Clin Transl Oncol (2010) 12:794-804 DOI 10.1007/s12094-010-0601-x

E D U C AT I O N A L S E R I E S

Red Series

CURRENT TECHNOLOGY IN CANCER RESEARCH AND TREATMENT

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignant disease Wenceslao Vásquez Jiménez · Luis González Bayón · José Luis García-Sabrido · Santiago González Moreno

Received: 19 September 2010 / Accepted: 13 October 2010

Abstract Peritoneal Malignant Disease (PMD) is the presence of tumoral tissue on the peritoneal surface from primary tumors or tumors from other locations (e.g. digestive or gynecologic). It is a regional disease with poor prognosis when treated with repeated “debulking” and traditional systemic chemotherapy. Cytoreduction plus hyperthermic intraperitoneal chemotherapy (HIPEC) is a combined multimodal regional procedure aimed at reducing the macroscopic tumoral mass as much as possible and treating with chemotherapy the microscopic disease that is out of the scope of the surgeon. This combined treatment may change the natural history of PMD, it is translated into a higher overall survival and cancer-free survival and it offers the option of cure in selected cases. The high-complexity procedure is also associated with complications and mortality, but in similar rates as other major oncologic procedures. Keywords Cytoreductive surgery · Hyperthermic intraperitoneal chemotherapy · Peritoneal malignant disease · Carcinomatosis

W. Vásquez Jiménez (쾷) · L. González Bayón · J.L. García-Sabrido Department of General Surgery Gregorio Marañón General Hospital Dr. Esquerdo, 46 ES-28007 Madrid, Spain email: [email protected] S. González Moreno Department of Surgical Oncology Peritoneal Surface Oncology Program Centro Oncológico M. D. Anderson International España Madrid, Spain

Introduction Peritoneal malignant disease (PMD) is the presence of malignant tissue on the peritoneal surface and may have a mesothelial primary origin or be secondary at spread of digestive, gynaecologic or retroperitoneal malignant tumours [1, 2]. The incidence of primary PMD is rare globally, e.g., malignant mesothelioma (2000/year), serous adenocarcinoma (20,000/year) and desmoplastic round cell tumours (100 cases/year). Furthermore, the incidence at secondary disease is considerable. In synchronous PMD, incidence is between 7% and 10% and in recurrence between 20% and 40% [1, 2]. The clinical manifestations of PMD are not specific and usually it starts with an increase of abdominal girth as an expression of accumulation of ascites, mucin or tumour, respiratory insufficiency due to increase in intra-abdominal pressure and limitation of diaphragmatic movement, abdominal pain, total or partial intestinal obstruction, and malnutrition. The median survival of PMD patients after diagnosis is between 3 and 6 months [3, 4]. At the beginning of the 1980s the concept of regional treatment for PMD was developed. This consisted of cytoreduction aimed at treating macroscopic disease and administration of perioperative intraperitoneal chemotherapy aimed at treating residual microscopic disease [5–7]. Cytoreduction plus perioperative intraperitoneal chemotherapy is the elective treatment for PMD of appendicular cancer [8] and colorectal [9, 10], mesothelioma [11, 12] and epithelial ovarian cancer [13, 14]. This is also efficacious and safe for peritoneal extensions of gastric cancer [15–17] and peritoneal sarcomatosis [18]. This therapeutic strategy is neither competitive nor exclusive with the current systemic treatment, and actually can be favoured over induction therapy to downsize perito-

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neal disease and/or as consolidation therapy after optimal cytoreduction.

Natural history of malignant peritoneal disease Structure of the peritoneal cavity To understand PMD, knowledge of the anatomical structure of the peritoneal cavity and the interactions among its components is necessary. The peritoneal cavity consists of a coating mesothelial layer and an underlying lymphatic and capillary network. The peritoneum is the first line of defence against tumour cells free in the abdominal cavity [19]. During administration of intraperitoneal cytotoxic drugs, the peritoneum– blood barrier allows the exposure of the peritoneal tissue to high drug concentrations with very little passage to the systemic circulation. These cytotoxic concentrations in intraperitoneal tissues are not reached with standard intravenous administration. The peritoneum–blood barrier mainly consists of the extracellular matrix below the mesothelium, muscle cells and glycoproteins of the endothelial layer of the capillary vessels [1, 2]. The peritoneal surface covers between 1 and 2 m 2, which is similar to the total body surface. The peritoneal mesothelium consists of 2 layers: the visceral peritoneum, which covers all organs, and the parietal peritoneum, which coats the anterior, lateral and posterior abdominal wall as well as the diaphragm and pelvis [2].

Dissemination mechanism Dissemination mechanisms may be spontaneous or iatrogenic. Spontaneous mechanisms are related to anarchic tumoral growth. In the case of digestive cancers these originate in the mucous layer and grow towards the serous layer. Once the tumours reach the visceral peritoneum the detachment of tumour cells into the peritoneal cavity takes place. This detachment is expedited by: (1) a reduction of intercellular adhesion molecules, especially cadherin E; (2) the absence of lymphatic drainage of the tumour, which causes increased interstitial pressure; and (3) ischaemic phenomena on the tumour surface [1, 20, 21]. Iatrogenic mechanisms include tumour handling with detachment of tumour cells, residual microscopic disease associated with insufficient surgical margins, and leakage of circulating tumour cells from lymphatic and blood vessels [2, 20, 21].

Dynamics of tumour cells Circulation of free tumour cells within the peritoneal cavity is due to: (1) gravity force, (2) respiratory diaphragmatic

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movement, which displaces the peritoneal fluid in a cephalic direction; and (3) ascitic fluid and tumour cell reabsorption in the greater omentum and diaphragmatic peritoneum. These mechanisms provoke a clockwise movement of fluid, which explains the deposit of tumour cells in slope zones such as Douglas’ pouch and the paracolic gutters. There are places of greater absorption such as the right diaphragmatic peritoneum and greater omentum. The higher concentration of tumour implants of plaque shape at these locations configures the liver scalloping and omental cake, respectively [1, 2, 21]. Visceral structures fixed to the retroperitoneum and with little movement, such as the ileocaecal valve and subpyloric space, also cause tumour cells to accumulate. In previously operated patients, visceral spaces that are fused due to adherences become “tumour sanctuaries”. Here, tumour cells are covered with fibrin, isolated from the cellular immune response and from the systemic cytostatic drugs [1, 2, 21]. Autonomous displacement movements within the peritoneal cavity have been described for colorectal tumour cells due to the force generated after polymerisation of actin microfilaments. These movements are known as lamellipodia and filipodia [22, 23].

Tumour cell adhesion Free tumour cells within the peritoneal cavity can adhere to mesothelial cells that coat the healthy peritoneum, to the extracellular matrix or to specialised structures such as the greater omentum and/or diaphragmatic peritoneum. The adhesion is provoked by ligand-receptor mechanisms. Mesothelial cells of the healthy peritoneum have molecules of cellular adhesion such as VCAM-1, ICAM-1 and PECAM-1. In areas without mesothelial cells, adhesion is possible due to the existence of proteins such as ß1 integrins [24, 25].

Implantation Tumour cells located on the peritoneal mesothelium have invasive capacity through the following mechanisms: (1) proliferation and hypoxia of mesothelial cells, which induces the production of angiogenic factors such as vascular endothelial growth factor A (VEGF-A) [26]; (2) disruption of intercellular gaps in response to inflammatory mediators (e.g., hepatocyte growth factor/scatter factor HGF/ SF) [27]; (3) degradation of the extracellular matrix by metalloproteinases (MMP-7 in gastric cancer-associated carcinomatosis and MMP-9 in ovarian cancer-associated carcinomatosis) [28, 29]; and (4) induction of apoptosis of mesothelial cells and penetration to the submesothelial space, as demonstrated by Heath et al [30]. The avidity of tumour cells to implant in tissues such as the greater omentum is explained by its structure without mesothelium. This allows direct exposure of the basal membrane and a high density of blood vessels and nutrients. On the other hand, there are immune conglomerates

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during the intraoperatory period and intraperitoneal methotrexate in the immediate postoperative period. At discharge, the patient was in good condition [38, 39]. In 1978, Robert Dedrick [40], at the US. National Cancer Institute, designed the first pharmacokinetical model of the treatment of peritoneal carcinomatosis due to ovarian cancer. Dedrick found that drug concentrations in the peritoneum can be as high as 100 times that in blood. Paul H. Sugarbaker [5–7] consolidated the regional approach of MPD and its multimodal combined treatment. He has published several basic science and clinical studies regarding this treatment with high impact on the scientific community. Currently, this treatment is used in 4 continents around the world. Fig. 1 Peritoneal carcinomatosis with bowel and omentum involvement

called “milky spots”, like lymphatic organs, on the greater omentum, and right diaphragmatic and pelvic peritoneum, which tumour cells [31, 32] (Fig. 1).

Regional approach to malignant peritoneal disease PMD has been considered for a long time as a systemic manifestation of highly aggressive cancers, with very short life expectancy, susceptible only to palliative treatment (debulking, intestinal bypass, multiple paracentesis, ostomies) and often only therapeutic abstention (“open and close”) [33]. Currently it is known that peritoneal carcinomatosis may be present in tumours, without lymph node or blood dissemination, exclusively with regional disease within the abdominal cavity, and susceptible to cure with the use of cytoreduction and perioperative intraperitoneal chemotherapy.

History of intraperitoneal treatment The first documented type of intraperitoneal treatment is from the 18th century (1744). Christopher Warrick, a British surgeon, administered a combination of “Bristol water” and “Claret” (a type of Bordeaux wine) in the peritoneal cavity of a woman with refractory ascites and he controlled her disease [34]. Afterwards, some attempts were made to administrate intraperitoneal “drugs” in order to control malignant peritoneal diseases (MPDs). The “drugs” included nitrogen mustard, radioactive gold and 5-fluorouracil, and their results were poor [35–37]. The first extensive cytoreduction and administration of hyperthermic intraperitoneal intraoperative chemotherapy was done by John Spratt in 1979, at the Surgery Department of the University of Louisville, Kentucky, USA. The patient had pseudomyxoma peritonei secondary to a pancreatic cystoadenoma. Intraperitoneal thiotepa was used

Technical aspects Cytoreduction Cytoreduction consists of the maximal removal of a malignant tumour from the peritoneal surface and abdominal viscera. Surgical cytoreduction includes visceral resection and peritoneal resections. Energy-mediated cytoreduction consists of electroevaporation of small nodules or tumour plaques [41, 42]. Visceral resections include gastric, colorectal, small intestine, spleen, uterus and ovaries. It is important to realise that small intestine resections should be conservative, as less than 200 cm of length is strongly associated with short-intestine syndrome, and it is even worse when chemotherapy has previously been administered [43–45]. In patients with peritoneal carcinomatosis due to colorectal cancer and single or peripheral liver metastases it is recommended to perform atypical liver resections in order to warrant complete cytoreduction. When hepatic resection was performed at the same time as cytoreduction, there was no significant impact on prognosis [46, 47]. In a recent study Franko et al. found that multivisceral resections (i.e., involving 2 or more viscera) were not associated with higher morbidity. However, the number of intestinal anastomoses did increase the risk of complications [48]. Peritonectomies were classified by Sugarbaker [41–43] into 6 regions: (1) anterior abdominal wall, (2) right hemidiaphragm and Glisson’s capsule, (3) left hemidiaphragm and greater omentum, (4) hepatoduodenal ligament, cholecystectomy and lesser omentum, (5) parietocolic gutters and (6) pelvic peritoneum. Most authors recommended resection of all of these regions in those patients with primary peritoneal tumours, such as serous papillary adenocarcinoma and peritoneal mesothelioma. A selective resection is preserved for those peritoneal regions affected by gynaecologic and digestive cancers [49]. Electroevaporation-mediated cytoreduction of small, isolated tumour implants is done on the gastric surface, Glisson’s capsule and small intestine. This procedure is performed either on the wall or on the mesenterium. Highvoltage electrocauterisation, radiofrequency (Tissuelink)

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Table 1 Mean cytotoxic drug use with HIPEC Tumor

Drug

MW (Da)

Ipd (mg/m2)

Drug penetration distance

Thermal potentiation

Digestive adenocarcinoma

Mitomycin C Oxaliplatin Docetaxel 5-Fluoracilo Cisplatin Carboplatin Adriamycin

334.3 397.3 861.9 130.1 300.1 371.3 543.5

35 460 40-156 650 90-120 350-800 60-75

2 mm 1-2 mm NA 0.2 mm 1-3 mm 0.5 mm 4-6 cells layers

+ + + – + + +

Ovarian epitelial tumor/primary peritoneal adenocarcinoma/ sarcomatosis

MW, molecular weight; Ipd, intraperitoneal dose

and/or Argon beam coagulator are the most successful techniques [43, 49]. It is important to be careful when using electroevaporation of hollow viscera (small intestine, colon) due to the high risk of ischaemia, unnoticed perforation and fistulisation [43]. Intraperitoneal administration of chemotherapy The peritoneum–blood barrier allows high concentrations of cytotoxic drugs within the peritoneal cavity, with scarce passage of drugs to the systemic circulation and therefore minimum systemic toxicity. The ideal chemotherapy for intraperitoneal administration should have: (1) demonstrated cytotoxic activity against the specific malignant cell to be treated, (2) no dependence on cell cycle, (3) a high molecular weight to assure its permanence within the peritoneal cavity, (4) independence from hepatic activation and no production of toxic hepatic metabolites, and (5) safe drug status, i.e., with low blood levels and without toxicity [50–52]. The pharmacokinetics of intraperitoneal cytostatics have been studied in several mathematical models. That of Dedrick et al. is the most accepted and has the best predictions [40]. This is a bicompartmental model, including an intravascular compartment (systemic blood circulation) and the intracavitary peritoneal compartment. These compartments are separated from each other by the peritoneum– blood barrier [40, 51]. Tissue penetration of an intraperitoneal cytostatic follows the calculation of pharmacokinetics and pharmacodynamics. Penetration is limited to about 1–2 mm or a few layers of tumoral cells [53–55] (Table 1). Therefore the largest benefit will occur in those patients with the smallest tumoral remnants (optimal cytoreduction CC0-CC1, equivalent to 0 mm or 25 mm). Complete cytoreduction is the most important predictive factor for survival. The perioperative administration could be hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC) with or without early postoperative intraperitoneal chemotherapy (EPIC).

tion is due to its direct harm to tumour cells, which are heatsensitive, the potentiating cytotoxic effect of some drugs and the enhancement of drug tissue penetration [56] (Table 1). The hyperthermic intraperitoneal intraoperative administration directly exposes tumour cells to the cytostatics, at concentrations that are not reached by systemic administration. Performing this administration before anastomosis is safe and allows these surfaces to be adequately treated, avoiding the implantation of these cells [57–59]. The hyperthermic intraperitoneal intraoperative administration may be performed by an open or a closed technique. The open technique consists of making a “coliseum” with a perfusion pump, which allows an almost constant flux of the cytostatic solution to be maintained. The closed technique consists of the temporary closure of the abdominal wall with the perfusion system and drainage let inside. Both techniques are valid and they are equally effective [60] (see Figs. 2 and 3).

EPIC The EPIC administration in normothermic conditions, from postoperative day 1 to 5, is becoming less frequent. In our experience EPIC has not demonstrated any positive effect on survival; however EPIC is associated with a higher risk of severe postoperative complications [61]. This is in line with the experience of other groups from Canada and Australia, which have also abandoned its use due to high toxicity [61–65]. Cytostatic administration is carried out according to the protocols for digestive and/or gynaecologic cancers (Table 1). Digestive/urinary reconstruction At this time, gastrointestinal anastomosis or ostomies are performed after HIPEC. Our group makes mechanical anastomosis with manual reinforcement. Sometimes, anastomoses of the urinary tract are needed.

Patient selection HIPEC Intraperitoneal intraoperative administration is done at 42– 43°C. The hyperthermic effect on the cytostatic administra-

For the adequate selection of patients it is necessary to evaluate the functional and biological reserve (ECOG

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A

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B

Fig. 2 a Intraoperative and intraperitoneal administration of open technique (“coliseum”). b Intraperitoneal intraoperative administration of hyperthermic chemotherapy through pump and heater machine

tic tumours (SRCDT), a pediatric tumour with a pattern of distribution exclusively located in the peritoneum and without accepted treatment, have become a natural candidate for maximal cytoreduction and HIPEC. This strategy has shown good outcomes (3-year survival of 71% for cytoreduction and HIPEC vs. 26% for either systemic chemotherapy or radiotherapy) [69]. Formally the selection of patients follows the following criteria: Inclusion criteria: – ECOG status performance <2 or Karnofsky >70% – absence of severe cardiac, pulmonary, renal and/or hepatic disease – absence of distant tumoral disease and/or unresectable hepatic or lymphatic disease Fig. 3 Survival in patients with pseudomyxoma peritonei syndrome with a different approach which included CR+HIPEC. Ref. [8], with authorisation

Exclusion criteria: – great vessel invasion – extensive biliary, urinary and/or intestinal obstruction Imaging

status/Karnofsky), the biology of the tumour and the extension of the peritoneal disease. Usually the profi le of candidate patients for cytoreduction and HIPEC consists of patients of median age, with a history of multiple surgeries, and with prior chemotherapy and/or radiotherapy [66]. Despite the opinion of most groups worldwide, we include patients up to 75 years old. We feel that this factor alone cannot be an impediment to receiving cytoreduction and HIPEC [61]. It is quite important to evaluate the functional and biological situation of the patient as demonstrated by Mueller et al. [67]. These investigators did not find significant differences in morbidity and mortality between 2 groups of patients with median ages of 65 and 75 who received cytoreduction and HIPEC. The experience in children for treatment of peritoneal carcinomatosis due to colorectal cancer and peritoneal mesothelioma is anecdotal [68]. Small round cell desmoplas-

The preoperative assessment with images is mainly based on multichannel helical CT scan with triple contrast (intravenous, oral and intrarectal). It is necessary to rule out extraabdominal disease and to evaluate the extension of the peritoneal disease as well as the compromised organs. It is known that an extensive disease in regions 2 (hepatic hilum compromising the hepatic artery, portal vein and the biliary tract) and 9–12 (small intestine) may not allow maximal cytoreduction [70–72]. The multichannel helical CT scan with triple contrast may underestimate the true extension of the peritoneal disease. Koh et al. studied the value of the CT scan in estimating the extension of peritoneal disease through the calculation of the peritoneal cancer index (PCI) in patients with carcinomatosis due to colorectal cancer. They found that the sensitivity of the index in determining the size of

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lesions was 60%. The underestimation rate was 33% and the overestimation was 7% of the cases [73]. The use of MRI is indicated in the assessment of the degree of compromise of the small intestine wall and its mesentery; however MRI is still a difficult test to interpret for oncologists and surgeons. A PET-CT offers the advantage of detecting extraabdominal disease and the disadvantage of lower sensitivity in carcinomatosis due to tumours with a low number of cells such as the mucinous appendicular tumours [74, 75]. The use of laparoscopy as a preoperative assessment method is associated with the true disease extension, but it is an invasive procedure. However, it may have benefit in those patients with doubtful imaging regarding the degree of extension of the small intestine [76].

Prognostic scores at cytoreduction Assessment of disease extension Several assessment tools exist for PMD extension. The PCI is the most commonly used and allows the assessment of disease according to the size of the implant (lesion size [LS] Score 0, absence of disease; LS 1, nodule up to 0.5 cm; LS 2, nodule between 0.5 and 5 cm; LS 3, nodule >5 cm or nodules forming a plaque) and also according to the regions compromised. PCI divides the abdominal cavity into 8 regions and the small bowel into another 4 regions. Minimal punctuation is 0 and maximal is 39 [41, 42, 77]. Extension of peritoneal disease is an important factor associated with prognosis, as has been concluded from retrospective studies for several types of tumours. The best PCI cut-offs associated with poor prognosis have been evaluated. For example, in PMD due to colorectal cancer the best cut-off lies between 16 and 20 [46, 61]. In PMD due to gastric cancer a PCI>10 is associated with poorer prognosis [78]. Also, in MPD due to mesothelioma a PCI>20 is the cut-off associated with worse prognosis [11]. However, in PMD due to appendicular cancer the best cut-off has not been determined, probably because it is difficult to determine the cellular/mucinous component of the disease.

Assessment of the degree of cytoreduction (CC score) The optimal category of remaining tumour nodules (completeness of cytoreduction [CC]-0 and CC-1) are those patients with residual disease between 0 and 0.25 cm. Suboptimal cytoreduction refers to tumoral remains larger than 0.25 cm (CC-2, CC-3). It has been proposed to adjust the categorisation of tumoral remains according to the histologic type, cellularity and invasion potential. In PMD due to gastric cancer and colorectal cancer, the best cytoreduction is CC0 and in other tumours, such as appendicular and

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mesothelioma tumours, the best cytoreduction is CC1 or CC2 (0.25 and 2.5 cm) [41, 42].

Outcomes Appendicular tumours Peritoneal pseudomyxoma is a syndrome that provokes abundant secretion of mucous ascites (“jelly belly”). It fills the peritoneal cavity and causes an increase in the abdominal perimeter, abdominal pain and malnutrition, and may generate intestinal obstruction. Peritoneal pseudomyxoma is a rare disease (1/106) that is more frequent in women. Most cases are secondary to the rupture of an epithelial appendicular tumour, perforated ovarian mucinous tumours, and, less frequently, colonic, pancreatic and gastric mucinous tumours. Appendicular tumours usually do not metastasise to the liver or lymph nodes; these tumours are classified as less aggressive, or ‘low grade’, and as more invasive and cellular, or ‘high grade’. The intermediate-grade appendicular tumours are included in the latter [79]. Traditional treatment of appendicular pseudomyxoma has been repeated ‘debulking’ limited to the tumour and, sometimes, systemic chemotherapy. However, none of these methods improved the disease and mucin accumulated again in a short period of time; they had no positive impact on survival. Miner et al. [80] studied the effect of extensive cytoreduction on 97 patients for a period of 22 years. They proposed that the best outcome of the treatment of pseudomyxoma peritonei was obtained in low-grade tumours and in those patients where complete cytoreduction was achieved. Survival at 5 years in low-grade tumours was 89% and in high-grade tumours was 41%; also, morbidity was 40% and disease-free survival only 2 years. The current gold standard of treatment of pseudomyxoma peritonei is maximal cytoreduction and HIPEC, providing a longer survival than other options. Sugarbaker studied 385 patients with pseudomyxoma peritonei and obtained a 20-year survival of 70% and morbidity of 27% (Fig. 3). This author found that good prognostic factors were the achievement of optimal cytoreduction and low-grade tumours [8]. Recently Elias et al. described the French experience in a multicentre study of 301 patients treated with cytoreduction and HIPEC. He found a 5-year survival of 73%, a 5-year disease-free survival of 56%, morbidity of 40% and procedure-related mortality of 4.4%. Independent prognostic factors for survival were extension of peritoneal disease and, secondarily, the tumour biology [81]. Our experience at Gregorio Marañón Hospital, Madrid, Spain, is similar to previous studies; our survival rate at 5 years is 87% and our disease-free survival at 5 years is 42% [61]. Although the evidence is in favour of the combined use of cytoreduction and HIPEC, it is necessary to establish

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Fig. 4 Kaplan-Meier survival estimates, by recidual. Long-term results of cytoreduction followed by HIPEC in colorectal carcinomatosis, divided according to completeness of cytoreduction (R1, no macroscopic residual disease; R2a, residual deposit <2.5 mm; and R2b, ≥2.5 mm). From Ref. [10], with authorisation

in clinical trials the contribution of the cytoreduction and HIPEC individually.

sis due to colorectal cancer with cytoreduction and HIPEC improved survival when compared with surgery and palliative treatment. Several phase I and II studies showed the benefits of this technique. Verwaal et al. [10], in a phase III study, compared a group receiving systemic chemotherapy and palliative surgery vs. a group receiving cytoreduction, HIPEC and adjuvant systemic chemotherapy. Median survival was larger in the second group (13 months vs. 22 months, p=0.03) (Fig. 4). One of the most important phase II studies on this disease included 523 patients with peritoneal carcinomatosis from 23 centres. Patients were treated with cytoreduction and HIPEC. The median survival was 30 months and severe morbidity (CTCAE III-IV) was 31% [46]. In the era of maximal cytoreduction and the use of new schemes of systemic chemotherapy (including monoclonal antibodies) for the treatment of colorectal metastases, the overall survival at 5 years (30–40%) of patients with peritoneal carcinomatosis treated with cytoreduction and HIPEC [10, 47, 61] is similar to that of those treated with liver resections (25–39%) [86] and pulmonary resections (21–43%) [85, 87] (Table 2).

Malignant peritoneal mesothelioma Colorectal cancer About 15% of patients with colorectal cancer have peritoneal metastases at the time of diagnosis. Those patients already treated with surgery and with curative intention usually have recurrence of 50%; among these patients, 25% have peritoneal extension only [82]. Survival of patients with carcinomatosis due to colorectal cancer and treated with surgery and palliative treatment used to be between 6 and 8 months. Currently metastatic colorectal cancer consists of hepatic and pulmonary metastasis and peritoneal carcinomatosis [83]. Studies with systemic chemotherapy and monoclonal antibodies have shown an increase in the median survival by 20 months [84]. However, the real effect of these treatments on the peritoneal disease component is not known. Cao et al. [47] found, in a meta-analysis of 4 trials and 43 observational studies, that the treatment of carcinomato-

Malignant peritoneal mesothelioma appears in and extends through the peritoneum and does not have metastasis to other organs. It is the fourth most frequent among all mesotheliomas; its incidence is very low, but has been diagnosed more frequently in recent years. This type of mesothelioma is directly associated with asbestos exposure and at the time of diagnosis 50% of patients also have pleural disease [88]. The traditional standard treatment for malignant peritoneal mesothelioma is surgery plus palliative chemotherapy/radiotherapy and it is associated with poor outcomes. Median survival is about 12 months. Treatment with cytoreduction and HIPEC is an ideal choice for regional disease. In a recent multicentre study, Yan et al. [11] studied 401 patients with a median overall survival of 53 months and 5-year survival of 47%. These authors concluded that the factors associated with good prognosis were to

Table 2 Cytoreduction for stage IV colorectal cancer Organ compromised

Treatment

Study

Best level of evidence available

Number of patients

SV at 5 years

Peritoneum + visceral

Cytoreduction and HIPEC

II

523

27%

Liver

Hepatic resection

II

929

36%

Lung

Lung resection

Elías D et al. J Clin Oncol. 2010 Apr 1;28(10):1808. Rees M. Ann Surg. 2008;247:125-135. Pfannschmidt J et al. J Thorac Cardiovas Surg. 2003 Sep; 126(3):732-739.

II

167

32%

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achieve complete cytoreduction, to receive HIPEC, to have epithelial histology and not to have lymphatic involvement.

Ovarian epithelial cancer Ovarian epithelial cancer is one of the solid tumours with the highest sensitivity to chemotherapy. However this cancer is the leading cause of mortality among all gynaecologic cancers and the mortality rates have remained stable over the years. The 5-year overall survival with standard treatment is 40–50%, but the 5-year disease-free survival is only 12%. At presentation, 75% of cases are already advanced (stages III–IV) [89, 90]. Similar to the effect on other tumours, maximal cytoreduction is essential when peritoneal disease is present. It was established that in ovarian cancer the cytoreduction of the tumour by 10% is associated with an increase in survival of 6% [91]. Cytostatic intraperitoneal administration exposes ovarian cancer cells to high concentrations of carboplatin and cisplatin about 18–20 times higher than those achieved by systemic administration; in the case of taxanes (docetaxel, paclitaxel) the concentrations are 120–1000 times higher [92]. Late perioperative intraperitoneal plus systemic administration has been demonstrated to improve the overall and disease-free survival when compared to only systemic administration in patients with stage IIIC disease and optimal cytoreduction. However, this multimodal therapeutic approach differs from the cytoreduction plus HIPEC with/ without EPIC [93]. A systematic review by Bijelic et al. evaluated 14 studies using cytoreduction and HIPEC. Ten of these studies had a positive effect on median survival (from 22 to 52 months) and the morbidity rate associated with treatment was between 5 and 36% [94]. There are several phase II studies evaluating cytoreduction and HIPEC for the treatment of carcinomatosis due to ovarian cancer. However, only 2 studies included more than 50 patients. It is important to highlight the recent experience of Ceelen et al. in “heavily pretreated” patients (i.e., those with recurrent peritoneal disease who had undergone surgery and several chemotherapy cycles): they found a median survival of 37 months and a 5-year overall survival of 41% [14]. Rufián et al. are achieving good results with the treatment of newly diagnosed and peritoneal recurrence, with 5-year survival higher than 60% in both scenarios. In our experience 5-year overall survival has been 39% and the 2-year disease-free survival 28%. When accounting for those patients who achieved optimal cytoreduction, 5-year overall survival increased to 60% [95]. Clinical trials comparing cytoreduction+the best available systemic chemotherapy with cytoreduction+HIPEC +the best available systemic chemotherapy are necessary.

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Sarcomatosis Peritoneal sarcomatosis is the dissemination of soft tissue sarcomas originating from intraabdominal organs (digestive or gynaecologic) or retroperitoneal locations with evidence of absence of extraabdominal disease. Soft tissue sarcoma is located in the peritoneal cavity or retroperitoneum in 30% of cases. Outcomes with only surgical treatment have been poor. Sarcomas are usually chemoresistant and the response to the combination of anthracyclin and ifosfamide is only 20–40%, with a median survival of 12 months. Radiotherapy response has only been demonstrated in extremity sarcomas and its use in peritoneal disease is associated with toxicity in the small and large bowel [96]. Rossi et al. [97] treated 60 patients with peritoneal sarcomatosis with optimal cytoreduction and HIPEC (doxorubicin and cisplatin), and obtained a median survival of 34 months and morbidity of 23%. These authors concluded that benefits on survival were higher in those patients treated with optimal cytoreduction in comparison to those with suboptimal cytoreduction.

Gastric cancer Thirty percent of patients with gastric cancer have peritoneal carcinomatosis at the time of diagnosis and 60% of patients will have it after curative treatment. Response to first- and second-line chemotherapy is usually lower than 50%, and survival seldom reaches 12 months [98]. In phase II trials, cytoreduction and HIPEC reach a median survival between 19 and 23 months, a morbidity between 17 and 42%, and mortality between 3 and 15%. However, in these series optimal cytoreduction was achieved in only 10–40% of patients [15–17]. Because of the impossibility of reaching optimal cytoreduction some strategies of intraperitoneal and systemic neoadjuvant therapy have been designed. These strategies diminish the tumoral mass, allowing an optimal cytoreduction between 54% and 86%, a median survival of 43 months, 2-year survival of 44% and 3-year survival of 33% to be reached. These results are better than those for any other support treatment [99, 100]. However, larger comparative studies are necessary, with standardised drugs and doses.

Morbidity, mortality and quality of life It is recommended that the complication notation and classification system be standardised in order to compare among several groups. The 5th Peritoneal Surface Malignancy Workshop (Milan 2006) established that the CTCAE system of the National Cancer Institute was the most recommended for the use of cytoreduction plus HIPEC

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due to complete notification of surgical complications and cytostatic toxicity. CTCAE I and II categories correspond to mild complications, CTCAE III and IV categories correspond to severe complications and CTCAE V category represents death due to complications [101, 102]. Severe morbidity (CTCAE III and IV categories) associated with cytoreduction plus HIPEC in referral centres is between 12 and 52%. The main intraabdominal complication is sepsis (intestinal fistula, abscess, perforation and anastomotic leakage). Among extraabdominal complications, intrahospitalary infections are the most frequent, followed by thrombosis/pulmonary embolism and renal failure. The reoperation rate is between 0% and 23%. Haematologic toxicity is between 0% and 28%, and procedurerelated mortality is between 1% and 6% [103–109]. These severe complications correspond to the radical procedure, as patients get several treatments, and also to a learning curve. This curve, also known as the “effort required in mastering a new skill” will translate into a better selection of patients, better surgical skills, higher percentage of patients getting optimal cytoreduction and better selection of cytostatics. It is known that the minimum number of patients a surgical team needs to demonstrate a decrease in operatory time, number of blood transfusion units, postoperative morbidity and hospital stay lies between 70 and 140 [110–112]. Morbidity and mortality of this procedure are similar to those of other complex oncological procedures (e.g., duodenopancreatectomy, oesophageal surgery). Currently the duodenopancreatectomy due to pancreatic cancer is performed with curative intention in referral centres with a morbidity of 40% and a 5-year survival between 0 and 18% [113, 114]. In the case of transthoracic and transhiatal oesophagectomy due to oesophageal cancer and with curative intention, the morbidity is between 47 and 49% and mortality between 6 and 10%. In high-volume centres specialised in oesophageal cancer the 5-year survival is 42% for adenocarcinoma and 37% for epidermoid carcinoma [115, 116]. Morbidity will define the short-term quality of life. McQuellon et al. found that the quality of life worsens immeReferences 1. Lifante JC, Glehen O, Cotte E et al (2007) Natural history of peritoneal carcinomatosis from digestive origin. In: Ceelen W (ed.) Peritoneal carcinomatosis: a multidisciplinary approach. Springer, New York, pp 119–129 2. Pingpank JF (2008) Diagnosis and treatment of peritoneal carcinomatosis. In: DeVita VT, Hellman S, Rosenberg SA (eds) Cancer: principles and practice of oncology, 8th edn. Lippincott, Williams and Wilkins, Philadelphia, pp 2389–2399 3. Sadeghi B, Arvieux C, Glehen O et al (2000) Peritoneal carcinomatosis from non-gynecologic malignancies: results of the EVOCAPE 1 multicentric prospective study. Cancer 88:358–363 4. Chu DZ, Lang NP, Thompson C et al (1989) Peritoneal carcinomatosis in nongynecologic malignancy. A prospective study of prognostic factors. Cancer 63:364–367

diately after the procedure, and that ability to manage daily life activities and sense of wellbeing progressively improve between 3 and 12 months. About 74% of patients have resumed more than 50% of their normal activities by 1 year after surgery. At 3 years after surgery 94% of patients have no limitations in performing moderately intense activities [117, 118]. Schmidt et al. studied quality of life with the EORTC QLQ-C 30 4 years after surgery and found that the global health status was similar to that in patients who had undergone a Whipple procedure [119].

Current controversies and future directions In recent years the number of publications related to cytoreduction plus HIPEC has increased considerably (594 publications up to 2000, 1440 publications up to August 2010 in Pubmed). However, more randomised clinical trials are necessary to confirm efficacy and the specific contribution of HIPEC to the results, as observational studies comparing two treatments may still carry a selection bias due to lack of randomisation. These trials would focus on evaluating intermediate and long-term survival and reaffirming the safety of the procedure. Regarding patient selection, it is necessary to increase diagnosis of PMD in the preoperative stage with the use of imaging, and especially evaluate the extension to the hepatoduodenal ligaments and small intestine. It is also necessary to standardise the protocols for intraperitoneal cytostatic administration, including technical aspects such as exposure time to drugs and addition of new cytostatics. Some referral centres in Europe already have waiting lists to perform cytoreduction plus HIPEC. These centres currently transfer patients to other regional centres or give induction chemotherapy until surgery is possible. It is necessary to improve these strategies according to the specific subgroup of tumour. Conflict of interest The authors declare that they have no conflict of interest relating to the publication of this manuscript.

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