5th International Workshop on Peritoneal Surface Malignacy

Epithelial ovarian cancer (EOC) is a clinically important health problem in Western countries, ranking fifth highest in incidence and fourth highest in site-specific causes of cancer deaths in women. In spite of the progress in surgical techniques and chemotherapy using platinum alone or platinum/taxane combination, the long-term survival rates remain poor and median survival is in the order of 36 months for advanced cases ([1]).

The conventional clinical approach for advanced (stage III/IV) EOC is based on cytoreductive surgery (CRS) followed by systemic chemotherapy. The initial relatively good responsiveness to chemotherapy is well known. Clinical studies have shown that cisplatin and/or taxol-based first-line chemotherapy allows the achievement of response rates of about 70-80%, with a significant proportion of complete responses ([2]). However, negative second-look laparotomy does not necessarily mean the patient is cured. Unfortunately a considerable percentage of these patients relapse and ultimately dye of chemoresistant disease.

1.1. Cytoreduction

A recent meta-analysis ([3]) has confirmed that maximal cytoreduction is one of the most powerful determinants of cohort survival in stage III-IV EOC.

However some authors challenge the independent influence of cytoreduction on final outcome arguing that complete cytoreduction in most cases is possible thanks to relatively small tumour burdens and presumed diminished tumour aggressiveness rather than to maximal surgical effort ([4],[5]). Some studies have shown differences in survival between patients who are already optimal at the beginning of operation and the ones who are optimal as a result of the first operation (5,[6]). According to Hoskins et al. the initial CRS would not allow a patient presenting with large volume tumor to have the same chance for survival as a patient found to have small-volume disease (4). On the other hand, Le et al did not find a significant difference between patients with initial microscopic disease and patients with large volume of disease at the time of exploration and tumour reduced to microscopic residuals ([7]).

Another criticism raised against cytoreduction is that it can only benefit a small proportion of patients. In fact, the rate of optimal cytoreduction has ranged from 25% to 40%, according to current literature (4,[8],[9],[10],[11]). Thus, ultra radical procedure has been proposed by some surgeons achieving a rate of optimal cytoreduction as high as 91% (5,[12],[13],[14],[15],[16]).

Whether maximal surgical effort could outweigh the inherent biological aggressiveness of the tumour to produce a favourable impact on the final outcome of patients is also a matter of heated debate in the literature. The extent of surgery has a direct and significant impact on the mortality and morbidity associated with the cytoreductive surgery.([17],[18],[19],[20])

Eisenkop et al evaluated 213 stage III EOC patients submitted to cytoreduction using procedures such as extrapelvic bowel resection, diaphragm stripping, full-thickness diaphragm resection, modified posterior pelvic exenteration, peritoneal implant ablation and/or aspiration, and excision of grossly involved retroperitoneal lymph nodes ([21]). They verified that survival was independently influenced only by the extent of peritoneal carcinomatosis that required removal. The necessity to use the above mentioned procedures as well as type of adjuvant chemotherapy did not impact the final outcome. The authors concluded that need to resect a widespread peritoneal carcinomatosis correlates with biological aggressiveness and diminished survival, but not significantly enough to justify abbreviation of the operative effort.

More recently, Eisenhauer et al. retrospectively reviewed the records of all patients with stages IIIC-IV EOC who underwent primary surgery. The cohort was divided into 3 groups. Group 1 patients required extensive upper abdominal surgery, such as diaphragm peritonectomy/resection, resection of parenchymal liver or porta hepatis disease and/or splenectomy with or without distal pancreatectomy, to achieve optimal cytoreduction (residual disease </=1 cm). Group 2 patients were optimally cytoreduced by standard surgical techniques, including hysterectomy, oophorectomy, omentectomy, and bowel resection. Group 3 patients were suboptimally cytoreduced. They concluded that patients requiring extensive upper abdominal procedures to achieve optimal cytoreduction demonstrated a similar initial response, progression-free survival, and overall survival to patients optimally cytoreduced by standard surgical techniques. The presence of bulky upper abdominal disease alone did not appear to indicate poor tumor biology. This initial maximal surgical effort was associated with improved survival in patients who would have otherwise been suboptimally cytoreduced.([22])

1.2. Secondary Cytoreduction

About 50% of the patients with EOC present residual disease after first line chemotherapy due to partial or no response. On the other hand, up to 47% of complete responders to first line chemotherapy relapse within 5 years and the disease-free survival does not generally exceed 18 months ([23],[24]).

Thus, several alternatives have been proposed as second line treatments. One of them is the surgical approach. However, the value of secondary cytoreduction has not been clearly defined. When performed at the moment of second look, the majority of studies, which are not randomized ([25],[26],[27],[28]) demonstrate some survival advantage for patients who can be cytoreduced to microscopic or small macroscopic residual disease. When the second look operation is performed and residual tumor is detected, it seems advisable to remove all macroscopic disease if technically feasible.

According to a retrospective review of the literature, optimal cytoreduction was achievable in 38-87% of the relapsing cases with acceptable perioperative morbidity and mortality. Unfortunately there is not yet randomized evidence supporting the use of secondary CRS as salvage therapy in EOC. Current data suggest that patients left with no gross residual disease after secondary cytoreduction seem to benefit from prolonged survival in the range of 44-60 months. ([29]) The actual evidence suggests that the removal of all recurrent macroscopic disease should be accomplished if technically feasible, particularly in patients with a disease-free interval of more than 12 months, platinum-sensitive tumours, and absence of ascites.([30]) In patients with platinum-sensitive tumour the following variables were proven to be independent prognostic factors on multivariate analysis: disease-free interval, the number of recurrence sites, and residual disease.([31])

1.3. Systemic second line therapies

During the last decade, several new drugs have been shown to present some activity in second line therapy. Paclitaxel, pegylated liposomal doxorubicin, topotecan, docetaxel, gemcitabine, oxaliplatin, vinorelbine, and ET-743 have been joined to more ‘classical’ drugs like carboplatin, cisplatin, epirubicin, ifosfamide, altretamine, or oral etoposide. Despite the growing number of randomized trials addressing second line treatments for EOC no drug, alone or in combination, has been elected as the best one. The management of recurrent disease constitutes a complex decision making process which requires the consideration of several parameters such as the platinum sensitivity and treatment free interval. The available data show overall response rates for the above chemotherapies ranging from 3.3 to 16% with median OS of 35 to 41 weeks in the subset of patients with platinum refractory EOC. ([32],[33]) (Table 1)

1.4. Secondary cytoreduction or second line systemic chemotherapy?

Gungor et al. ([34]) reported on 75 patients with EOC from which 44 had salvage surgery and 31 patients had salvage chemotherapy alone for the treatment of gross recurrent disease. All patients had been clinically free of disease more than 6 months from the completion of primary treatment. Survival was significantly longer in patients who had salvage surgery compared to those who had salvage chemotherapy alone (P = 0.03). The authors concluded that patients with recurrent EOC may benefit in terms of outcome from a salvage surgical cytoreduction specially if macroscopically complete.

The EORTC (Protocol# 55963) is conducting a randomized trial to provide more conclusive data to the management of recurrent EOC. The inclusion criteria for this trial are disease recurrence, after a minimum of three cycles of primary chemotherapy and a disease-free interval ≥12 months. Patients are randomized to either 6 cycles of single-agent platinum (carboplatin or cisplatin) or 3 cycles of the same chemotherapy, followed by surgical exploration and 3 more cycles of chemotherapy. They are stratified by initial stage, progression-free survival (<24 vs. >24 months), initial response to primary therapy, and tumor burden. Anticipated accrual is 700 patients and survival is the primary endpoint.

In summary, the standard treatment strategy for patients with relapsing or persistent EOC after completion of upfront first line chemotherapy has not been clearly defined yet.

2. Regional treatment approach for EOC

2.1. Intraperitoneal chemotherapy under normothermic condition

The rationale for regional treatment approach for EOC, is based on the natural history of this clinical entity that remains confined in the peritoneal cavity for most of its natural history. This pattern of spread would seem to indicate the potential usefulness of selectively increasing drug concentration in the tumour-bearing area by direct intraperitoneal chemotherapy instillation [35].

A large intergroup trial randomized 546 optimally cytoreduced stage III patients with EOC to intraperitoneal cisplatin plus intravenous cyclophosphamide or intravenous cisplatin plus intravenous cyclophosphamide [36]. Intraperitoneal therapy was associated with a significantly improved median survival (49 versus 41 months) and fewer toxic side effects.

In a subsequent Gynecologic Oncology Group trial, 523 patients were randomized to intravenous cisplatin/paclitaxel or high-dose carboplatin followed by intraperitoneal cisplatin plus intravenous paclitaxel. The preliminary results demonstrated a significant increase in recurrence-free interval (28 versus 22 months), without the same favourable impact on overall survival. [37]

The most recent randomized study, GOG-172, reported a median survival of 66 months for patients on the IP arm versus 50 months for patients who received IV administration of cisplatin and paclitaxel
(P=.0338) Toxic effects were greater in the IP arm, contributed to in large part by the cisplatin dose per cycle (100 mg/m2) and by sensory neuropathy from the additional IP as well as from the IV administration of paclitaxel. Completion of 6 cycles of treatment was also lower in the IP arm (42% vs. 83%) because of the toxic effects.

Notwithstanding these problems, IP therapy for patients with optimally debulked EOC is receiving wider adoption, and efforts are underway by the GOG to examine some modifications of the IP regimen used in GOG-172 to improve its tolerability (e.g., to reduce by at least 25% the total amount of cisplatin given and shift from the less practical 24-hour IV administration of paclitaxel to a 3-hour IV administration). A clinical alert was issued by the National Cancer Institute so physicians not familiar with the technique may refer patients to appropriate centers.([38]) (table 1)

2.2. Cytoreductive Surgery (peritonectomy procedure) and Hyperthermic intraperitoneal chemotherapy for epithelial ovarian cancer: rationale

The intraperitoneal chemotherapy under normothermia was generally judged to create more logistical problems than survival benefit. Poor drug distribution from surgical adhesions, inadequate drug penetration into tumor nodules or tumor entrapped in scar tissue, and repeated failures with long-term peritoneal access have led to this conclusion.

Thus a new multimodality treatment approach comprising cytoreductive surgery (CRS) and Hyperthermic intraperitoneal chemotherapy (HIPEC) was conceived in order to overcome these drawbacks. Using intraperitoneal chemotherapy as a planned part of a cytoreduction for carcinomatosis, these logistical problems may no longer occur. All adhesions are taken down and scar tissue is resected, visible cancer nodules are resected. The intraperitoneal chemotherapy is required to eradicate microscopic residual disease, however it should be performed under hyperthermic perfusion.

The rationale for the use of hyperthermia is multifactorial. Hyperthermia itself has a direct cytotoxic effect caused by denaturation of proteins, induction of heat-shock proteins which may serve as receptors for natural killer-cells, induction of apoptosis and inhibition of angiogenesis ([39],[40],[41]). The biophysical effects of hyperthermia also include alterations in multimolecular complexes such as the insulin receptor [42] and in the cytoskeleton [43], and changes in enzyme complexes for DNA synthesis and repair [44]. Moreover, the architecture of the vasculature in solid tumours is chaotic, resulting in regions with low pH, hypoxia and low glucose level [45]. This susceptible microenvironment renders solid tumors more sensitive to hyperthermia. In addition hyperthermia also acts in synergism with chemotherapies such as mitomycin C, cisplatin, mitroxantrone, taxanes and doxorubicin. Increased cell-membrane permeability at higher temperatures, can increase drug uptake by tumour tissue [46]. Pharmacokinetics of these drugs can also be affected by altered active drug transport and cell metabolism. Furthermore, at 40-42°C, neoplastic cells become more chemosensitive due to an increase in the intracellular concentration of drugs and in their activation process, especially for alkylating agents, and to alterations in the DNA repair process ([47],[48]). It has been demonstrated that the formation of platinum-DNA adducts after cisplatin exposure in hyperthermic conditions is enhanced and/or adduct removal is decreased in heated cells, resulting in relatively higher DNA damage ([49],[50]). Besides this synergistic effect hyperthermia can also diminish the systemic toxicity of some drugs (e.g. doxorubicin and cyclophosphamide) by increasing their alkylation and/or excretion [51].

2.2.1. Eligibility

The eligibility for the procedure includes the following aspects: the patient’s general clinical status, resectability of the tumor, impact on prognosis, risk of morbidity and mortality.

2.2.1.1. General clinical condition:

Performance status<2;

Good liver, renal, bone marrow, and cardiovascular function;

Absence of severe co-morbidity.

2.2.1.2. Concerning the prognostic factors see section 2.2.7

2.2.1.3. Concerning the morbidity and mortality due to the procedure see section 2.2.8. Unfortunately the high risk groups for the emergence of severe complications have not been identified in the literature.

2.2.1.4. Resectability of the tumor.

The most frequent factors associated with non resectable tumor are: [52]

peritoneum implants greater than 2 cm in maximum diameter in the porta hepatis, intersegmental fissure, gall bladder fossa, subphrenic space, gastrohepatic ligament, gastrosplenic ligament, lesser sac, or root of the small bowel mesentery;
retroperitoneal adenopathy greater than 2 cm in maximum diameter above the renal hila;
hepatic metastases, or abdominal wall invasion.

2.2.2.Technique of CRS+HIPEC

2.2.2.1 Peritonectomy procedure

The peritonectomy procedure described by Sugarbaker is adopted [53]. The surgical procedure starts with a xyphopubic, midline incision, and the successive layers of abdominal wall are dissected until the parietal peritoneum is visualized. Then, the dissection of parietal peritoneum from the abdominal wall starts without opening the peritoneal cavity and continues until the identification of major retroperitoneal structures such as lower segment of aorta, vena cava, the iliac arteries/veins and the ureters. The parietal peritoneum is then incised and full access to the abdominal cavity is achieved through the use of a Thompson self-retaining retractor. A ball-tip electrosurgical handpiece is used to dissect the tumour on peritoneal and visceral surfaces from normal tissue [54]. The electrosurgery is used on pure cut at high voltage.

Each procedure that composes the peritonectomy technique has a definite resection that requires an orderly sequence of surgical maneuvers. One or more of the following steps can be performed depending on the previously performed surgical procedures or disease extension at the time of laparotomy: 1) infragastric resection of great omentum, right parietal peritonectomy and right colon resection; 2) left upper quadrant peritonectomy, splenectomy and left parietal peritonectomy; 3) right upper quadrant peritonectomy and Glisson’s capsule resection; 4) lesser omentectomy, cholecystectomy, stripping of omental bursa +/- antrectomy; 5) pelvic peritonectomy with sigmoid colon resection +/- hysterectomy + bilateral salpingo-oophorectomy if still present; 6) other intestinal resection and/or abdominal mass resection.

Some considerations are worth discussing. The oncological principle of en bloc resection should be followed especially in cases requiring resection of pelvic viscera (rectosigmoid +/- genital tract) along with the pelvic peritoneum (16,[55]). The dissection of the pelvic peritoneum starts on the right and left sides of the bladder. The apex of the bladder is maintained on strong traction with clamps. Broad traction on the entire anterior parietal peritoneal surface and frequent saline irrigation reveals the cleavage plain that is precisely located between the bladder musculature and its adherent fatty tissue. The peritoneum with the underlying fatty tissue are stripped away from the surface of the bladder down to the uterine cervix. The stripping of the peritoneum continues in a centripetal fashion in the rest of the pelvis. Attention must be paid in the lateral aspects of the bladder near to its base, where we can localize the ureters. Sometimes a dissection of the ureters from the parametrium is required to assure a better visualization of their entry point into the bladder. The uterine arteries are ligated extraperitoneally, just above the ureter and close to the base of the bladder. The bladder is moved gently off the cervix and the vagina is entered. The vaginal cuff anterior and posterior to the cervix is transacted, and the rectovaginal septum is entered. A linear stapler is used to divide the sigmoid colon at the junction of sigmoid and descending colon or just above the limits of the pelvic tumor. The vascular supply of the distal portion of the bowel is traced back to its origin on the aorta. The inferior mesenteric artery and vein are ligated, sutured, and divided. Ball tipped electrosurgery is used to divide the perirectal fat beneath the peritoneal reflection. This ensures that all tumours that occupy the cul-de-sac are removed intact with the specimen. The rectal musculature is skeletonized and the lower half of the rectum is preserved. A roticular stapler is used to close off the rectal stump and the rectum is sharply divided above the stapler.

2.2.2.2 Limits of radicality: residual disease

The concept of optimal residual disease in EOC was elaborated with the GOG protocol 97, published in the middle of last decade.[56] From the 458 stage III and stage IV patients who participated in this randomized study, 294 stage III patients selected to a separate analysis to define what is optimal cytoreduction. Multivariate analysis revealed a relative risk of dying as follows: residual disease < 2 cm, relative risk 1.00; 2 to 2.9 cm, relative risk 1.90; 3 to 3.9 cm, relative risk 1.91; 4 to 5.9 cm, relative risk 1.74; 6 to 7.9 cm, relative risk 1.85; 8 to 9.9 cm, relative risk 2.16; > or = 10 cm, relative risk 1.82. The difference in survival between those with < 2 cm residual disease and those with > or = 2 cm residual disease was significant (p < 0.01). There was no significant difference in the risk of dying between groups with residual disease > or = 2 cm.

Currently, there is no universally accepted definition of “optimal” cytoreduction among gynaecologic oncologists. A survey of the Society of Gynecologic Oncologists (SGO) in 2000 revealed 12.0% to think of removing all visible disease as “optimal”, 13.7% use a 0.5 cm residual disease threshold, 60.8% a 1 cm threshold, 3.6% a 1.5 cm threshold, 8.7% a 2.0 cm threshold and 1.3% use other criteria such as the total estimated weight and/or volume of residual disease.[59]

With the advent of local-regional therapy (CRS+HIPEC) for the treatment of peritoneal surface malignancies, narrower limits of radicality have been established based on experimental and clinical evidences. The surgical effort should aim for a cytoreduction down to nodules less than 2.5 mm and not the traditional cut-off of 2 cm. The rationale for this new concept is that the depth of maximum tumor penetration of Cisplatin used for HIPEC is no more than 2.5 mm. [58]

Some points are worth discussing. The intratumoral penetration ability varies according to the chemotherapy. Drugs such as doxorubicin, carboplatin and oxaliplatin have much lower intratumoral penetration capacity. Moreover, the EOCs present a remarkably better chemo sensitivity with respect to other peritoneal surface malignancies. Their complete response to systemic chemotherapy is also frequently seen with intraperitoneal chemotherapy solutions or a bidirectional (intraperitoneal combined with intravenous chemotherapy) approach. All these situations show that “completeness of cytoreduction” is a dynamic concept and that the definition of “complete cytoreduction” might need to be reconsidered according to the clinical circumstance, disease process and chemotherapies being used. Further experimental and clinical studies are required to clarify the optimal limits of cytoreduction in the context of local-regional regional treatment of EOC.

Regarding the residual disease classification system an agreement was achieved by the Methodological consensus statement conducted before the 5th International Workshop on peritoneal surface malignancy that the Sugarbaker criteria ([59]) could be the most suitable one: cc-0: no residual disease; cc-1: minimal residual disease: 0-2.5mm; cc-2: residual disease 2.5mm-2.5 cm; cc-3: residual disease >2.5cm.

2.2.2.3 Hyperthermic intraperitoneal chemotherapy (HIPEC)

2.2.2.3.1 The device

HIPEC requires the employment of a lung-heart machine, comprised by a roller pump, a thermostat, a heat exchanger and an extra-corporeal circuit. The perfusate flow-rate is controlled and the heat exchanger adjusts the temperature of perfusate, by circulating water at a desired temperature in the arterial phase of circuit. The extra-corporeal circuit consists of interconnected tubes which has: a) an input section (inflow); b) an output section (outflow); c) an axis of rapid filling up; d) a central body connected with a filter; e) a deflow section; f) a series of multiperforated catheters in their extremities. The device should be approved by C.E accreditation.

2.2.2.3.2. The perfusate, modalities of HIPEC, optimal temperature level

Technical variations regarding the type of perfusate, modality of perfusion (open, closed abdomen), and optimal temperature level do not seem to influence the results of the procedure in the circumstance of EOC local-regional treatment both in terms of morbidity or outcome. An agreement has been recently attained with respect to these issues among the International experts on local-regional therapy during the Methodological consensus statement. The results will be presented in the 5th International Workshop on Peritoneal Surface Malignancy (Milan December 2006).

2.2.2.2.3. Optimal drug combination

Various drug combinations for EOC have been tested by experimental and phase I/II clinical studies: cisplatin alone ([60],[61]), carboplatin alone [62], mitoxantrone alone[63], paclitaxel alone [64], cisplatin+doxorubicin [65], docetaxel [66, carboplatin+Interferon-α [62], The criteria for choosing the ideal combination should be based on the pharmacokinetic profile of drugs, tumour chemo sensitivity and toxicity. Ideally the drug must be water-soluble and of high molecular weight in order to guarantee a low peritoneal clearance. This, combined with a high systemic clearance, will result in pharmacological advantage expressed by a higher exposure of tumour to the agent (high AUCpe/AUCpl ratio). For intraperitoneal therapy to be oncologically effective, the drug must have a good tumor penetration ability. Moreover, the influence of temperature in the cytotoxicity should also be of concern, so that the higher the cell killing capacity of the drug due to the hyperthermia the better. Finally, non cell-cycle specific drugs are preferred because they are cytotoxic after even a relatively short exposure time.

Since its advent, cisplatin has become the most widely used agent in the systemic treatment of EOC with the response rate of 50%. When cisplatin was employed intraperitoneally, in the treatment of EOC, a comparable distinctive antiblastic effect was shown. Cisplatin has a high AUCpe/AUCpl ratio, as compared to other cytostatic drugs, a deep tumour penetration ability and partial response rate of up to 65% in normothermic conditions [68].

Another eligible agent for HIPEC is carboplatin. Despite a better therapeutic index than cisplatin, with substantially less renal toxicity, nausea and neurotoxicity, carboplatin does not have as favourable a pharmacokinetic profile as cisplatin [62]. In fact, the AUCpe/AUCpl ratio, tumour penetration capacity and response rate are markedly lower ([70],[71]).

Doxorubicin has one of the highest AUCpe/AUCpl ratio of about 80 ([72],[73]). Irrespective of its limited tumour diffusion ability (not more than several cell layers) a response rate of 30% was reported when doxorubicin was administered intraperitoneally, under normothermic conditions [74]. The dose-limiting toxicity,
chemically-induced peritonitis, makes doxorubicin feasible for HIPEC only at very low dose.

Oxaliplatin [75], gemcitabine[76] and docetaxel (66) are also promising for HIPEC in the treatment of EOC. However, since they are still under experimental or have not been tested in phase II clinical investigations, they should be further investigated before been evaluated in a prospective phase III trial.

In summary, the best chemotherapy combination for HIPEC for patients with EOC is still to be defined. In table 2 the main pharmacokinetics characteristics of the drugs fro HIPEC already tested in EOC are outlined.

2.2.3. Literature data on CRS+HIPEC in the treatment of EOC

Many centers worldwide have initiated regional therapy programs for carcinomatosis secondary to EOC (Table 3) assuming the promising results obtained by phase II and III trials testing the combined approach of CRS+HIPEC in other types of cancer.

In the experience of NCI of Milan 40 patients [77] with pathologically confirmed advanced EOC were treated by CRS and HIPEC. Median follow up 26.1 months (range: 0.3-117.6). Thirteen patients were treated in a second look setting and 27 in a salvage setting. The median number of systemic chemotherapy lines was 2 (range: 1-5) which consisted of cisplatin based, taxol based or taxol/platinum containing regimens. The HIPEC was performed with the closed abdomen technique, with cisplatin (25mg/m2/l) + Mitomycin-C (3.3mg/m2/l) or Cisplatin (43.0 mg/l of perfusate) and Adriamycin (15.25 mg/l of perfusate). After the CRS, 33 (83%) patients presented no macroscopic residual disease. Five-year overall survival (OS) was 15%; the mean overall and progression-free survivals were 41.4 and 23.9 months, respectively. Three variables were shown to be of prognostic significance: completeness of cytoreduction, WHO performance status and extent of carcinomatosis. The treatment-related morbidity was 5%. Six (15%) patients presented mild acute toxicity. There was no treatment-related mortality.

Hager et al. in 2001 [78] conducted a prospective clinical trial on 36 patients with EOC treated by CRS+HIPEC. Median OS time from the first HIPEC chemotherapy treatment was 19 +/- 4 months. The 5-year OS rate of all patients from the start of the first HIPEC was 16 +/- 7%. The complications were mild especially compared to systemic chemotherapy. In 3 out of 162 treatments clinical ileus were observed.

Piso et al. [79] reported on 19 patients with EOC (11 recurrent and 8 primary). Intraperitoneal chemotherapy consisted of either cisplatin or mitoxantrone. Complete cytoreduction < 2 mm was achieved in 9 patients. A 5-year survival rate of 15% was reported despite a total of 9 patients with concomitant liver metastases. Survival was the same for both primary and recurrent cases.

Zanon et al. treated 30 patients affected with a relapsing EOC [80]. Patients underwent CRS followed by intraoperative HIPEC with cisplatin. Complete cytoreduction down to (CC0-CC1) was obtained in 23 patients (77%). One patient died postoperatively from a pulmonary embolism. Major postoperative morbidity was 5/30 (16.7%). Complications were one case of anastomotic leakage, a spontaneous ileum perforation, a postoperative cholecystitis, a hydrothorax, and one patient with bone marrow toxicity. Median locoregional relapse-free survival and median overall survival were 17.1 months and 28.1 months, respectively.

Ryu et al. (67) published a retrospective series on ovarian cancer patients treated by CRS with or without HIPEC consisting of carboplatin and interferon-α. All patients had undergone in the past the primary standard staging procedure for ovarian cancer. A total of 117 patients were reviewed and 74 of them had stage III disease. For this subgroup of patients, the median survival was 60.9 months for the 35 patients receiving both CRS and HIPEC compared with only 22.3 months for patients in the CRS only group (P =.0015). Five-year OS was 53.8% for the former and 33.3% for the latter. As for the 5-year disease-free survival it reached 26.9% for the former and 10.3% for the latter (P = .0070). The use of HIPEC was shown to be a positive independent prognostic factor along with residual disease < 1 cm. The originality of this report relates to the intraperitoneal administration on interferon-α. This immunotherapy was not associated with a higher complications rate than after conventional chemotherapy administered intraperitoneally. The inclusion of patients with histological subtype different from the epithelial (which is characterized by a better prognosis) and early staged disease could account for the best results in terms of survival rate among the authors of the literature.

Gori J et al., [81] investigated the effect of HIPEC as consolidation therapy in stage III EOC, following CRS and systemic chemotherapy (cisplatin-cyclophosphamide). In a multicenter prospective trial, 29 patients with complete or optimal CRS and systemic treatment were included in the consolidation group and received HIPEC which was performed with open-abdomen technique, using cisplatin 100 mg/m2, for 60 min. Disease-free survival, overall survival, and side effects were compared with a control group of patients who refused a second-look surgery and intraperitoneal chemotherapy. The consolidation therapy group showed a better 5-year survival rate and lower recurrent disease rate, but differences were not statistically significant.

Rufian et al. conducted a retrospective study on a series of 33 patients diagnosed of peritoneal carcinomatosis for epithelial EOC (stage III). They were submitted to radical surgery-peritonectomy and HIPEC with paclitaxel was included in this study; 19 primary EOC and 14 recurrent EOC. The 5 yr OS rates were 37% and 51% for primary and recurrent patients, respectively. Cytoreduction R0 (P = 0.018) and negative lymph nodes (P = 0.005) were variables for major prognostic survival. Patients with optimal cytoreduction R0 obtained survival rates of 63% at 5 years in recurrent EOC and 60% in primary EOC, 71% and 63%, respectively with associated subtotal infra-abdominal peritonectomy, and even better results if negative lymph nodes.

It is hard to ascertain to which extent this apparent promising survival rates (5yr OS ranging from 16% to 64%) reported by clinical studies resulted from individual physicians selection bias.

2.2.4. The advisable timing for CRS+HIPEC performance

In the table 4, the same trials on CRS+HIPEC in EOC are outlined with details regarding the study design and the timing in which the procedure were performed. The definition of the advisable circumstance of the disease for CRS+HIPEC performance (front line, interval surgery, consolidation, at time of second-look surgery, recurrent, etc) is problematic based on the current available data. The studies were conducted on inadequately sized and heterogeneous populations, characterized by different staged diseases (early and advanced), at different time-points in the natural history of the entity (primary and recurrent), with the inclusion sometimes of histological subtypes other than the epithelial one. Moreover, the authors do not make a clear distinction between platinum sensitive and resistant tumours and the majority of the authors rarely reported results for each subsets described above. The evidence supporting the application of the procedure is Type R as front line therapy and as interval surgery. While for diseases partially responsive to first line therapy and recurrence the level of evidence is Type 3.

2.2.5. Attempt for Phase III protocol

In order to confirm the apparently encouraging results provided by the growing number of phase II studies, the SITILO (Italian Society of integrated locoregional therapy) is conducting a prospective multicentric randomized study to test the effectiveness of secondary CRS associated with HIPEC in patients with cisplatin resistant advanced EOC ([82]). Patients with EOC stage III/IV, submitted to surgical staging and 6 courses of first-line platinum based chemotherapy, and with persistent but clinically resectable disease, or early relapsing tumours (< 6 months after the completion of first line chemotherapy) is randomly allocated to one of these treatment groups: 1) Study group: secondary CRS and HIPEC followed by second line chemotherapy; 2) Control group: second line chemotherapy. Patients will be stratified according to participating centres. Anticipated accrual is 100 patients per arm and the primary endpoint is overall and progression-free survivals. The study interested nearly 20 European centers. However the study is under discussion to be closed due to poor patient accrual.

2.2.6. Prognostic factors in EOC patients treated with CRS+HIPEC

The main prognostic factors are outlined in the table 5.

2.2.7. Morbidity and mortality of CRS+HIPEC

The main complications reported in the literature due to the procedure are outlined in the table 6. No risk factors for the emergence of severe complications has been identified yet.