World J. Surg. 28, 1040–1045, 2004 DOI: 10.1007/s00268-004-7461-x

WORLD Journal of

SURGERY © 2004 by the Socie´te´ Internationale de Chirurgie

Cytoreductive Surgery and Intraperitoneal Chemohyperthermia for Recurrent Peritoneal Carcinomatosis from Ovarian Cancer Claudio Zanon, M.D.,1 Renzo Clara, M.D.,1 Isabella Chiappino, M.D.,2 Massimiliano Bortolini, M.D.,1 Silvia Cornaglia, M.D.,1 Paolo Simone, M.D.,1 Francesco Bruno, M.D.,1 Leonarda De Riu1 Mario Airoldi, M.D.,1 Fulvia Pedani, M.D.1 1

Department of Oncology, S. Giovanni Battista Antica Sede Hospital, Via Cavour 31, 10100 Torino, Italy Department of Oncology, San Giovanni Battista Hospital, Corso Bramante 88, 10100 Torino, Italy

2

Published Online: September 29, 2004

Abstract. Aggressive surgical cytoreduction has been shown to have a positive impact on survival of patients with ovarian cancer. After first-line chemotherapy, 47% of patients relapse within 5 years, and median survival after second line chemotherapy is 10–15 months. Adding intraperitoneal chemohyperthermia (IPCH) to surgical cytoreduction could further control ceolomic spread of disease. The aim of this study was to determine morbidity and mortality, regional relapse-free survival and, preliminarily, overall survival after combining cytoreductive surgery with IPCH for the treatment of peritoneal carcinomatosis from ovarian epithelial cancer relapsed after prior chemotherapy. Thirty women affected with such a relapse were included. Patients underwent extensive cytoreductive surgery including tumor resections and peritonectomy, followed by intraoperative IPCH with cisplatin. Complete surgical cytoreduction down to nodules less than 2.5 mm (CC0–CC1) was obtained in 23 patients (77%). One patient died postoperatively from a pulmonary embolism. Major postoperative morbidity was 5/30 (16.7%). We registered one case of anastomotic leakage, a spontaneous ileum perforation, a postoperative cholecystitis, a hydrothorax, and one patient with bone marrow toxicity. Kaplan-Meier estimates of median locoregional relapse-free survival and median overall survival were 17.1 months and 28.1 months, respectively. Patients with CC0–CC1 had locoregional relapse-free and overall survival rates of 24.4 and 37.8 months, whereas the remainder had survival rates of 4.1 and 11.0 months. We concluded that cytoreductive surgery combined with IPCH is feasible with acceptable morbidity and mortality and seems to promise good results in selected patients affected with peritoneal carcinomatosis from ovarian cancer.

Ovarian epithelial cancer is the leading cause of death among gynecological malignancies and it is frequently diagnosed at an advanced stage. Current standard therapy for disease confined to the peritoneal cavity consists in cytoreductive surgery whenever possible, followed by systemic platinum- based chemotherapy resulting in 60%–80% complete remission, and an average median survival rate of 35–38 months [1, 2]. However, long-term results are disappointing, as most patients with advanced disease will ultimately relapse. Platinum-sensitive patients who develop recurrence at intervals

Correspondence to: Claudio Zanon, M.D., e-mail: [email protected]

greater than 6 months can further respond to platinum-based salvage treatments, with increasing frequency as the platinum-free interval is increased. But in platinum-refractory patients, chemotherapy results in a low response rate and short survival. Carcinoma of the ovary typically spreads in a diffuse intraabdominal fashion, often limited to the peritoneal cavity, and less frequently it metastasizes via the hematogenous or lymphatic route. Considering this, it would be useful for ovarian cancer treatment to intensify peritoneal therapy and eradicate the locoregional tumor completely. Phase I trials of the intraperitoneal (IP) administration of cisplatin have shown that the drug can be safely delivered by this route with a major increase in exposure (approximately tenfold) of the cavity to the cytotoxic agent and lesser exposure to the systemic compartment [3]. Three consecutive phase III trials have all documented superior overall survival or progression-free survival associated with IP administration of cisplatin in patients with phase III optimally resected disease [4–6]. But long-term IP chemotherapy treatment encounters some difficulties that can outweigh its benefits, mainly the presence of extensive intraperitoneal fibrosis and adhesions resulting from prior surgical interventions, and consequent impaired drug distribution. In theory, if exposure of the peritoneal surface at risk can be guaranteed, combining surgery, with the aim of removing most or all of the macroscopic tumor, and IP chemotherapy can eradicate microscopic residual disease and avoid regrowth of tumor cells in peritoneal carcinomatosis. To achieve this goal, peritoneal washing with antineoplastic agents as part of the surgical procedure has been developed [7]. Mild hyperthermia, in contrast to normothermic treatment, has been shown to have selective cytotoxicity against cancer cells while normal cells recover [8], and it also increases the IP delivered cisplatin concentration to tumor tissues [9]. In addition, mild hyperthermia has been shown to enhance cytotoxicity of cisplatin in animals models [10]. In the surgical setting, adding intraperitoneal chemohyperthermia (IPCH) has been shown to be safe and feasible [11–13]. In this study we aimed to evaluate the results in terms of tolerance and complications, regional relapse-free survival, and, preliminarily, overall survival of a procedure combining cytoreductive

Zanon et al.: Surgery and IHPC for Ovarian Cancer

surgery with IPCH for the treatment of peritoneal carcinomatosis from ovarian cancer relapsed after prior chemotherapy. Patients and Methods This study was an open, prospective, non-randomized, monocentric, phase II study performed at the Center of Surgical Oncology, San Giovanni Battista Antica Sede Hospital, Torino, Italy. The inclusion criteria were age younger than 75 years, histologically confirmed intraoperative peritoneal tumor nodules, a previous histologically or cytologically confirmed diagnosis of ovarian epithelial cancer with peritoneal involvement, and completion of at least a first-line chemotherapy with a platinum-based regimen. Other inclusion criteria were Zubrod performance status grade 2 or less, expected survival of longer than 12 weeks, and adequate liver, kidney, and bone marrow function. The exclusion criteria were extraabdominal metastases; unresectable tumor; chemotherapy within the preceding 4 weeks; serious ongoing infection or comorbidity; pregnancy, breast-feeding, stroke, or myocardial infarction in the 6 months before treatment; and mental confusion causing inability to understand and sign written consent. All participating patients were required to give signed informed consent before entering the study. The pretreatment evaluation consisted of a complete medical history and physical examination, blood counts, blood coagulation tests, chemistry profile with hepatic and renal function test, and computed tomography scans to document disease extent as well as and any other exam indicated by the clinical presentation. At exploratory laparotomy, the Preoperative Peritoneal Cancer Index (PCI) was recorded, according to the staging scheme for peritoneal carcinomatosis [14], as the sum of the lesion size scores for the different abdominal regions. The treatment consisted of extensive cytoreductive surgery and IPCH. Postoperative systemic chemotherapy starting at least 6 weeks after surgery and IPCH was recommended, according to the general status of the patient. Surgical Procedure Careful abdominal exploration was made through a median incision from xyphoid to pubis under general anesthesia and hemodynamic monitoring. In cases of primary intervention (for those patients who had only been treated by prior chemotherapy), hysterectomy, bilateral ovariectomy, omentectomy, and appendectomy were performed following European Organization for Research and Treatment of Cancer (EORT) guidelines. Visceral and parietal adhesions were carefully lysed to allow distribution of the perfusion solution to the whole peritoneal surface. The goal of the surgical procedure was eradication of every tumor with a diameter greater than 2.5 mm. When necessary, total or partial resection of an involved organ was performed. Peritonectomy was performed according to the method of Sugarbaker [15] and adapted to the location of the malignant nodules. In cases of mesenteric implantation, acceptable small bowel resections and/or destruction of nodules by electrosurgical fulguration were used for debulking. For complete staging, standard surgical cytology from peritoneal washing, biopsies in the right and left paracolic and subdiaphragmatic spaces, and retroperitoneal lymph node sampling were always performed. Gastrointestinal anastomoses and other reconstructive proce-

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dures were performed after cytoreductive surgery, and four drains for chemohyperthermic inflow/outflow, and temperature monitoring were positioned (two 27 French tubes, placed in the right and the left diaphragmatic cupola for inflow, one 30 French tube placed in the Douglas pouch for outflow, and one 24 French tube placed in the central abdomen to serve as a peritoneal thermal probe). The abdominal wall was then definitively and completely closed with a single watertight absorbable continuous suture for the peritoneum and the muscular fascia. All surgical procedures were recorded, as were the number and typology of gastrointestinal anastomoses and other reconstructive procedures. The Completeness of Cytoreduction Score following surgery was evaluated as proposed by Sugarbaker: CC0: no residual disease; CC1: residual nodules measuring less than 2.5 mm; CC2: residual nodules measuring between 2.5 mm and 2.5 cm; CC3: residual nodules greater than 2.5 cm [16]. Intraperitoneal Chemohyperthermia Immediately after surgery, IPCH was carried out under general anesthesia and hemodynamic monitoring. Three thermal probes were positioned to monitor peritoneal temperatures: one near the first jejunal loop, the other two outside the abdominal wall, at the inflow and outflow drains. Two further thermal probes were placed, one in the rectal ampulla and the other in the esophagus to monitor core temperatures. The inflow/outflow drains were connected to a closed extracorporeal sterile circuit composed of a biopump and a heat exchanger. The abdomen was perfused with 4–6 L of circulating physiologic solution with an inflow temperature of 44°–46°C and a flow rate of 900–1,200 ml/min. When peritoneal and outflow temperatures reached a thermal plateau of 41.5°C (generally within 20–25 min) cisplatin was infused and circulated for 60 min. The dose of cisplatin was 100 mg/m2 in nine patients, and 150 mg/m2 in the remaining 21 patients, combined with systemic infusion of thiosulfate in 16 of these (9 g/m2 in 1 hr, followed by 12 g/m2 in 6 hr) to avoid renal toxicity. Trendelenburg/anti-Trendelenburg and latero/lateral inclinations of the recumbent patients were changed every 5 min to guarantee perfusion of the entire peritoneal surface. Following the procedure, the abdomen was washed with 3–4 L of physiologic solution at 37°C. Postoperative Work-up and Follow-up During the first postoperative period (minimum 12 hr), patients were transferred to an intensive care unit (ICU). Every patient was carefully monitored for potential complications and/or symptoms due to the disease, cytoreductive/IPCH procedures, or previous treatments. Major complications were defined as life threats, prolonged hospitalization, prolonged recovery in ICU, notable permanent disability, or serious clinical significance, such as pulmonary embolism, sepsis, etc. Any other complication was defined as minor. Each significant toxic reaction and treatment (i.e., surgical reintervention or dialysis) was recorded. Postoperative mortality was defined as death occurring within 30 days. Patients were followed-up at 1 month, and every 6 months thereafter with abdominal CT scans, serum CA125, complete blood cell counts, blood creatinine, bilirubin, transaminases, and any further evaluation indicated by the patient’s clinical presentation.

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Fig. 1. Kaplan-Meier estimate of locoregional relapse-free survival in all patients and CC0–CC1 and CC2 groups.

Statistical Analysis Data were expressed as median and range. Regional relapse-free survival and overall survival were estimated from the date of surgery and IHPC, using the Kaplan-Meier method of analysis and the 95% Andersen confidence interval (CI). Kendall’s rank correlation was used to compare dependence between PCI and CC). Results From January 1998 to September 2003, 30 patients meeting the selection criteria were included in the study. Median age was 60 years (range: 38–73 years). Eight patients had been previously treated with systemic chemotherapy alone, and they underwent hysterectomy, ovariectomy, and omentectomy during the cytoreductive surgery. Of 22 patients who had primary surgery, thirteen had undergone one line of previous systemic chemotherapy and nine had undergone two or more. After surgery 23 patients (77%) had CC0 or CC1 cytoreduction scores (diameter of residual nodes less than 2.5 mm), whereas 7 patients had a CC2 score (residual nodes between 2.5 mm and 2.5 cm). In the latter group, IPCH was performed with palliative intent, considering the prior chemotherapy treatments and the patient’s good performance status. Intraperitoneal and outflow temperatures were maintained between 41.5° and 42.5°C. Mean intraperitoneal temperature was 41.8°C; mean outflow temperature, 42°C. Mean time necessary for reaching the IPCH threshold temperature (41.5°C) was 22 min (range: 13–38 min). Mean IPCH run time was 88 min (range: 78– 103 min). The mean length of the procedure was 410 min (range: 236–541 min). Esophageal and rectal temperatures were maintained under 39.5°C and returned to normal values within 2 hr after IPCH. In one patient systemic temperature was maintained at < 39.5°C by placing ice over the femoral vessels. Circuit flow volume ranged between 900 and 1,200 ml/min. In one case the IPCH was interrupted after 40 min for misperfusion of the solution in the abdominal wall, and in another, after 55 min, for misperfusion in the pleural cavity. In five patients, the circuit was inverted using the

Douglas tube for inflow and the subdiaphragmatic tubes for outflow so as to provide a flow volume greater than 900 ml/min. Postoperative mortality was one patient out of 30 (3.3%). The patient (a 73-year-old woman who underwent splenopancreatectomy, appendectomy, parietal peritonectomy, CC1 cytoreduction, and IPCH with 100 mg/m2 cisplatin) died after discharge on the 30th postoperative day from a massive pulmonary embolism. Major postoperative morbidity was observed in five patients (16.7%). Two patients had complications that required further surgery. The first was a spontaneous ileal perforation in a patient who underwent aortoiliac lymphadenectomy and right subdiaphragmatic peritonectomy without any surgical procedure involving the small intestine. On the fifth postoperative day, the patient underwent a second laparotomy for suturing the ileal perforation and washing the peritoneal cavity. She was discharged on the 19th postoperative day. The second patient requiring further surgery underwent a cholecystectomy on the eighth postoperative day because of postoperative acalculus cholecystitis. Only one case of anastomotic leakage was observed (laterolateral ileocolic anastomosis), that was resolved by positioning a percutaneous computed tomography-guided drain. A fourth patient, who underwent right diaphragmatic peritonectomy, needed placement of a thoracic tube to drain a massive pleural effusion from leakage of perfusate into the pleural cavity. Finally, bone marrow toxicity (platelets 34,000 on the eighth postoperative day) prolonged the ICU stay of one heavily pretreated patient. Minor complications occurred in eight patients (27%). We registered two cases of transient polyuria, four cases of prolonged postoperative ileus that required use of a nasogastric tube for more than 4 days, and one case of transient white blood cell decrease. Both cases of renal toxicity occurred in patients who did not receive thiosulfate infusion. Median postoperative hospitalization was 12 days (range: 7–29 days). After a mean follow-up of 18.9 months (range: 2.0–68.2 months), median regional relapse-free survival was 17.1 months (95% CI: 11.0–23.2, Fig. 1). Median overall survival estimated by the KaplanMeier curve was 28.1 months (95% CI: 21.4–34.7, Fig. 2), with a

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Fig. 2. Kaplan-Meier estimate of overall survival in all patients and CC0–CC1 and CC2 groups.

60% 2-year survival. Patients with CC0–CC1 scores had regional relapse free survival and overall survival respectively of 24.4 months (95% CI 21.2–27.5) and 37.8 months (95% CI 29.4–46.1); for the CC2 group these were 4.1 months (95% CI 2.8–5.4) and 11.0 months (95% CI 2.1–19.9). CC scores were significantly related (p < 0.01) to the preoperative PCI. All 17 patients with PCI up to 12 were cytoreduced to CC0–CC1, whereas seven of the 13 patients with PCI greater than 12 could not be satisfactorily treated by cytoreduction (CC2). Discussion Since the 1980s new therapeutic approaches to the treatment of peritoneal carcinomatosis have emerged. Of great interest is the combination of cytoreductive surgery with IPCH, used, with a variety of different devices and techniques, to treat disseminated colorectal cancer and pseudomyxoma peritonei by many teams all over the world [17]. The best results have been achieved in cases with small volume peritoneal carcinomatosis, with aggressive surgery to reduce tumor volume. Smaller residual tumor size after cytoreductive surgery is an important favorable factor in patients with ovarian cancer. A survival benefit has been confirmed in patients with residual tumor diameter not exceeding 1–2 cm, and chiefly if residual tumor mass does not exceed 5 mm [18]. The best results of intraperitoneal chemotherapy and IPCH are achieved if the treatment is combined with cytoreductive surgery [19, 20]. Cytoreductive surgery can remove bulky tumor, whereas IPCH can treat residual microscopic disease. Hyperthermia combined with intraperitoneal administration of antineoplastic agents can, theoretically, increase synergistic activity against cancer cells. At 42°C, hyperthermia is cytotoxic by itself, increasing membrane permeability, inhibiting DNA repair, and promoting macrophagic lysosomal exocytosis with consequent apoptosis [21, 22]. Cancer cells are sensitive to heat because of their chronic hypoxia, which results in a lower pH and abnormal metabolism. Furthermore, increasing temperature to 42°–43°C sensitizes tumor cells to anticancer drugs, enhancing vascular permeability and increasing intracellular drug concentrations. Antineoplastic agents used for IHPC (cisplatin,

mitomycin, 5-fluorouracil) have quite high molecular weights, and can only partially penetrate the peritoneal–plasma barrier, with an intraabdominal drug concentration higher than in the rest of the body. The cytotoxicity of cisplatin in vivo and in vitro is enhanced by hyperthermia. The synergism of simultaneously administered hyperthermia and cisplatin depends on increased cisplatin uptake and cisplatin-DNA adduct formation at 41°C, with no clear further enhancement of toxicity at 43°C. Pharmacokinetic studies of IPCH have shown that the proportion of cisplatin reaching the systemic circulation is only about 20%, with great individual variability [23]. In comparison to cisplatin, other drugs now used in the treatment of ovarian cancer have demonstrated either no synergism with heat, as with carboplatin [24], or sometimes a greater activity but also an enhanced toxicity, as with docetaxel [25]. Various IPCH techniques have been developed either with the open abdomen using peritoneal expanders, or with the temporarily closed abdomen, before completion of gastrointestinal anastomoses and other reconstructive procedures. In the past decade, closed abdomen IPCH procedures after completion of surgical anastomoses have been described with acceptable results and an acceptable level of side effects [12, 13] In this study we recorded an acceptable major morbidity rate. Anastomotic leakage occurred in only one patient out of 16 who had gastrointestinal anastomoses performed, and there was spontaneous closure of the fistula after placement of a percutaneous drain. Prolonged serious postoperative ileum was never observed. The higher rate of such complications reported in other studies of IPCH for gastrointestinal cancer is likely to be related to the intraperitoneal drug infused, such as mitomycin C or 5-fluorouracil, as observed by van der Vange et al. [26]. Moreover, peritonectomy procedures in ovarian carcinomatosis are generally less complicated, because peritoneal implants related to ovarian cancer tend to be less penetrating than those from gastrointestinal cancer. Surgical debulking combined with IPCH with cisplatin seems feasible with acceptable toxicity in patients affected with relapsed ovarian cancer, but it suits only a selected group of patients. Not every patient can take advantage of the more favorable pharmacokinetics and the higher cisplatin-DNA adduct formation resulting from intraperitoneal hyperthermic administration, because plati-

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num adduct formation decreases with distance from the surface of the tumor nodule [27]. The critical point of this approach is cytoreduction down to nodules of less than few millimeters, to allow to hyperthermal intraperitoneal chemotherapy to act. In platinum-refractory patients second-line intravenous chemotherapy results in a low response rate and short survival. Median survival of recurrent epithelial ovarian cancer with second-line chemotherapy is 10–15 months [28, 29]. New antineoplastic agents such as liposomal doxorubicin and topotecan were compared in a randomized trial involving 474 patients with recurrent ovarian cancer [30]. There was about a 20% response rate, with 17 weeks progression-free survival and 60 weeks overall survival. Our study shows this technique to be safe enough to deserve further evaluation in a subset of patients with minimal residual disease after cytoreduction, who could most likely benefit from the advantage of localized chemotherapy. Selection criteria (good general status, acceptable renal and myocardial functions, no extraabdominal metastasis, exclusion of patients with unresectable tumor) may have introduced a selection bias; however, our results are similar to those obtained in other recent studies. Deraco et al. [31] reported a median locoregional relapse-free survival of 21.8 months and a 2-year overall survival of 55% in 27 heavily pretreated ovarian cancer patients, whereas Panteix et al. [23] reported a 3-year overall survival of 37.5% in 16 patients with advanced ovarian cancer. Patients receiving suboptimal surgical debulking (CC2) should not be treated with IPCH, as shown by the poor overall and locoregional progression-free survival registered for ovarian peritoneal carcinomatosis in our study, and by Glehen et al. [32] in the treatment of carcinomatosis from different primary tumors. But overall and locoregional progression-free survival rates of 37.8 and 24.4 months, respectively, in patients who had debulking CC0–CC1, are very promising. An advantage in overall survival seems possible from the combination of aggressive cytoreductive surgery and IPCH in selected pretreated patients affected with relapsed or advanced ovarian cancer. This approach should not replace conventional IV therapy as secondline therapy for ovarian cancer, but its use in light of indications, patient selection criteria, and IPCH techniques for treatment of peritoneal carcimomatosis from ovarian cancer raise the question of standardization, and further studies are needed. Only patients with peritoneal carcinomatosis from relapsed ovarian cancer were entered into this study. However IPCH combined with primary surgery could be useful and deserves evaluation as a combined treatment strategy in a population with a high probability to be platinum-sensitive. Re´sume´. Il a ´ete´ de´montre´ que la cytore´duction agressive pouvait avoir un impacte positif sur la survie des patientes atteintes de cancer de l’ovaire. Apre`s une chimiothe´rapie de premie`re ligne, 47 % des patientes re´cidivent en moins de 5 ans et la survie me´diane apre`s chimiothe´rapie de seconde intention est de 10–15 mois. L’addition a ` la cytore´duction chirurgicale d’une chimiothe´rapie hyperthermique intrape´ritone´ale (CHIP) pourrait ame´liorer le contro ˆle de l’extension pe´ritone´ale de la maladie. Le but de cette ´etude a ´ete´ de de´terminer la morbidite´ et mortalite´, la survie sans re´cidive locore´gionale et, de fac¸on pre´liminaire, la survie globale des patientes ayant eu une chirurgie cytore´ductive combine´e a ` une CHIP pour carcinose pe´ritone´ale conse´cutive a ` un cancer de l’ovaire ´epithe´lial, re´cidive´ apre`s chimiothe´rapie. Trente femmes atteintes d’une telle re´cidive ont ´ete´ incluses. Les patientes ayant eu une chirurgie cytore´ductive ´etendue comprenant une re´section tumorale et une pe´ritonectomie, suivies d’une CHIP a ` base de cis-platine. Une chirurgie de re´duction tumorale enlevant tous les nodules supe´rieurs a ` 2.5 mm (CC0-CC1) a ´ete´ obtenue chez 23 patients (77%). Un patient est de´ce´de´ en post-ope´ratoire d’une embolie

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pulmonaire. La morbidite´ postope´ratoire majeure a ´ete´ de 5/30 (16.7%). Nous avons note´ une fistule anastomotique, une perforation ile´ale spontane´e, un cas de chole´cystite postope´ratoire, un cas d’hydrothorax et un cas de toxicite´ de la moelle osseuse. La survie sans re´cidive locore´gionale et la me´diane de survie globale selon Kaplan-Meier ont ´ete´, respectivement, de 17.1 et de 28.1 mois. La survie sans re´cidive locore´gionale et globale des patients ayant eu une CC0-CC1 ont ´ete´, respectivement, de 24.4 et de 37.8 mois, alors que celle des autres ont ´ete´, respectivement, de 4.1 et de 11.0 mois. En conclusion, la chirurgie de re´duction tumorale combine´ a ` la CHIP est faisable avec une morbidite´ et une mortalite´ acceptables. Elle pourrait fournir de bons re´sultats chez certaines patientes atteintes de carcinose pe´ritone´ale provenant d’un cancer d’origine ovarienne. Resumen. La citorreduccio ´n quiru ´rgica agresiva ha demostrado tener un impacto positivo sobre la supervivencia de pacientes con ca ´ncer ova ´rico. Luego de quimioterapia de primera lı´nea, 47% de las pacientes hacen relapso en los primeros cinco an ˜ os y la media de supervivencia luego de quimioterapia de segunda lı´nea es de 10–15 meses. La adicio´n de quimiohipertermia intraperitoneal (QHIP) a la citorreduccio ´n puede ayudar en el control ulterior de la extensio ´n celo ´mica de la enfermedad. El propo ´sito del presente estudio fue determinar la morbilidad y mortalidad, la supervivencia libre de relapso regional y, preliminarmente, la supervivencia global luego de la combinacio´n de cirugı´a citorreductora con QHIP en el tratamiento de la carcinomatosis peritoneal por ca ´ncer epitelial del ovario recurrente luego de quimioterapia previa. Treinta mujeres que padecı´an tal relapso fueron incluidas en el grupo de estudio. Estas pacientes fueron sometidas a extensa cirugı´a citorreductora incluyendo resecciones tumorales y peritoneoectomı´a seguida de QHIP intraoperatoria con cisplatino. Se logro ´ una citorreduccio ´n completa hasta no ´dulos menores de 2.5mm (CC0-CC1) en 23 pacientes (77%). Una paciente murio´ en el postoperatorio por embolismo pulmonar. La morbilidad postoperatoria mayor fue 5/30 (16.7%). Registramos una fuga anastomo ´tica, una perforacio ´n esponta ´nea del ´leon, ı una colecistitis postoperatoria, un hidroto´rax y un caso de toxicidad de me´dula o ´sea. Las estimaciones de Kaplan-Meier de la media de supervivencia libre de relapso local-regional y de la media de supervivencia global fueron 17.1 y 28.1 meses. Las pacientes con CC0-CC1 exhibieron supervivencias libres de relapso local-regional y global de 24.4 y 37.8 meses, respectivamente, en tanto que las restantes exhibieron 4.1 y 11.0 meses. Nuestra conclusio ´n es que la cirugı´a citorreductora combinada con QHIP es factible con morbilidad y mortalidad aceptables y que parece ser promisoria de buenos resultados en pacientes seleccionadas que padezcan carcinomatosis peritoneal por ca ´ncer ova ´rico.

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