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Limited Survival in Patients With Carcinomatosis From Foregut Malignancies After Cytoreduction and Continuous Hyperthermic Peritoneal Perfusion
Limited Survival in Patients With Carcinomatosis From Foregut Malignancies After Cytoreduction and Continuous Hyperthermic Peritoneal Perfusion Jeffrey M. Farma, M.D., James F. Pingpank, M.D., Steven K. Libutti, M.D., David L. Bartlett, M.D., Susan Ohl, R.N., Tatiana Beresneva, M.D., H. Richard Alexander, M.D.
Peritoneal carcinomatosis is a frequent mode of metastasis in patients with gastric, duodenal, or pancreatic cancer. Survival in this setting is short and therapeutic options are limited. This analysis examines the outcomes of 18 patients treated with operative cytoreduction and continuous hyperthermic peritoneal perfusion. Eighteen patients (6 males and 12 females) with gastric (n 5 9), pancreatic (n 5 7), or duodenal (n 5 2) cancer were treated on protocol. Patients underwent optimal cytoreduction (complete gross resection, 11; minimal residual disease, 7) and a 90-minute perfusion with cisplatin. Clinical parameters and tumor and treatment characteristics were analyzed. Survival curves were estimated using the Kaplan-Meier method. Procedures included gastrectomy (n 5 8), pancreaticoduodenectomy (n 5 3), and hemicolectomy (n 5 2). After cytoreduction, patients had no evidence of residual disease (n 5 11), fewer than 100 implants less than 5 mm (n 5 1), more than 100 implants between 5–10 mm (n 5 3), or multiple implants with greater than 1 cm (n 5 3). Five patients received a postoperative intraperitoneal dwell with 5-fluorouracil and paclitaxel. There was one perioperative mortality, and complications occurred in 10 patients. The median progression-free survival was 8 months (mean, 10 months; range, 1–47 months) with a median overall survival of 8 months (mean, 18 months; range, 1–74 months). In this cohort, peritoneal perfusion with cisplatin used to treat foregut malignancies has a high incidence of complications and does not significantly alter the natural history of the disease. Investigation of novel therapeutic approaches should be considered. ( J GASTROINTEST SURG 2005;9:1346– 1353) Ó 2005 The Society for Surgery of the Alimentary Tract KEY WORDS: Regional therapy, peritoneal carcinomatosis, peritoneal perfusion, gastric cancer, duodenal cancer, pancreatic cancer
Peritoneal dissemination from primary gastric, duodenal, and pancreatic cancer is frequently found on exploration for curative resection of these malignancies. In a subset of patients, disease is confined to the abdominal cavity and has not yet spread systemically. It has been shown, through recurrence patterns after curative resection, that the peritoneum is frequently one of the first sites of recurrence. In gastric cancer, peritoneal recurrence accounts for 50%–60% of deaths after surgical resection with curative intent.1–3 Even with complete resection, microscopic disease remains, leading to
this early recurrence pattern and eventual death. The median survival for these patients remains exceedingly low. Over the past decade, little progress has been made to improve survival in these neoplasms. Systemic chemotherapy and radiation have thus far failed to meaningfully affect outcomes with these malignancies. Researchers have looked at novel therapies to provide better treatments over surgery alone, systemic chemotherapy, or radiation.4,5 Regional therapy is a rational approach in a disease process confined to the abdominal cavity. One of
Presented at the Forty-Sixth Annual Meeting of The Society for Surgery of the Alimentary Tract, Chicago, Illinois, May 14–18, 2005 (poster presentation). From the Surgery Metabolism Section (J.M.F., J.F.P., S.K.L., S.O., T.B., H.R.A.), Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Department of Surgery (D.L.B.), University of Pittsburgh Cancer Center, Pittsburgh, Pennsylvania. Reprint requests: H. Richard Alexander, Jr., M.D, Surgical Metabolism Section, Surgery Branch, National Cancer Institute/NIH, CRC, Room 4W-5952, 10 Center Drive, MSC 1201, Bethesda, Maryland 20892-1201. e-mail: [email protected] Ó 2005 The Society for Surgery of the Alimentary Tract
1346 Published by Elsevier Inc.
1091-255X/05/$dsee front matter doi:10.1016/j.gassur.2005.06.016
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these approaches uses continuous hyperthermic peritoneal perfusion (CHPP), either intraoperatively or in the perioperative period, as a method to prevent or inhibit peritoneal dissemination of disease. The synergism of hyperthermia and chemotherapy allows a significantly higher concentration of therapeutic agent to be administered while limiting systemic toxicities.6,7 This approach has been developed with the hope of palliating peritoneal recurrence and is currently undergoing trials for multiple different peritoneal malignancies.8 Numerous reports exist studying the effects of CHPP using predominantly mitomycin-C in the treatment and palliation of these aggressive upper gastrointestinal malignancies, most concentrating on gastric carcinoma.9–12 The methods of the procedures vary; nonetheless, some investigators have reported an increase in time to recurrence and overall survival in gastric cancer when combining surgical resection and perfusion.13,14 Our study is composed of 18 patients enrolled in clinical trials with upper gastrointestinal malignancy; including gastric, duodenal, and pancreatic adenocarcinoma, to determine time to recurrence and overall survival after CHPP with cisplatin.
MATERIAL AND METHODS Patient Eligibility and Enrollment From September 1993 through April 2002, 18 patients with gastric, duodenal, or pancreatic adenocarcinoma were referred to the Surgery Branch of the National Cancer Institute. These patients were treated following one of four Surgery Branch protocols approved by the Institutional Review Board of the National Cancer Institute. Study patients were required to be over 18 years of age with histologically or cytologically proven metastatic carcinoma in the peritoneal cavity. Additional eligibility criteria included (1) Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2; (2) lack of a comorbid disease that prevents them from being an operative candidate; (3) a life expectancy greater than or equal to 8 weeks; (4) adequate renal function (serum creatinine !1.5 or creatinine clearance of !70 ml/min; (5) normal hepatic function (normal bilirubin, prothrombin time/partial thromboplastin time, enzymes !2 times the upper limit of normal; (6) adequate hematopoietic parameters (white blood cell count O3000/ml and platelet count greater than 75,000); (7) absence of previous ineffective intraperitoneal platinum therapy; (8) patient’s weight more than 30 kg; and (9) no chemotherapy, radiotherapy, or immuno-
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therapy in the past 30 days. None of the peritoneal carcinoma patients had evidence of extra-abdominal metastases at the time of treatment. Patients were treated with one of four related and similar protocols of cytoreduction and hyperthermic peritoneal perfusion, including (1) escalating dose of cisplatin administered via a 90-minute CHPP; (2) neoadjuvant and intraoperative adjuvant CHPP with cisplatin/mitomycin-C; (3) CHPP with cisplatin followed by early postoperative escalating-dose 5fluorouracil (5-FU) and paclitaxel administered as a single intraperitoneal dwell (2–8 days postoperatively); or (4) CHPP with cisplatin followed by early postoperative 5-FU and paclitaxel administered as a single intraperitoneal dwell (2–8 days postoperatively). All patients underwent pretreatment counseling and gave written informed consent according to institutional and federal guidelines. CHPP Technique Patients underwent an exploratory laparotomy, lysis of adhesions, tumor cytoreduction, and CHPP as previously described.5 Every attempt was made at cytoreduction to leave no gross evidence of disease. Major bowel or abdominal organ resections were performed when deemed necessary to attain adequate debulking. At the completion of cytoreduction, two large-bore catheters were inserted through the abdominal wall; the inflow catheter was placed over the right lobe of the liver with the outflow catheter in the pelvis. Temperature probes were placed beneath the peritoneal lining on each side of the abdomen and in the pelvis. The abdominal fascia was temporarily closed. The catheters were connected to a closed circuit consisting of a roller pump, heat exchanger, and a reservoir (Fig. 1). Chemotherapy containing the perfusate was heated and recirculated for 90 minutes through the peritoneal cavity. The perfusion flow rate was maintained at 1.5 L/min with a perfusate volume that varied from 3 to 7 L depending on the size of the potential space of the peritoneal cavity (sufficient to moderately expand the peritoneum correlating with intra-abdominal pressures between 5 mm Hg and 15 mm Hg). After stable perfusion parameters were obtained and the peritoneal cavity was warmed to a median temperature of 41.4 C, cisplatin was added to the perfusate. Perfusion was continued for 90 minutes, during which there was constant, manual agitation of the abdomen to minimize streaming and ensure optimal and even distribution of perfusate throughout the abdominal cavity. Sodium thiosulfate was given via a loading dose of 7.5 g/m2 intravenously over 20 minutes before the addition of cisplatin, followed by
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Fig. 1. Continuous hyperthermic peritoneal perfusion perfusion circuit. After aggressive optimal cytoreduction, two large-bore catheters were then inserted through the abdominal wall. Temperature probes were placed beneath the peritoneal lining. The catheters were connected to a closed circuit consisting of a roller pump, heat exchanger, and a reservoir. Chemotherapy containing the perfusate was heated and recirculated for 90 minutes throughout the peritoneal cavity.
a continuous infusion at 2.13 g/m2/hr for 12 hours as described.15 Sodium thiosulfate has been shown to bind cisplatin in the serum and decrease systemic toxicity from intraperitoneal administration of cisplatin.16 Urine output was maximized through aggressive hydration (central venous pressure 12 mm Hg 30 minutes before CHPP) and diuretics to maintain urine output at greater than 200 ml/hr during the perfusion; this was continued for 12 hours postoperatively. Urine output was maintained at 100 ml/hr for an additional 12 hours. The patient’s mean core temperature was measured with an esophageal probe and maintained at a median of 38.5 C (range, 37.2 –39.8 ) using a cooling blanket and topical ice packs. At the completion of the perfusion, the fascia was opened, the temperature probes and catheters were removed, the residual perfusate was evacuated, and the peritoneal cavity was irrigated with warm saline. A Tenckhoff catheter was inserted through the abdominal wall if postoperative dwell therapy was planned as deemed by the protocol.
Pretreatment and Follow-up Evaluation Before treatment, each patient underwent a full history, physical examination, routine laboratory studies, and a computed tomography (CT) scan of the chest, abdomen, and pelvis. Intraoperatively, the residual disease after cytoreduction was assessed as B-0, no residual disease; B-1, fewer than 100 lesions and all smaller than 5 mm; B-2, more than 100 total lesions with some being greater than 5 mm but less than 1 cm; and B-3, residual tumors greater than 1 cm. Patients were monitored in the intensive care unit for at least 24 hours. Routine laboratory screening was performed daily for the first 5 postoperative days and then twice weekly until the patient was discharged. All complications were recorded. The patients were seen in follow-up at 6 weeks from the time of discharge. At this visit, physical examination and routine laboratory screening were performed. The patients were then followed every 3 months for 1 year and then every 6 months for laboratory screening, physical examination, and CT
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scans of the chest, abdomen, and pelvis. Special attention was paid to accumulation of ascites, new fluid collections, or soft tissue masses suspicious for recurrence. Statistics Progression-free and overall survival curves were estimated using the Kaplan-Meier method.
RESULTS Patient Characteristics Clinical features of the 18 patients are shown in Table 1. Eighteen patients were treated with CHPP for gastric, duodenal, or pancreatic carcinoma on one of four different protocols. The median age was 48 years (range, 32–72 years). Six males and twelve females were treated. Nine of the patients had gastric carcinoma (50%), seven patients had pancreatic carcinoma (39%), and two patients had duodenal cancer (11%). Seven of the patients had received initial surgery before being enrolled on one of our protocols. One patient had a subtotal gastrectomy; two patients had a pancreaticoduodenectomy; one patient had a colectomy, distal pancreatectomy, and splenectomy; one patient had a gastric bypass; and one patient underwent a total abdominal hysterectomy, bilateral salpingo-oopherectomy, and omentectomy with a retroperitoneal lymph node dissection. All patients had pathologically confirmed intraperitoneal disease at the time of CHPP. Four of the patients had received prior systemic chemotherapy, and one patient received prior radiation therapy. Surgery and Hyperthermic Peritoneal Perfusion Table 2 demonstrates the various surgical resections performed as cytoreductive procedures prior to peritoneal perfusion. Eight patients underwent either a subtotal or a total gastrectomy. Three patients underwent a pancreaticoduodenectomy; one was delayed 6 weeks until after recovering from a neoadjuvant peritoneal perfusion. Two patients underwent a right hemicolectomy. The majority of patients (n 5 11) had successful cytoreduction to no residual evidence of disease (B-0). One patient had fewer than 100 lesions, all being less than 5 mm (B-1). Two patients had more than 100 lesions, greater than 5 mm and less than 1 cm (B-2). Three patients had lesions greater than 1 cm (B-3). The median total operative time was 7.3 hours (range, 4.3–14 hours). The median operative time was 7.3 hours for patients with gastric carcinoma, 5.4 hours for
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Table 1. Patient characteristics No. of patients Median age (range) (yr) Male-to-female ratio Histology Gastric carcinoma Pancreatic carcinoma Duodenal carcinoma Prior systemic chemotherapy Prior laparotomy Bowel resection/anastomosis Received cisplatin Received 5-FU dwell Received Taxol dwell
18 48 (32–72) 6:12 9 7 2 4 7 12 18 5 5
Values given as number of patients unless otherwise indicated.
duodenal carcinoma, and 7.1 hours for pancreatic carcinoma. All 18 patients received cisplatin in the perfusate for a full 90 minutes, and 5 patients received cisplatin followed by 5-FU and paclitaxel administered as a postoperative intraperitoneal dwell. The median dose of 5-FU was 1296 mg/m2 (range, 858–1740 mg/m2), and of paclitaxel, 191 mg/m2 (range, 71– 225 mg/m2). Hyperthermic perfusion with cisplatin was given at doses ranging from 150 to 300 mg/m2, with a median total dose of 453 mg (range, 186–676 mg). Total perfusate volume ranged from 3 to 7 L and varied depending on abdominal wall distention. Hyperthermia was obtained with perfusate inflow temperatures of 47 –48 C. Perfusate flow was maintained at 0.85–1.55 L/min. Systemic temperatures ranged from 37.2 –39.8 C. There were no intraoperative complications. Perioperative mortality was 5.6%, and postoperative complications occurred in 10 (55.6%) patients (Table 2). There was one perioperative death in a patient with gastric carcinoma who had a postoperative cerebrovascular accident. Five patients became neutropenic. Three patients had postoperative transient renal insufficiency. Two patients developed wound infections. There was one postoperative leak at the gastrojejunostomy anastomosis. One patient each developed biliary sepsis, postoperative small bowel obstruction, intra-abdominal abscess, urinary tract infection, and enterocutaneous fistula. Outcomes Table 3 summarizes progression-free survival and overall survival in these 18 patients treated with CHPP. There were no operative deaths. Nine
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Table 2. Tumor and treatment characteristics 5-FU IP dwell dose (mg/m2)
Taxol IP dwell dose (mg/m2)
Patient
Pathology
Cisplatin dose (mg/m2)
1 2
Gastric Pancreatic
186 676
d d
d d
3
Gastric
581
d
d
4
Gastric
576
d
d
5
Pancreatic
*
d
d
6 7
Pancreatic Pancreatic
500 470
d d
d d
8 9
Pancreas Gastric
400 450
d d
d d
10
Pancreatic
400
d
d
11 12
Gastric Gastric
455 350
d 858
d 71
13
Pancreas
425
d
d
14 15
Gastric Duodenal
434 550
1740 d
87 d
16 17
Duodenal Gastric
450 460
1296 1440
203 225
18
Gastric
383
1224
191
Procedures
Debulking Right hemicolectomy, gastrojejunostomy Subtotal gastrectomy Subtotal gastrectomy, small bowel resection Debulking, lysis of adhesions Pancreaticoduodenectomy Pancreaticoduodenectomy Debulking Total gastrectomy, splenectomy, distal pancreatectomy Debulking, lysis of adhesions Gastrectomy Total gastrectomy Debulking pancreaticoduodenectomy Subtotal gastrectomy Debulking, omentectomy Debulking, omentectomy Partial gastrectomy, omentectomy, debulking, revision Roux-en-Y Total gastrectomy, right hemicolectomy, debulking
Complications
None Renal insufficiency, anastomotic leak, VDRF Renal insufficiency, pleural effusion stroke, death None None Biliary sepsis Delayed gastric emptying, SBO, neutropenia None Neutropenia
None None Intra-abdominal abscess, neutropenia Enterocutaneous fistula, VDRF Wound infection Renal insufficiency, wound infection, UTI None Neutropenia
Neutropenic fever
VDRF 5 ventilator-dependent respiratory failure; SBO 5 small bowel obstruction; UTI 5 urinary tract infection. *Not available.
patients with gastric adenocarcinoma were treated. Of these patients, three underwent tumor cytoreduction to no residual disease, with an overall survival of 1, 7, and 74 months. The patient who had 1-month overall survival had a postoperative cerebrovascular accident, which led to her eventual death. One patient had tumor cytoreduction to B-1, with an overall survival of 12 months; two patients had tumor cytoreduction to B-2, with an overall survival of 8 and 10 months; and two patients had tumor cytoreduction to B-3, with an overall survival of 6 and 7 months. Two patients with duodenal adenocarcinoma were treated. One of these patients had tumor
cytoreduction to no residual disease with an overall survival of 46 months. The other patient had tumor cytoreduction to B-2 with an overall survival of 15 months. Seven patients with pancreatic carcinoma were treated. Six of these had tumor cytoreduction to no residual disease, with an overall survival of 2, 8, 8, 16, 25, and 62 months. The patient who had the 2month overall survival died from a traumatic accident unrelated to her disease. One patient had tumor cytoreduction to B-3, with an overall survival of 5 months. Five patients were treated with a postoperative intraperitoneal infusion of 5-FU and paclitaxel. Four
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Table 3. Treatment results after continuous hyperthermic peritoneal perfusion Residual disease*
Progression-free survival (mo)
Overall survival (mo)
Gastric
0 0 0 0 1 2 2 3 3
1 5 9 d 9 8 6 2 3
1 7 9 74 12 8 10 6 7
Duodenal
0 2
d 3
46 15
Pancreas
0 0 0 0 0 0 3
Pathology
†
8 8 8 8 36 2
2 8 8 16 25 62 5
*Residual disease as B-score as described in text. † Mortality from other causes.
of these patients had gastric carcinoma, with an overall survival of 7, 8, 9, and 10 months. One patient had duodenal carcinoma and she is currently alive at 63 months. Figure 2 demonstrates the Kaplan-Meier survival curve for progression-free and overall survival for the 18 patients treated. The median progression-free survival was 8 months. The median overall survival was 8 months. Only two patients are alive: one patient with gastric carcinoma at 74 months and one patient with duodenal carcinoma at 63 months.
DISCUSSION Regional therapy to treat peritoneal carcinomatosis using intraoperative hyperthermic peritoneal perfusion has been associated with long-term survival in multiple different neoplasms, including peritoneal mesothelioma and colorectal disease. Feldman et al.17 published results for 49 patients with peritoneal mesothelioma treated by CHPP with cisplatin and postoperative dwell therapy with 5-FU and paclitaxel. In this cohort, median actuarial progression-free survival was 17 months with a median actuarial overall survival of 92 months. Factors associated with improved survival were a history of previous debulking surgery, absence of deep tissue
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invasion, minimal residual disease after surgical resection (overall survival only), and age younger than 60 years (overall survival only). In 2003, Verwaal et al.18 published a prospective trial in which 105 patients with peritoneal carcinomatosis from colorectal cancer were randomized to receive either standard treatment consisting of systemic chemotherapy (5-FU/leucovorin) with or without palliative surgery, or aggressive cytoreduction surgery with hyperthermic intraperitoneal chemotherapy, followed by the same systemic chemotherapy regimen. Median survival of the standard therapy group and the treatment group was 12.6 and 22.3 months, respectively (P 5 .032). Yonemura et al.19 recently published their series of 107 patients with peritoneal dissemination from a primary gastric cancer treated with peritonectomy and intraoperative chemohyperthermic peritoneal perfusion with mitomycin-C, cisplatin, and etoposide. Complete cytoreduction was achieved in 47 (43.9%) of patients. Postoperative complications occurred in 23 (21.5%) patients treated. Completeness of cytoreduction and peritonectomy were significant prognostic factors in univariate and multivariate analyses. The median survival of all patients was 11.5 months, with a 5-year survival rate of 6.7%. The 5-year survival increased to 27% in patients with complete cytoreduction and peritonectomy combined with CHPP; however, this was demonstrated in only four patients. Glehen et al.20 prospectively looked at their series of 49 patients with peritoneal dissemination from primary gastric carcinomas that were treated with cytoreductive surgery and peritoneal perfusion with mitomycin-C. Similarly, they found preoperative ascites and completeness of cancer resection by cytoreductive surgery to be independent predictors of survival. Overall median survival was 10.3 months. However, median survival was 21.3 months in patients who had a macroscopic complete resection or resection to residual nodules less than 5 mm compared with a median survival of 6.1 months in patients who had a diameter of residual nodules of greater than 5 mm. Few studies have been published of the use of CHPP for the treatment of peritoneal dissemination from pancreatic cancer. This is in part due to the fact that a large majority of these patients have hepatic metastases that are found at the time of exploration. In our cohort of patients, CHPP with cisplatin was associated with a high complication rate with little, if any, apparent effect on the natural progression of the disease. Mitomycin-C may have improved efficacy in histology over cisplatin when used in the perfusion circuit and combined with optimal tumor
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Fig. 2. Kaplan-Meier survival curves of 18 patients treated with continuous hyperthermic peritoneal perfusion with cisplatin and/or postoperative dwell therapy. (A) Progression-free survival. (B) Overall.
cytoreduction. Although this procedure may have some future role in the treatment of peritoneal dissemination in gastric, pancreatic, and duodenal cancers, it is clear that novel agents and/or approaches are necessary to combat these highly aggressive tumors. REFERENCES 1. Pilati P, Mocellin S, Rossi CR, et al. Cytoreductive surgery combined with hyperthermic intraperitoneal intraoperative chemotherapy for peritoneal carcinomatosis arising from colon adenocarcinoma. Ann Surg Oncol 2003;10:508–513. 2. Murakami T. Surgical treatment of gastric cancer. In: Bockus HL, ed. Bockus Gastroenterology, Vol. 1. 3rd ed. Philadelphia: WB Saunders, 1974, pp 983–997.
3. Maehara Y. Postoperative immunochemotherapy including streptococcal lysate OK-432 is effective for patients with gastric cancer and serosal invasion. Am J Surg 1994;168: 36–40. 4. Bartlett DL, Buell JF, Libutti SK, et al. A phase I trial of continuous hyperthermic peritoneal perfusion with tumor necrosis factor and cisplatin in the treatment of peritoneal carcinomatosis. Cancer 1998;83:1251–1261. 5. Alexander HR, Buell JF, Fraker DL. Rationale and clinical status of continuous hyperthermic peritoneal perfusion (CHPP) for the treatment of peritoneal carcinomatosis. In: DeVita V, Hellman S, Rosenberg S, eds. Principles and Practices of Oncology Updates, 9th ed. Philadelphia: JB Lippincott, 1995, pp 1–9. 6. Markman M. Intraperitoneal paclitaxel in the management of ovarian cancer. Semin Oncol 1995;22:86–87.
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7. Alexander HR, Fraker DL. Continuous hyperthermic peritoneal perfusion with cisplatin in the treatment of peritoneal carcinomatosis. Regul Cancer Treat 1995;8:2–7. 8. Park BJ, Alexander HR, Libutti SK, et al. Treatment of primary peritoneal mesothelioma by continuous hyperthermic peritoneal perfusion (CHPP). Ann Surg Oncol 1999;6: 582–590. 9. Fujimoto S, Shgrestha RD, Kokubun M, et al. Intraperitoneal hyperthermic perfusion combined with surgery effective for gastric cancer patients with peritoneal seeding. Ann Surg 1988;208:36–41. 10. Fujimura T, Yonemura Y, Fushida S, et al. Continuous hyperthermic peritoneal perfusion for the treatment of peritoneal dissemination in gastric cancers and subsequent second-look operation. Cancer 1990;65:65–71. 11. Fujimura T, Yonemura Y, Muraoka K, et al. Continuous hyperthermic peritoneal perfusion for the prevention of peritoneal recurrence of gastric cancer: randomized controlled study. World J Surg 1994;18:150–155. 12. Koga S, Hamazoe R, Maeta M, Shimizu N, Murakami A, Wakatsuki T. Prophylactic therapy for peritoneal recurrence of gastric cancer by continuous hyperthermic peritoneal perfusion with mitomycin C. Cancer 1988;61:232–237. 13. Yonemura Y, Fujimura T, Fushida S, et al. Intraoperative chemohyperthermic peritoneal perfusion as an adjuvant to gastric cancer: final results of a randomized controlled study. Hepato-gastroenterology 2001;48:1776–1782.
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14. Rossi CR, Pilati P, Mocellin S, et al. Hyperthermic intraperitoneal intraoperative chemotherapy for peritoneal carcinomatosis arising from gastric adenocarcinoma. Suppl Tumori 2003;2:S54–S57. 15. Howell SB, Pfeifle CE, Wung WE. Intraperitoneal cisplatin with sodium thiosulfate protection. Ann Intern Med 1982; 97:845–851. 16. Howell SB, Pfeifle CE, Wung WE, Olshen RA. Intraperitoneal cis-diamminedichloroplatinum with systemic thiosulfate protection. Cancer Res 1983;43:1426–1431. 17. Feldman AL, Libutti SK, Pingpank JF, et al. Analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma undergoing surgical debulking and intraperitoneal chemotherapy. J Clin Oncol 2003;21:4560–4567. 18. Verwaal VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 2003;21:3737–3743. 19. Yonemura Y, Kawamura T, Bandou E, Takahashi S, Sawa T, Matsuki N. Treatment of peritoneal dissemination from gastric cancer by peritonectomy and chemohyperthermic peritoneal perfusion. Br J Surg 2005;92:370–375. 20. Glehen O, Schreiber V, Cotte E, et al. Cytoreductive surgery and intraperitoneal chemohyperthermia for peritoneal carcinomatosis arising from gastric cancer. Arch Surg 2004;139: 20–26.
Peritoneal carcinomatosis is a frequent mode of metastasis in patients with gastric, duodenal, or pancreatic cancer. Survival in this setting is short and therapeutic options are limited. This analysis examines the outcomes of 18 patients treated with operative cytoreduction and continuous hyperthermic peritoneal perfusion. Eighteen patients (6 males and 12 females) with gastric (n 5 9), pancreatic (n 5 7), or duodenal (n 5 2) cancer were treated on protocol. Patients underwent optimal cytoreduction (complete gross resection, 11; minimal residual disease, 7) and a 90-minute perfusion with cisplatin. Clinical parameters and tumor and treatment characteristics were analyzed. Survival curves were estimated using the Kaplan-Meier method. Procedures included gastrectomy (n 5 8), pancreaticoduodenectomy (n 5 3), and hemicolectomy (n 5 2). After cytoreduction, patients had no evidence of residual disease (n 5 11), fewer than 100 implants less than 5 mm (n 5 1), more than 100 implants between 5–10 mm (n 5 3), or multiple implants with greater than 1 cm (n 5 3). Five patients received a postoperative intraperitoneal dwell with 5-fluorouracil and paclitaxel. There was one perioperative mortality, and complications occurred in 10 patients. The median progression-free survival was 8 months (mean, 10 months; range, 1–47 months) with a median overall survival of 8 months (mean, 18 months; range, 1–74 months). In this cohort, peritoneal perfusion with cisplatin used to treat foregut malignancies has a high incidence of complications and does not significantly alter the natural history of the disease. Investigation of novel therapeutic approaches should be considered. ( J GASTROINTEST SURG 2005;9:1346– 1353) Ó 2005 The Society for Surgery of the Alimentary Tract KEY WORDS: Regional therapy, peritoneal carcinomatosis, peritoneal perfusion, gastric cancer, duodenal cancer, pancreatic cancer
Peritoneal dissemination from primary gastric, duodenal, and pancreatic cancer is frequently found on exploration for curative resection of these malignancies. In a subset of patients, disease is confined to the abdominal cavity and has not yet spread systemically. It has been shown, through recurrence patterns after curative resection, that the peritoneum is frequently one of the first sites of recurrence. In gastric cancer, peritoneal recurrence accounts for 50%–60% of deaths after surgical resection with curative intent.1–3 Even with complete resection, microscopic disease remains, leading to
this early recurrence pattern and eventual death. The median survival for these patients remains exceedingly low. Over the past decade, little progress has been made to improve survival in these neoplasms. Systemic chemotherapy and radiation have thus far failed to meaningfully affect outcomes with these malignancies. Researchers have looked at novel therapies to provide better treatments over surgery alone, systemic chemotherapy, or radiation.4,5 Regional therapy is a rational approach in a disease process confined to the abdominal cavity. One of
Presented at the Forty-Sixth Annual Meeting of The Society for Surgery of the Alimentary Tract, Chicago, Illinois, May 14–18, 2005 (poster presentation). From the Surgery Metabolism Section (J.M.F., J.F.P., S.K.L., S.O., T.B., H.R.A.), Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland; and Department of Surgery (D.L.B.), University of Pittsburgh Cancer Center, Pittsburgh, Pennsylvania. Reprint requests: H. Richard Alexander, Jr., M.D, Surgical Metabolism Section, Surgery Branch, National Cancer Institute/NIH, CRC, Room 4W-5952, 10 Center Drive, MSC 1201, Bethesda, Maryland 20892-1201. e-mail: [email protected] Ó 2005 The Society for Surgery of the Alimentary Tract
1346 Published by Elsevier Inc.
1091-255X/05/$dsee front matter doi:10.1016/j.gassur.2005.06.016
Vol. 9, No. 9 2005
these approaches uses continuous hyperthermic peritoneal perfusion (CHPP), either intraoperatively or in the perioperative period, as a method to prevent or inhibit peritoneal dissemination of disease. The synergism of hyperthermia and chemotherapy allows a significantly higher concentration of therapeutic agent to be administered while limiting systemic toxicities.6,7 This approach has been developed with the hope of palliating peritoneal recurrence and is currently undergoing trials for multiple different peritoneal malignancies.8 Numerous reports exist studying the effects of CHPP using predominantly mitomycin-C in the treatment and palliation of these aggressive upper gastrointestinal malignancies, most concentrating on gastric carcinoma.9–12 The methods of the procedures vary; nonetheless, some investigators have reported an increase in time to recurrence and overall survival in gastric cancer when combining surgical resection and perfusion.13,14 Our study is composed of 18 patients enrolled in clinical trials with upper gastrointestinal malignancy; including gastric, duodenal, and pancreatic adenocarcinoma, to determine time to recurrence and overall survival after CHPP with cisplatin.
MATERIAL AND METHODS Patient Eligibility and Enrollment From September 1993 through April 2002, 18 patients with gastric, duodenal, or pancreatic adenocarcinoma were referred to the Surgery Branch of the National Cancer Institute. These patients were treated following one of four Surgery Branch protocols approved by the Institutional Review Board of the National Cancer Institute. Study patients were required to be over 18 years of age with histologically or cytologically proven metastatic carcinoma in the peritoneal cavity. Additional eligibility criteria included (1) Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2; (2) lack of a comorbid disease that prevents them from being an operative candidate; (3) a life expectancy greater than or equal to 8 weeks; (4) adequate renal function (serum creatinine !1.5 or creatinine clearance of !70 ml/min; (5) normal hepatic function (normal bilirubin, prothrombin time/partial thromboplastin time, enzymes !2 times the upper limit of normal; (6) adequate hematopoietic parameters (white blood cell count O3000/ml and platelet count greater than 75,000); (7) absence of previous ineffective intraperitoneal platinum therapy; (8) patient’s weight more than 30 kg; and (9) no chemotherapy, radiotherapy, or immuno-
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therapy in the past 30 days. None of the peritoneal carcinoma patients had evidence of extra-abdominal metastases at the time of treatment. Patients were treated with one of four related and similar protocols of cytoreduction and hyperthermic peritoneal perfusion, including (1) escalating dose of cisplatin administered via a 90-minute CHPP; (2) neoadjuvant and intraoperative adjuvant CHPP with cisplatin/mitomycin-C; (3) CHPP with cisplatin followed by early postoperative escalating-dose 5fluorouracil (5-FU) and paclitaxel administered as a single intraperitoneal dwell (2–8 days postoperatively); or (4) CHPP with cisplatin followed by early postoperative 5-FU and paclitaxel administered as a single intraperitoneal dwell (2–8 days postoperatively). All patients underwent pretreatment counseling and gave written informed consent according to institutional and federal guidelines. CHPP Technique Patients underwent an exploratory laparotomy, lysis of adhesions, tumor cytoreduction, and CHPP as previously described.5 Every attempt was made at cytoreduction to leave no gross evidence of disease. Major bowel or abdominal organ resections were performed when deemed necessary to attain adequate debulking. At the completion of cytoreduction, two large-bore catheters were inserted through the abdominal wall; the inflow catheter was placed over the right lobe of the liver with the outflow catheter in the pelvis. Temperature probes were placed beneath the peritoneal lining on each side of the abdomen and in the pelvis. The abdominal fascia was temporarily closed. The catheters were connected to a closed circuit consisting of a roller pump, heat exchanger, and a reservoir (Fig. 1). Chemotherapy containing the perfusate was heated and recirculated for 90 minutes through the peritoneal cavity. The perfusion flow rate was maintained at 1.5 L/min with a perfusate volume that varied from 3 to 7 L depending on the size of the potential space of the peritoneal cavity (sufficient to moderately expand the peritoneum correlating with intra-abdominal pressures between 5 mm Hg and 15 mm Hg). After stable perfusion parameters were obtained and the peritoneal cavity was warmed to a median temperature of 41.4 C, cisplatin was added to the perfusate. Perfusion was continued for 90 minutes, during which there was constant, manual agitation of the abdomen to minimize streaming and ensure optimal and even distribution of perfusate throughout the abdominal cavity. Sodium thiosulfate was given via a loading dose of 7.5 g/m2 intravenously over 20 minutes before the addition of cisplatin, followed by
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Fig. 1. Continuous hyperthermic peritoneal perfusion perfusion circuit. After aggressive optimal cytoreduction, two large-bore catheters were then inserted through the abdominal wall. Temperature probes were placed beneath the peritoneal lining. The catheters were connected to a closed circuit consisting of a roller pump, heat exchanger, and a reservoir. Chemotherapy containing the perfusate was heated and recirculated for 90 minutes throughout the peritoneal cavity.
a continuous infusion at 2.13 g/m2/hr for 12 hours as described.15 Sodium thiosulfate has been shown to bind cisplatin in the serum and decrease systemic toxicity from intraperitoneal administration of cisplatin.16 Urine output was maximized through aggressive hydration (central venous pressure 12 mm Hg 30 minutes before CHPP) and diuretics to maintain urine output at greater than 200 ml/hr during the perfusion; this was continued for 12 hours postoperatively. Urine output was maintained at 100 ml/hr for an additional 12 hours. The patient’s mean core temperature was measured with an esophageal probe and maintained at a median of 38.5 C (range, 37.2 –39.8 ) using a cooling blanket and topical ice packs. At the completion of the perfusion, the fascia was opened, the temperature probes and catheters were removed, the residual perfusate was evacuated, and the peritoneal cavity was irrigated with warm saline. A Tenckhoff catheter was inserted through the abdominal wall if postoperative dwell therapy was planned as deemed by the protocol.
Pretreatment and Follow-up Evaluation Before treatment, each patient underwent a full history, physical examination, routine laboratory studies, and a computed tomography (CT) scan of the chest, abdomen, and pelvis. Intraoperatively, the residual disease after cytoreduction was assessed as B-0, no residual disease; B-1, fewer than 100 lesions and all smaller than 5 mm; B-2, more than 100 total lesions with some being greater than 5 mm but less than 1 cm; and B-3, residual tumors greater than 1 cm. Patients were monitored in the intensive care unit for at least 24 hours. Routine laboratory screening was performed daily for the first 5 postoperative days and then twice weekly until the patient was discharged. All complications were recorded. The patients were seen in follow-up at 6 weeks from the time of discharge. At this visit, physical examination and routine laboratory screening were performed. The patients were then followed every 3 months for 1 year and then every 6 months for laboratory screening, physical examination, and CT
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scans of the chest, abdomen, and pelvis. Special attention was paid to accumulation of ascites, new fluid collections, or soft tissue masses suspicious for recurrence. Statistics Progression-free and overall survival curves were estimated using the Kaplan-Meier method.
RESULTS Patient Characteristics Clinical features of the 18 patients are shown in Table 1. Eighteen patients were treated with CHPP for gastric, duodenal, or pancreatic carcinoma on one of four different protocols. The median age was 48 years (range, 32–72 years). Six males and twelve females were treated. Nine of the patients had gastric carcinoma (50%), seven patients had pancreatic carcinoma (39%), and two patients had duodenal cancer (11%). Seven of the patients had received initial surgery before being enrolled on one of our protocols. One patient had a subtotal gastrectomy; two patients had a pancreaticoduodenectomy; one patient had a colectomy, distal pancreatectomy, and splenectomy; one patient had a gastric bypass; and one patient underwent a total abdominal hysterectomy, bilateral salpingo-oopherectomy, and omentectomy with a retroperitoneal lymph node dissection. All patients had pathologically confirmed intraperitoneal disease at the time of CHPP. Four of the patients had received prior systemic chemotherapy, and one patient received prior radiation therapy. Surgery and Hyperthermic Peritoneal Perfusion Table 2 demonstrates the various surgical resections performed as cytoreductive procedures prior to peritoneal perfusion. Eight patients underwent either a subtotal or a total gastrectomy. Three patients underwent a pancreaticoduodenectomy; one was delayed 6 weeks until after recovering from a neoadjuvant peritoneal perfusion. Two patients underwent a right hemicolectomy. The majority of patients (n 5 11) had successful cytoreduction to no residual evidence of disease (B-0). One patient had fewer than 100 lesions, all being less than 5 mm (B-1). Two patients had more than 100 lesions, greater than 5 mm and less than 1 cm (B-2). Three patients had lesions greater than 1 cm (B-3). The median total operative time was 7.3 hours (range, 4.3–14 hours). The median operative time was 7.3 hours for patients with gastric carcinoma, 5.4 hours for
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Table 1. Patient characteristics No. of patients Median age (range) (yr) Male-to-female ratio Histology Gastric carcinoma Pancreatic carcinoma Duodenal carcinoma Prior systemic chemotherapy Prior laparotomy Bowel resection/anastomosis Received cisplatin Received 5-FU dwell Received Taxol dwell
18 48 (32–72) 6:12 9 7 2 4 7 12 18 5 5
Values given as number of patients unless otherwise indicated.
duodenal carcinoma, and 7.1 hours for pancreatic carcinoma. All 18 patients received cisplatin in the perfusate for a full 90 minutes, and 5 patients received cisplatin followed by 5-FU and paclitaxel administered as a postoperative intraperitoneal dwell. The median dose of 5-FU was 1296 mg/m2 (range, 858–1740 mg/m2), and of paclitaxel, 191 mg/m2 (range, 71– 225 mg/m2). Hyperthermic perfusion with cisplatin was given at doses ranging from 150 to 300 mg/m2, with a median total dose of 453 mg (range, 186–676 mg). Total perfusate volume ranged from 3 to 7 L and varied depending on abdominal wall distention. Hyperthermia was obtained with perfusate inflow temperatures of 47 –48 C. Perfusate flow was maintained at 0.85–1.55 L/min. Systemic temperatures ranged from 37.2 –39.8 C. There were no intraoperative complications. Perioperative mortality was 5.6%, and postoperative complications occurred in 10 (55.6%) patients (Table 2). There was one perioperative death in a patient with gastric carcinoma who had a postoperative cerebrovascular accident. Five patients became neutropenic. Three patients had postoperative transient renal insufficiency. Two patients developed wound infections. There was one postoperative leak at the gastrojejunostomy anastomosis. One patient each developed biliary sepsis, postoperative small bowel obstruction, intra-abdominal abscess, urinary tract infection, and enterocutaneous fistula. Outcomes Table 3 summarizes progression-free survival and overall survival in these 18 patients treated with CHPP. There were no operative deaths. Nine
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Table 2. Tumor and treatment characteristics 5-FU IP dwell dose (mg/m2)
Taxol IP dwell dose (mg/m2)
Patient
Pathology
Cisplatin dose (mg/m2)
1 2
Gastric Pancreatic
186 676
d d
d d
3
Gastric
581
d
d
4
Gastric
576
d
d
5
Pancreatic
*
d
d
6 7
Pancreatic Pancreatic
500 470
d d
d d
8 9
Pancreas Gastric
400 450
d d
d d
10
Pancreatic
400
d
d
11 12
Gastric Gastric
455 350
d 858
d 71
13
Pancreas
425
d
d
14 15
Gastric Duodenal
434 550
1740 d
87 d
16 17
Duodenal Gastric
450 460
1296 1440
203 225
18
Gastric
383
1224
191
Procedures
Debulking Right hemicolectomy, gastrojejunostomy Subtotal gastrectomy Subtotal gastrectomy, small bowel resection Debulking, lysis of adhesions Pancreaticoduodenectomy Pancreaticoduodenectomy Debulking Total gastrectomy, splenectomy, distal pancreatectomy Debulking, lysis of adhesions Gastrectomy Total gastrectomy Debulking pancreaticoduodenectomy Subtotal gastrectomy Debulking, omentectomy Debulking, omentectomy Partial gastrectomy, omentectomy, debulking, revision Roux-en-Y Total gastrectomy, right hemicolectomy, debulking
Complications
None Renal insufficiency, anastomotic leak, VDRF Renal insufficiency, pleural effusion stroke, death None None Biliary sepsis Delayed gastric emptying, SBO, neutropenia None Neutropenia
None None Intra-abdominal abscess, neutropenia Enterocutaneous fistula, VDRF Wound infection Renal insufficiency, wound infection, UTI None Neutropenia
Neutropenic fever
VDRF 5 ventilator-dependent respiratory failure; SBO 5 small bowel obstruction; UTI 5 urinary tract infection. *Not available.
patients with gastric adenocarcinoma were treated. Of these patients, three underwent tumor cytoreduction to no residual disease, with an overall survival of 1, 7, and 74 months. The patient who had 1-month overall survival had a postoperative cerebrovascular accident, which led to her eventual death. One patient had tumor cytoreduction to B-1, with an overall survival of 12 months; two patients had tumor cytoreduction to B-2, with an overall survival of 8 and 10 months; and two patients had tumor cytoreduction to B-3, with an overall survival of 6 and 7 months. Two patients with duodenal adenocarcinoma were treated. One of these patients had tumor
cytoreduction to no residual disease with an overall survival of 46 months. The other patient had tumor cytoreduction to B-2 with an overall survival of 15 months. Seven patients with pancreatic carcinoma were treated. Six of these had tumor cytoreduction to no residual disease, with an overall survival of 2, 8, 8, 16, 25, and 62 months. The patient who had the 2month overall survival died from a traumatic accident unrelated to her disease. One patient had tumor cytoreduction to B-3, with an overall survival of 5 months. Five patients were treated with a postoperative intraperitoneal infusion of 5-FU and paclitaxel. Four
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Table 3. Treatment results after continuous hyperthermic peritoneal perfusion Residual disease*
Progression-free survival (mo)
Overall survival (mo)
Gastric
0 0 0 0 1 2 2 3 3
1 5 9 d 9 8 6 2 3
1 7 9 74 12 8 10 6 7
Duodenal
0 2
d 3
46 15
Pancreas
0 0 0 0 0 0 3
Pathology
†
8 8 8 8 36 2
2 8 8 16 25 62 5
*Residual disease as B-score as described in text. † Mortality from other causes.
of these patients had gastric carcinoma, with an overall survival of 7, 8, 9, and 10 months. One patient had duodenal carcinoma and she is currently alive at 63 months. Figure 2 demonstrates the Kaplan-Meier survival curve for progression-free and overall survival for the 18 patients treated. The median progression-free survival was 8 months. The median overall survival was 8 months. Only two patients are alive: one patient with gastric carcinoma at 74 months and one patient with duodenal carcinoma at 63 months.
DISCUSSION Regional therapy to treat peritoneal carcinomatosis using intraoperative hyperthermic peritoneal perfusion has been associated with long-term survival in multiple different neoplasms, including peritoneal mesothelioma and colorectal disease. Feldman et al.17 published results for 49 patients with peritoneal mesothelioma treated by CHPP with cisplatin and postoperative dwell therapy with 5-FU and paclitaxel. In this cohort, median actuarial progression-free survival was 17 months with a median actuarial overall survival of 92 months. Factors associated with improved survival were a history of previous debulking surgery, absence of deep tissue
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invasion, minimal residual disease after surgical resection (overall survival only), and age younger than 60 years (overall survival only). In 2003, Verwaal et al.18 published a prospective trial in which 105 patients with peritoneal carcinomatosis from colorectal cancer were randomized to receive either standard treatment consisting of systemic chemotherapy (5-FU/leucovorin) with or without palliative surgery, or aggressive cytoreduction surgery with hyperthermic intraperitoneal chemotherapy, followed by the same systemic chemotherapy regimen. Median survival of the standard therapy group and the treatment group was 12.6 and 22.3 months, respectively (P 5 .032). Yonemura et al.19 recently published their series of 107 patients with peritoneal dissemination from a primary gastric cancer treated with peritonectomy and intraoperative chemohyperthermic peritoneal perfusion with mitomycin-C, cisplatin, and etoposide. Complete cytoreduction was achieved in 47 (43.9%) of patients. Postoperative complications occurred in 23 (21.5%) patients treated. Completeness of cytoreduction and peritonectomy were significant prognostic factors in univariate and multivariate analyses. The median survival of all patients was 11.5 months, with a 5-year survival rate of 6.7%. The 5-year survival increased to 27% in patients with complete cytoreduction and peritonectomy combined with CHPP; however, this was demonstrated in only four patients. Glehen et al.20 prospectively looked at their series of 49 patients with peritoneal dissemination from primary gastric carcinomas that were treated with cytoreductive surgery and peritoneal perfusion with mitomycin-C. Similarly, they found preoperative ascites and completeness of cancer resection by cytoreductive surgery to be independent predictors of survival. Overall median survival was 10.3 months. However, median survival was 21.3 months in patients who had a macroscopic complete resection or resection to residual nodules less than 5 mm compared with a median survival of 6.1 months in patients who had a diameter of residual nodules of greater than 5 mm. Few studies have been published of the use of CHPP for the treatment of peritoneal dissemination from pancreatic cancer. This is in part due to the fact that a large majority of these patients have hepatic metastases that are found at the time of exploration. In our cohort of patients, CHPP with cisplatin was associated with a high complication rate with little, if any, apparent effect on the natural progression of the disease. Mitomycin-C may have improved efficacy in histology over cisplatin when used in the perfusion circuit and combined with optimal tumor
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Fig. 2. Kaplan-Meier survival curves of 18 patients treated with continuous hyperthermic peritoneal perfusion with cisplatin and/or postoperative dwell therapy. (A) Progression-free survival. (B) Overall.
cytoreduction. Although this procedure may have some future role in the treatment of peritoneal dissemination in gastric, pancreatic, and duodenal cancers, it is clear that novel agents and/or approaches are necessary to combat these highly aggressive tumors. REFERENCES 1. Pilati P, Mocellin S, Rossi CR, et al. Cytoreductive surgery combined with hyperthermic intraperitoneal intraoperative chemotherapy for peritoneal carcinomatosis arising from colon adenocarcinoma. Ann Surg Oncol 2003;10:508–513. 2. Murakami T. Surgical treatment of gastric cancer. In: Bockus HL, ed. Bockus Gastroenterology, Vol. 1. 3rd ed. Philadelphia: WB Saunders, 1974, pp 983–997.
3. Maehara Y. Postoperative immunochemotherapy including streptococcal lysate OK-432 is effective for patients with gastric cancer and serosal invasion. Am J Surg 1994;168: 36–40. 4. Bartlett DL, Buell JF, Libutti SK, et al. A phase I trial of continuous hyperthermic peritoneal perfusion with tumor necrosis factor and cisplatin in the treatment of peritoneal carcinomatosis. Cancer 1998;83:1251–1261. 5. Alexander HR, Buell JF, Fraker DL. Rationale and clinical status of continuous hyperthermic peritoneal perfusion (CHPP) for the treatment of peritoneal carcinomatosis. In: DeVita V, Hellman S, Rosenberg S, eds. Principles and Practices of Oncology Updates, 9th ed. Philadelphia: JB Lippincott, 1995, pp 1–9. 6. Markman M. Intraperitoneal paclitaxel in the management of ovarian cancer. Semin Oncol 1995;22:86–87.
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7. Alexander HR, Fraker DL. Continuous hyperthermic peritoneal perfusion with cisplatin in the treatment of peritoneal carcinomatosis. Regul Cancer Treat 1995;8:2–7. 8. Park BJ, Alexander HR, Libutti SK, et al. Treatment of primary peritoneal mesothelioma by continuous hyperthermic peritoneal perfusion (CHPP). Ann Surg Oncol 1999;6: 582–590. 9. Fujimoto S, Shgrestha RD, Kokubun M, et al. Intraperitoneal hyperthermic perfusion combined with surgery effective for gastric cancer patients with peritoneal seeding. Ann Surg 1988;208:36–41. 10. Fujimura T, Yonemura Y, Fushida S, et al. Continuous hyperthermic peritoneal perfusion for the treatment of peritoneal dissemination in gastric cancers and subsequent second-look operation. Cancer 1990;65:65–71. 11. Fujimura T, Yonemura Y, Muraoka K, et al. Continuous hyperthermic peritoneal perfusion for the prevention of peritoneal recurrence of gastric cancer: randomized controlled study. World J Surg 1994;18:150–155. 12. Koga S, Hamazoe R, Maeta M, Shimizu N, Murakami A, Wakatsuki T. Prophylactic therapy for peritoneal recurrence of gastric cancer by continuous hyperthermic peritoneal perfusion with mitomycin C. Cancer 1988;61:232–237. 13. Yonemura Y, Fujimura T, Fushida S, et al. Intraoperative chemohyperthermic peritoneal perfusion as an adjuvant to gastric cancer: final results of a randomized controlled study. Hepato-gastroenterology 2001;48:1776–1782.
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14. Rossi CR, Pilati P, Mocellin S, et al. Hyperthermic intraperitoneal intraoperative chemotherapy for peritoneal carcinomatosis arising from gastric adenocarcinoma. Suppl Tumori 2003;2:S54–S57. 15. Howell SB, Pfeifle CE, Wung WE. Intraperitoneal cisplatin with sodium thiosulfate protection. Ann Intern Med 1982; 97:845–851. 16. Howell SB, Pfeifle CE, Wung WE, Olshen RA. Intraperitoneal cis-diamminedichloroplatinum with systemic thiosulfate protection. Cancer Res 1983;43:1426–1431. 17. Feldman AL, Libutti SK, Pingpank JF, et al. Analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma undergoing surgical debulking and intraperitoneal chemotherapy. J Clin Oncol 2003;21:4560–4567. 18. Verwaal VJ, van Ruth S, de Bree E, et al. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol 2003;21:3737–3743. 19. Yonemura Y, Kawamura T, Bandou E, Takahashi S, Sawa T, Matsuki N. Treatment of peritoneal dissemination from gastric cancer by peritonectomy and chemohyperthermic peritoneal perfusion. Br J Surg 2005;92:370–375. 20. Glehen O, Schreiber V, Cotte E, et al. Cytoreductive surgery and intraperitoneal chemohyperthermia for peritoneal carcinomatosis arising from gastric cancer. Arch Surg 2004;139: 20–26.