gastric cancer ( gc ) is the fourth most common cancer and the second leading cause of cancer death in the world [ 1 , 2 ] . the principal risk factors in development of gc are helicobacter pylori infection , atrophic gastritis , intestinal metaplasia , dysplasia , male gender , cigarette smoking , partial gastrectomy , menetrier 's disease , and genetic factors .
global incidence of primary tumour locations and the histological types are constantly changing : in united states and in western europe the incidence of esophagogastric junction ( barrett 's type ) and gastric cardia adenocarcinoma is increasing   while there has been a reduction of incidence of distal gc since the 1970s , especially in western countries .
although gc mortality has been reduced , it remains a disease with poor prognosis and high mortality , second only to lung tumour .
the prognosis of gc depends on stage and location : proximal gastric tumours ( i.e. , cardia tumor ) have poorer prognosis compared to those in the pyloric antrum and when the disease is confined to the stomach mucosa , 5-year survival is near to 95% , while the reported 5-year survival rate for advanced gc varies from 10 to 20% .
metastatic dissemination in gc may occur through the hematic torrent or by dissemination to the peritoneal cavity ; this last condition is called peritoneal carcinomatosis ( pc ) , and it is considered a stage iv of gc .
only 40% of gc deaths have hepatic metastases , while in 5360% disease evolves through pc .
pc is considered the end stage of primary peritoneal malignant disorders ( such as peritoneal mesothelioma ) and a common manifestation of digestive - tract and gynaecological advanced cancers ( such as appendicle tumour , ovarian cancer , colorectal cancer , or gastric cancer ) .
it is generally associated with a poor prognosis ; patients with pc of gastric origin have an extremely bad prognosis with a median survival estimate at 13 months [ 3 , 14 ] .
data from the literature show that 15% of patients present pc ab initio and 35% of patients die of intraperitoneal recurrence for pc confined exclusively into the peritoneum .
systemic chemotherapy improves median survival in metastatic gastric cancer to 710 months , but in patients with pc from gc the same improvement has not been reported .
currently , at the intraoperative abdominal examination , peritoneal seeding is found in 1020% of patients scheduled for potentially curative resection and in 40% of those at stage ii - iii [ 15 , 18 , 19 ] ; 2050% of patients treated with radical surgery will develop postoperatory peritoneal recurrence , and intraperitoneal spread of tumour cells is observed in 54% of patients who died of recurrence after surgery in advanced gc . during the last 30 years multimodal therapeutic approaches on pc improved , resulting in a modified role of surgery : not a simple debulking operation anymore but a complete tumour cytoreduction with no macroscopic residual disease .
sugarbaker investigated the synergism of the effects of hyperthermia and intraperitoneal anticancer chemotherapy against tumour cells ; he found the existence of pc originating by low grade malignancy tumours without invasion capacity ( like pseudomyxoma peritonei ) that can be treated with cytoreductive surgery ( crs ) and hyperthermic intraperitoneal chemotherapy ( hipec ) . in 1995 sugarbaker
definitively codified , in terms of rationale and surgical technique , the procedure of peritonectomy . following these innovative studies ,
peritoneal dissemination of free cancer cells happens through exfoliation and leads to direct invasion of the serosa .
tumour cells can also diffuse passing through the  stomata  : big communicating orifices present in the peritoneal surface , between peritoneal cavity and lymphatic vessels .
cells distribution into peritoneal cavity is also conditioned by physical factors : tumour primary site , effects of gravity , presence or presence of fluids ( ascites , mucus , etc . ) , and intrinsic biological aggressiveness [ 2325 ] .
some studies showed that there are tumours with a distinct capability to give peritoneal metastases , without giving distant metastases .
for preoperative diagnosis of pc , useful imaging techniques are ultrasound ( us ) , computerized tomography ( ct ) , magnetic resonance imaging ( mri ) , and 18f - fluorodeoxyglucose positron emission tomography - ct ( fdg pet - ct ) , but all these imaging techniques have major limitations in diagnosing pc because of the low - volume density of peritoneal nodules . ct and mri are important mainly in evaluating unresectable disease and cancer staging [ 26 , 27 ] .
pet - ct seem to be a good option , but are expensive and have drawbacks for lesions smaller than 5  mm in diameter . concerning pc from gc , yang et al .  
report an accuracy of pet - ct of 87% , with a sensitivity and specificity of 72.7% and 93.6% , respectively , with a sensitivity better than ct , while for primary gc and lymph node metastases the accuracy for pet - ct is 54% .
ct is not accurate ( 817% of sensitivity ) particularly for malignant granulations less than 5  mm in diameter and for small bowel nodulations . due to the low accuracy given by the imaging , the main diagnosing methods currently used to evaluate peritoneal surface are diagnostic laparoscopy or laparotomy and peritoneal cytological examination that show a greater accuracy in diagnosing pc .
diagnostic laparoscopy , with or without peritoneal washing for malignant cells , has only a iii b degree of recommendation ; it is used to exclude metastatic disease in tumours that are considered potentially resectable .
a standardized technique minimizes the risk of tumour contamination of the trocars insertion sites ; this method , compared with laparotomy , is also free from risks related to the complications of diagnostic laparotomy   and allows staging before and after crs + hipec and during the follow - up .
moreover , exploratory laparoscopy could be used in order to evaluate the efficacy of neoadjuvant chemotherapy .
the three main different scoring systems for intraperitoneal cancer dissemination that have been published until today are as follows.japanese rules of gc [ 14 , 29 ] is a classification into five categories that only considers the presence of cancerous implants and/or of malignant cells in the peritoneal washing fluid , without considering the size of malignant nodules.gilly staging system for pc [ 14 , 19 ] , also called the lyon score , is based on the size and distribution of malignant granulations ( localized or diffused ) .
it demonstrates that the use of complete ( r0-r1 ) or incomplete ( r2 ) cytoreduction , in order to assess the entirety of surgical clearance of cancer , is successful .
r0 and r1 can be grouped together as the outcome of these two groups is very similar .
this system was also revealed to be an important prognostic indicator , as the median survival of patients with stage i or ii is significantly higher than those with stage iii or iv , and they can be candidates for crs and hipec .
however , this system does not clearly indicate the potential resectability of pc .jacquet and sugarbaker peritoneal cancer index ( pci )   is based on quantitative distribution and size of peritoneal nodules .
the abdomen cavity is divided into 13 regions and the lesion size is scored in each region . after a meticulous intraoperative inspection , the extent of the disease can be summed as a numerical score ( 0 to 39 ) .
the pci has a prognostic value , allowing for an estimate of the probability of complete cytoreduction ; it is the only method that shows in detail the nodules localization .
japanese rules of gc [ 14 , 29 ] is a classification into five categories that only considers the presence of cancerous implants and/or of malignant cells in the peritoneal washing fluid , without considering the size of malignant nodules .
gilly staging system for pc [ 14 , 19 ] , also called the lyon score , is based on the size and distribution of malignant granulations ( localized or diffused ) .
it demonstrates that the use of complete ( r0-r1 ) or incomplete ( r2 ) cytoreduction , in order to assess the entirety of surgical clearance of cancer , is successful .
r0 and r1 can be grouped together as the outcome of these two groups is very similar .
this system was also revealed to be an important prognostic indicator , as the median survival of patients with stage i or ii is significantly higher than those with stage iii or iv , and they can be candidates for crs and hipec .
jacquet and sugarbaker peritoneal cancer index ( pci )   is based on quantitative distribution and size of peritoneal nodules .
the abdomen cavity is divided into 13 regions and the lesion size is scored in each region . after a meticulous intraoperative inspection , the extent of the disease can be summed as a numerical score ( 0 to 39 ) .
the pci has a prognostic value , allowing for an estimate of the probability of complete cytoreduction ; it is the only method that shows in detail the nodules localization . 

the completeness of cytoreduction ( ccr ) could be evaluated using the sugarbaker and the lyon scores combined , as they indicate a direct relation between ccr , prognosis , and survival .
pharmacokinetic and peritoneal permeability studies demonstrate a higher intraperitoneal concentration of drugs with chemotherapy administered intraperitoneally than with systemic administration [ 23 , 24 ] .
the peritoneal plasma barrier maintains a positive gradient of chemotherapy in the peritoneum , increasing the local effects of the drugs and reducing the systemic toxicity .
moreover , when chemotherapy treatment is associated with hyperthermia , the locoregional effects are considerably extended , with an increased penetration up to 36  mm into malignant nodules and an increased antimitotic effect .
several studies confirm that hyperthermia ( 42 - 43c ) enhances the effects of antitumoral drugs , especially of oxaliplatin , mitomycin c , doxorubicin , cisplatin , paclitaxel , and irinotecan , also increasing the chemosensibility of neoplastic cells . the intraabdominal temperature
, however , should not exceed the temperature of 43c , in order to avoid the risk of bowel perforation . according to surgical - oncologic principles ,
the treatment of non - metastatic gc consists of resection with total gastrectomy and d1 and/or d2 lymphadenectomy .
different trials proposed multiple chemotherapy protocols using drugs like epirubicine , cisplatin and 5-fluorouracil ( ecf ) , or epirubicin , cisplatin and capecitabina ( ecx ) , that do not need a central venous access device .
s-1 , a new drug recently introduced in japan , combined with cisplatinum , paclitaxel , docetaxel or irinotecan has become the standard treatment for pc from gc .
correct radiological , clinical , and cytological stadiation is essential requirement for a better prognosis after hipec in gc .
it is necessary to distinguish pc in early or advanced gc from pc as a recurrence of already operated gc .
in fact , in the former case it is easier to succeed with a complete cytoreduction ( ccr-0 , r0 ) , while in the latter , previous surgical treatment and adhesion development decrease the possibility to achieve a complete cytoreduction .
common contraindications for hipec are age > 70  yrs , important comorbidities , clinical aggravation with systemic chemotherapy , malnutrition , extra abdominal metastases , liver metastases when unresectable , and massive retroperitoneal bulk disease or lymph node involvement .
other minor exclusion criteria are body mass index ( bmi ) > 40 , history of pelvic irradiation , carcinomatosis extended at the ct or clinically significant , more than 4 surgical procedures , occlusion , and no drop markers with neoadjuvant chemotherapy .
different studies presented contrasting data about survival rates ; however , they all agreed with the necessity of a complete ( tables 1 and 2 ) cytoreduction to improve survival .
show that in patients with a cc ( completeness of cytoreduction ) score of 0 or 1 overall median survival was 15 months   ( versus 7.9 months in patients with cc 2 score ) , with an overall mortality rate of 4.8% .
gc randomized into 3 groups ( hipec and surgery , intraperitoneal normothermic chemotherapy plus surgery , and surgery alone ) show that in the first group the survival rate was significantly higher ( 61% versus 43% and 42% of the other two groups ) , particularly in patients with serosal infiltration and lymph node positive metastases .
ii - iii gc patients , and by kim and bae   in patients affected by stage iii and iv gc treated with hipec + crs versus surgery alone . 

kim and bae   analysed 103 patients with gc stage iii - iv : 51 underwent surgical resection alone and 52 received surgery plus hipec .
it was higher but not statistically significant in the hipec + crs group ( 32.7% versus 27.1% control group ) .
the difference , considering exclusively the survival rate of the 65 patients with stage iii gc , was statistically significant ( 58.6% versus 44.4% control group ) . in a retrospective multicentric french study undertaken between february 1989 and august 2007 , glehen et al .  
evaluated 159 patients that underwent cytoreductive surgery and perioperative intraperitoneal chemotherapy ( hipec and epic or both ) and showed 1- , 3- , and 5-year survival rates of 43% , 18% , and 13% , respectively , that increase up to 61% , 30% , and 23% , respectively , in patients with a complete cytoreduction .
thanks to multivariate analysis , the authors reported the completeness of cytoreduction as being the principal independent prognostic factor . in order to correctly execute cytoreduction ,
the study showed that if cytoreductive surgery does not allow a sufficient downstaging , particularly in hipec , the survival rates are poor ( median survival of 68 months ) .
three recent meta - analysis [ 1113 ] of rcts , assessing patients with gc ( with or without pc ) , demonstrates the survival benefit offered by hipec . already in 2007 , yan et al .   conducted 13 studies on 1648 patients and demonstrated the positive effects in terms of overall survival rates , when adding hipec or hipec with epic to surgery .
jin - yu et al .   analyzed 15 rcts and demonstrated that hipec and niic should be recommended in treating patients with gc , as they significantly improve the overall survival rates .
this meta - analysis demonstrated that adding postoperative intraperitoneal chemotherapy ( pic ) to hipec has no additional effect on overall survival rates but it improves costs and toxicity .
this study also showed that intraperitoneal chemotherapy ( ipc ) has no effect on prevention of lymph metastasis , but could decrease by 73% the rate of hepatic metastasis .
authors demonstrated that ipc does not increase perioperative mortality and postoperative anastomotic leaks , ileus , or bowel perforation rates , but it increases the risk of marrow depression , intra - abdominal abscess , and fever .
in the last decade an interesting new drug , called catumaxomab , has been developed in germany .
the catumaxomab is a rat - mouse hybrid monoclonal antibody that is now used for patients with malignant ascites in phase ii / iii randomized trial .
two studies [ 32 , 33 ] demonstrate that this drug seems to improve progression - free survival in patients with gc ( median 71 versus 44 days ; p = 0.03 ) and that it seems to improve the survival in gastrointestinal epcam+ tumours ( epcam : antiepithelial cell adhesion molecule ) in intraperitoneal use .
crs and hipec are associated with significant morbidity and mortality , also in high volume centers , and reported rates are included between 0.95.8% and 1252% , respectively .
the main postoperative complications after crs and hipec are intra - abdominal abscess , gastric or small intestinal perforation , postoperative ileus , anastomotic leakage , postoperative bleeding , fistula , sepsis , respiratory distress , hematologic toxicity , and urinary disturbance [ 6 , 19 ] . in the same group of patients ,
the main causes of death include anastomotic leakage , sepsis , postoperative bleeding , intestinal fistula , and disseminated intravascular coagulation ( dic ) .
recently , yonemura et al . [ 9 , 14 ] proposed a multimodal strategy that associates neoadjuvant intraperitoneal and systemic chemotherapy ( nips ) , crs + hipec and epic .
the rationale of this method is to reduce tumour burden before surgery with nips , a bidirectional chemotherapy that attacks pc from both sides of peritoneum ( from the peritoneal cavity and from subperitoneal blood vessels ) , together with crs and hipec , in order to reduce macroscopic and microscopic pc .
the aim of epic is then to eradicate residual intraperitoneal cancer cells before the development of adhesions .
the nips technique is characterized by a first phase in which patients are treated with 60  mg / m of oral s-1 for 21 days , followed by one week of rest .
a port system has been previously placed into the abdominal cavity under local anesthesia , with the tip in the douglas pouch . on the 1st , 8th , and 15th postoperative days ,
30  mg / m of taxotere and 30  mg / m of cisplatinum with 500  ml of saline are infused into the peritoneal cavity .
complications after nips have been reported in 4 out of 79 patients ( 1 with grade 4 of bone marrow toxicity , 3 with a renal dysfunction ) . in 3 patients , infections around the periportal space , that led to the port remotion ,
this study shows a washing cytology negativization in 41 out of 79 patients ( 63% ) .
, in a retrospective multicentre study , recommend the routine use of neoadjuvant chemotherapy to improve surgical results and to exclude patients who do not respond to the therapy form hipec treatment .
the aforementioned procedures should be exclusively performed in highly experienced centres because of the special surgical expertise needed to achieve high rates of complete cytoreduction [ 14 , 19 ] .
patient selection is very crucial and should be carried out by a multidisciplinary group of specialists ( anaesthetists , surgeons , clinicians , and oncologists ) in order to achieve better results and to reduce the high costs related to these procedures and relevant complications .
an interdisciplinary approach should be developed further : the association of nips , crs , hipec , and epic could increase the rate of cc-0 procedures and consequently survival rates , particularly for pci 6 [ 5 , 11 , 21 , 32 ] .
neoadjuvant chemotherapy , routinely recommended for management of gc without pc , may improve survival also in pc from gc [ 10 , 3437 ] and adjuvant chemotherapy could prevent recurrence from gc .
finally , the study of molecular and serum tumour markers could provide valuable prognostic information and would allow for a better selection of subsequent treatment combinations [ 14 , 38 ] .
 gastric cancer ( gc ) is the fourth most common cancer and the second leading cause of cancer death in the world ; 5360% of patients show disease progression and die of peritoneal carcinomatosis ( pc ) . 
 pc of gastric origin has an extremely inauspicious prognosis with a median survival estimate at 13 months . 
 different studies presented contrasting data about survival rates ; however , all agreed with the necessity of a complete cytoreduction to improve survival . 
 hyperthermic intraperitoneal chemotherapy ( hipec ) has an adjuvant role in preventing peritoneal recurrences . 
 a multidisciplinary approach should be empowered : the association of neoadjuvant intraperitoneal and systemic chemotherapy ( nips ) , cytoreductive surgery ( crs ) , hipec , and early postoperative intraperitoneal chemotherapy ( epic ) could increase the rate of completeness of cytoreduction ( cc ) and consequently survival rates , especially in patients with peritoneal cancer index ( pci ) 6 . 
 neoadjuvant chemotherapy may improve survival also in pc from gc and adjuvant chemotherapy could prevent recurrence . in the last decade 
 an interesting new drug , called catumaxomab , has been developed in germany . 
 two studies showed that this drug seems to improve progression - free survival in patients with gc ; however , final results for both studies have still to be published . 