%), and as upfront treatment in 55 (29.1%) cases. Adjuvant systemic chemotherapy with carboplatin and taxanes was given in 134 (70.9%) women. The remainder did not receive adjuvant chemotherapy. The peritonectomy procedures that were performed are listed in Table 2. In addition to these procedures, appendectomy was performed in 30 cases, segmental intestinal resection in 28, colectomy other than sub-total and low anterior resection in 19, abdominopelvic lymph node resection in 19, sub-total colectomy in 17, and gastrectomy in 14 cases. Postoperative Morbidity Hospital morbidity was recorded in 63 patients (33.3%) (Table 3). The re-operation rate was 2.9% (4 patients). Grade 1, Grade 2, Grade 3, Grade 4, and Grade 5 complications comprised 4.4% (6 patients), 11.0% (15 patients), 8.8% (12 patients), 11.7% (16 patients), and 4.4% (6 patients) respectively. The performance status, the tumor volume, the completeness of cytoreduction, the presence of ascites, the extent of peritoneal dissemination, and the use of HIPEC as upfront treatment were found to be related to morbidity (p<0.05). The prognostic variables of morbidity were found to be the PCI (HR=2.873, p<0.001, 95% CI=1.882-3.003). Hospital mortality The hospital mortality was 2.6% (5 patients). Correlation Kendall’s Tau analysis showed that PSS, and PCI were related to hospital mortality (p<0.05). Multivariate analysis suggested that PSS was the single prognostic indicator of hospital mortality (HR=0.378, p<0.001, 95% CI=0.138-1.038). Follow-up The median follow-up time was 16 months (1-111). During follow-up 94 patients (49.7%) were recorded with recurrence. Distant and local-regional recurrences were recorded in 37 (19.6%), and 57 (30.2%) patients respectively. The use of systemic chemotherapy, HIPEC, the degree of differentiation, the tumor volume, the PSS, the 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 CC-score, and the presence of metastasis to lymph nodes were closely related to the development of recurrences. The degree of differentiation, and systemic chemotherapy were found to be the prognostic indicators of recurrence (Table 4). Survival The overall 5-year, and the median survival was 41%, and 51 months respectively. Univariate analysis showed that the performance status, the degree of differentiation, the PCI, the PSS, the CC-score, the presence of ascites, and the use of HIPEC were found to be strongly related to survival (Table 5). The use of HIPEC as upfront treatment showed that there was a trend of significantly better survival (64% vs 40%, p=0.069) (Figure 1). 5-year survival rate in patients with PSS-0 was 62% (Figure 2). Multivariate analysis showed that the CC-score, the performance status, and the use of HIPEC were found to be the prognostic indicators of survival (Table 5). DISCUSSION Cytoreductive surgery is the first line of treatment for advanced epithelial ovarian cancer [15]. What remains at the discretion of the surgeon, the medical oncologist and the Multidisciplinary Team, is the classification of patients as “operable” or “inoperable”. The patients are then stratified to either receive “upfront surgery” or “neoadjuvant chemotherapy”. This unintentionally biased selection and the rather arbitrary concept of “maximal surgical effort” remain the weak points of many otherwise brilliant clinical trials on overall survival of epithelial ovarian cancer. The earliest recognized predictor of survival and recurrence in ovarian cancer is the volume of the residual disease [16]. Retrospective studies [17] and meta-analyses confirmed this result [18]. Published data and the personal expertise of surgeons led to a gradual change from the concept of “tumor debulking” to “complete cytoreduction”. Cytoreductive surgery was advanced by P.H. Sugarbaker who suggested that maximal cytoreduction is possible by standard peritonectomy procedures [13]. This approach has been proved effective in rare malignancies like mesothelioma or pseudomyxoma peritonei and it drew the attention of general surgeons and gynecologists who treat patients with advanced ovarian cancer [7-10], which is more frequent than peritoneal mesothelioma. This demanding approach should become more readily available to patients, and this can happen mostly in designated referral centers where complete or near complete cytoreduction can be achieved [19]. The experience of the same standard surgical unit may explain the achieved 86.2% of CC-0 and CC-1 operations despite the rather high median PCI of our patients. A direct implication of surpassing the learning curve in cytoreductive surgery is the re-direction of more patients towards upfront surgical treatment. Cytoreductive surgery is about learning to operate according to the physiology of the peritoneal surface malignancy. For example, the greater omentum has been recognized as the most important site of absorption of the peritoneal fluid [13]. As a result, total greater omentectomy with skeletonization of the greater curvature of the stomach is required and not only infracolic omentectomy. The majority of PSS-2 patients had previously undergone infracolic omentectomy and all had been found to have residual disease in the remnant of the greater omentum. Therefore, additional resection of the remnant of the greater omentum was required. The lesser omentum is another important site of peritoneal fluid absorption [19]. To our opinion lesser omentectomy is always required among other peritonectomies in advanced ovarian cancer even if the lesser 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 omentum is not involved. In cases with extensive peritoneal involvement resection of various organs is mandatory: splenectomy, segmental intestinal resection, partial or sub-total colectomy if the entire large bowel is involved, antrectomy, sub-total gastrectomy or even total gastrectomy may be required if the stomach is involved [201]. Complex surgery that involves all abdominal regions in cancer patients carries a high morbidity rate. The extent of peritoneal carcinomatosis among other indicators has been shown to be a significant prognostic factor for postoperative morbidity and in-hospital mortality [20-2]. In our study morbidity was found to be strongly related to PCI and this should be distinctly disclosed to all patients. Usually a high PCI means that more organ resections should be performed. Although not yet statistically evident, it is our belief that a deliberate use of temporary or permanent stomas may decrease the overall morbidity. Mortality is a consequence of high morbidity rate and is more often related to surgical septic complications [22]. Overtreatment of very sick patients leads to the conclusion that the combination of HIPEC and EPIC increases postoperative mortality. Even if complete cytoreduction has been achieved and no macroscopically visible tumor has been left behind, microscopic residual disease always remains in the peritoneal cavity. The eradication of the microscopic residual tumor may be possible with the use of intraperitoneal administration of cytotoxic drugs. However, intraperitoneal chemotherapy is not effective in eradicating residual tumor with diameter > 2.5mm because the cytostatic drugs cannot penetrate deeper than 2.5-3mm. Therefore, patients that underwent CC-2 cytoreduction did not receive perioperative intraperitoneal chemotherapy. The intraperitoneal administration of chemotherapy as first line treatment in ovarian cancer has been studied in a small number of randomized phase III clinical trials. Kirmani has failed to show any difference in response and survival in a trial with limited number of patients randomized to receive intraperitoneal cis-platin and etoposide versus intravenous cis-platin and cylophosphamide [23]. On the other hand, Alberts in a larger trial showed that patients treated with intraperitoneal cis-platin and intravenous cyclophosphamide had significantly improved survival compared to patients treated with intravenous cis-platin and cyclophosphamide [24]. A third randomized trial has shown that intravenous carboplatin followed by intraperitoneal paclitaxel and intravenous cisplatin yielded significant improvement in progression free-survival compared to intravenous cisplatin and paclitaxel [25]. In these studies, the patients received normothermic intraperitoneal chemotherapy. Another trial with a variability in what is described as residual disease failed to demonstrate any benefit for patients receiving intraperitoneal chemotherapy [26]. Armostrong et al. has shown that patients treated with intravenous paclitaxel combined with intraperitoneal cisplatin and paclitaxel had significantly improved survival compared to patients treated with intravenous paclitaxel and cisplatin [27]. A recent French Multicenter study showed that the PCI proved to be the most important prognostic factor of survival. Some irregularities in results may be explained as the effect of the learning curve and the spread of the cases in many centers [28]. In general, it appears that intraperitoneal chemotherapy, when maximal cytoreduction is possible may offer a survival benefit to women with advanced ovarian cancer. Complete or near complete cytoreduction was possible in 86.2% of the patients although half of them had extensive peritoneal carcinomatosis. As a consequence, patients with a high PCI value (>13) should not necessarily be excluded from aggressive cytoreductive surgery; this is also supported by several other studies [5, 28]. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Maximal cytoreduction in combination with HIPEC has until recently been reserved for women undergoing secondary cytoreduction because this approach is considered as salvage treatment for platinum resistant patients or for patients with recurrence. There is evidence that both the overall survival and the disease free survival rate are acceptable when HIPEC is used in treatment naïve patients [8, 11]. However, it is doubtful whether overall survival is significantly increased. Although the analysis of the data shows that HIPEC is a prognostic indicator of survival, and is strongly related to recurrence, HIPEC as upfront treatment has shown a trend to statistical significance, but not strictly significant. A significant prognostic factor of survival that was probably underestimated in the past is the extent of previous surgery which is assessed by the PSS. This implies that the initial cytoreduction is of utmost importance for long-term survival [7, 29]. Bearing in mind that the initial surgical effort is a significant indicator for long-term survival and that the rate of recurrence is still high after standard treatment with maximal cytoreduction, HIPEC may be justified as an adjunct to upfront treatment for advanced ovarian cancer [8, 11]. According to our data, PSS-0 women treated with maximal cytoreduction combined with HIPEC and adjuvant systemic chemotherapy are offered the significant benefit of 62% 5-year survival. A possible systematic error in our, and many other studies, may arise from the quality of information we receive about the completeness of cytoreduction at the time of initial surgery. Presumably, if those patients had a high rate of suboptimal debulking this could overestimate the survival advantage in patients who received upfront combination cytoreduction and HIPEC compared to those who did not. Nevertheless, when complete cytoreduction is achieved upfront, patients get the most out of all possible treatments. It will be very difficult to actually prove in a randomized trial if it is extensive surgery or HIPEC that makes the difference in survival. Complex abdominal surgery, the surgeon’s estimate of what constitutes “operable disease” and what is a “CC-0 operation” will never be factors applicable to proper statistical analysis. 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