BACKGROUND:  Intraperitoneal hyperthermic chemoperfusion (IHCP), which
is a locoregional treatment used in peritoneal micrometastases in
intra-abdominal tumours was first applied in 1980, and since then it
has been used as an adjuvant treatment in locally advanced tumours and
as palliation in inoperable tumours, especially in tumours of genital
and gastrointestinal system origin.  AIM:  In this study the
effectiveness of adjuvant IHCP in treating gastric cancer with serosal
invasion after curative surgery was investigated.  SETTING AND DESIGN: 
This study was designed in the Department of General Surgery in the
Ankara Oncology Hospital. IHCP was done immediately after cytoreductive
surgery.  METHODS:  After cytoreductive surgery in 10 patients with
locally advanced gastric cancer, two drains were placed into the
peritoneal cavity and after the closure of the wound, IHCP was done
with 10mg/L mitomycin-C at 42\ub0C for 60-90 minutes.  RESULTS:  No
systemic and local complications were seen after perfusion except
atelectasis in one patient. Local recurrence and metastatic tumour at
the porta hepatis was seen in one patient each, hepatic metastases in
five patients, and one patient died from myocardial infarction. The
survival analysis was done with Kaplan-Meier method and the 1, 2, and
5-year overall and disease-free survival rates were 80, 70, 40% and 90,
60, 30% respectively.  CONCLUSION:  Although this study was conducted
for a small number of patients it appears that IHCP can be used safely
in the adjuvant locoregional treatment of gastric cancer

Erhan Erdem, Haluk Alagol

Bioline International

277© 2003 Indian Journal of Surgery www.indianjsurg.comIndian Journal of Surgery 2004 Volume 66 Issue 5 (October)The effectiveness of adjuvant intraperitoneal hyperthermicchemoperfusion after cytoreductive surgery in locallyadvanced gastric cancerErdem Erhan, Alagöl HalukDepartment of General Surgery, Ankara Oncology Training and Research Hospital, Turkey.ABSTRACTBackground: Intraperitoneal hyperthermic chemoperfusion (IHCP), which is a locoregional treatment used inperitoneal micrometastases in intra-abdominal tumours was first applied in 1980, and since then it has been usedas an adjuvant treatment in locally advanced tumours and as palliation in inoperable tumours, especially in tumoursof genital and gastrointestinal system origin.Aim: In this study the effectiveness of adjuvant IHCP in treating gastric cancer with serosal invasion after curativesurgery was investigated.Setting and design: This study was designed in the Department of General Surgery in the Ankara OncologyHospital. IHCP was done immediately after cytoreductive surgery.Methods: After cytoreductive surgery in 10 patients with locally advanced gastric cancer, two drains were placedinto the peritoneal cavity and after the closure of the wound, IHCP was done with 10mg/L mitomycin-C at 42°C for60-90 minutes.Results: No systemic and local complications were seen after perfusion except atelectasis in one patient. Localrecurrence and metastatic tumour at the porta hepatis was seen in one patient each, hepatic metastases in fivepatients, and one patient died from myocardial infarction. The survival analysis was done with Kaplan-Meier methodand the 1, 2, and 5-year overall and disease-free survival rates were 80, 70, 40% and 90, 60, 30% respectively.Conclusion: Although this study was conducted for a small number of patients it appears that IHCP can be usedsafely in the adjuvant locoregional treatment of gastric cancer.KEY WORDSHyperthermic chemoperfusion, gastric cancerHow to cite this article: Erhan E, Haluk A. The effectiveness of adjuvant intraperitoneal hyperthermic chemoperfusion after cytoreductivesurgery in locally advanced gastric cancer. Indian J Surg 2004;66:277-80.Original ArticleAddress for correspondence: Erhan Erdem, Oguzlar Mah. Ceyhun Atif Kansu Cad. 50. Sok. 6/4, 06520 / Balgat, Ankara/ Turkey.E-Mail: erhanerdem@ttnet.net.trPaper Received: July 2004. Paper Accepted: September 2004. Source of Support: Nil.4INTRODUCTIONHyperthermic perfusion chemotherapy is a locoregionaltreatment modality that is used as adjuvant treatmentin locally advanced operable tumours, and as palliationin inoperable tumours. Thus intraperitonealhyperthermic chemoperfusion (IHCP) is also a methodof locoregional treatment that is used in peritonealseedings and peritoneal micrometastases in intra-abdominal tumours, especially in the gastrointestinalsystem and genital tumours. Intraperitonealadministration of chemotherapy has the benefit ofhigher concentrations of drugs delivered locally to thesite of the tumour while diminishing the systemic toxiceffects. This method is regarded as the best treatmentfor the prevention and/or healing of peritoneal seedingfrom gastrointestinal cancer, especially for gastriccancers, which have a high rate of locoregional278 Indian Journal of Surgery 2004 Volume 66 Issue 5 (October)recurrence and peritoneal micrometastases.1-3 It’sknown that in these cases systemic chemotherapy ismostly ineffective.4-6The purpose of this study was to assess the role ofIHCP as an adjuvant therapy in locally advanced gastriccancer patients after radical surgery.MATERIALS AND METHODSTen patients who were diagnosed microscopically ashaving gastric cancer underwent macroscopiccytoreductive surgery and IHCP between December1996 and December 2001. The study was approvedby the Ethics Committee of the Ankara OncologyTraining and Research Hospital (procedures followedin accordance with the standards ethical committeeon human experimentation and with the HelsinkiDeclaration of 1975). Cytoreductive surgery consistedof the removal of all gross tumours and involvedorgans or peritoneum. So R0 gastric resection wasundertaken in all patients with greater and lesseromentectomy, splenectomy and localizedperitonectomy (left or right upper quadrant) if therewas any involvement or metastasis at peritonealsurface, then D2 lymph node dissection was added.At the end of the operation two drains were insertedin the peritoneal cavity and after the closure of theabdomen, an extra-corporeal circuit conducted IHCP,allow perfusate circulation with at 300-500 ml/minand hyperthermia ranging 40-42o C for 60-90 minutes.The perfusate consisted of 3 L. of saline solution withcytotoxic drugs. We used 10-mg/L mitomycin-Cbecause of its high penetration rate to micronodulesand low absorption rate across the peritoneal surface.At the end of the perfusion 1 L. of perfusate wasemptied and the rest of it was left in the abdomen for12 hours.Statistical AnalysisThe Kaplan-Meier method was used for the calculationof the overall and disease-free survival rates.RESULTSIn a total of 10 patients, 5 underwent total and 5subtotal  gastr ectomies with omentectomy,splenectomy and D2 lymph node dissection.Localized peritonectomy was also added in 3 ofthem who had peritoneal involvement. The patients’tumours were all T3 or T4 and none had organmetastases at the time of surgery. On microscopicexamination 1 had musinous and 9 had adenoidcancer and 6 of them  had histopathologicallyproven lymph node metastasis. The patientsconsisted of 6 women and 4 men with an averageage of 59 years (range 25-74). Al l  patientsunderwent IHCP with mitomycin-C after the surgery.The average hospital stay was 10 days and nosystemic and local complications were seen exceptone atelectasis. The patients were followed-up withregular physical  examinat ions includinghaematological analysis and tumour markers (CEA,CA 19-9, CA-125) every 3 months, abdominalultrasonography and upper gastrointest inalendoscopy every 6 months, and abdominalcomputerized tomography every year. At the endof the first year 2 patients died, one of them frommyocardial infarction and she had no evidence oftumour, and the other one from hepatic metastases.In the 24-48 months period 4 other patients alsodied from liver metastasis and only one of themhad peritoneal recurrence. Four patients whocompleted 5-year survival are still alive and onlyFigure 1a: Overall survival rateFigure 1b: Disease-free survival rate1,21,0,8,6,4,20,00 6 12 18 24 30 36 42 48 54 60CumSurvivalSurvival FunctionMonthsErhan E, et al1,21,0,8,6,4,20,00 6 12 18 24 30 36 42 48 54 60CumSurvivalSurvival FunctionMonths279© 2003 Indian Journal of Surgery www.indianjsurg.comIndian Journal of Surgery 2004 Volume 66 Issue 5 (October)one of them has a tumour at porta hepatis. Threepatients have no complaints, no evidence of tumouror elevation of tumour markers. The 1,2 and 5-yearoverall and disease-free survival rates were 80, 70,40% and 90, 60, 30% respectively (Figures 1a, 1b).DISCUSSIONThe intraperitoneal administration of cytotoxic agentshas been used since 1980.7 The first aim of this methodis the eradication of microscopic residual disease. Ithas the benefit of higher concentrations of drugsdelivered locally to the tumour site while preventingthe systemic toxic effects compared with intravenousadministration. The efficacy of a drug is calculated bythe ratio of the peritoneal cavity area under theconcentration/time curve (AUCc) to the plasma areaunder the concentration/time curve (AUCp).8 This ratiois between 250-1400 for 5-Flourourasil, 12-20 forcisplatin and 75-80 for mitomycin-C.2,9,10 The efficacyis increased with the slow absorption rate of thecytotoxic drug. Hydrophilic drugs like 5-Flourourasil,cisplatin and mitomycin-C are absorbed very slowlyfrom the peritoneal surface so they are the most usefuldrugs for IHCP. Beyond this the direct tumourabsorption of drugs occurs to a level of 5 mm beneaththe tumour surface, that means tumour nodulesexceeding 5 mm are not suitable for IHCP.7,9,11,12 In thistechnique hyperthermia also enhances the efficacy withits own cytotoxic effect by maximizing the diffusion ofthe drugs to the tumoral nodules.In gastric cancer IHCP can also be used as neoadjuvantaim for down-staging but the most preferential use isthe adjuvant route. Takahashi and Hagiwara usedactivated carbon particles in the peritoneal cavity,which adsorbed a large amount of mitomycin-C ingastric cancer patients with definite serosalinvolvement.13,14 They found 14 and 18% of survivaladvantage in 2 and 3-year times respectivelycompared with control groups. In other studies thatused cisplatin or mitomycin-C in early postoperativeintraperitoneal chemotherapy, statistically significantsurvival advantages were found against controlgroups and it was determined that this advantageappeared especially in Stage III diseases.3,15-17 Fujimuraet al reported 40% complete remission and 67% and40% of 1 and 2-year survival rates after IHCP in gastriccancer patients with peritoneal seeding.18,19 Fujimotoet al also reported the results of 141 patients withlocally advanced gastric cancer who underwentcytoreductive surgery, and 71 of them also underwentIHCP.20 In this trial it was seen that in the IHCP groupthe 2, 4, and 8 year-survival rates were 88, 76, and62% while in control group they were 77, 58, and49% respectively. Hamazoe et al also found 64% 5-year survival rates of patients in IHCP.21 Similarly, long-term survival rates of 25-50% have also beendescribed in patients who underwent cytoreductivesurgery and IHCP, and in these studies it seems thatthe survival advantage of IHCP is better thanintraperitoneal chemotherapy alone.22-24 The mostimportant reasons behind this result are the use ofhyperthermia and maximum drug concentration inIHCP.With the help of these data the treatment algorithmhas been evolved for the management of operablegastric cancer was determined in 1996 by Kelsen.25Today this algorithm is still valid, but has beenmodified to included IHCP (Figure 2). In the use ofIHCP there are also some restrictions in that IHCP onlytreats peritoneal disease so it is contraindicated whenextraperitoneal metastases are found. Beyond this,macroscopic cytoreductive surgery must beperformed before IHCP. The residual disease or thenodules in the peritoneal cavity must be smaller than5 mm, and there must be no adhesion in the peritonealcavity that restrict the homogeneity of distribution ofthe cytotoxic agents.In this study, although the number of patients is small,the effective control of local peritoneal recurrence (10%)and improved overall and disease free survival havebeen encouraging.Figure 2: Treatment algorithm in operable gastric cancer(Modified from25). CT: Chemotherapy, IHCP: intraperitonealhyperthermic chemoperfusion.Endoscopic BiopsyAdeno CANo systemicmetastasisLaparoscopyLaparotomyT1-2 N 0Radical Surgery T 3-4 N xRadical SurgeryFollow/Systemic CTRadical Surgery+ IHCPPreoperative CTSurgeryIHCP in gastric cancer280 Indian Journal of Surgery 2004 Volume 66 Issue 5 (October)REFERENCES1. Elias D, Dube P, Blot F, Bonvallot S, Eggenspieler P, Sabourin JC,et al. Peritoneal carcinomatosis treatment with curative intent:The Institut Gustave-Roussy experience. 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Br J Surg 2000;87:1006-15.23. Nomura E, Niki M, Fujii K, Shinohara H, Nishiguchi K, Sonada T,et al. Efficacy of intraperitoneal and intravenous chemotherapyand left upper abdominal evisceration for advanced gastric can-cer. Gastric Cancer 2001;4:75-82.24. Yonemura Y, Ninomiya I, Kaji M, Sugiyawa F, Fujimura K, Sansa T,et al. Prophylaxis with intraoperative chemohyperthermia againstperitoneal recurrence of serosal invasion-positive gastric cancer.World J Surg 1995;19:450-5.25. Kelsen DP. Adjuvant and neoadjuvant therapy for gastric cancer.Sem in Oncol 1996;23:379-89.Erhan E, et alAnnouncementsPlease use email for faster communication:For article related enquiry: editor@indianjsurg.comFor subscriptions/advertisements: ijs@medknow.comFor non-receipt of issues by ASI members and change of address: ijs@medknow.com andasi@md5.vsnl.net.in

The effectiveness of adjuvant intraperitoneal hyperthermic chemoperfusion after cytoreductive surgery in locally advanced gastric cancer

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