Intraperitoneal therapy for peritoneal tumors: biophysics and clinical evidence

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1 reviews Intraperitoneal therapy for peritoneal tumors: biophysics and clinical evidence Wim P. Ceelen and Michael F. Flessner Abstract In patients with tumors confined to the peritoneal cavity, there is established pharmacokinetic and tumor biology related evidence that intraperitoneal drug administration is advantageous. Three large randomized trials in patients with stage III ovarian cancer who underwent optimal cytoreduction have demonstrated a significant survival benefit when intraperitoneal chemotherapy was added to systemic therapy. Although intraperitoneal therapy is associated with locoregional toxic effects, recent trials suggest that with some modification of the local delivery methods this approach is safe in 80% of patients in an ambulatory setting. Surgical cytoreduction immediately followed by intraoperative hyperthermic intraperitoneal chemoperfusion (HIPEC) ensures intraperitoneal delivery of the drug to all peritoneal surfaces and the advantages of combined hyperthermia to be exploited. An increasing number of centers are initiating this multimodality therapy in ovarian cancer and colorectal cancer. Clearly, intraperitoneal drug delivery is an important adjunct to surgery and systemic chemotherapy in selected patients. The optimal drug, dose and schedule for intraperitoneal delivery, the exact role of added HIPEC compared with cytoreduction alone, and the potential role of HIPEC in ovarian cancer and peritoneal mesothelioma are still undefined. Several randomized controlled trials addressing these uncertainties have been initiated. Ceelen, W. P. & Flessner, M. F. Nat. Rev. Clin. Oncol. 7, (2010); published online 15 December 2009; doi: /nrclinonc Department of Surgery, University Hospital, De Pintelaan 185, B 9000 Ghent, Belgium (W. P. Ceelen). Department of Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA (M. F. Flessner). Correspondence to: W. P. Ceelen wim.ceelen@ugent.be Introduction A significant proportion of patients with digestive or gynecological malignancies will develop spread of cancer to the peritoneum. Peritoneal carcinomatosis is notoriously resistant to therapy, and is known to induce considerable suffering due to ascites, bowel obstruction, and pain. For most patients, little more than palliative measures are available. Intraperitoneal administration of cytotoxic drugs during or after surgical cytoreduction allows their therapeutic index to be increased by exploiting the peritoneal transport barrier. Intraperitoneal delivery of anticancer drugs for abdominal malignancy is not a new concept. The earliest intraperitoneal drug therapy was reported in 1744 by the English surgeon Christopher Warrick, who injected a mixture of Bristol water and claret (a Bordeaux wine) into the peritoneal cavity of a woman suffering from intractable ascites. 1 Since the discovery of the antineoplastic potential of nitrogen mustard during World War II, intraperitoneal chemotherapy has been studied in clinical trials for more than 50 years. 2 The results from recent randomized trials in ovarian and colorectal cancer patients have led to a renewed interest in the concept of intraperitoneal cytotoxic drug therapy. 64,80 82 In this Review we summarize the underlying principles of intraperitoneal drug delivery and critically review the results obtained in clinical practice. Competing interests The authors declare no competing interests Pharmacokinetics of IP drug therapy The pharmacokinetic rationale for intraperitoneal cytotoxic drug administration was first proposed by Dedrick et al. 3 in 1978, based on the existence of a peritonealplasma barrier. The presence of this barrier, consisting of the mesothelium and underlying submesothelial tissue, results in a peritoneal drug clearance that is much slower than the plasma clearance. This allows the peritoneal tumor tissue to be exposed to much higher drug concen trations compared with those achieved by systemic delivery. 4 The drug concentration in the peritoneum is an important determinant of intraperitoneal chemotherapy efficacy for several reasons. First, small (that is, less than 1 mm) peritoneal tumor nodules are characterized by pronounced hypoxia and a poorly developed or absent vasculature that compromises intravenous drug delivery. 5 Any increase in the concentration gradient between the peritoneal compartment and the tumor stroma will theoretically enhance drug delivery. Second, most cytotoxic drugs exhibit a steep (near exponential) dose effect relationship, which is even more pronounced in small, rapidly growing tumor deposits that have not yet reached the plateau phase of Gompertzian growth kinetics. 6 Indeed, the proliferation rate of cancer cells decreases as the tumor grows, resulting in a Gompertzian curve. Preclinical data with cisplatin showed an exponential dose related reduction in survival of human ovarian cancer cells. 7 Also, higher intracellular drug concen trations can partially help to overcome platinum resistance. 8 Of note, the alkylating 108 february 2010 volume 7

2 agents and platinum compounds commonly used for intraperitoneal therapy are cell cycle independent and, therefore, their acti vity is mainly a function of concentration. The activity of agents, such as the antimetabolites (5 fluorouracil, gemcitabine, pemetrexed), is primarily time dependent requiring prolonged exposure times. 9 It has been shown that the peritoneal mesothelial lining itself does not constitute a barrier to drug absorption. 10,11 The main absorption barrier consists of submesothelial connective and muscle tissue and, ultimately, the endothelial lining of the microvascular network. Interestingly, the endo thelial glycocalyx was recognized as a primary barrier in transendothelial solute and water transport. 12 Since approximately 70% of the mesothelial surfaces cover the viscera, transport of drugs from the peritoneal to the vascular compartment occurs mainly via the portal circulation. Importantly, cytotoxic drugs absorbed systemically will access the microcirculation of peritoneal nodules and thus act synergistically with the intra peritoneal administered therapy. 13 The pharmacokinetic advantage associated with intraperitoneal administration was expressed by Dedrick as the parameter R d, calculated as (C P /C B )IP/(C P /C B )Iv, with C P and C B the peritoneal and blood concentrations, respectively. 14 Theoretically, the regional pharmaco kinetic advantage will be inversely proportional to the peritoneal clearance and proportional to the plasma clearance. The pharmacokinetic behavior of intra peritoneal administered drug can also be summarized by the ratio of the area under the concentration versus time curve (AuC) in peritoneal perfusate versus plasma. Table 1 summarizes the pharmacokinetic properties of cytostatic drugs commonly used for intraperitoneal therapy. Pharmacodynamics of IP drug therapy The pharmacodynamic efficacy of cytotoxic drug therapy administered intraperitoneally depends on several physico chemical variables, which are summarized in Figure 1. The two main physical mechanisms of drug transport into tumor tissue are diffusion and convection. For small agents (molecular weight <6,000 Daltons), transport occurs mainly by diffusion, see Box 1. large solutes, such as proteins diffuse much more slowly, and their transport is typically governed by solvent drag or convection. malignant tumors are characterized by an elevated interstitial fluid pressure (IFP), which represents a barrier to convective drug transport. 17 In vivo experiments have shown that measures to reduce the IFP such as surgical removal of the tumor capsule did not enhance tissue penetration of antibodies administered via the intraperitoneum, indicating that the structure of the intercellular matrix is the major resistance to macromolecular drug transport. 18 In practice, the tumor penetration distance measured experimentally following intraperitoneal drug delivery is limited, ranging from a few cell layers to a maximum of 3 5 mm After systemic administration of chemotherapy, however, the penetration distance of extravasated drug has been shown to be very limited. 23 In xenografts, the concentration of doxo rubicin was shown Key points Intraperitoneal drug delivery has proven efficacy in patients with minimal or microscopic residual disease following surgery In large randomized trials a significant improvement in outcome of stage III ovarian cancer was demonstrated when intraperitoneal platinum based chemotherapy was added to systemic therapy Methodological issues concerning these trials and locoregional toxic effects have prevented widespread adoption of intraperitoneal chemotherapy in ovarian cancer Surgical cytoreduction immediately followed by intraoperative hyperthermic intraperitoneal chemoperfusion (HIPEC) ensures intraperitoneal delivery of the drug to all peritoneal surfaces at risk Cytoreduction and HIPEC are optimal therapies for mucinous appendiceal tumors; one randomized trial showed a superior outcome of the combined approach versus palliation in peritoneal metastases from colorectal cancer The potential of HIPEC as an adjunct to surgery in ovarian cancer and peritoneal mesothelioma is promising but has not been demonstrated in controlled randomized trials to fall exponentially to half its (peri)vascular concentration after a distance of μm. 24 In preclinical models, intraperitoneal drug penetration could be enhanced by lowering the IFP, by using hypotonic carrier fluids, or by increasing the intraperitoneal pressure The efficacy of the drug ultimately depends on the intracellular concentrations that result from active and passive transport across the cell membrane. Recent evidence suggests that the copper transporter, CTR1, mediates the transport of cisplatin into tumor cells, and that exposure of the cell to cisplatin triggers downregulation of CTR1. 19,20 Implementation of IP drug delivery The practical implementation of intraperitoneal cytotoxic drug therapy in cancer patients has developed along two paths. The first method is to administer the drug in a saline solution by means of an indwelling peritoneal catheter. The presence of a peritoneal access route allows repeated intraperitoneal drug administration. In order to ensure maximal contact of the instilled drug with the peritoneal surfaces, it is imperative to instill a sufficient volume of carrier fluid resulting in a belly bath. 28,29 It should be realized, however, that in the postoperative setting, extensive adhesions usually preclude uniform access of the instilled solution to all peritoneal surfaces at risk. This method of intraperitoneal drug delivery has been used extensively in ovarian cancer trials. A second approach is to administer the drug as an intraoperative continuous chemoperfusion circuit immediately following surgical cytoreduction. This approach evidently ensures uniform distribution of the cytotoxic drug throughout the peritoneal cavity, because adhesions are either absent or surgically taken down. Intraoperative chemoperfusion can be performed after temporary skin closure ( closed perfusion) or with the abdominal cavity left open and the abdominal wall attached to a retractor frame ( open or coliseum technique). Theoretical advantages of closed perfusion include prevention of contamination of the operative environment and the possibility to enhance drug delivery by increasing the intra abdominal nature REvIEWS ClInICAl oncology volume 7 FEBRuARy

3 Table 1 Properties of cytotoxic agents used during intraoperative or early postoperative intraperitoneal chemotherapy Drug Alkylating agents Molecular weight (Daltons) Intraperitoneal dose (mg/m 2 ) Area under concentration-time curve ratio* Drug penetration distance Mitomycin C mm + Platinum compounds Cisplatin mm + Carboplatin mm + Oxaliplatin mm + Antimicrotubule agents Paclitaxel More than 80 cell layers Docetaxel Topoisomerase interactive agents Mitoxantrone cell layers ± Doxorubicin cell layers + Antimetabolites 5 Fluorouracil mm Thermal enhancement Not studied *Only data referring to clinical studies with hyperthermic chemoperfusion + and refer to observed (or not) thermal enhancement of efficacy. Abbreviation:, not available. pressure. 27 Chemoperfusion with the abdomen left open, on the other hand, allows manipu lation of the abdominal contents in order to ensure homogeneous exposure of all serosal surfaces. The main rationale for using a recirculating perfusion circuit during intraoperative chemoperfusion is the possibility of administering the drug under hyperthermic conditions. First described by Spratt in 1980, hyperthermic intraperitoneal chemoperfusion (HIPEC) is increasingly used as an adjunct to surgery in patients with peritoneal surface malignancy. 30 The rationale for hyperthermic drug administration is based mainly on thermal enhancement of the cytotoxicity of many cytostatic drugs including alkylating agents and platinum compounds. 31 moreover, moderate hyperthermia increases tumor blood supply and oxygenation resulting in increased sensitivity to both radiotherapy and chemotherapy. 32 Hyperthermia has also been shown to enhance drug penetration into solid tumors. los and colleagues demonstrated a significant increase in peritoneal tumor platinum concentrations when intra peritoneal cis platin therapy was combined with regional hyperthermia (41.5 C) in a rat colon cancer model. 33 A similar effect was reported when hyperthermia was used with intraperitoneal carboplatin, but the increased tumor platinum concentrations were the result of increased systemic drug exposure. 34 Hyperthermic enhancement of cytotoxic drug delivery in preclinical models has also been demonstrated for oxaliplatin and doxorubicin. 35,36 Some authors have combined cytoreduction and HIPEC with early postoperative intraperitoneal chemotherapy using a daily instillation of 5 fluorouracil (5 Fu) during 5 days. 37 This approach might be reasonable in patients with minimal residual disease after surgery. Direct comparisons of the different therapy modalities are not yet available. Postoperative adjuvant IP chemotherapy ovarian cancer numerous phase I and II trials were initiated using platinum based intraperitoneal chemotherapy as a second line therapy in patients with persistent or recurrent epithelial ovarian cancer following systemic chemotherapy. The results of these trials showed complete response rates ranging from 20% to more than 40%. 38,39 The biological effectiveness of intraperitoneal chemotherapy is optimal in patients with small size residual tumor depo sits, previous platinum sensitivity, and low preoperative CA125 level. 40,41 Interestingly, in a phase I pharmaco logical study using intraperitoneal paclitaxel, dose levels more than 60 mg/m 2 resulted in cytotoxic intra peritoneal paclitaxel concentrations that remained up to 1 week after drug administration. 42 Subsequently, intra peritoneal platinum based chemotherapy was studied as a first line treatment in patients with minimal residual disease follow ing initial cytoreduction in several large rando mized trials performed by us cooperative groups (Table 2). These trials demonstrated a consistent and clinically meaningful improvement of progressionfree and overall survival, which lead the us national Cancer Institute in January 2006 to recommend that strong consideration is given to a regimen containing intraperitoneal cisplatin and a taxane following optimal cyto reduction in women with stage III ovarian cancer. 43 Further support for intra peritoneal drug therapy was provided by meta analysis by the Cochrane group and data from Kyrgiou et al. 44 who demonstrated that intraperitoneal chemotherapy was 98% likely to represent the most effective chemotherapy regimen for ovarian cancer. nevertheless, intra peritoneal chemotherapy for ovarian cancer remains a matter of debate for a number of reasons. 45 First, technical problems and locoregional 110 february 2010 volume 7

4 toxic effects could limit the applicability of locoregional drug therapy. Second, optimal cytoreduction often entails colorectal procedures and many clinicians will hesitate to implant an intraperitoneal delivery system in this circumstance. Finally, heterogeneous intravenous and intraperitoneal regimens were used in randomized trials, and some of the control arms included intra venous regimens that were no longer considered the standard of care at the time of analysis. Colorectal cancer Approximately one in five patients with colorectal cancer (CRC) harbor peritoneal minimal residual disease after surgical resection while peritoneal carcinomatosis develops in about one in seven patients. 46 Therefore, there is a strong rationale for intraperitoneal chemo therapy following complete resection of locally advanced (T3 or T4) CRC. In animal models of CRC, intra peritoneal administration of chemotherapy successfully prevented tumor development following intraperitoneal injection of cancer cells. 47 Clinical studies have thus far not shown any benefit of adjuvant intraperitoneal chemo therapy in CRC. vaillant and coworkers randomly allocated 267 stage II and III CRC patients to either surgery alone or surgery combined with intraoperative intravenous 5 Fu and postoperative intra peritoneal 5 Fu. 48 Overall, the experimental therapy failed to improve disease free survival (DFS), overall survival, or the frequency of peritoneal recurrence. An unplanned subgroup analysis of the data indicated a DFS benefit in patients with stage II disease. Similarly, the randomized trial by nordlinger et al. 49 failed to show any benefit of immediate post operative regional chemotherapy (intraperitoneal or intraportal according to treatment center) followed by intravenous chemotherapy compared with intravenous chemotherapy alone in patients with resected stage II or III CRC. Both of these trials, however, are unable to definitely determine the role of adjuvant intra peritoneal chemotherapy in patients with CRC at high risk of peritoneal recurrence. Drug supply Dose concentration IFP, cell density, vascularity, ECM properties Blood vessels Drug supply Diffusion Convection Tumor nodule Figure 1 Schematic representation of drug penetration into peritoneal tumors. Drug supply is a function of pharmacokinetic parameters such as dose, concentration, and exposure time. Drugs enter the periphery of the tumor by diffusion and convection. The extent of penetration will depend on the chemical properties of the drug and on biophysical tumor tissue structure. Once inside the cell, the drug will accumulate into tumor cells by binding to target structures, nonspecific binding, and sequestration in cellular organelles. A fraction of the drug will be altered by metabolic pathways. Drugs present in the microcirculation will also be absorbed into the tumors in the immediate vicinity of blood vessels (that is, ovals). Systemic drug absorption occurs both in submesothelial tissue space and in tumor tissue. Abbreviations: ECM, extracellular matrix; IFP, interstitial fluid pressure; MW, molecular weight. Hyperthermic intraperitoneal chemoperfusion ovarian cancer The theoretical rationale for HIPEC for the treatment of stage III ovarian cancer is to combine the demonstrated biological activity of intraperitoneal chemotherapy in this disease with the advantages of intraoperative chemo perfusion, that is, the possibility to exploit thermal enhancement of cytotoxicity, to provide a complete and homogeneous peritoneal surface exposure and to prevent free tumor cell implantation to surgical wound surfaces. A variety of chemotherapeutic regimens and delivery methods have been reported in various phase II trials of HIPEC in advanced or recurrent ovarian cancer. Only two trials, however, have reported on more than 50 patients. 50,51 A systematic review of the available early phase clinical data suggested promising overall survival outcomes (range months) while the associated morbidity and mortality (5% 36% and 3%, respectively) are in keeping with that of other major abdominal procedures. 52 There is a clear need for well designed randomized trials to define the place of HIPEC as an adjunct to optimal cytoreduction in patients with stage III ovarian cancer. 53 A randomized trial of secondary cytoreduction with or without HIPEC was initiated at the netherlands Cancer Institute and is expected to complete enrollment in 2011 (OvHIPEC trial; ClinicalTrials.gov identifier: nct nct ). Appendiceal mucinous tumors Appendiceal mucinous neoplasms represent a rare, histologically heterogeneous entity that encompass mucinous adenoma, mucinous neoplasms with uncertain or low malignant potential, and mucinous carcinoma. 54 When ruptured, low grade tumors can cause accumulation of mucinous ascites, giving rise to the pseudomyxoma peritonei syndrome, which is a clinical or radiological descriptor rather than a histopathological diagnosis. 55 Impressive long term survival results using extensive cytoreduction and HIPEC procedures have been achieved in patients with this syndrome Therefore, this approach has been proposed as the standard of care in patients with low grade appendiceal tumors associated with pseudomyxoma peritonei. 59 Others have argued that the outcome achieved in these patients is because of a favorable tumor biology and that, given the proven prognostic impact of complete surgical cytoreduction, the contribution of intraperitoneal chemoperfusion remains uncertain. 60 Colon cancer Since peritoneal carcinomatosis without systemic spread is found in 3% of patients with CRC, this subgroup MW, size, charge, ionization, temperature, water/lipid solubility Binding, metabolism, sequestration Submesothelial tissue nature REvIEWS ClInICAl oncology volume 7 FEBRuARy

5 Box 1 Drug transport by diffusion The rate of diffusive mass transport (DMT) can be described by the following equation: 15 DMT = MTC A (C per C pl ) where MTC represents the mass transfer coefficient which is related to the square root of the molecular weight of the agent, A the peritoneal contact area, C per and C pl the peritoneal and plasma concentrations respectively. The rate of solute convection (rsc) can be modeled as: rsc = K T C pl R i A dp/dx where K T is the hydraulic conductivity of the tissue, R i the fraction of drug that passes through the interstitial space at the same rate as the solvent, and dp/dx the slope of the hydrostatic pressure profile in the tissue. 16 This pressure profile results from the difference between the intraperitoneal pressure and the interstitial fluid pressure (IFP) within the tumor. might benefit from cytoreduction followed by HIPEC. 61 The results from a multinational retrospective analysis of 506 patients with CRC treated with cytoreduction and HIPEC showed an overall median survival of 19 months; patients in whom a complete cytoreduction was achieved had a median survival of 32.4 months. 62 multivariate analysis revealed that other variables associated with survival were treatment by a second procedure, limited disease extent, age <65 years, and use of adjuvant chemotherapy. verwaal and co authors reported a randomized controlled trial comparing systemic 5 Fu/ leucovorin and palliative surgery when required versus extensive cytoreduction and HIPEC using mitomycin C followed by systemic 5 Fu/lv in patients with perito neal carcinomatosis from colorectal origin. 63,64 The median disease specific survival was 12.6 months in the control arm and 22.2 months in the cyto reduction with HIPEC arm (P = 0.028); the survival was significantly better in patients with no more than five of seven abdominal regions affected and in patients in whom a macro scopically complete resection was achieved. The significance of this trial is somewhat limited by the use of systemic chemotherapy that is no longer regarded as the standard of care in this setting, and by the fact that the question of whether extensive cyto reduction in itself (without added HIPEC) would achieve a similar outcome remains un answered. The systematic review by yan et al. 37 confirmed the importance of achieving a complete cyto reduction because this procedure translated into a median survival from 28 to 60 months and 5 year overall survival ranging from 22% to 49%. The overall quality of the available evidence is, however, rather low and a potentially serious post operative compli cation rate should be taken into account. A consistent finding is that optimal results can be expected in patients with a limited disease burden in whom a complete resection can be achieved. Several scoring methods have been proposed in an effort to quantify both the extent of peritoneal disease and the completeness of resection. The peritoneal cancer index (PCI), first described by Sugarbaker in 1996, is a detailed score (range 0 39) obtained by summating the tumor size in 13 abdominal regions. 65 Other, simpler scoring methods were shown to be as effective as the PCI in predicting the probability of a complete resection. 66 One possible explanation for this finding is the fact that the possibility to obtain a complete resection depends not so much on the size and number of peritoneal lesions but on their location. The results of cytoreduction and HIPEC in CRC should be weighed against what can be achieved with modern systemic chemotherapy. Only very limited data are available on the efficacy of systemic chemotherapy in peritoneal cancer from CRC origin. In chemo therapy trials of metastatic CRC including information on the patient s peritoneal cancer status, the presence of perito neal cancer was associated with a significantly worse response rate, progression free survival, and overall survival. 67,68 Elias et al. 69 performed a retro spective compa rison of a group of patients who underwent cytoreduction and HIPEC with a matched group who received systemic chemo therapy containing oxaliplatin or irino tecan. A significant survival advantage was found in favor of cytoreduction and HIPEC (median overall survival 23.9 months versus 62.7 months, P<0.05). Taken together, these results suggest a potentially important role for cytoreduction and HIPEC in patients with completely resectable peritoneal cancer from CRC origin although the specific role of HIPEC itself remains unclear. Important data in this regard could be generated by the Prodige 7 multicenter randomized trial initiated in France by the Fédération nationale des Centres de lutte Contre le Cancer, which will compare cyto reduction alone versus cytoreduction with HIPEC in patients with peritoneal cancer from CRC (ClinicalTrials.gov Identifier: nct show/nct ). other tumor types Promising results have been obtained using cytoreduction and HIPEC in patients with malignant peritoneal mesothelioma, a condition for which very few other effective therapy options are available. A recent systematic review of six published series totaling 240 patients, showed a median survival ranging from 34 to 92 months. 70 In patients with ct3 resectable gastric cancer at high risk of peritoneal recurrence, surgery with adjuvant HIPEC has been studied in 13 small randomized trials. A metaanalysis of these trials showed a significant improvement in overall survival using surgery and adjuvant HIPEC (HR = 0.60; 95% CI = ; P = 0.002) or surgery and adjuvant HIPEC combined with early postoperative intraperitoneal chemotherapy compared with surgery alone (HR = 0.45; 95% CI = ; P = ). 71 Toxic effects of IP chemotherapy The results of relevant randomized trials have shown that when used as a component of adjuvant firstline therapy in minimal residual disease ovarian cancer, intra peritoneal chemotherapy is associated with a signifi cant risk of catheter related complications and 112 february 2010 volume 7

6 Table 2 randomized trials of first line platinum based intraperitoneal chemotherapy study number of patients Therapy Intravenous Intraperitoneal Median PFs (months) Hazard ratio results Median os (months) Hazard ratio Alberts et al. (1996) Cyclophosphamide 600 mg/m 2 Cyclophosphamide 600 mg/m 2 plus cisplatin 100 mg/m 2 Cisplatin 100 mg/m Markman et al. (2001) Carboplatin AUC 9 plus paclitaxel 135 mg/m 2 Paclitaxel 135 mg/m 2 plus cisplatin 75 mg/m 2 Cisplatin 100 mg/m Armstrong et al. (2006) Paclitaxel 135 mg/m 2 plus paclitaxel 60 mg/m 2 Paclitaxel 135 mg/m 2 plus cisplatin 75 mg/m 2 Cisplatin 100 mg/m 2 plus paclitaxel 60 mg/m Abbreviation: AUC, area under the concentration versus time curve. locoregional toxi city. 72 The incidence of life threatening (grade 3 or 4) bone marrow toxic effects were significantly increased in the intraperitoneal arm (containing cisplatin and paclitaxel) of the GOG172 trial, but in the other six randomized trials comparing intravenous with combined intravenous and intra peritoneal chemotherapy either no significant difference was detected or intraperitoneal therapy was associated with a reduced risk. 43 locoregional toxic effects (abdominal pain, infection) and catheter related problems such as obstruction or dislocation caused the completion rate of intra peritoneal regimens to vary between 40 and 70%. In subsequent reports the com pletion rate of intraperitoneal chemo therapy has been much higher due to technical precautions such as the avoidance of catheters with fenes trations or Dacron cuffs, the systematic use of implantable ports, and delayed insertion when bowel resection is necessary. 73 Although cytoreduction with HIPEC represents a considerable undertaking, the associated mortality and morbidity do not differ from that of other major abdo minal procedures. The documented mortality rates ranges from 3 8% while postoperative morbidity rates from 20 50% have been described. 74,75 Chemoperfusion with highdose oxaliplatin, which has to be administered in dextrose 5%, causes manageable electrolyte and metabolic disturbances. 76 The adverse effects associ ated with hyperthermia itself consists mainly of prolonged post operative ileus and temperature dependent edema of the small bowel. In animal models, colonic anas tomotic healing was impaired by a combination of hyperthermia with either chemotherapy or radiotherapy, but not by hyperthermia alone. 77,78 Jacquet and coauthors noted increased morbidity and mortality with rising intra abdominal target temperature, suggesting that mild hyperthermia (<41 C) might be safer than pronounced hyperthermia. 79 Conclusions and future perspectives Intraperitoneal drug delivery has demonstrated efficacy in patients with minimal or microscopic residual tumors confined to the peritoneal cavity. As a first line therapy in ovarian cancer, three large randomized trials have shown a significant improvement in survival with the addition of a platinum based intraperitoneal adjuvant chemotherapy component. Additional clinical trials that use less toxic intraperitoneal regimens and incorporating intravenous regimens currently regarded as the standard of care are needed to definitively establish the role of intraperitoneal adjuvant chemotherapy in the management of stage III ovarian cancer. Intraperitoneal drug delivery should be regarded as complementing intravenous chemotherapy, not as a competing strategy. Promising results have been obtained in a variety of tumor types using cytoreduction and HIPEC. This multimodal approach is regarded as the optimal therapy of mucinous appendiceal neoplasms, and a rando mized trial has demonstrated a significant survival gain compared with palliative therapy alone in peritoneal meta stases from colorectal cancer. The adverse effects associated with the combined approach are, however, substantial and randomized trials are urgently needed in order to better define the patient populations who might benefit, and to promote uniformity amongst the myriad of available hyper thermic drug delivery methods. Review criteria A systematic search was performed using the ISI Web of Knowledge (Thomson reuters). The search identified articles published before 1 May 2009 and no language restrictions were applied. A boolean search was initiated using the search terms intraperitoneal or intracavitary and chemother* or cytotoxic. Additional references were retrieved from the reference lists of identified papers and from several books published on the topic. 1. Warrick, C. 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7 of ovarian cancer. Cancer Treat. Rep. 62, 1 (1978). 4. Markman, M. Strategies to examine new compounds for intraperitoneal use in ovarian cancer. Int. J. Gynecol. Cancer 18, (2008). 5. Li, X. F. et al. visualization of hypoxia in microscopic tumors by immunofluorescent microscopy. Cancer Res. 67, (2007). 6. Jakobsen, A. & Mortensen, L. S. On the importance of sensitivity to the dose effect relationship in chemotherapy. Acta Oncol. 36, (1997). 7. Alberts, D. S., Young, L., Mason, N. & Salmon, S. E. In vitro evaluation of anticancer drugs against ovarian cancer at concentrations achievable by intraperitoneal administration. Semin. Oncol. 12, (1985). 8. Andrews, P. A., velury, S., Mann, S. C. & Howell, S. B. Cis Diamminedichloroplatinum(Ii) accumulation in sensitive and resistant human ovarian carcinoma sells. Cancer Res. 48, (1988). 9. Matsushima, Y. et al. Time schedule dependency of the inhibiting activity of various anticancer drugs in the clonogenic assay. Cancer Chemother. 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Penetration and binding of vinblastine and 5 fluorouracil in cellular spheroids. Cancer Chemother. Pharmacol. 13, (1984). 22. van de vaart, P. J. M. et al. Intraperitoneal cisplatin with regional hyperthermia in advanced ovarian cancer: Pharmacokinetics and cisplatin D adduct formation in patients and ovarian cancer cell lines. Eur. J. Cancer 34, (1998). 23. Minchinton, A. I. & Tannock, I. F. Drug penetration in solid tumors. Nat. Rev. Cancer 6, (2006). 24. Primeau, A. J., rendon, A., Hedley, D., Lilge, L. & Tannock, I. F. The distribution of the anticancer drug doxorubicin in relation to blood vessels in solid tumors. Clin. Cancer Res. 11, (2005). 25. Jang, S. H., Wientjes, M. G. & Au, J. L. S. Enhancement of paclitaxel delivery to solid tumors by apoptosis inducing pretreatment: Effect of treatment schedule. J. Pharmacol. Exp. Ther. 296, (2001). 26. Kondo, A. et al. Hypotonic intraperitoneal cisplatin chemotherapy for peritoneal carcinomatosis in mice. Br. J. Cancer 73, (1996). 27. Esquis, P. et al. High intra abdominal pressure enhances the penetration and antitumor effect of intraperitoneal cisplatin on experimental peritoneal carcinomatosis. Ann. Surg. 244, (2006). 28. Jones, r. B. et al. High volume intraperitoneal chemotherapy with methotrexate in patients with cancer. Cancer Res. 41, (1981). 29. Devita, v. T. Let s return to the belly bath. Nat. Clin. Pract. Oncol. 3, 405 (2006). 30. Spratt, J. S., Adcock, r. A., Muskovin, M., Sherrill, W. & Mckeown, J. Clinical delivery system for intra peritoneal hyperthermic chemotherapy. Cancer Res. 40, (1980). 31. Issels, r. D. Hyperthermia adds to chemotherapy. Eur. J. Cancer 44, (2008). 32. Sun, X. r. et al. Changes in tumor hypoxia induced by mild temperature hyperthermia as assessed by dual tracer immunohistochemistry. Radiother. Oncol. 88, (2008). 33. Los, G. et al. Optimization of intraperitoneal cisplatin therapy with regional hyperthermia in rats. Eur. J. Cancer 27, (1991). 34. Los, G. et al. 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