Topic Highlight
Copyright ©2010 Baishideng. All rights reserved.
World J Gastrointest Oncol. Feb 15, 2010; 2(2): 102-108
Published online Feb 15, 2010. doi: 10.4251/wjgo.v2.i2.102
Peritoneal carcinosis of ovarian origin
Anna Fagotti, Valerio Gallotta, Federico Romano, Francesco Fanfani, Cristiano Rossitto, Angelica Naldini, Massimo Vigliotta, Giovanni Scambia
Anna Fagotti, Valerio Gallotta, Federico Romano, Francesco Fanfani, Cristiano Rossitto, Angelica Naldini, Massimo Vigliotta, Giovanni Scambia, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, 100168, Rome, Italy
Author contributions: Fagotti A designed the paper; Fagotti A, Gallotta V and Romano F wrote the paper; Fanfani F, Rossitto C, Naldini A and Vigliotta M performed data gathering; Scambia G was the responsible surgeon and supervised the paper.
Correspondence to: Anna Fagotti, MD, Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, L. go A. Gemelli, 100168, Rome, Italy. annafagotti@libero.it
Telephone: +39-6-30154979 Fax: +39-6-30154979
Received: July 31, 2009
Revised: October 2, 2009
Accepted: October 9, 2009
Published online: February 15, 2010

Abstract

Epithelial ovarian cancer (EOC) is the second most common genital malignancy in women and is the most lethal gynecological malignancy, with an estimated five-year survival rate of 39%. Despite efforts to develop an effective ovarian cancer screening method, 60% of patients still present with advanced disease. Comprehensive management using surgical cytoreduction to decrease the tumor load to a minimum, and intraperitoneal chemotherapy to eliminate microscopic disease on peritoneal surface, has the potential to greatly improve quality of life and to have an impact on survival in ovarian cancer patients. Despite achieving clinical remission after completion of initial treatment, most patients (60%) with advanced EOC will ultimately develop recurrent disease or show drug resistance; the eventual rate of curability is less than 30%. Given the poor outcome of women with advanced EOC, it is imperative to continue to explore novel therapies.

Key Words: Peritoneal carcinosis, Ovarian cancer, Intraperitoneal hyperthermic chemotherapy, Cytoreduction


Citation: Fagotti A, Gallotta V, Romano F, Fanfani F, Rossitto C, Naldini A, Vigliotta M, Scambia G. Peritoneal carcinosis of ovarian origin. World J Gastrointest Oncol 2010; 2(2): 102-108
INTRODUCTION

Epithelial ovarian cancer is the second most common genital malignancy in women and it is the most lethal gynecological malignancy, with an estimated five-year survival rate of 39%[1]. Despite efforts to develop an effective ovarian cancer screening method, 60% of patients still present with advanced (Stages III-IV) disease[2]. CA-125 serum levels, transvaginal ultrasound, and pelvic examination have long been thought to be potentially effective screening tools. However, none of them have proved effective in decreasing mortality from ovarian cancer.

An epithelial ovarian tumor arises from the serosal lining of the ovary, which communicates with the serosal lining of the abdomino-pelvic cavity known as the peritoneum. As a consequence of tumor growth, malignant cells exfoliate and shed, becoming free floating in the peritoneal fluid. They typically implant in the pelvis and subdiaphramatic recesses owing to gravity and the incumbent position. This spread of the tumor within the peritoneum is termed peritoneal carcinomatosis, and it is a typical feature of cancer spread in patients with primary advanced or recurrent epithelial ovarian cancers. Intraoperatively, it is characterized by the presence of macroscopic tumor nodules of variable sizes and consistencies that can coalesce to form plaques or masses within the abdominopelvic cavity. Tumor dissemination from the peritoneal cavity into the pleural cavity might also occur through the lymphatic lacunae within the diaphragmatic peritoneum. This results in severe pleural effusion which compromises lung and cardiac function. It typically presents with vague gastrointestinal symptoms, such as abdominal bloating, distension, weight loss, and fatigue. Due to the heterogeneity and lack of specificity of these early clinical symptoms, diagnosis is often delayed. In the final stages of this disease, patients suffer from severe symptoms of profound anorexia, dyspnea, and severe pain from malignant bowel obstruction, abdominal distension for ascites, and pleural effusion as a result of the extensive burden of tumors that characterizes this fatal deterioration. In the past, peritoneal carcinomatosis was considered a terminal condition and patients were treated with palliatively. However, despite extensive dissemination within the abdominopelvic cavity, this condition is now considered a loco-regional disease.

In many patients, the natural history of ovarian cancer is similar to gastrointestinal tumors with peritoneal surface dissemination. In fact, in both cases, the late consequences of peritoneal carcinomatosis are debilitating ascites and intestinal obstruction. With the full knowledge of the natural history of this progressive disease, the targets of the treatment should be both the peritoneal surface diffusion and the systemic metastases. There is no doubt that the eradication of the peritoneal surface components of this disease would be a major contribution to the overall, and disease-free, survival, as well as improving the quality of life of ovarian cancer patients. Comprehensive management using surgical cytoreduction to decrease the tumor load to a minimum, and intraperitoneal chemotherapy to eliminate microscopic disease on peritoneal surface, has the potential to greatly improve quality of life and have an impact on survival in these patients. In the setting of primary disease, optimal cytoreductive surgery (residual tumor < 1 cm) and platinum-based chemotherapy have been established as the most important determinants of clinical outcome.

THE CLINICAL AND BIOLOGICAL RATIONALE FOR MAXIMAL CYTOREDUCTION IN OVARIAN CANCER

More than 20 years after Griffiths’ major paper[3], a recent meta analysis by Bristow et al[4] examined the effect of maximal cytoreductive surgery on survival in advanced ovarian cancer. The author concluded that maximal cytoreduction was one of the most powerful reasons of cohort survival for patients with this disease. Eisenkop et al[5] found that cytoreduction had a more significant influence on survival than the extent of metastatic disease observed before surgery. Incorporating extensive upper abdominal debulking procedures with standard pelvic cytoreduction (rectosigmoid resection, peritoneal stripping, diaphragm stripping, extensive bowel resection, splenectomy, partial gastrectomy, and resection of liver and kidney) not only significantly improved the disease-free survival rate of patients left with optimal residual disease (85%), but also led to a significant improvement in overall survival.

The apparent value of primary cytoreductive surgery is based on the following reasons: (1) Surgery is thought to remove resistant clones of tumor cells and thus decreases the likelihood of the early onset of drug resistance; (2) The removal of large masses likely to be associated with poorly vascularized areas of tumors supposedly improves the probability of delivering adequate drug doses to the remaining cancer cells; (3) The higher growth fraction in better vascularized small masses enhances the effect of chemotherapy; (4) In principle, smaller masses require fewer cycles of chemotherapy and thus decrease the likelihood of drug resistance; (5) Removal of bulky disease theoretically enhances the immune system; (6) The patients feel better after removal of ascites and large tumor masses, particularly from the omentum; and (7) Surgery alleviates the associated nausea and satiety these patients feel.

PREOPERATIVE SELECTION CRITERIA TO EVALUATE THE INTRAPERITONEAL DIFFUSION OF THE DISEASE

Residual disease after primary surgery is one of the most important prognostic factors in advanced ovarian cancer patients. However, a certain percentage of women, ranging between 25% and 90%[6,7], are not suitable for optimal cytoreduction after exploratory laparotomy, and are treated by neoadjuvant chemotherapy. To preoperatively identify patients with unresectable tumors, which can be spared an unnecessary exploratory laparotomy, several approaches have been attempted, including the evaluation of CA-125 serum levels and the radiological assessment of tumor spread. However, the accuracy of these parameters has been unsatisfactory, and has been limited by the retrospective nature of the studies and the highly variable rates of optimal cytoreduction in different series[7]. In this context, a genetic analysis by microarrays has been attempted to identify some biologic characteristics underlying the possibility of optimal debulking, resulting in a low predictive accuracy[8]. Laparoscopy is well known for offering a direct and magnified vision of the peritoneal cavity and a better view of the upper abdomen. It allows the pathological assessment of the disease without an open surgical procedure, with a shorter operating time, and better results in terms of postoperative morbidity. Indeed, it has been demonstrated to be an effective procedure for restaging early ovarian cancer[9-11]. A recent pilot study by Fagotti et al[12] demonstrated that laparoscopy is an adequate and reliable procedure for the assessment of the chances of optimal cytoreduction (RT < 1 cm) in clinically advanced ovarian cancer patients. Since then, other investigators have been confirming the role of laparoscopy in the evaluation of the possibility of achieving optimal residual disease in the same clinical subset[13,14]. Subsequently, in a consecutive prospective series of 113 advanced ovarian cancer patients, the presence of omental cake, peritoneal and diaphragmatic extensive carcinomatosis, mesenteric retraction, bowel and stomach infiltration, and spleen and/or liver superficial metastasis were investigated by laparoscopy. Each parameter received a score based on a specificity > 75%, positive predictive value (PPV), negative predictive value (NPV) > 50%, and accuracy > 60% with respect to the chances of achieving an optimal cytoreduction. By summing the scores relative to the presence of every aforementioned parameter, an overall laparoscopic value for each patient (total predictive index value = PIV) was calculated. Sensitivity, specificity, PPV, NPV, and accuracy with respect to optimal RT were calculated for each PIV. Finally, the authors concluded that the proposed laparoscopic model appears a reliable and flexible tool to predict optimal cytoreduction in advanced ovarian cancer. More recently, this model has been applied in a different center from that in which it was developed[15]. The results from this study have shown that even when utilized in a different setting of patients, the laparoscopic PIV can identify advanced ovarian cancer cases that are likely to be suitable for optimal debulking.

SURGICAL PROCEDURES IN THE MANAGEMENT OF ADVANCED OVARIAN CANCER

Worldwide, there are more than two hundred thousand new cases of ovarian cancer diagnosed annually, accounting for about 4% of female cancers.

In 1994, the National Institutes of Health[16] convened a 14-member panel of experts in the management of ovarian cancer to generate a consensus statement of recommendations. The panel concluded that: “Adequate and complete surgical intervention is a mandatory primary therapy for ovarian cancer, permitting precise staging, accurate diagnosis, and optimal cytoreduction. The procedure is best conducted by a qualified gynecologic oncologist, when there is a high probability of ovarian cancer. All women with suspected ovarian cancer should be offered a preoperative consultation with a gynaecologic oncologist”. During the past decade, compelling published work has accumulated to lend support to these consensus recommendations. These reports show that initial surgery for ovarian cancer is most appropriately done by gynaecological oncologists, preferably in centers with expertise in the multidisciplinary management of this disease. Engelen et al[17] recently described a population-based observational study of patterns of care for 680 women with ovarian cancer in the northern Netherlands. The patients were treated between 1994 and 1997. The main objective of the study was the effect of surgery performed by a gynaecological oncologist on the quality of surgery and survival outcome compared with surgery by a general gynaecologist without subspecialty training. In all disease stages, patients received surgical treatment according to prevailing surgical guidelines more frequently when operated on by a gynaecological oncologist. The risk of death for patients who did not have surgery according to accepted guidelines was almost twice that for patients who had surgery according to the guidelines. In this study, patients with stage I/II disease were more likely to be staged by gynaecological oncologists than general gynaecological surgeons, resulting in a more accurate assignment of disease stage and administration of adjuvant treatment. For patients with stage III disease, five-year survival was 32% when the guidelines were followed and 11% when guidelines were not (hazard ratio 1.97, 95% CI: 1.45-2.68, P < 0.001). Furthermore, more patients with stage III disease had complete debulking (24% vs 12%) and reduced residual disease (< 2 cm) (62% vs 45%) by a gynaecological oncologist when compared to a gynaecologist. These data, as well as similar population-based studies, lend support to three main conclusions about the delivery of cancer care services for women with suspected ovarian cancer[18-21]: (1) the disparity in survival outcomes according to the specialty of operating surgeon, after confounding factors have been accounted for, supports the long-held hypothesis that the surgically-attained maximum diameter of residual disease is inversely proportional to survival outcome. Consequently, primary cytoreductive surgery offers the best opportunity for achieving extended survival and should be considered the standard of care for women with advanced-stage epithelial ovarian cancer; (2) the consistent and positive effect of a surgeons’ specialty on survival provides irrefutable evidence that surgical care in ovarian cancer should be concentrated in centers with gynaecological oncologists. These surgical subspecialists have the necessary expertise to stage patients with early-stage disease as well as to perform the cytoreductive surgery necessary to achieve minimal residual disease in patients with advanced-stage tumors. Adequate and complete initial intervention is among the most powerful clinician-driven determinants of survival for women with ovarian cancer; and (3) the above conclusions call for widespread and consistent support by the medical community and governmental organizations in recognising specialty training in gynaecological oncology as a necessary component for comprehensive health care for women[22].

The standard of therapy in patients with advanced ovarian cancer is the surgical exploration of the pelvis and the upper abdomen and a maximum cytoreduction. The aim of surgery is to remove all tumor-infiltrated organs including the peritoneum, bowel, spleen, hepatic tissue etc., thus surgery is not limited to the pelvis, the omentum and the lymph nodes. Bristow et al[23] showed that even in patients with un-resectable liver metastasis, optimal de-bulking of extra-hepatic disease is associated with a significant survival advantage. Therefore, the intent of surgery is not to leave any macroscopic intraabdominal disease[24]. In a high percentage of patients, this aim can be reached by an encouraged, ultraradical, consequent, multivisceral surgery. Eisenkop et al[24] achieved 85% of optimal cytoreduction in a series of 163 patients with stage III and IV ovarian cancer. In our opinion, the limit of resectability can be defined by the extent of miliaric carcinomatosis on the serosa of the small bowel and by the infiltration of the major abdominal vessels. In conclusion, we should answer a crucial question to support the role of cyto-reduction in the management of advanced ovarian cancer: is attainment of an optimal outcome largely related to philosophy and skill of the surgeons or does it reflect a less aggressive tumor biology? These issues are still being studied and debated after more than 20 years. We believe that the better understanding of tumor biology can help in the planning of surgical strategy in cases of recurrent ovarian cancer, but the patient’s general health, the presence of diffuse carcinomatosis, and the surgical philosophy are correlated with the achievement of an optimal surgical outcome.

NOVEL APPROACHES AND THE ROLE OF INTRAPERITONEAL CHEMOTHERAPY IN THE MANAGEMENT OF ADVANCED OVARIAN CANCER

Only about 50% of patients show a complete clinical response to systemic platinum/taxol based chemotherapy, and 30% of them have microscopic metastasis at second look surgery. Despite achieving clinical remission after completion of initial treatment, most patients (60%) with advanced epithelial ovarian cancer will ultimately develop recurrent disease or show drug resistance, and their rate of curability is less than 30%. The recurrence rate ranges between 30% and 50% for patients who show no lesion at the time of second look surgery[25]. In these patients, the median disease-free survival is only 24 mo.

These factors are major limitations in treatment of patients with ovarian cancer[26]. Different treatment modalities have been attempted to overcome these limits, such as secondary cytoreduction, second-line chemotherapeutic drugs, high-dose chemotherapy, intraperitoneal chemotherapy (IP), radiotherapy, immunotherapy, and hormone therapy. In fact, it is conceivable that recurrences in platinum-responsive patients might be prevented by higher doses of drugs to eradicate less sensitive clones of tumor cells that became resistant to platinum when lower doses are given during initial treatment[27].

To date, except for IP chemotherapy, none of these approaches has been found to have a significant impact on survival. IP chemotherapy refers to the administration of cytotoxic agents directly at the predominant disease site: the peritoneal cavity. The rationale is that a higher concentration of cytotoxic drugs and longer duration of exposure can be achieved while reducing the toxicity normally associated with intravenous therapy. In fact, cytotoxic drugs administered IP can directly target tumor masses confined to the abdominal cavity, thus bypassing the poor vascularization of small-volume disease and, therefore, increasing peri- and intra tumoral drug concentration. Cisplatin can penetrate small-volume tumors to a maximum depth of 1-3 mm; therefore, a benefit of this schedule can be obtained only for patients with microscopic residual disease. By the use of large doses of intraperitoneal cisplatin, the surface of the tumor can be exposed to high concentrations of cisplatin with a sufficient amount of drug leaking into the circulation. Thus, the level of drug reaching the tumor through capillaries is doubled compared with a maximally tolerated dose of cisplatin delivered intravenously[28].

Two large phase III trials published in 1996 and 2001 have documented some outcome advantages for IP therapy[29,30]. Recently, a 3rd randomized trial showed that IP chemotherapy provides better long-term outcome than IV drug delivery in patients with advanced ovarian cancer[31]. In the United States, the National Cancer Institute and the Society of Gynecologic Oncologists have endorsed the use of intraperitoneal chemotherapy in recent position papers. However, some concerns have been raised about the use of IP therapy: (1) the effectiveness of IP therapy depends on uniform drug distribution. It is essential that fluid circulates freely throughout the peritoneal cavity. After cytoreductive surgery, the risk of IP adhesion formation is increased, which might limit the access of the active drug to the tumor areas; and (2) various complications have been attributed to IP catheter, such as infections.

The intraoperative administration of intraperitoneal chemotherapy has been designed to overcome such obstacles. The use of intraoperative intraperitoneal chemotherapy avoids the pitfalls of postoperative adhesions and inconsistent drug distribution. Overall, intraoperative chemotherapy allows optimal drug distribution to all peritoneal surfaces. This produces a regional pharmacokinetic advantage with the amount of drug delivered to the tumor greater than that delivered systemically.

Intraperitoneal hyperthermic chemotherapy (HIPEC) is a new treatment modality that is based on increasing the sensitivity of cancer cells to the direct cytotoxic effect of chemotherapeutic agents at high temperature and increasing the concentration of chemotherapeutic agents that penetrate cancer tissues[32-34]. In fact, it has been proved that high temperature damages cancer cell membranes and promotes cellular apoptosis by increasing the intracellular calcium concentration and DNA fragmentation. Another mechanism is the destabilization of thymidine kinase 1, which is involved in DNA synthesis in cancer cells[35]. At 42°C, hyperthermia is cytotoxic by itself, increasing membrane permeability, inhibiting DNA repair, and promoting macrophage lysosomal exocytosis with consequent apoptosis[36]. The treatment modulates the activity of cytokines[37], and increases the antigenicity of tumor cells by the production of heat shock proteins and the activation of natural killer cells[38]. In conclusion, the biophysical effects of HIPEC are: membrane protein denaturation, increased vascular permeability, and alterations of multimolecular complex for DNA synthesis and repair. Moreover, the architecture of the vasculature in solid tumors is chaotic, resulting in regions with low pH, hypoxia, and low glucose levels. This microenvironment makes solid tumors more susceptible to hyperthermia[39].

Cisplatin has been shown to penetrate deeper into tumor tissue under hyperthermic conditions compared to normothermic conditions. At 40-43°C, neoplastic cells become more chemo-sensitive due to an enhancement of intracellular concentrations of drugs and to alterations in the DNA repair process, especially for alkylating agents[40,41]. In addition, it has been shown that these events have a greater intensity in cisplatin-resistant rather than cisplatin-sensitive ovarian cancer cells lines. Formation of platinum-DNA adducts after cisplatin exposure is enhanced in heated cells, thus resulting in relatively greater DNA damage[42].

The critical point of this approach is cytoreduction down to nodules of less than few millimetres, to allow HIPEC to act. The possible synergy between hyperthermia and chemotherapy agents has sparked clinical trials utilizing this combination in many disease types. With regard to situations analogous with ovarian carcinoma, in which the disease may be widespread within the peritoneal cavity, studies in gastric cancer, malignant mesothelioma, appendix cancer, and colorectal cancer have shown promising results. A phase III randomized study of hyperthermic intraperitoneal chemotherapy following cytoreductive surgery compared with traditional iv chemotherapy in patients with peritoneal spread of colorectal carcinoma showed a statistically significant prolongation of life in the experimental arm[43]. In addition, this combined treatment has been suggested as the standard of care for peritoneal dissemination from neoplasm of the appendix[44,45] and diffuse malignant peritoneal mesothelioma[46]. With long-term follow-up, cytoreductive surgery plus HIPEC is the only treatment associated with a cure for these diseases.

EOC is a logical target for directed intraperitoneal therapy in combination with heat, and there are reports of clinical studies looking at hyperthermic intraperitoneal chemotherapy following surgical debulking in this disease[47-56]. In 2001, Hager et al[54] reported that HIPEC significantly increased the survival and response rates, and improved the quality of life, in 36 stage III and IV ovarian cancer patients who showed resistance to systemic chemotherapy. Deraco et al[57] reported that HIPEC significantly increased two-year survival to 55% and delayed tumor progression in 27 patients with recurrent ovarian cancer after extensive surgery to nodules less than 2.5 mm in diameter. Nevertheless, the few clinical studies looking at HIPEC following surgical debulking suffer from some limitations: relatively small numbers of patients, retrospective studies, different clinical settings and drugs. In fact, published data show that different groups of patients have been often mixed together, in terms of number of recurrence (persistent, first, second, and third), type of recurrence (single, multiple, and carcinosis) and PFI (platinum-sensitive or -resistant). More recently, we reported an interesting series on the use of HIPEC and cytoreductive surgery in a specific setting of patients, where ovarian cancer women at their first recurrence with a PFI of at least 6 mo presented to a gynecological oncology referral centre[58]. All cases were strictly selected before inclusion in the protocol, utilizing AGO-DESKTOP II criteria for secondary cytoreduction and performing an FDG-PET/CT and S-LPS in all cases before attempting surgery. The preoperative evaluation allowed a complete cytoreduction in 100% of the patients (23 CC-0 and two CC-1), that is an excellent result when compared to 50% of complete cytoreduction shown in a recent meta-analysis on secondary surgery[4]. As might be expected, this satisfying result was achieved at the cost of multiple organ resections, but peri-operative mortality and morbidity rates were 0% and 30%, respectively, which are well balanced with data reported in the recent literature, even if cytoreductive surgery alone is considered[59]. In conclusion, considering the potential advantages of HIPEC associated with cytoreductive surgery and the low morbidity and mortality rates, such a promising approach should be encouraged for long-term survival in platinum-sensitive recurrent ovarian cancer patients. We await larger prospective randomized studies with longer follow-up times.

Footnotes

Peer reviewer: Francesco Fiorica, MD, Department of Radiation Oncology, University Hospital S’Anna, Corso Giovecca 203, Ferrara I-44100, Italy

S- Editor Li LF L- Editor Stewart GJ E- Editor Lin YP

References
1.  Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, Feuer EJ, Thun MJ. Cancer statistics, 2004. CA Cancer J Clin. 2004;54:8-29.  [PubMed]  [DOI]
2.  Munkarah AR, Coleman RL. Critical evaluation of secondary cytoreduction in recurrent ovarian cancer. Gynecol Oncol. 2004;95:273-280.  [PubMed]  [DOI]
3.  Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr. 1975;42:101-104.  [PubMed]  [DOI]
4.  Bristow RE, Puri I, Chi DS. Cytoreductive surgery for recurrent ovarian cancer: a meta-analysis. Gynecol Oncol. 2009;112:265-274.  [PubMed]  [DOI]
5.  Eisenkop SM, Friedman RL, Wang HJ. Secondary cytoreductive surgery for recurrent ovarian cancer. A prospective study. Cancer. 1995;76:1606-1614.  [PubMed]  [DOI]
6.  Axtell AE, Lee MH, Bristow RE, Dowdy SC, Cliby WA, Raman S, Weaver JP, Gabbay M, Ngo M, Lentz S. Multi-institutional reciprocal validation study of computed tomography predictors of suboptimal primary cytoreduction in patients with advanced ovarian cancer. J Clin Oncol. 2007;25:384-389.  [PubMed]  [DOI]
7.  Everett EN, Heuser CC, Pastore LM, Anderson WA, Rice LW, Irvin WP, Taylor PT. Predictors of suboptimal surgical cytoreduction in women treated with initial cytoreductive surgery for advanced stage epithelial ovarian cancer. Am J Obstet Gynecol. 2005;193:568-574; discussion 574-576.  [PubMed]  [DOI]
8.  Berchuck A, Iversen ES, Lancaster JM, Dressman HK, West M, Nevins JR, Marks JR. Prediction of optimal versus suboptimal cytoreduction of advanced-stage serous ovarian cancer with the use of microarrays. Am J Obstet Gynecol. 2004;190:910-925.  [PubMed]  [DOI]
9.  Leblanc E, Querleu D, Narducci F, Occelli B, Papageorgiou T, Sonoda Y. Laparoscopic restaging of early stage invasive adnexal tumors: a 10-year experience. Gynecol Oncol. 2004;94:624-629.  [PubMed]  [DOI]
10.  Manolitsas TP, Fowler JM. Role of laparoscopy in the management of the adnexal mass and staging of gynecologic cancers. Clin Obstet Gynecol. 2001;44:495-521.  [PubMed]  [DOI]
11.  Littell RD, Hallonquist H, Matulonis U, Seiden MV, Berkowitz RS, Duska LR. Negative laparoscopy is highly predictive of negative second-look laparotomy following chemotherapy for ovarian, tubal, and primary peritoneal carcinoma. Gynecol Oncol. 2006;103:570-574.  [PubMed]  [DOI]
12.  Fagotti A, Fanfani F, Ludovisi M, Lo Voi R, Bifulco G, Testa AC, Scambia G. Role of laparoscopy to assess the chance of optimal cytoreductive surgery in advanced ovarian cancer: a pilot study. Gynecol Oncol. 2005;96:729-735.  [PubMed]  [DOI]
13.  Deffieux X, Castaigne D, Pomel C. Role of laparoscopy to evaluate candidates for complete cytoreduction in advanced stages of epithelial ovarian cancer. Int J Gynecol Cancer. 2006;16 Suppl 1:35-40.  [PubMed]  [DOI]
14.  Angioli R, Palaia I, Zullo MA, Muzii L, Manci N, Calcagno M, Panici PB. Diagnostic open laparoscopy in the management of advanced ovarian cancer. Gynecol Oncol. 2006;100:455-461.  [PubMed]  [DOI]
15.  Brun JL, Rouzier R, Selle F, Houry S, Uzan S, Daraï E. Neoadjuvant chemotherapy or primary surgery for stage III/IV ovarian cancer: contribution of diagnostic laparoscopy. BMC Cancer. 2009;9:171.  [PubMed]  [DOI]
16.  NIH consensus conference. Ovarian cancer. Screening, treatment, and follow-up. NIH Consensus Development Panel on Ovarian Cancer. JAMA. 1995;273:491-497.  [PubMed]  [DOI]
17.  Engelen MJ, Kos HE, Willemse PH, Aalders JG, de Vries EG, Schaapveld M, Otter R, van der Zee AG. Surgery by consultant gynecologic oncologists improves survival in patients with ovarian carcinoma. Cancer. 2006;106:589-598.  [PubMed]  [DOI]
18.  Paulsen T, Kjaerheim K, Kaern J, Tretli S, Tropé C. Improved short-term survival for advanced ovarian, tubal, and peritoneal cancer patients operated at teaching hospitals. Int J Gynecol Cancer. 2006;16 Suppl 1:11-17.  [PubMed]  [DOI]
19.  Carney ME, Lancaster JM, Ford C, Tsodikov A, Wiggins CL. A population-based study of patterns of care for ovarian cancer: who is seen by a gynecologic oncologist and who is not? Gynecol Oncol. 2002;84:36-42.  [PubMed]  [DOI]
20.  Junor EJ, Hole DJ, McNulty L, Mason M, Young J. Specialist gynaecologists and survival outcome in ovarian cancer: a Scottish national study of 1866 patients. Br J Obstet Gynaecol. 1999;106:1130-1136.  [PubMed]  [DOI]
21.  Hillner BE, Smith TJ, Desch CE. Hospital and physician volume or specialization and outcomes in cancer treatment: importance in quality of cancer care. J Clin Oncol. 2000;18:2327-2340.  [PubMed]  [DOI]
22.  Bristow RE, Berek JS. Surgery for ovarian cancer: how to improve survival. Lancet. 2006;367:1558-1560.  [PubMed]  [DOI]
23.  Bristow RE, Montz FJ, Lagasse LD, Leuchter RS, Karlan BY. Survival impact of surgical cytoreduction in stage IV epithelial ovarian cancer. Gynecol Oncol. 1999;72:278-287.  [PubMed]  [DOI]
24.  Eisenkop SM, Spirtos NM, Lin WC. Splenectomy in the context of primary cytoreductive operations for advanced epithelial ovarian cancer. Gynecol Oncol. 2006;100:344-348.  [PubMed]  [DOI]
25.  Sagae S, Berek JS, Fu YS, Chang N, Dauplat J, Hacker NF. Peritoneal cytology of ovarian cancer patients receiving intraperitoneal therapy: quantitation of malignant cells and response. Obstet Gynecol. 1988;72:782-788.  [PubMed]  [DOI]
26.  Rubin SC, Hoskins WJ, Saigo PE, Chapman D, Hakes TB, Markman M, Reichman B, Almadrones L, Lewis JL Jr. Prognostic factors for recurrence following negative second-look laparotomy in ovarian cancer patients treated with platinum-based chemotherapy. Gynecol Oncol. 1991;42:137-141.  [PubMed]  [DOI]
27.  Vasey PA. Resistance to chemotherapy in advanced ovarian cancer: mechanisms and current strategies. Br J Cancer. 2003;89 Suppl 3:S23-S28.  [PubMed]  [DOI]
28.  Dedrick RL, Flessner MF. Pharmacokinetic problems in peritoneal drug administration: tissue penetration and surface exposure. J Natl Cancer Inst. 1997;89:480-487.  [PubMed]  [DOI]
29.  Alberts DS, Liu PY, Hannigan EV, O'Toole R, Williams SD, Young JA, Franklin EW, Clarke-Pearson DL, Malviya VK, DuBeshter B. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med. 1996;335:1950-1955.  [PubMed]  [DOI]
30.  Markman M, Markman J, Webster K, Zanotti K, Kulp B, Peterson G, Belinson J. Duration of response to second-line, platinum-based chemotherapy for ovarian cancer: implications for patient management and clinical trial design. J Clin Oncol. 2004;22:3120-3125.  [PubMed]  [DOI]
31.  Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ, Walker JL, Burger RA. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.  [PubMed]  [DOI]
32.  Dudar TE, Jain RK. Differential response of normal and tumor microcirculation to hyperthermia. Cancer Res. 1984;44:605-612.  [PubMed]  [DOI]
33.  Brown SL, Hunt JW, Hill RP. Differential thermal sensitivity of tumour and normal tissue microvascular response during hyperthermia. Int J Hyperthermia. 1992;8:501-514.  [PubMed]  [DOI]
34.  Los G, van Vugt MJ, Pinedo HM. Response of peritoneal solid tumours after intraperitoneal chemohyperthermia treatment with cisplatin or carboplatin. Br J Cancer. 1994;69:235-241.  [PubMed]  [DOI]
35.  Demeter A, Abonyi M, Look KY, Keszler G, Staub M, Weber G. Differences in thermostability of thymidine kinase isoenzymes in normal ovary and ovarian carcinoma. Anticancer Res. 2001;21:353-358.  [PubMed]  [DOI]
36.  Pontiggia P, Barni S, Mathé G, Bertone V, Pontiggia E. Lysosomal exocytosis induced by hyperthermia: a new model of cancer cell death. II. Effect on peritoneal macrophages. Biomed Pharmacother. 1995;49:429-430.  [PubMed]  [DOI]
37.  Katschinski DM, Wiedemann GJ, Longo W, d'Oleire FR, Spriggs D, Robins HI. Whole body hyperthermia cytokine induction: a review, and unifying hypothesis for myeloprotection in the setting of cytotoxic therapy. Cytokine Growth Factor Rev. 1999;10:93-97.  [PubMed]  [DOI]
38.  Multhoff G. Heat shock protein 72 (HSP72), a hyperthermia-inducible immunogenic determinant on leukemic K562 and Ewing's sarcoma cells. Int J Hyperthermia. 1997;13:39-48.  [PubMed]  [DOI]
39.  Ceelen WP, Hesse U, de Hemptinne B, Pattyn P. Hyperthermic intraperitoneal chemoperfusion in the treatment of locally advanced intra-abdominal cancer. Br J Surg. 2000;87:1006-1015.  [PubMed]  [DOI]
40.  Engelhardt R. Hyperthermia and drugs. Recent Results Cancer Res. 1987;104:136-203.  [PubMed]  [DOI]
41.  Teicher BA, Kowal CD, Kennedy KA, Sartorelli AC. Enhancement by hyperthermia of the in vitro cytotoxicity of mitomycin C toward hypoxic tumor cells. Cancer Res. 1981;41:1096-1099.  [PubMed]  [DOI]
42.  Hettinga JV, Konings AW, Kampinga HH. Reduction of cellular cisplatin resistance by hyperthermia--a review. Int J Hyperthermia. 1997;13:439-457.  [PubMed]  [DOI]
43.  Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003;21:3737-3743.  [PubMed]  [DOI]
44.  Yan TD, Black D, Savady R, Sugarbaker PH. Systematic review on the efficacy of cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma. J Clin Oncol. 2006;24:4011-4019.  [PubMed]  [DOI]
45.  Sugarbaker PH. New standard of care for appendiceal epithelial neoplasms and pseudomyxoma peritonei syndrome? Lancet Oncol. 2006;7:69-76.  [PubMed]  [DOI]
46.  Kusamura S, Deraco M, Baratti D, Inglese MG, Costanzo P, Favaro M, Manzi R, Gavazzi C. Cytoreductive surgery followed by intra peritoneal hyperthermic perfusion in the treatment of peritoneal surface malignancies: morbidity and mortality with closed abdomen technique. J Exp Clin Cancer Res. 2003;22:207-212.  [PubMed]  [DOI]
47.  Rufián S, Muñoz-Casares FC, Briceño J, Díaz CJ, Rubio MJ, Ortega R, Ciria R, Morillo M, Aranda E, Muntané J. Radical surgery-peritonectomy and intraoperative intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis in recurrent or primary ovarian cancer. J Surg Oncol. 2006;94:316-324.  [PubMed]  [DOI]
48.  Cavaliere F, Di Filippo F, Botti C, Cosimelli M, Giannarelli D, Aloe L, Arcuri E, Aromatario C, Consolo S, Callopoli A. Peritonectomy and hyperthermic antiblastic perfusion in the treatment of peritoneal carcinomatosis. Eur J Surg Oncol. 2000;26:486-491.  [PubMed]  [DOI]
49.  van der Vange N, van Goethem AR, Zoetmulder FA, Kaag MM, van de Vaart PJ, ten Bokkel Huinink WW, Beijnen JH. Extensive cytoreductive surgery combined with intra-operative intraperitoneal perfusion with cisplatin under hyperthermic conditions (OVHIPEC) in patients with recurrent ovarian cancer: a feasibility pilot. Eur J Surg Oncol. 2000;26:663-668.  [PubMed]  [DOI]
50.  Panteix G, Beaujard A, Garbit F, Chaduiron-Faye C, Guillaumont M, Gilly F, Baltassat P, Bressolle F. Population pharmacokinetics of cisplatin in patients with advanced ovarian cancer during intraperitoneal hyperthermia chemotherapy. Anticancer Res. 2002;22:1329-1336.  [PubMed]  [DOI]
51.  Helm CW, Martin RS, Metzinger DS, Edwards RP. Secondary surgical cytoreduction and hyperthermic intraperitoneal chemotherapy for recurrent ovarian and endometrial cancer. Int Gynecol Cancer Soc. 2004;14:167.  [PubMed]  [DOI]
52.  Zanon C, Clara R, Chiappino I, Bortolini M, Cornaglia S, Simone P, Bruno F, De Riu L, Airoldi M, Pedani F. Cytoreductive surgery and intraperitoneal chemohyperthermia for recurrent peritoneal carcinomatosis from ovarian cancer. World J Surg. 2004;28:1040-1045.  [PubMed]  [DOI]
53.  Reichman TW, Cracchiolo B, Sama J, Bryan M, Harrison J, Pliner L, Harrison LE. Cytoreductive surgery and intraoperative hyperthermic chemoperfusion for advanced ovarian carcinoma. J Surg Oncol. 2005;90:51-56; discussion 56-58.  [PubMed]  [DOI]
54.  Hager ED, Dziambor H, Höhmann D, Mühe N, Strama H. Intraperitoneal hyperthermic perfusion chemotherapy of patients with chemotherapy-resistant peritoneal disseminated ovarian cancer. Int J Gynecol Cancer. 2001;11 Suppl 1:57-63.  [PubMed]  [DOI]
55.  Piso P, Dahlke MH, Loss M, Schlitt HJ. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from ovarian cancer. World J Surg Oncol. 2004;2:21.  [PubMed]  [DOI]
56.  Roviello F, Marrelli D, Neri A, Cerretani D, de Manzoni G, Pedrazzani C, Cioppa T, Nastri G, Giorgi G, Pinto E. Treatment of peritoneal carcinomatosis by cytoreductive surgery and intraperitoneal hyperthermic chemoperfusion (IHCP): postoperative outcome and risk factors for morbidity. World J Surg. 2006;30:2033-2040; discussion 2041-2042.  [PubMed]  [DOI]
57.  Deraco M, Rossi CR, Pennacchioli E, Guadagni S, Somers DC, Santoro N, Raspagliesi F, Kusamura S, Vaglini M. Cytoreductive surgery followed by intraperitoneal hyperthermic perfusion in the treatment of recurrent epithelial ovarian cancer: a phase II clinical study. Tumori. 2001;87:120-126.  [PubMed]  [DOI]
58.  Fagotti A, Paris I, Grimolizzi F, Fanfani F, Vizzielli G, Naldini A, Scambia G. Secondary cytoreduction plus oxaliplatin-based HIPEC in platinum-sensitive recurrent ovarian cancer patients: a pilot study. Gynecol Oncol. 2009;113:335-340.  [PubMed]  [DOI]
59.  Onda T, Yoshikawa H, Yasugi T, Yamada M, Matsumoto K, Taketani Y. Secondary cytoreductive surgery for recurrent epithelial ovarian carcinoma: proposal for patients selection. Br J Cancer. 2005;92:1026-1032.  [PubMed]  [DOI]