Gastrectomy, peritonectomy, and perioperative ... peritonectomy, and... · Perioperative...

Seminars in Surgical Oncology 2003; 21:233–248

Gastrectomy, Peritonectomy, andPerioperative Intraperitoneal Chemotherapy:The Evolution of Treatment Strategies for

Advanced Gastric Cancer

PAUL H. SUGARBAKER, MD, FACS, FRCS,1* WANSIK YU, MD,2 AND YUTAKA YONEMURA, MD3

1Washington Cancer Institute, Washington, D.C.2Department of Surgery, Kyungpook National University Hospital, Samduk-dong Taegu, Korea

3Surgery II, School of Medicine, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho,Sunto-gun, Shizuoka, Japan

Gastric cancer disseminates by hematogenous, lymphatic, and transcoelomic routes. Formaximal containment of the malignant process, perioperative intraperitoneal chemotherapyis necessary in two groups of patients in whom the primary cancer can be resected. Thosepatients who have been resected for cure and have a high likelihood of microscopic residualdisease require intraperitoneal chemotherapy. This includes all T3 and T4 patients, andpatients with N2 nodes present. A series of randomized and nonrandomized clinical studieshave established the benefits of perioperative intraperitoneal chemotherapy in this group ofpatients. Patients with stage IV disease who are able to undergo a palliative resection requirethese treatments if peritoneal seeding is observed. Systemic chemotherapy is largelyineffective for peritoneal seeding, while intraperitoneal chemotherapy is most likely toproduce a response with small volume, surgically debulked carcinomatosis. In addition,intraperitoneal chemotherapy can eliminate the future development of debilitating ascites.Sufficient data are available from the gastric cancer literature to support the use of thesecombined treatments on a routine basis if the primary cancer is resectable and gastrointestinalfunction can be reestablished. Semin. Surg. Oncol. 21:233–248, 2003. � 2003Wiley-Liss, Inc.

KEY WORDS: intraperitoneal chemotherapy; gastric cancer; mitomycin C;5-fluorouracil; peritonectomy; lymphadenectomy

INTRODUCTION

Gastric cancer remains one of the deadliest gastro-intestinal malignancies. In 1997, gastric cancer wasdiagnosed in an estimated 22,400 patients in the UnitedStates, and 14,400 patients died of the disease. Thepotentially curative resection rates in the Japanese andWestern series were 58.6% and 17.8%, respectively, andthe 5-year survival rates were 60.5% and 39.4%, respec-tively. These statistics suggest that surgery alone is not anadequate treatment for gastric cancer. In clinical studiesreporting sites of surgical treatment failure, 40% to 50%ofpatients who had undergone curative resection developedlocoregional recurrence 1–3 years after surgery. More-over, 31% of patients in the United States and 9.2% ofpatients in Japan had stage IV disease at the time of pre-sentation and were unresectable for cure.

PERIOPERATIVE INTRAPERITONEALCHEMOTHERAPY IN PATIENTS

RESECTED FOR CUREA. Rationale for PerioperativeIntraperitoneal Chemotherapy

The long-term results of treatment for resectable gastriccancer have not shown any significant improvement inrecent decades [1]. Many efforts have been made todevelop adjuvant therapies, but large randomized trials of

*Correspondence to: Paul H. Sugarbaker, Washington Cancer Institute,110 Irving St. NW, Washington, D.C.E-mail:[email protected] 10.1002/ssu.10042Published online in Wiley InterScience (www.interscience.wiley.com).

� 2003 Wiley-Liss, Inc.

intravenous chemotherapy or radiotherapy have failed todemonstrate improved survival [2–4]. Wanebo andcolleagues [5] (American College of Surgeons Survey)did not report any beneficial trend from the use ofmultimodality therapy.

Analyses of recurrence patterns after curative resectionhave shown that local and intra-abdominal disease siteshave an impact on survival in that they are the only sites offirst recurrence in approximately 50% of patients. Even atdeath, the tumor often remains confined to the abdomen[6–8]. The anatomic sites of treatment failure with post-operative adjuvant treatments and neoadjuvant chemo-therapy are essentially the same as those observed aftersurgery alone [9–10]. After extended lymphadenectomy,the peritoneal surfaces and the liver remain the major sitesof recurrence, and the rate of locoregional relapse is con-siderably lower when compared to more limited surgery[11–13].

From this analysis of the clinical data on surgical treat-ment failure, intraperitoneal chemotherapy as an adjuvantto surgery may be considered a rational therapeutic moda-lity. There is a strong theoretical basis for the use of peri-operative intraperitoneal chemotherapy. The tumor cellentrapment hypothesis suggests that manipulation of thecancer-bearing organ, transection of lymphatic channels,and blood loss from the cancer specimen result in freeintraperitoneal cancer cells. These cells become fixed infibrin as thewound-healing process is initiated (Fig. 1). Allof the available data indicate that gastric cancer cellspresent in the peritoneal cavity are 100% lethal [14–17].

Review of the Gastric Cancer Literature RegardingPerioperative Intraperitoneal Chemotherapy

The Medline bibliographic database (1985–1999) wasused to identify randomized and nonrandomized trialsregarding the use of perioperative intraperitoneal chemo-therapy vs. surgery alone for resectable gastric cancer(stages I–IV) and advanced gastric cancer (stage IV withor without peritoneal seeding). Only studies published inEnglish were included. Whenever possible, the use ofperioperative intraperitoneal chemotherapy was sepa-rately evaluated as adjuvant treatment in patients re-sected for cure, as compared to palliative treatment forestablished peritoneal seeding. Data were collectedregarding the number of patients, the P-value, and themorbidity, mortality, and survival rates.

Journal articles using intraperitoneal chemotherapywere considered to have perioperative administration ifused in one of two different ways. Heated intraoperativeintraperitoneal chemotherapywas administered on the dayof surgery, before or after the abdominal wall was closed.The chemotherapy solution was heated by a perfusioncircuit for 60–120 minutes by a series of tubes and drainsinto the peritoneal cavity. The other perioperative treat-ment used was early postoperative intraperitoneal chemo-therapy administered during postoperative days 1–5. Thechemotherapy solution was delivered in the abdominalcavity through a Tenckhoff catheter. The dwell and drain-age times were 23 hours and 1 hour, respectively, prior tothe next administration of chemotherapy.

Fig. 1. The tumor cell entrapment hypothesis describes themechanismwhereby single gastric cancer cellsthat are free in the abdomen at the time of surgery are lethal.

234 Sugarbaker et al.

Eight studies were identified that reported the use ofperioperative intraperitoneal chemotherapy in patientswho had potentially curative (R0 resection) [18–25].Perioperative chemotherapy was used during surgicalprocedures in seven studies, and immediately after sur-gery in one study. All eight studies were prospective andrandomized.

In the adjuvant-treatment group, we were able toperform a meta-analysis in which the survival rates fromeight studies were incorporated. The log relative risk(log ratio of proportion of perioperative intraperitonealchemotherapy survival to that of surgery only) and itsvariance were calculated for each study. The weight foreach study was taken as the reciprocal of the variance.The common log risk ratio was calculated as a weightedaverage of the study log risk ratios.

A single study was identified in which the administra-tion of intraperitoneal chemotherapy was delayed starting10–28 days after gastrectomy [26]. This study was notincluded in Table I or in the meta-analysis.

Table I shows statistically significant data for a 3-yearsurvival rate in the Fujimura et al. [20] study (P¼ 0.01)and a 5-year survival rate in the other studies (Hamazoeet al. [19], P¼ 0.02; Yu et al. [23], P¼ 0.0278; andFujimoto et al., P¼ 0.0362). A statistically significantsurvival advantage was not seen in three studies, but thetrend with small numbers of patients was for benefit withadjuvant intraperitoneal chemotherapy. Moreover, perito-neal recurrencewas shown to be lower in two study groupstreated with perioperative intraperitoneal chemotherapy(Hamazoe et al. [19],P¼ 0.0854; and Fujimoto et al. [24],P< 0.0001). Taken together, these reports strongly suggest

improved overall survival in the adjuvant-treatment group,which received chemotherapy given intraoperatively orimmediately following surgery, as compared with patientswho underwent gastrectomy alone.

Of interest is a report by Sautner et al. [26], whorandomized patients to receive or not receive intraper-itoneal cisplatin between postoperative days 10 and 28after gastrectomy. No improvement in survival was seen.It has been suggested that both the route (intraperitonealvs. intravenous) and the timing (perioperative vs. delayed)of this surgically directed chemotherapy were crucialfactors in the benefits observed in certain trials [27–29].

Certain groups of randomized patients benefited morefrom perioperative intraperitoneal chemotherapy thanother groups. A study by Ikeguchi et al. [22] did not showstatistically significant benefits for all patients in the trial.However, in 72 patients who had 1–9 positive nodes, thesurvival rate was 44% in the control group and 66% inpatients treated by intraperitoneal chemotherapy. In astudy by Yu et al. [23], patients with N2-positive lymphnodes had 5-year survival rates of 15% (control group) and44% (patients treated by intraperitoneal chemotherapy)(P¼ 0.03). Patients with lymph nodes positive for gastriccancer may be at special risk for cancer dissemination,which perioperative intraperitoneal chemotherapy caneradicate.

Investigators must use some caution when interpretingthe results of these randomized studies of adjuvant per-ioperative intraperitoneal chemotherapy. Because of thedifficulty of accurately staging patients prior to treatment,some patients with resectable stage IV cancer wereincluded in the randomization. Therefore, true adjuvant

TABLE I. Eight Reports of Adjuvant Treatment With Perioperative Intraperitoneal Chemotherapy in Gastric CancerHaving an R-0 Resection*

No. of patients Survival rates % Study/control Study/control

Reference Location study/control study/control P morbidity % mortality %

Koga et al. [18] Yonago 26/21 2.5-year NS 3.1/7.1 NA

83/67.3

Hamazoe et al. [19] Yonago 42/40 5-year 0.02 4.8/7.50 0

61.3/52.5

Fujimura et al. [20] Kanazawa 22/18 3-year 0.01 36/NA 0

68/23

Yonemura et al. [21] Kanazawa 79/81 3-year 0.052 3/2.5 3/2.5

55/38

Ikeguchi et al. [22] Yonago 78/96 5-year NS 1.2/2.08 1.2/2.08

51/46

Yu et al. [23] Taegu 125/123 5-year 0.0278 28.8/20.3 6.4/1.6

54.1/38.1

Fujimoto et al. [24] Chiba 71/70 5-year 0.0362 2.81/2.85 0

69/55

Kim et al. [25] Seoul 52/51 5-year NS NA NA

34.6/31.4

*Negative margins of excision and absence of disseminated disease.

NA, not available; NS, not significant.

Treatment Strategies for Gastric Cancer 235

results are combined with the use of intraperitonealchemotherapy in patients with stage IV cancer who wereable to have a gastrectomy.

These eight prospective randomized trials for theadjuvant treatment of gastric cancer may be suitable formeta-analysis. They involved only patients with a well-defined clinical entity: resectable gastric cancer withoutvisible peritoneal seeding. They represent all randomizedclinical trials that have been presented to date, with noexclusions. Also, the trials were sufficiently similar interms of treatment to make the calculation of averageeffects medically meaningful. The average treatmenteffect (shown in Fig. 2) has a hazard ratio of 1.3. In otherwords, a patient with resectable gastric cancer treated bygastrectomyplus perioperative intraperitoneal chemother-apy was 1.3more timesmore likely to survive 5 years thana patient treated by gastrectomy alone.

According to these survival data, cure after resection ofgastric cancer increased significantly in five of eight trials,and showed a trend toward improvement in the other threewhen adjuvant perioperative intraperitoneal chemother-apy was used. This is in sharp contrast with a previouslypublished meta-analysis of adjuvant systemic chemother-apy randomized trials [2]. The advantages of adjuvantintraperitoneal chemotherapy were especially evident inpatients with stage III gastric cancer.

Implications of Adjuvant PerioperativeIntraperitoneal Chemotherapy Data for the

Natural History of Gastric Cancer

The high percentage of locoregional recurrence aftercurative resection has two sources: spontaneous dissemi-nation from the primary tumor, and traumatic dispersal ofcancer cells as a result of the surgical procedure. Spon-taneous seeding of cancer cells is more frequent in tumors

involving the serosal surface. Serosal invasion by cancer isa source of exfoliating cancer cells and is causally relatedto peritoneal dissemination. Indeed, a high proportion ofpatients have viable cancer cells found intraperitoneally[14–17].

During gastrectomy, cancer cells are released fromtransected lymphatic channels, tissue at the narrowmargins of resection, and tumor-contaminated blood lostin the surgical field from the cancer specimen. Thecytological examination of peritoneal fluid immediatelyafter laparotomy often shows malignant cells in suchpatients. Adherence of these spontaneously or iatrogeni-cally disseminated cancer cells takes placewithinminutes,and is facilitated by fibrin entrapment and the wound-healing process. The persistence of microscopic residualdisease at the resection site and on peritoneal surfacesresults in a high incidence of intra-abdominal recurrenceof gastric cancer. Tumor progression may be assisted by aplethora of cytokines (growth factors) produced by thehealing surgical wound. These events are collectivelyreferred to as ‘‘tumor cell entrapment.’’ This pheno-menon is an important factor in our understanding ofthe pathogenesis of resection-site and peritoneal-surfacerecurrence, as well as the beneficial effects of adjuvantperioperative intraperitoneal chemotherapy.

Intraperitoneal chemotherapy was conceived for thepurpose of eradicating the microscopic residual diseasethat the surgeon does not see and therefore cannot remove.Conceptually, the peritoneal cavity may qualify as a‘‘pharmacologic sanctuary’’ because intravenously in-jected drugs penetrate poorly at this site. This may be onereason why gastric cancer patients with peritonealdissemination respond poorly to systemic therapy. In thiscontext, the use of hyperthermic chemoperfusion onperitoneal surfaces was introduced for the treatment ofgastric cancer.Hyperthermia and chemotherapy have beenshown to have a synergistic relationship.

Perioperative intraperitoneal chemotherapy can eradi-cate cancer cells by cytotoxic activity within the fibrin thatis produced in large quantities as part of thewound-healingprocess. A delay in the administration of intraperitonealchemotherapy allows fibrin to convert to scars (adhesions),which trap free intraperitoneal tumor cells, and results in anonuniform chemotherapy distribution. Experimentalstudies have revealed that changes in residual tumorcell kinetics occur within 24 hours of a primary tumorresection. The cytotoxic effect of chemotherapy deliveredboth systemically and intraperitoneally may be evidentonly when drugs are utilized during the intraoperative orearly postoperative periods. These factors, and perhapsothers, may explain the success of adjuvant intraperitonealchemotherapy in trials involving intraoperative or earlypostoperative timing or chemotherapy administration, asopposed to delayed drug delivery.

Fig. 2. Meta-analysis of eight reports of adjuvant treatment withperioperative intraperitoneal chemotherapy in gastric cancer.


Regional chemotherapy used in such a manner can notbe expected to effectively eradicate disease left behindin lymph nodes. It is likely that extended lymph nodedissection is necessary to obtain the beneficial effects ofperioperative intraperitoneal chemotherapy. This treat-ment is designed to eradicate microscopic residual diseasepresent in theperitoneal cavity after cancer resection. It hasbeen demonstrated that intraperitoneal chemotherapyalters the pattern of dissemination after curative surgery,but is not a treatment for residual disease in lymphnodes orsystemic metastases.

PALLIATIVE GASTRECTOMY IN STAGE IVGASTRIC CANCER

One group of gastric cancer patients who have a poorprognosis and are treated with a variety of approaches arethose who present with peritoneal seeding. Judgmentsregarding optimal approaches for such patients continue tobe controversial. Overall, 10% to 20% of patients beingexplored for potentially curative resection will be foundto have peritoneal seeding at the time of abdominalexploration. This occurs most frequently in patients whohave the signet-ring type of gastric cancer, as opposed tointestinal-type pathology. Sometimes the detection of asmall amount of fluid by a CT scan or ultrasound can alertthe clinician to the presence of peritoneal seeding. On CT,subtle linear densities associated with the fat that con-stitutes the omentum or small bowel mesentery maysuggest peritoneal carcinomatosis. When confronted inthe operating room with peritoneal seeding from gastriccancer, the clinician must make a decision regarding thepossible risks andbenefits of aggressive treatments vs. bestsupportive care.

Other treatments for this group of patients have notbeen shown to be effective. Neoadjuvant chemotherapyfor patients with peritoneal seeding has been uniformlydisappointing. Preusser et al. [30] observed a responserate to aggressive chemotherapy of 50% in patients withadvanced gastric cancer, but the response rate was lowestin patientswith peritoneal carcinomatosis. Ajani et al. [31]treated patients prior to gastrectomy. At exploration,peritoneal carcinomatosis was the most common indica-tion of failure of the intensive chemotherapy regimen.Radiation therapy has also been reported to be of no valuein this situation.

A. Rationale for Palliative Gastrectomy inPatients With Carcinomatosis

The rationale for palliative gastrectomy in patients withperitoneal seeding rests on an assumption that the primarygastric cancer will result in gastric obstruction, perfora-tion, or bleeding prior to the onset of symptoms from theperitoneal surface dissemination. The gastrectomy shouldbe associated with removal of gross disease immediately

adjacent to the stomach, especially that associatedwith thegreater and lesser omentum. Not only will perforation,obstruction, and bleeding be averted, but with periopera-tive intraperitoneal chemotherapy therewill be a reductionin the incidence of debilitating ascites, which frequentlyoccur as part of the terminal events in these patients.

A second rationale for palliative gastrectomy in thesepatients is more theoretical. If a significant proportion ofthe gastric cancer is removed, then chemotherapy may beexpected to show a greater response. The gastric lesionshould not be considered unresectable until explorationproves it to be so. As long as the primary cancer andthe organs to which it adheres can be removed withoutexcessive morbidity or mortality, every attempt should bemade to resect the primary lesion regardless of its size andthe other organs involved. Leaving behind a primary tumormass in the stomach not only invites bleeding and per-foration during the chemotherapy treatment, it also greatlydiminishes the likelihood of a response from chemother-apy. If it is technically possible, the primary gastric cancershould be palliatively resected in a majority of patients.

Review of the Gastric Cancer Literature RegardingPalliative Gastrectomy With Peritoneal Seeding

Although surgeons will proceed with a palliative sub-total gastrectomy, they are often reluctant to perform totalgastrectomy or esophagogastrectomy for palliation inpatients with peritoneal carcinomatosis. An early study byLawrence and McNeer [32] from the Memorial Sloan-Kettering Cancer Institute showed the effectiveness ofsurgery for the palliation of incurable gastric cancer. Inthat study the relief of symptoms was of major concern.The authors enthusiastically recommended subtotal ratherthan total gastrectomy; however, even at that early date(1958) they advocated total gastrectomy for cases inwhichit is necessary to relieve obstruction. They concluded thatthe relief of symptoms may not be ideal with a totalgastrectomy, but is ‘‘sometimes worthwhile.’’

In 1975, Stern et al. [33] (Roswell Park MemorialInstitute) published a study on palliative resection foradvanced carcinoma of the stomach. They comparedpalliative resection in 39 patients who were matched to73 patients who had not undergone resection. All of thepatients had stage III and IV carcinoma. Their data showeda median survival of 15.5 months in 23 patients who wereresected, as compared to 5.6 months in 55 patients whowere not resected. The difference in survival wassignificant (P-value< 0.001). Patients who underwentsubtotal or total gastrectomy were combined in the dataanalysis. In that study, palliative gastric resection wasnot associated with an increased incidence of surgicalcomplications, as compared to a bypass procedure. In fact,the incidence of surgical complications in the resectedgroup of patients was 19% vs. 20% for those who had


exploration only. The authors concluded that every effortshould be made to palliatively resect the primary tumor inorder to prolong survival.

In 1980, Ekbom and Gleysteen [34] (Milwaukee, WI)examined palliative gastric resection in 55 patients andcompared the results with those obtained by gastrojeju-nostomy in 20 patients. The operative mortality was 25%with gastrojejunostomy and 15% with palliative gastrect-omy. The complication rate was 20% with gastroje-junostomy and 33% with gastrectomy. Total or proximalgastrectomy with esophagectomy did not have a sig-nificantly different mortality rate than gastrojejunostomy.After palliative resection, patients obtained relief fromsymptoms for a significantly longer period of time(P< 0.01). The authors concluded that gastrojejunostomyprovides less palliation of significantly shorter durationwhen compared to resection without reduction of post-operative gastrointestinal complications or operativemortality.

In 1982, the Gastrointestinal Tumor Study Group [35]reported their results with combination chemotherapy andradiation therapy vs. chemotherapy alone for patients withlocally advanced gastric carcinoma. Approximately 50%of these patients had gross residual tumor followingexploration, and 50% had microscopic residual tumor.Seventy-three percent of the patients underwent a palli-ative resection, and 27% underwent biopsy only. In bothgroups of patients (chemotherapy alone or chemotherapyplus radiation therapy), the survival was superior in theresected patients. The effect of resection on survival wassignificant, with a P-value of 0.05. This improvement insurvival of the patients who had a palliative resectionwas independent of the form of postoperative therapyemployed.

In 1983, Meijer et al. [36] (Free University Hospital,Amsterdam) studied 51 patients who had undergone apalliative procedure for advanced carcinoma of thestomach. Twenty-six of these patients underwent a palli-ative resection. There were 14 total and 12 partialgastrectomies. The authors described palliation as goodin 13 patients,moderate in 7 patients, and poor in 4 patients(50%, 27%, and 5%, respectively). Palliation after gastro-enterostomy in 25 patients was poor in all patients (0%).They concluded that palliative total and partial gastrect-omy can produce good palliation in advanced gastriccancer.

Boddie et al. [37] (M.D. Anderson Hospital, Houston,TX) reported their data on palliative total gastrectomy andesophagogastrectomy for advanced gastric cancer in 1983.Their patients presented with symptoms of dysphagia,pain, nausea, vomiting, and bleeding (both with andwithout a transfusion requirement). They examined45 patients who had undergone palliative total gastrect-omy or esophagogastrectomy. There was evidence of

distant intra- or extra-abdominal metastases in 95.6% ofthese patients. When it was feasible, extended gastric re-sections were attempted in the palliative resection group,but in all of these patients, gross residual disease was leftbehind or therewere documented distantmetastases. Theirresults with palliative total gastrectomy or esophagogas-trectomy were compared with results from patients whohad undergone the same procedure with curative intent, orwho had undergone exploration or bypass only. Post-operative death occurred with 17.8% of the palliativeresections and in 23.8% of the exploration and bypass-only group. Therewere statistically significant differencesin survival between the palliative resection and theexploration/bypass groups. Median survival with pallia-tive resectionwas 10.4months, and for exploration/bypassit was 3.6 months. The authors concluded that palliativetotal gastrectomy and esophagogastrectomy were asso-ciated with modest improvement in median survival overexploration alone, and that the occasional long-termsurvivals justify the use of these procedures in selectedgood-risk patients. The authors noted that the operativemorbidity and mortality for total gastrectomy and esopha-gogastrectomy are steadily decreasing. As the morbidityand mortality decrease, a more liberal application of thesepalliative surgical treatments becomes appropriate.

In 1987, Bozzetti et al. [38] (Italian Cancer Institute,Milan) reviewed their experience with palliative surgicalprocedures for carcinoma of the stomach. Sixty-one oftheir patients had noncurative resections,with an operativemortality rate of 11.5%. Exploratory laparotomy andbypass were associated with 2.8- and 3.5-month survivals,respectively. Resection was associated with an 8-monthsurvival, and 6% of these patients survived more than5 years. When patients were stratified into three groups(according to the spread of disease) as local, distant, orlocal plus distant, resection was a superior treatment in allgroups. The authors suggested that resection is associatedwith a prolongation of life, and should be performed if it isanatomically possible.

In the United Kingdom, Hallissey et al. [39] reviewedcases (n¼ 13,175) of palliative surgery for gastric cancerin 1988, using the Birmingham Cancer Registry as theirdatabase. Patients who had a palliative resection showedthe best survival in the presence of both locally advancedand metastatic disease (P< 0.001). The authors sug-gested that the best palliative procedure for patients withincurable disease is resection of the primary malignancy.Considering that 79.6% of their database presentedwith stage IV disease, the importance of an establishedmanagement plan for this group of patients was clear.The palliative resection was performed in patients withliver metastasis or peritoneal dissemination. When thesurvival rates after palliative resection in patients withhepatic metastases, peritoneal metastases, ormetastases at


other sites were compared, no differences were observed.One exception was a reduced survival in those patientswho had metastasis to more than one site. The authorsrecommended laparotomy as the method of choice forassessing cancer dissemination and the feasibility ofresection. They suggested that resection is the best formof treatment of gastric carcinoma, even in the presence oflocally advanced or metastatic disease.

Butler et al. [40] (Torrance, CA) reported on totalgastrectomy in the treatment of advanced gastric cancer in1989. Their operative mortality was only 4%, althoughpostoperative morbidity was 48%. They suggested thattotal gastrectomy produced excellent palliation (25 oftheir 26 patients were tolerating solid food at the time ofhospital discharge). Furthermore, 21 patients were ableto maintain oral alimentation until just prior to death.The median survival following total gastrectomy was15 months; 62% of their patients were alive at 1 year, and38% were alive at 2 years after the procedure. Theseauthors concluded that their long median survival, suc-cessful relief of symptomatology, and low operativemortality support a uniform application of palliative totalgastrectomy for patients with advanced gastric cancer.

Haugstvedt et al. [41], along with members of theNorwegian Stomach Cancer Trial, presented data on thesurvival benefit of resection in patients with advancedstomach cancer. Therewere 503 patients in the Norwegianmulticenter experience who had noncurative gastriccancer treatments: 182 (36%) of these patients had agastric resection, and 64 (13%) of the patients includedtotal gastrectomy. Seventy patients (14%) underwent abypass procedure, 156 (31%) had an exploratory laparo-tomy only, and 78 (16%) had no surgery at all. Whenpatient characteristics using a Cox proportional-hazardsmodel were included in the analysis, resection doubled themedian survival for both stage III and stage IV disease.In stage IV patients, the survival increased from 3 to6 months when nonresection or no operation was com-pared to resection. These authors concluded that resectionis justified in patients with advanced stomach cancer,since a survival benefit was documented. The operativemortality for total gastrectomy, subtotal gastrectomy,proximal gastrectomy, and distal resectionwas 12%, 18%,14%, and 11%, respectively. Nonresectional procedurescarried the same or greater mortality (14%).

In 1991, Monson et al. [42] reported the Mayo Clinicexperience. This was a follow-up to a study by ReMine[43], from the same institution, published in 1979. In theearlier study, palliative total gastrectomy was not found tobe a satisfactory palliative operation [39]. The evolution intreatment strategies for palliation of gastric cancer isdemonstrated in the more recent publication from thesame institution. Monson et al. [42] examined 53 con-secutive patients who had undergone total gastrectomy for

advanced gastric adenocarcinoma. All but one of thesepatients had serosal invasion or peritoneal seeding. Therewas an 8% postoperative mortality. The median survivalwas 19 months, with 13 patients (24%) staying alive formore than 2 years. The quality of life was graded in sur-vivors as good in 59%, satisfactory in 28%, and poor in13% of patients. The extent of serosal involvement didnot affect the cumulative survival in patients with S1 orS2 disease. However, patients with S3 disease showed asignificantly worse survival (P< 0.0001). These authorsconcluded that a policy that refuses to recommend totalgastrectomy in patients with advanced disease will deny asizable number of patients a significant prolongation ofgood-quality life. They recommended that qualifiedsurgeons should not hesitate to resort to total gastrectomyin selected patients when it is technically feasible, even inthe face of extensive tumor.

The therapeutic significance of palliative operations forgastric cancer concerning both survival and quality of lifewere studied by Ouchi et al. [44] at the Miyagi CancerCenter Hospital, Natori, Japan. Their database consistedof 95 patients undergoing palliative operations for ad-vanced gastric cancer. Their patients were divided intogroups by P stage: P0 included patients with no peritonealseeding, P1 indicated seeding in the upper abdomen, P2indicated small-volume seeding throughout the abdomen,and P3 indicated extensive peritoneal dissemination.Overall, palliative gastrectomy significantly correlatedwith better and longer survival. When total gastrectomywas performed in patients with P2 or P3 disease, therewasa poorer outcome thanwith total gastrectomyperformed inpatients with P0 or P1 disease. The authors concluded thatpalliative resection with P2 or P3 peritoneal disseminationhad less beneficial effects on the prolongation of survivalor improved quality of life in patients with gastric cancer.They also showed that total gastrectomy for P0 or P1metastases offered improved survival compared to totalgastrectomy for P2 or P3 metastases. However, theseauthors did not directly compare the quality of life orsurvival of patients treated conservatively with thosetreated with resection. An important finding in that studywas that the hospital-free survival of patientswith P2 or P3peritoneal dissemination who underwent total gastrect-omy was poor, with only about half of the patients in thatgroup having a hospital-free survival of >3 months.

Kikuchi et al. [45] (Kitasato University, Kanagawa,Japan) studied 122 patientswho had implants to the distantperitoneum. There were 63 patients in the gastrectomizedgroup and 59 patients in the group that underwent otherprocedures. The median survival in patients who under-went gastrectomy was 12.2 months. The patients whounderwent other procedures had a median survival of5.5 months. In this study the extent of peritoneal meta-stases did not significantly affect prognosis. The authors


concluded that when palliative gastrectomy was feasible,it had a beneficial effect on survival, and that it wasindicated for patients regardless of the extent ofmetastasesto the peritoneum if the primary tumor was surgicallyresectable and there was no evidence of liver metastases.

Since more patients have now undergone noncurativegastric cancer resection, it is possible to describe certainclinical features that enable more knowledgeable patientselection. On the basis of these data, clinical judgmentscan be made as to which patients are not likely to benefitfrom gastrectomy. This information comes from extensivestudies in Japan and Korea. In Osaka, Isozaki et al. [46]examined the long-term results of noncurative resection.Patients were categorized by five prognostic factors: N,distant lymph node metastasis; P, positive for peritonealdissemination; H, positive liver metastasis; S, serosalinvasion of adjacent organs, andM, cancer invasion of theresection margins. The 5-year survival was 33% for asingle factor (76 patients), 10% for two factors (28patients), and 0% for three factors (13 cases). The 5-yearsurvival for patients with peritoneal seeding alone was26% (13 cases). The authors recommended an aggres-sive surgical approach in patients who had a single poorprognostic factor.

In Kyushu, Maekawa et al. [47] analyzed their data ina similar manner and reached the same conclusions.Gastrectomy can improve survival in patients with one ortwo types of poor prognostic factors (P, S, H, orM), but notin those with more than two.

In a collaborative effort by the Taegu Gastric CancerAssociation, Bae et al. [48] studied four main prognosticfactors for advanced gastric cancer. Patients were cate-gorized by four main prognostic factors: T, invasion toadjacent organs; N, involvement of distant lymph nodes;H, hepatic metastases; and P, peritoneal dissemination.A total of 478 patients were studied at five institutions inTaegu City. In patients with a single prognostic factorfor advanced gastric cancer, gastrectomy significantlyincreased mean survival. In 89 patients who underwentresection of gastric cancer with peritoneal seeding, themedian survival was 612� 50 days. In the nonresectiongroup, the survival was 208� 35 days. This survival wassignificantly improved (P¼ 0.0001). However, the authorsalso reported that gastrectomy with more than onepoor prognostic factor showed no survival benefit withgastrectomy. This was true for peritoneal seeding with

distant positive nodes, peritoneal seeding in combinationwith hepatic metastases, and peritoneal seeding in com-bination with distant nodes and hepatic metastases. Theclinical conditions that are contraindications to gastrect-omy are listed in Table II.

In summary, a review of multiple journal articles pub-lished over the last 20 years strongly supports palliativeresection as the treatment of choice for stage IV gastriccancer (Table III). The data indicate that both quality of lifeand survival benefit from resection. Also, the morbidityand mortality with resection compare favorably withbypass and other nonresection palliative procedures. In amajority of these articles, the number of patients classifiedas stage IV because of peritoneal seeding is not given.However, peritoneal carcinomatosis was not recom-mended as an exclusion criterion in any article.

Ouchi et al. [44] were the only authors who suggestedthat gastrectomy should be reserved for patients with aminimal amount (P1) of peritoneal seeding, and thatresection with moderate or extensive seeding (P2 or P3)had no beneficial effect on prolongation, survival, orquality of life. Additional journal articles emphasized thatpatientswith peritoneal seeding plus other poor prognosticfeatures, such as liver metastases or extensive lymph nodemetastases, are not likely to benefit from gastrectomy[46–48]. Selection factors are important considerations inachieving optimal results. In the light of these clinical data,surgeons cannot refuse to consider gastrectomy as a treat-ment option in patients with stage IV disease because ofperitoneal seeding. Rather, knowledgeable patient selec-tion is essential for management of this disease. Clinicalfeatures that call for an aggressive approach to gastriccancer with peritoneal seeding are listed in Table IV.

PERITONECTOMY PROCEDURES FORGASTRIC CANCER RESECTION

The major objective of palliative resection for gastriccancer is to eliminate the catastrophic complicationscaused by the primary malignancy. In addition, resectionof the gastric cancer greatly reduces the volume of re-sidual cancer. In this situation, the responses to subsequentchemotherapy should be maximized. Peritonectomy canbe used to further reduce and, in some patients, eveneliminate all visual evidence of disease. Sugarbaker [49]reported on the use of five different peritonectomy pro-cedures for carcinomatosis. The peritonectomies that are

TABLE II. Contraindications to Palliative Gastrectomy in Patients With Peritoneal Carcinomatosis

High operative risk because of age and comorbidity.Inability to resect the primary cancer (extensive lymphadenopathy, invasion of pancreas).

Liver metastases (H2 or H3), distant nodal metastases (N2 or N3) or other clinically significant metastases that will result in a short survival.

Large (> 2.5 cm) peritoneal implants widely distributed on small bowel surfaces (P3) that cannot be resected by peritonectomy and that prevent the

resumption of adequate oral nutrition.


specific to patients with gastric cancer have also beendescribed [50–54]. These peritonectomy proceduresmaximally cytoreduce the peritoneal surface malignancy,and optimally prepare the patient for a response to sub-sequent intraperitoneal and systemic chemotherapy.Theo epigastric peritonectomy includes any prior midlineabdominal scar in continuity with the preperitonealepigastric fat pad, the xiphoid process, and the roundand falciform ligaments of the liver (Fig. 3). The antero-lateral peritonectomy removes the greater omentum with

the anterior layer of the peritoneum from the transversemesocolon, peritoneum of the right paracolic gutter alongwith the appendix, and the peritoneum in the rightsubhepatic space. In some patients, the peritoneum cover-ing the left paracolic gutter must be stripped (Fig. 4). Thesubphrenic peritonectomy removes the peritoneal surfacesfrom the medial portion of the right and left hemidiaph-ragm, along with a resection of the left triangular ligament(Fig. 5). The omental bursa peritonectomy is initiated witha cholecystectomy. The peritoneal covering of the portahepatis; the hepatoduodenal ligament; the hepatogastricligament; and the peritoneal floor of the omental bursa,including the peritoneum overlying the pancreas, areresected (Fig. 6). In patients who have a tumor within thecul-de-sac, a pelvic peritonectomy is indicated. High-voltage electrosurgery is used to strip the peritoneum fromthe pouch of Douglas (Fig. 7). Occasionally, the pelvicperitonectomy will require removal of the rectosigmoidcolon so that the tumor can be cleanly removed from thecul-de-sac (Fig. 8).

Yonemura and colleagues [51,52] presented theKanazawa approach to peritonectomy for gastric cancerwith peritoneal seeding. In this approach, the visceralperitonectomy procedures involve an abdominal colect-omy if necessary to remove gastric cancer implants. Theseperitonectomy procedures are integrated into the total orsubtotal gastric resection.

Hagiwara et al. [54] showed that peritonectomy may beof benefit in patients with peritoneal seeding even if in-traperitoneal chemotherapy is not used. Improved survival

TABLE III. Journal Articles Since 1980 From the English Literature Supporting Palliative Gastrectomy

Reference Location Treatment and no. Survival

Ekbom and Gleysteen [34]a Milwaukee, WI No resection, 20 0% (2 year minimum)

Palliative gastrectomy, 147 16% (2 year minimum)

GITSG [35] Washington, DC No resection, 53 P< 0.05

Palliative gastrectomy, 147

Meijer et al. [36]a Amsterdam, Netherlands No resection, 25 4.2 m (median)

palliative gastrectomy, 26 9.6 m

Boddie et al. [37]b Houston, TX No resection, 21 3.6 m (median)


Bozzetti et al. [38] Milan, Italy No resection, 185 3.0 m


Hallissey et al. [39] Birmingham, UK No resection, 9,597 P< 0.001

palliative gastrectomy, 884

Butler et al. [40]a Torrance, CA palliative total gastrectomy, 27 15.0 m

Haugstvedt et al. [41]b Norway No resection, 311 4.0 m (median)


Monson et al. [42]a Rochester, NY No resection, 226 3.5 m (median)


Ouchi et al. [43]a Natori, Japan No resection, 31 6.0 m P< 0.01


Kikuchi et al. [44] Kanagawa, Japan No resection, 59 5.5 m P< 0.0001


aMarked symptom relief documented.bMarked patients for symptoms and stage.

TABLE IV. Selection of Patients With Peritoneal Carcinomatosisfor Palliative Gastrectomy, Peritonectomy and PerioperativeChemotherapy

Suggests Suggests conservative

Clinical feature gastrectomy management

Young age (<65 years) Yes No

Low operative risk Yes No

(no other diseases)

Patient symptoms

Pain Yes No

Bleeding Yes No

Perforation Yes No

Obstruction Yes No

Ascites Yes No

Lymph nodes negative Yes No

No liver metastases Yes No

Miliary disease vs. gross Yes No

peritoneal implants

Expect complete clearing Yes No

primary cancer


was observed only in patients with limited (P0 and P1)peritoneal seeding.

In Table V the data regarding peritonectomy combinedwith gastrectomy to achieve a complete cytoreductionare reviewed [55–58]. In these four journal articles, a

complete removal of gastric cancer so that no visibleevidence of dissemination remained was associated withprolonged survival. In all four reports this aggressivesurgical approach was combined with intraperitonealchemotherapy given with surgery or in the early post-operative period.

PERIOPERATIVE INTRAPERITONEALCHEMOTHERAPY COMBINED WITH

GASTRECTOMY FOR GASTRIC CANCERWITH PERITONEAL SEEDING

Fujimoto et al. [59] presented phase II studies in patientswith primary gastric cancer and peritoneal seeding. Theirresults were obtained with gastrectomy followed by in-traperitoneal hyperthermic perfusion. The chemotherapywas mitomycin C and misonidazole, a thermosensitizingdrug. All 15 of their patients tolerated the procedure well.Theymaintained temperatureswithin the peritoneal cavityat 43.0–44.58C.

One year later, in 1989, the same authors reported theirexperience with 59 patients who underwent gastrectomycombined with intraperitoneal hyperthermic perfusion

Fig. 4. Anterolateral peritonectomy removes the greater omentum andthe peritoneal surface of the right and left paracolic sulcus.

Fig. 5. Subphrenic peritonectomy.

Fig. 3. Epigastric peritonectomy.

Fig. 6. Omental bursa peritonectomy removes the lesser omentumandthe floor of the omental bursa.


using mitomycin C [60]. Compared to historical controls,the patients treated with intraperitoneal hyperthermicperfusion showed a statistically significant improvementin survival (P¼ 0.001). The results were even morestriking in patients who had demonstrated peritonealseeding. Median survival of the untreated group wasapproximately 6 months. Median survival of the patientstreated with intraperitoneal hyperthermic perfusion wasapproximately 18 months. Again, these results werestatistically significant (P¼ 0.001).

In 1990, Fujimura et al. [61] examined continuoushyperthermic peritoneal perfusion for the treatment ofperitoneal dissemination of gastric cancer. Thirty-onepatients with gastric cancer and peritoneal disseminationreceived cisplatin and mitomycin C. The peritoneal fluidwas heated to 528C, but temperatures in the abdomenwere41–438C. This group used a special peritoneal cavityexpander in an attempt to improve distribution of chemo-therapy and heat. The surgeon could manipulate the smallbowel with his hand during the chemotherapy treatments.There were no postoperative deaths, but 6 of 31 patientshad amajor complication. All but one of these patients hadperitoneal dissemination assessed as P3. Two of theirpatients showed a >2-year survival (6%).

In 1991, Fujimura et al. [62] updated the studies inKanazawa with hyperthermic chemotherapy combinedwith cytoreductive surgery for the treatment of gastriccancer with peritoneal dissemination. They now hadresults on 41 patients with peritoneal dissemination ofgastric cancer in the absence of liver metastasis treatedover a 6-year period. The overall median survival was14.6 months, with 4 patients (9.8%) having a 3-yearsurvival. In 7 of 9 patients with ascites, the ascites disap-peared after continuous hyperthermic peritoneal perfusion.These authors suggested that continuous hyperthermicperitoneal perfusion with mitomycin C and cisplatin iseffective in the treatment of gastric cancer with peritonealdissemination.

Noh et al. [63] studied 40 patients who receivedintraoperative chemotherapy and then early postoperativeintraperitoneal chemotherapy. Seventy percent of thesepatients had poorly differentiated signet ring cell carci-noma. Two patients died postoperatively. Twenty-threepatients underwent total or subtotal gastrectomy. Survivalin the resection group as compared to the nonresectiongroup was superior. The longest survival in the group was13 months. The group undergoing cytoreductive surgeryhad a median survival of 7 months. These authors con-cluded that cytoreductive surgery plus intraoperative andearly postoperative intraperitoneal chemotherapy appearsto be relatively safe and provides a better outcome.

Yonemura et al. [64] updated their experience in 1995.They reported on 43 patients who had peritonectomy inaddition to continuous hyperthermic peritoneal perfusionwith mitomycin C, cisplatin, and etoposide. Patients whohad a complete cytoreduction had a median survival of419 days, a 1-year survival of 61%, and a 5-year survivalof 17%. Patients with residual disease had a mediansurvival of 205 days, a 1-year survival of 30%, and a 5-yearsurvival of 2%. The survival of patients with completecytoreduction (n¼ 28) as compared to patients withresidual disease (n¼ 55) was significant (P¼ 0.034).Twenty-eight patients underwent a second-look operation.In 8 patients who had a complete response recorded at the

Fig. 7. Limited pelvic peritonectomy.

Fig. 8. Complete pelvic peritonectomy involves a resection of allpelvic peritoneal surfaces and the uterus, ovaries, Fallopian tubes, andrectosigmoid colon.


time of second-look surgery, therewas a 5-year survival of47%. These authors concluded that chemotherapy is mosteffective in patients who have a small tumor burden as aresult of cytoreductive surgery. They concluded thatcytoreductive surgery and continuous hyperthermic peri-toneal perfusion is an effective therapy for peritonealdissemination of gastric cancer.

Yonemura et al. [65] updated this information in 1995,and described the effects of this treatment strategy in83 patients. The overall 1-year survival was 43%, and5-year survivalwas 11%.Again, patientswho underwent acomplete cytoreduction survived significantly longer thanthose with residual disease, and those who had a completeresponse to chemotherapy, as observed at the time ofsecond-look surgery, did better than those with a partialresponse or no response. Five of their patients survivedlonger than 5 years (6%).

Yu et al. [23], from Taegu, reported on 64 patients withstage IV gastric cancer. Half of these patients had gastrec-tomy only, and half underwent gastrectomy plus earlypostoperative intraperitoneal chemotherapy. The mediansurvival was 4.9 vs. 27.8 months (P¼ 0.0098).

Hirose et al. [66] studied the use of hyperthermicperitoneal perfusion to treat gastric cancer with peritonealmetastasis in 17 patients. The patients who underwentcontinuous hyperthermic peritoneal perfusion showed asignificantly better survival than 20 control patients. Therewas an 11- vs. 6-month median survival time and a 1-yearsurvival rate of 44% vs. 15% (P¼ 0.00479). All 5 patientswho had a complete cytoreduction prior to continuoushyperthermic peritoneal perfusion survived more than14months.ACoxmultivariate regression analysis showedthat complete resection of localized peritoneal metastasiswas an independent prognostic factor (P¼ 0.0062). Inthese patients, continuous hyperthermic peritoneal per-fusion was not a statistically independent prognosticvariable.

Yoo et al. [54] reported the effectiveness of earlypostoperative intraperitoneal chemotherapy on 91 patientswith stage IV gastric cancer. Additional cycles of

intraperitoneal chemotherapy were administered on amonthly basis for four cycles. The results were comparedwith those from 140 historical controls who had surgeryonly. The overall 3-year survival in the group treated withchemotherapy was 17.3%, and in the surgery-alone groupit was 11.4%.

In these reports, approximately 360 patients with peri-toneal seeding were treated with gastrectomy (with orwithout peritonectomy) and intraperitoneal chemotherapy.There were both randomized and historical controlpopulations in these phase II efforts (Table VI). Whenresection of advanced gastric cancer was accomplished,the perioperative intraperitoneal chemotherapy showedbenefit in all of these reports.

CURRENT ‘‘STANDARD OF CARE’’ FORPATIENTS WITH ADVANCED GASTRIC CANCER

There has been an evolution of treatment strategiesfor patients with gastric cancer. Combined treatmentshave been applied to patients undergoing gastric cancerresection for cure, aswell as for palliation (TableVII). Thelist of patients with gastric cancer currently recommendedfor perioperative intraperitoneal chemotherapy includethose at high risk for locoregional recurrence, and those forwhom a treatment response with small-volume peritonealsurface disease will improve both the quality and thelength of survival (Table VIII).

An important goal for all gastric cancer surgeons isthe standardization of procedures for peritonectomy,chemotherapy, and heated intraoperative intraperitonealchemotherapy. Peritonectomy procedures that allow theremoval of all gross and microscopic peritoneal implantshave been described [49–54]. Techniques for admi-nistering intraperitoneal chemotherapy have also beendescribed. Yonemura et al. [67] utilized a peritoneal cavityexpander that allowed the small bowel to float in solution.Sugarbaker et al. [68] also described an open technique inwhich the edges of the abdominal incision were tented upon a self-retaining retractor to provide a reservoir for theheated chemotherapy solution (Fig. 9). In addition, early

TABLE V. Complete vs. Incomplete Cytoreduction for Far-Advanced Gastric Cancer in PatientsGiven Perioperative Chemotherapy

Reference Location Results (patients) Survival % P-value

Yonemura et al. [55] Kanagawa Complete (28) 17 (5 years) 0.03

Incomplete (55) 2

Fujimoto et al. [56] Chiba Complete (79) n.a. <0.0001

Incomplete (33)

Hirose et al. [57] Fukui Complete (5) n.a. 0.006

Incomplete (12)

Yoo et al. [58] Seoul R0 complete 36

R1 incomplete (91) 19 (3 years) n.a.

R2 incomplete 20


postoperative intraperitoneal chemotherapywith 5-fluoro-uracil can be administeredwithout a significant increase inmorbidity and mortality [69].

FUTURE PROSPECTS

The next step in continuing this clinical effort involvesproper patient selection. More precise quantitation ofperitoneal seeding in these patients is indicated to identifypatientswhowill derive the greatest benefits. In addition tothe clinical data presented in Tables II, IV, and VII, theperitoneal cancer index has enabled more knowledgeablepatient selection for colon cancer and sarcoma [70,71].It has promise as an accurate quantitative prognosticindicator in gastric cancer.

The survival advantage limited to patients with stage IIIgastric cancer and the risk of increased morbidity justifya selection of patients in future adjuvant trials of per-ioperative intraperitoneal chemotherapy. Increasingly,sophisticated methodologies are becoming available forthe selection of high-risk patients. Preoperative stagingmethods, such as endoscopic ultrasound, can be useful asthey become more widely available. Standard preopera-tive staging and careful intraoperative examination of theperitoneal cavity with biopsies performed, as needed, toverify macroscopic findings, may become a means ofselecting patients for perioperative intraperitoneal che-

motherapy. The major selection criteria may be lymphnode involvement within the second tier of lymph nodes.In patients with resectable gastric cancer, special attentionmust be paid to the exclusion of patients with stage I and IItumors for these adjuvant treatments.

ALTERNATIVE TREATMENTS

A very important aspect of treatment for patients withstage IV gastric cancer is adequate informed consent.Patients with stage IV gastric cancer need to realize thatsurvival without aggressive treatments is a median of6 months, whereas survival with aggressive treatments, asoutlined here, approaches 18 months. Patients need toknow that there may be an alternative approach, althoughits benefits may not have been established. Systemicchemotherapy or chemotherapy plus radiation therapy canbe used preoperatively in an attempt to ‘‘downstage’’ thecancer. It is thought that this preoperative treatment willallow narrow margins of resection to become moreacceptable. Also, the problemswith tumor cell entrapmentand intraperitoneal dissemination of cancer cells may bereduced by preoperative therapy. In this approach, aggres-sive chemotherapy is used prior to any surgical event, andthen surgery is proposed if there is a significant response.

There are many problems with this neoadjuvantapproach. The major one concerns the very limited

TABLE VI. Treatment of Peritoneal Seeding With Gastrectomy Plus Perioperative Intraperitoneal Chemotherapy

Reference Location Treatment Survival Survival (median)

(patients) Survival % years months P-value

Fujimoto et al. [59] Chiba IP chemo (30)a 80.4 1 n.a. <0.001

Hist control (29)a 34.2 n.a.

IP chemo (20) 78.0 1 n.a. <0.001

Hist control (7) 0.0 n.a.

Yonemura et al. [61] Kanazawa IP chemo (41) 28.5 3 n.a. n.a.

Yonemura et al. [62] Kanazawa IP chemo (32) 55.0 3 n.a. < 0.001

Rand control (35) 7.0 n.a.

Yonemura et al. [65] Kanazawa IP chemo (83)a 11.0 5 n.a. n.a.

Yu et al. [23] Taegu IP chemo (33)a 33.0 n.a. 2.78 0.0098

Rand control (31)a 31.0 n.a. 4.9

Hirose et al. [66] Fukui IP chemo (32) n.a. n.a. 11.0 0.0479

Hist control (20) n.a. n.a. 6.0

Yoo et al. [54] Seoul IP chemo (91)a 17.3 3 n.a. <0.0000

Hist control (140)a 11.0 n.a.

n.a., not available; hist, historical; rand, randomized; IP chemo, intraperitoneal chemotherapy.aIncludes other patients with stage IV disease.

TABLE VII. Evolution of Treatment Strategies for Advanced Gastric Cancer

Resection

Resectionþ extended lymphadenectomy

Resectionþ extended lymphadenectomyþ perioperative intraperitoneal chemotherapy

Resectionþ peritonectomyþ extended lymphadenectomyþ perioperative intraperitoneal chemotherapy

Resectionþ peritonectomyþ extended lymphadenectomyþ perioperative intraperitoneal

chemotherapyþcombined delayed IP and IV chemotherapy


‘‘adequate response’’ of this group of patients. Very fewshow such a robust response that resection is then possible.If they do show a response and are resected, they are atincreased risk for postoperative morbidity and mortalitybecause of their prior aggressive chemotherapy treat-ments. Unfortunately, a majority of these patients pro-gress while on chemotherapy. Many patients who mightbenefit from gastrectomy are denied that benefit becausetheir disease progressed while they were receivingchemotherapy.

Finally, patients who have undergone resection, and inwhom disease dissemination in the peritoneal cavity wasprevented by intraperitoneal chemotherapy, are theoreti-cally most responsive because of the great reduction in the

volume of disease. By this rationale, patients with stage IVgastric cancer have everything to gain and nothing to loseby receiving preoperative treatment.

CONCLUSIONS

The data reviewed in this work suggest that resection ofgastric cancerwith peritoneal seeding orwith other sites ofdisease dissemination is advisable. First, patients whoundergo palliative resection show statistically improvedsurvival compared to patients who have a bypass only,exploration only, or no surgery. With the data currentlyavailable, one cannot realistically suggest that patients areharmed by resection. Rather, all of these studies suggestthat a patient’s quality of life can be greatly improved byresection. Second, peritonectomy procedures have beendescribed thatwill allow the resection of all tumors, exceptfor those that are located on small bowel surfaces. Thisleaves the patient with minimal residual disease, whichshould be more responsive to the intraoperative che-motherapy. Finally, multiple studies show that the survivalof patients with peritoneal seeding from gastric cancer isprolonged if the resection is combined with perioperativeintraperitoneal chemotherapy. This review presents abody of data indicating that gastrectomy, peritonectomy,and heated intraoperative intraperitoneal chemotherapyshould be considered a current standard treatment basedon evidence from the surgical literature for selectedpatients with this condition. In the light of these reports,surgeons must carefully evaluate their responsibilities sothat optimal treatments for patients with advanced gastriccancer are available at their institution.

TABLE VIII. Patients with Gastric Cancer Recommended forPerioperative Intraperitoneal Chemotherapy

Stage III

Positive peritoneal cytology

Ovarian involvement

Peritoneal seeding on the serosal surface of the stomach

Linnitis plastica

Rupture of a necrotic tumor mass

Adjacent organ involvement

Intraoperative tumor spill

Perforation of the primary tumor

Gross involvement of lymph nodes at the margin of excision

Limited peritoneal seeding, PCI �20

Limited peritoneal seeding so that a return of gastrointestinal

function is expected

Fig. 9. Heated intraoperative intraperitoneal chemotherapy by the Coliseum technique. Continuousmanipulation of the viscera causes uniform distribution of heat and chemotherapy to all peritoneal surfaces.


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