Hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis of digestive and peritoneal origin: rationale.

Up to a few years ago peritoneal carcinomatosis was considered as an "incurable" disease. The aim of this paper is to review the surgical approach with curative intent to carcinomatosis: it consists of complete resection of macroscopic disease (R1), associated with hyperthermic intraperitoneal chemotherapy (HIPEC) to treat residual microscopic disease, and to evaluate its indications. Overall 5-year survival of patients with peritoneal carcinomatosis treated by HIPEC is similar to that of patients with hepatic metastases treated with curative intent. Those patients should no longer be considered as patients with a terminal disease but as patients with a potentially treatable localized disease.

[Surgical treatment of peritoneal carcinomatosis]. / Traitement chirurgical des carcinoses péritonéales: 2--la chimiohyperthermie.

Surgical treatment of peritoneal carcinomatosis with curative intent involves the resection of all macroscopic malignant tissue and the treatment of microscopic residual tissue with local chemotherapy. Intraperitoneal chemotherapy is efficient only when associated with hyperthermia. This article details the technical aspect of intraperitoneal chemohyperthermia. These techniques involve specific and important features. At these conditions, peritoneal carcinomatosis can be cured in two-thirds of cases.

Efficacy of intraperitoneal chemohyperthermia with oxaliplatin in colorectal peritoneal carcinomatosis. Preliminary results in 24 patients.

BACKGROUND: The complete resection of macroscopic colorectal peritoneal carcinomatosis (PC), followed by intraoperative intraperitoneal chemohyperthermia (IPCH) to treat residual microscopic disease, leads to cure in some patients. We report preliminary results on survival in a phase II study using oxaliplatin (LOHP). PATIENTS AND METHODS: Twenty-four patients with macroscopic colorectal PC underwent complete resection of the PC followed by IPCH with LOHP performed in an open abdominal cavity. The dose of LOHP was 460 mg/m(2) in 2 l/m(2), during 30 min at 43 degrees C, at a flow rate of 2 l/min. During the hour preceding IPCH, they received an intravenous administration of 5-fluorouracil (400 mg/m(2)) and leucovorin (20 mg/m(2)). RESULTS: Mean peritoneal tumoral extension (Sugarbaker's Index) was 16.9 +/- 9.5, median operative duration was 490 min and median blood loss was 965 ml. There were two postoperative deaths (8%) by intracerebral hemorrhage, and morbidity rate was 41.6%. Minimal follow-up was 18 months and median follow-up was 27.4 months (range 18.3-49.6). At 1, 2 and 3 years, overall survival rates were 83%, 74% and 65%, and disease-free survival rates were 70%, 50% and 50%, respectively. Only 32% of the 22 postoperative living patients presented a peritoneal recurrence. A peritoneal index >24 influenced survival, with a 17% recurrence rate at 2 years versus 63% when it was <24 (P = 0.005). CONCLUSION: This new modality of treatment, when feasible, gives encouraging preliminary results, with a promising 3-year survival rate of 65%.

[Resectional treatment of peritoneal carcinomatosis followed by intraperitoneal chemotherapy, practical aspects]. / Traitement des carcinoses péritonéales par résection suivie de chimiothérapie intrapéritonéale, aspects pratiques.

Surgical resection with curative intent for peritoneal carcinomatosis (PC) requires the excision of all macroscopic disease followed by immediate intraperitoneal chemotherapy to treat the residual microscopic metastases. Hyperthermia improves the effectiveness of this approach. The techniques for excision of PC are rather specific and are not undertaken unless it is possible to remove all visible disease larger than 1 mm. and to assure a post-operative quality of life which is more or less normal. Intraperitoneal hyperthermic chemotherapy techniques must be draconian in order to be effective. If these conditions can be met, peritoneal metastases can be definitively cured in two thirds of colorectal PC and pseudomyxoma peritonei, and in nearly half of mesotheliomas.

Human pharmacokinetic study of heated intraperitoneal oxaliplatin in increasingly hypotonic solutions after complete resection of peritoneal carcinomatosis.

PURPOSE: We studied the pharmacokinetics of heated intraoperative intraperitoneal (i.p.) oxaliplatin (LOHP) solution and its safety profile in increasingly hypotonic solutions. This is the first clinical study of i.p. chemohyperthermia with hypotonic solutions. METHODS: Patients with peritoneal carcinomatosis (PC) underwent complete cytoreductive surgery followed by intraoperative i.p. chemohyperthermia (IPCH) with successive dextrose solutions of 300, 200, 150 and 100 mosm/l. LOHP (460 mg/m(2)) was administered in 2 liters of solution/m(2) at an i.p. temperature of 42-44 degrees C for 30 min. IPCH was performed using an open procedure (skin pulled upwards) with a continuous closed circuit. Patients received intravenous leucovorin (20 mg/m(2)) and 5-fluorouracil (400 mg/m(2)) just before IPCH to maximize the effect of LOHP. i.p. plasma and tissue samples were analyzed by means of atomic absorption spectrophotometry. Sixteen consecutive patients with PC of either gastrointestinal or peritoneal origin were treated. The safety of the procedure was studied. RESULTS: Pharmacokinetics: The mean duration of the entire procedure was 7.7 +/- 2.6 h. Half the LOHP dose was absorbed within 30 min at all dose levels. Absorption was not higher with hypotonic solutions than with isotonic solutions. The area under the curve of LOHP in plasma did not increase with decreasing osmolarity of the i.p. solutions. Intratumoral LOHP penetration was high; it was similar to that at the peritoneal surface, and about 18 times higher than that in nonbathed tissues. LOHP penetration was not significantly increased by using hypotonic solutions. SAFETY: There was a very high incidence of unexplained postoperative peritoneal bleeding (50%) and unusually severe thrombocytopenia in the 150 and 100 mosm/l groups. CONCLUSION: Contrary to experimental studies, this clinical study showed no increase in tumoral or systemic penetration of LOHP with i.p. hypotonic solutions (200, 150 or 100 mosm/l) during IPCH. A high incidence of i.p. hemorrhage and thrombocytopenia was observed.

[Complications and tolerance of heated intraperitoneal chemotherapy and cytoreductive surgery for peritoneal carcinomatosis: results of a phase I-II study of peritoneal carcinomatosis from different sources]. / Complications et tolérance de la chimio-hyperthermie intrapéritonéale (CHIP) après exérèse chirurgicale des carcinoses péritonéales (CP): résultats d'une étude de phase I-II portant sur des CP de différentes origines.

Peritoneal carcinomatosis represents the terminal stage of adenocarcinomas of the gastrointestinal tract. A new treatment combining cytoreductive surgery and intraperitoneal chemotherapy-hyperthermia has been used with encouraging results. The purpose of this study was to report the complications associated with this treatment. Fourty procedures were carry out in 37 patients. Death occurred in 3 patients. Major medical complications were 13 pulmonary infections, 11 acute renal failure (with only 3 who needed dialysis) and 10 patients with neutropenia grade 3 and 4 toxicity. Intra-abdominal complications occurred in 16 patients (there were 11 anastomotic leak and/or bowel perforation, and 12 intra-abdominal infections). Some complications like secretory diarrhea or tubulopathia which were related to these treatment need further investigations. Six procedures were without any complications, 6 presented minor ones and 22 major complications. Adverse effects were relatively important with this new treatment strategy. This was maybe due to a learning process; there is no death and only one anastomotic leak in our last study including 30 patients with cytoreductive surgery and intraperitoneal chemotherapy-hyperthermia.

Research on the best chemohyperthermia technique of treatment of peritoneal carcinomatosis after complete resection.

BACKGROUND: The complete or almost complete resection of peritoneal carcinomatosis (PC) followed by intraperitoneal chemohyperthermia (IPCH) is potentially capable of curing some patients presenting with disease confined to the peritoneum. AIMS: The aim of this prospective phase I-II study was to develop an efficient IPCH procedure with good thermal homogeneity and good spatial diffusion, that would be reproducible (and thus could be standardized and exported), and to evaluate patient tolerance and its efficiency in eradicating tumor tissue. METHODS: Seven IPCH procedures were tested successively in 32 patients (up to a total of 35 IPCH). Each procedure was tested in at least 4 patients before modifications for technical reasons or due to inacceptable tolerance. Five of them were followed by early postoperative intraperitoneal chemotherapy (EPIC) lasting 4 days. Thermal homogeneity was measured with 6 thermal probes placed in different positions inside the abdominal cavity. Spatial diffusion was studied in the last patients by adding methylene blue to the IPCH liquid. The mean follow-up was 23.85 months for the series. RESULTS: From the technological point of view, we have progressively shown that procedures with closure of the abdomen are not satisfactory: it was impossible to obtain thermal homogeneity when the entire parietal wound was closed, but markedly improved when only the skin was closed. However, these "closed" procedures did not allow us to treat all surfaces at risk. The peritoneal cavity "expander" did not permit treatment of the parietal wound and an indeterminate amount of the perfusion oozed out at its periphery. The open technique with traction of the skin upwards was superior. Using different procedures successively undermined the quality of the postoperative results. Three patients (8.6%) died and morbidity (albeit minimal) occurred in 27 patients (77%) during the postoperative course. Mortality and morbidity were significantly correlated (P = 0.02) with the peritoneal index (scoring the extent of PC). The 2-year survival rate was 60% and PC did not recur in 49% of the patients. The survival rate was correlated with the extent of PC (peritoneal index greater than or below 15) (P = 0.004), and with the absence of extraperitoneal disease (P = 0.01).

[Treatment of peritoneal carcinomatosis using complete excision and intraperitoneal chemohyperthermia. A phase I-II study defining the best technical procedures]. / Traitement des carcinoses péritonéales par exérèse complète et chimiohyperthermie intrapéritonéale. Etude de phase I-II permettant de définir la meilleure procédure technique.

OBJECTIVES: The complete or quasi complete resection of peritoneal carcinomatosis (PC) followed with IPCH is potentially able to cure some patients with a disease confined to the peritoneum. The aim of this prospective phase I-II study was to elaborate an efficient IPCH procedure with a good thermal homogeneity and a good spatial diffusion, which should be reproductible (and so standardizable and exportable), and to appreciate its tolerance and its carcinologic impact. PATIENTS AND METHODS: Seven IPCH procedures were successively tested in 32 patients (for a total of 35 IPCH); each of these were tested in at least four patients before being modified for technical or tolerance reason. Five of them were followed with an immediate postoperative intraperitoneal chemotherapy (IPIC) lasting four days. Thermal homogeneity was measured with six thermal probes situated in different places inside the abdominal cavity. Spatial diffusion was studied in the last patients by adding methylene blue in the IPCH liquid. The precise extent of the PC was reported, for each intra-abdominal region, and scored with a peritoneal index (ranging from 1 to 39). The mean follow-up was 23.85 months for the series. RESULTS: Procedures with the closure of the abdomen were not efficient: thermal homogeneity was almost satisfactory when only the skin was closed, but these 'closed' procedures did not permit the treatment of all the risky surfaces. The peritoneal cavity 'expander' did not permit the treatment of the parietal wound, and an undetermined amount of the perfusion oozed out at its periphery. The open technique by tracking the skin upwards was the best one. Death occurred in three patients (9.4%), and complications occurred in 24 patients (75%) during the postoperative course. Intra-abdominal complications were significantly correlated (P = 0.02) with the peritoneal index (scoring the extent of the PC). The two year survival rate was 60%, and PC did not recur in 50% of the patients. CONCLUSION: An efficient and reproducible procedure for IPCH was defined: an open procedure with an upwards traction of the skin. The post-IPCH IPIC was abandoned because it did not treat all the risky peritoneal surfaces. Patients with an extended PC and with extraperitoneal localization did not seem to have benefited from this therapeutic approach. Progress is needed in the chemotherapeutical procedure and indications must be more finely defined.

[5-fluorouracile and cisplatinum combination chemotherapy for metastatic squamous-cell anal cancer]. / Carcinome épidermoïde métastatique de l'anus: étude rétrospective de l'efficacité de l'association de 5-fluoro-uracile en perfusion continue et de cisplatine.

Anal cancers (AC) represent rare gastrointestinal tumors and there are only a few studies dealing with the treatment of AC at the metastatic stage. We report here the results of one chemotherapy regimen based on the experience of the Gustave-Roussy Institute. Between 1985 and 1996, 19 patients: 3 males, 16 females, have been treated with a combination of 5-fluorouracil (5FU) and cisplatinum (CDDP) (FUP regimen). Their median age was 58, their performance status (WHO grade: G) was G0-1 in 68% and G2 in 32% of the cases. Metastasis were synchronous in 6 cases and metachronous in 13 cases. Metastatic sites were the liver (10 cases), the lymph nodes 11 cases (paraaortic 5, iliac 4 and inguinal 2) and pulmonary in 3 cases; in 9 cases the lymph nodes metastasis were isolated, in 7 cases the liver metastasis were isolated. One patient received FUP as an adjuvant treatment has been only considered for toxicity and survival. The FUP regimen combined an IV 5FU continuous infusion (1 g/m2/d (5 days) and a short infusion of CDDP (100 mg/m2) on day 2, every 4 weeks: 10 patients received further local treatment. According to WHO criteria, 18 patients were evaluable for the efficacy and 19 for the tolerance. The median number of cycles was 4. The response rate was 66% (standard error : 22%) with 1 complete response and 11 partial response; there were also 4 stabilisations and 2 progressions. Toxicity rate was neutropenia grade (G) 3-4 in 13% of the patients without febrile neutropenia, G3 nausea in 30%, no G2 or 3 mucositis or diarrhoea, and 2 patients experienced a nephrotoxicity G1-2. The actuarial survival was 62.2% at 1 year and 32.2% at 5 years and the median survival was 34.5 months. Three patients are still alive at 4, 5 and 7 years and benefited from additional local treatment (the patient treated with adjuvant chemotherapy after hepatic resection and 2 patients treated after response to the FUP regimen, by surgery or radiotherapy). The FUP combination gave a high response rate with an acceptable toxicity in patients with metastatic anal cancer. Combined with local treatment it does allow prolonged survivals for some patients.

Adjuvant portal-vein infusion of fluorouracil and heparin in colorectal cancer: a randomised trial. European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group, the Gruppo Interdisciplinare Valutazione Interventi in Oncologia, and the Japanese Foundation for Cancer Research.

BACKGROUND: There is conflicting evidence on the efficacy of regional adjuvant chemotherapy, via portal-vein infusion (PVI), after resection of colorectal cancer. We undertook a randomised controlled multicentre trial to investigate the efficacy of PVI (500 mg/m2 fluorouracil plus 5000 IU heparin daily for 7 days). METHODS: 1235 of about 1500 potentially eligible patients were randomly assigned surgery plus PVI or surgery alone (control). The patients were followed up for a median of 63 months, with yearly screening for recurrent disease. The primary endpoint was survival; analyses were by intention to treat. FINDINGS: 619 patients in the control group and 616 in the PVI group met eligibility criteria. 164 (26%) control-group patients and 173 (28%) PVI-group patients died. 5-year survival did not differ significantly between the groups (73 vs 72%; 95% Cl for difference -6 to 4). The control and PVI groups were also similar in terms of disease-free survival at 5 years (67 vs 65%) and the number of patients with liver metastases (79 vs 77%). INTERPRETATION: PVI of fluorouracil, at a dose of 500 mg/m2 for 7 days, cannot be recommended as the sole adjuvant treatment for high-risk colorectal cancer after complete surgical excision. However, these results cannot eliminate a small benefit when PVI is used at a higher dosage or in combination with mitomycin.

Prognostic factors in resectable gastric cancer: results of EORTC study no. 40813 on FAM adjuvant chemotherapy.

BACKGROUND: The high incidence of locoregional recurrences and distant metastases after curative surgery for gastric cancer calls for improved locoregional control and systemic adjuvant treatment. METHODS: In a randomized clinical trial on adjuvant FAM2 chemotherapy, quality of surgery was evaluated by comparing surgical and pathology data. Univariate and multivariate analysis was made to evaluate the effect of prognostic factors on survival and time of recurrence in relation to patients, tumor, and therapy. RESULTS: Of 314 patients randomized from 28 European institutions, 159 comprised the control and 155 the FAM2 group. After a median follow-up of 80 months, no statistically significant difference was found between survivals. However, for recurrence time, treated patients had a significant advantage over controls (p = 0.02). At univariate analysis, statistically significant differences in survival and time to progression emerged for T, N, disease stage and "adequacy" of surgery. The multivariate analysis retained preoperative Hb level, T, N, and "adequacy" of surgery for time of survival; and T, N, "adequacy" of surgery and adjuvant chemotherapy for recurrence time. CONCLUSIONS: Disease stage is the most important prognostic factor. "Adequate" surgery has an important effect. Adjuvant FAM2 delayed time of recurrence, but did not influence overall survival.

Treatment of peritoneal carcinomatosis by intraperitoneal chemo-hyperthermia: reliable and unreliable concepts.

Intraoperative peritoneal chemo-hyperthermia (IPCH) is a promising treatment of peritoneal carcinomatosis arising from digestive tumors. After presenting the rationale for the use of IPCH, this review reports the results published to date by different groups. Unfortunately, data with respect to technical aspects, indications and results are unclear, inhomogeneous and questionable. The discussion presents reliable and unreliable points, mainly concerning the technical aspects of IPCH: what is the maximal desirable tumor thickness before initiating treatment? What is the ideal temperature? Is central hyperthermia beneficial? What is the ideal duration? What is the most effective antimitotic drug? A new classification of peritoneal seeding before cytoreductive surgery and before the initiation of IPCH, is proposed, and a suggestion concerning the reporting of drug concentrations made. Numerous prospective studies need to be conducted to test different technical modalities and to evaluate the results of IPCH.

[Intraperitoneal hyperthermic chemotherapy (IPHC), a promising treatment of peritoneal carcinomatosis]. / La chimio-hyperthermie intrapéritonéale (CHIP), un traitement prometteur mais encore mal connu de la carcinose péritonéale.

Intraperitoneal hyperthermic chemotherapy (IPHC) appears to be a promising treatment of peritoneal carcinomatosis. This paper reports the physio-pathological background of IPHC and the various studies which have been published in the literature. It points out the heterogeneity of these series and discuss the most critical points as surgical indications, choice of the antineoplastic drugs, their doses, temperatures of the IPHC, extend of the cytoreductive surgery, morbidity and mortality. Finally, several options are proposed for those points which are not yet standardized.

Neoadjuvant chemotherapy in locally advanced gastric carcinoma--a phase II trial with combined continuous intravenous 5-fluorouracil and bolus cisplatinum.

Locally advanced gastric adenocarcinomas (LAGC) have a poor prognosis, particularly when tumours are bulky, located in the cardia or in the event of locoregional lymph node involvement. Patients bearing these tumours were entered in a phase II trial of neoadjuvant chemotherapy, combining continuous intravenous 5-fluorouracil (5FU) (1000 mg/m2 for 5 days) and cisplatinum (CDDP) (100 mg/m2 on day 2) repeated every 4 weeks, for one to six cycles according to response and tolerance. 30 patients have been entered, 26 after clinical evaluation (CAT scan and upper gastrointestinal endoscopy) and 4 with unresectable tumours at prior laparotomy. Median age was 60 years, 15/30 patients had a tumour of the cardia, 15/30 had enlarged lymph nodes and 7/30 had linitis plastica (diffuse type). A mean number of three cycles was administered (range 1-6). 27 of the 30 patients were evaluable for response. One patient achieved a complete response (CR) and 14 a partial response (56%; 95% confidence interval 38-74%). No patient had tumour progression, and only 1/6 with linitis plastica responded. 28 patients underwent surgery, and 23 had a macroscopically complete resection (77% of the 30 entered patients); RO resections were performed in 60% of the cases, mainly after an objective response (13/15 versus 4/12 in nonresponders). No pathological CR were seen. Grade 4 neutropenia was observed in eight cycles (5 patients), with five septic complications and one death due to toxicity. Four postoperative complications were observed: 2 cases of severe pneumonia and 2 subphrenic abscesses. One postoperative death, due to intravascular disseminated coagulation, was observed at day 30. Median survival was 16 months and the 1-, 2- and 3-year survival was 67, 42 and 38%, respectively. Patients with linitis plastica had a significantly shorter survival (P < 0.002). We conclude that neodjuvant chemotherapy is feasible in LAGC, although randomised trials are warranted to demonstrate its efficacy on survival and resection rates.

Transcatheter chemoembolization of progressive carcinoid liver metastasis.

PURPOSE: The authors report their experience treating progressive liver metastases from carcinoid tumor with doxorubicin, iodized oil, and gelatin sponge embolization. MATERIALS AND METHODS: Of 23 patients, 18 had carcinoid syndrome and 19 had elevated urinary 5-hydroxyindoleacetic acid (5-HIAA) levels. Relief of symptoms, changes in 5-HIAA levels, and changes in tumor size could be evaluated in 10, 11, and 17 patients, respectively. RESULTS: Symptomatic response was complete (average duration, 29 months) in 70% and partial in 30% of evaluated patients. Biologic response was complete (average duration, 21 months) in 73%, partial in 18%, and minor in 9% of evaluated patients. Morphologic response was complete in 11%, partial in 24%, and minor in 24% of evaluated patients. Survival after diagnosis of primary tumor, diagnosis of hepatic metastases, and first chemoembolization was 81, 47, and 24 months, respectively. Eight patients were alive at the end of the study. No mortality was related to chemoembolization. CONCLUSION: Chemoembolization is safe and effective for palliation of carcinoid liver metastases.

[Pseudo-continent perineal colostomies after amputation of the rectum for cancer]. / Colostomies périnéales pseudo-continentes après amputation rectale pour cancer.

From February 1989 to February 1982, 23 pseudocontinent perineal colostomies (PC), performed after abdominoperineal excision for rectal carcinoma, were evaluated. Perineal colostomy was performed using a free autotransplant of smooth muscle, according to Schmidt, associated with colonic irrigations. This procedure was proposed to the younger and more alert patients without advanced rectal carcinoma. These 23 cases represented 35% of the rectal extirpations performed during the same period. Four patients did not accept a PC and preferred, after being fully informed about both types of colostomies, to have a classical iliac colostomy which they thought to be safer. The advantages of this procedure were mainly psychological, as the body scheme and corporeal image were not disturbed. Continence was evaluated in only 21 cases, because two patients had non-specific complications (necrosis of the colonic extremity, and colonic perforation due to enema material). Ten patients were incontinent to flatus, but did not have to wear a sanitary towel, while 11 patients had occasional, minor soiling, requiring the use of a sanitary towel. None of the patients had major incontinence requiring a secondary iliac colostomy. When asked what they thought of results, none said that they were dissatisfied. The degree of satisfaction was subjective and was not correlated with the quality of functional results as seven patients declared themselves satisfied although they had minor soiling, and conversely, two patients were not completely satisfied, even though they had no soiling. Six months after operation, the muscular transplanted ring had disappeared in half of the patients, but this did not seem to have any repercussion of the quality of functional results.(ABSTRACT TRUNCATED AT 250 WORDS)

[Neoadjuvant chemotherapy in locally advanced gastric adenocarcinoma. Preliminary results]. / Chimiothérapie néoadjuvante pour les adénocarcinomes gastriques localement avancés. Résultats préliminaires.

Gastric adenocarcinoma locally advanced or located at the cardia, or of large size or with local lymphadenopathies are of bad prognosis. To improve the surgical results we have tested the feasibility and tumoral efficacity of pre-operative (neoadjuvant) chemotherapy. Twenty patients have been included between 6/87 and 12/88. Median age was 63 years (36-74); all patients were in good general condition (OMS 0-1). The tumors were located at the cardia in 50%. The tumor median size was 10 cm (6-19), pathological lymph nodes were seem at CAT. Scan in 10/20. The neoadjuvant chemotherapy was continuous IV, 5 FU 1 g/m2/day for 5 days + CDDP 100 mg/m2, day 1. The cycles were repeated every 4 weeks. The median number of cycles prior surgery was 2 (1-4) and depended of tolerance and efficacy. We have observed (WHO criteria). 1 CR, 12 PR (Responsible rate: 65%). 6 MR or S. One patient was non evaluable because coronary insufficiency complicating the first cycle. The neoadjuvant chemotherapy toxicity was mainly hematological. The surgical procedure was curative in 15/20 patients; palliative 4 and non feasible for progression 1. Normal rate of post-operative complications was encountered: 2 subphrenic abscess, 1 pneumopathy, 1 stercoral peritonitis. At this date 3/20 patients died (17 patients are still alive, among them 14 are NED (the overall median survival is more than 10 months). This study demonstrated the feasibility and high response rate of neoadjuvant chemotherapy in patients with locally advanced gastric carcinomas. A randomized trial is warranted to demonstrate the survival benefit.