Intraoperative radiotherapy and external beam radiation therapy in gastric adenocarcinoma with R0-R1 surgical resection.

INTRODUCTION: The aims of this study were to evaluate the results of intraoperative radiotherapy (IORT) and external beam therapy (EBRT) in the treatment of gastric adenocarcinoma. METHODS: From 1986 to 1999, 87 patients who underwent surgical resection for gastric adenocarcinoma combined with IORT were reviewed. A R0 surgical resection was performed in 82 patients and five underwent R1 resection. The stage was: pT1 in 12, pT2 in 19, pT3 in 44 and pT4 in seven. Thirteen patients were pN1 and 43 were pN2, The IORT dose ranged from 12 to 23 Gy. Patients with pT3 and/or pN tumours underwent EBRT with a standard dose of 44-46 Gy. RESULTS: The post-operative mortality and morbidity rates were 2.3 and 6.8%, respectively. The 5-year survival rate for R0 patients was 60%, for R0-pN0 was 90% and for R0-pN+ patients was 55%. The local failure rate in the 19 pN+ patients was 21%. CONCLUSION: IORT and EBRT combined with surgical resection may provide overall survival, improving the local control after gastrectomy.

Intraoperative radiation therapy combined with limited lymph node resection in gastric cancer: an alternative to extended dissection?

PURPOSE: To describe the results of a series of 63 Western patients presenting with gastric adenocarcinoma and treated with surgery and intraoperative radiation therapy (IORT) over a 8-year period and to discuss the role of IORT when combined with limited lymph node dissection. METHODS AND MATERIALS: From 1986 to 1993, 63 patients with gastric adenocarcinoma have been operated in the department of radiation oncology of the Hospices Civils de Lyon. The stage was: I in 17, II in 11, IIIA in 9, IIIB in 20, and IV in 6. The lymph node dissection was considered to be limited in 56 patients and extended in 7. The IORT dose ranged from 12 to 23 Gy (median: 15). Thirty patients also underwent a postoperative external beam irradiation with a standard dose of 44-46 Gy. RESULTS: The postoperative mortality rate was 4.8%. The 5-year overall survival in the entire series was 47% and was 82, 55, 78, 20, and 0% in Stages I, II, IIIA, IIIB, and IV, respectively. Loco-regional relapse occurred in 15 of 63 patients and metastases in 15 of 63. CONCLUSION: In Western patients treated by gastrectomy for adenocarcinoma of the stomach, IORT combined with limited lymph node dissection may provide overall survival similar to that observed after gastrectomy with extended lymph node dissection but with less postoperative mortality.

Intraoperative radiotherapy in resected pancreatic cancer: feasibility and results.

BACKGROUND AND PURPOSE: To evaluate the impact of intraoperative radiotherapy (IORT) combined with postoperative external beam irradiation in patients with pancreatic cancer treated with curative surgical resection. MATERIALS AND METHODS: From January 1986 to April 1995 25 patients (11 male and 14 female, median age 61 years) underwent a curative resection with IORT for pancreatic adenocarcinoma. The tumour was located in the head of the pancreatic gland in 22 patients, in the body in two patients and in the tail in one patient. The pathological stage was pT1 in nine patients, pT2 in nine patients, pT3 in seven patients, pN0 in 14 patients and pN1 in 11 patients. All the patients were pM0. A pancreaticoduodenectomy was performed in 22 patients, a distal pancreatectomy was performed in two patients and a total pancreatectomy was performed in one patient. The resection was considered to be complete in 20 patients. One patient had microscopic residual disease and gross residual disease was present in four patients. IORT using electrons with a median energy of 12 MeV was performed in all the patients with doses ranging from 12 to 25 Gy. Postoperative EBRT was delivered to 20 patients (median dose 44 Gy). Concurrent chemotherapy with 5-fluorouracil was given to seven patients. RESULTS: The overall survival was 56% at 1 year, 20% at 2 years and 10% at 5 years. Nine local failures were observed. Twelve patients developed metastases without local recurrence. Twenty patients died from tumour progression and two patients died from early postoperative complications. Three patients are still alive; two patients in complete response at 17 and 94 months and one patient with hepatic metastases at 13 months. CONCLUSION: IORT after complete resection combined with postoperative external beam irradiation is feasible and well tolerated in patients with pancreatic adenocarcinoma.

Adenocarcinoma of the body and tail of the pancreas: is there room for adjuvant radiotherapy?

AIMS AND BACKGROUND: Adenocarcinoma of the body and tail of the pancreas is a rare malignancy with a poor prognosis. Few long-term survivors have been reported in the literature. The role of adjuvant treatment after curative resection has not yet been assessed. This retrospective study aims to describe the patterns of failure and the survival of 10 patients treated with resection and adjuvant radiotherapy. MATERIALS AND METHODS: From 1982 to June 1994, 10 patients with adenocarcinoma of the body and tail of the pancreas received adjuvant radiotherapy in our department. There were 4 females and 6 males, with a median age of 63 years (range, 45-77). The pT distribution was 2 pT1, 4 pT2, 4 pT3 and for pN it was 7 pN0 and 3 pN1. Four patients had stage I, 3 stage II and 3 stage III disease. All the patients underwent a resection: distal pancreatectomy in 7, partial resection of the body in 1, and total pancreatectomy in 2. Gross residual disease was present in 2 cases. Three patients received intraoperative radiotherapy up to a dose of 12-15 Gy. Postoperative radiotherapy was given in 9 patients with a dose ranging from 40 to 50 Gy (median, 45). One patient who received intraoperative radiotherapy had no postoperative radiotherapy. In 4 patients, chemotherapy with 5-fluorouracil was given during the first week of irradiation. RESULTS: Six patients experienced a local-regional relapse and 3 developed metastases. The median survival was 21 months. The 5-year overall survival was 15%. Eight patients died of progressive disease. One patient who presented with stage I disease was alive and free of disease at 24 months from diagnosis and, interestingly, one with stage III disease was alive at 111 months. No severe treatment-related complications were observed. CONCLUSIONS: As in carcinoma of the head of the pancreas, adjuvant radiotherapy should be considered as an adjuvant treatment of resected adenocarcinoma of the body and tail of the pancreas. Further evaluation is necessary to assess the role of intraoperative radiotherapy.

[Role of peroperative radiotherapy in the treatment of uterine cancers. Preliminary experience in Lyon]. / Place de la radiothérapie peropératoire dans le traitement des cancers de l'utérus. Expérience lyonnaise préliminaire.

AIM: Retrospective analysis of Intra operative Radiotherapy (IORT) in recurrent uterine carcinoma (RUC) and prospective pilot study of IORT in advanced cervix cancer (ACC) with high risk of local failure. PATIENTS-TREATMENTS: 1) RUC: from 1988 to 1991, 34 patients with RUC have been treated. Primary cancer was: cervix uterus: 28, endometrium: six. Site of recurrence: centro pelvis: four, latero pelvis: 25, lombo aortic: five. Total gross resection was only possible in 12 patients. A dose of 15 to 22 Gy was given by IORT according to the residual tumour size. External beam irradiation was added in 16 patients; 2) ACC: January 1991 to November 1992, 20 patients were included in this pilot study, stage IIB: seven, stage III: 12, stage IV: 1. Preoperative retroperitoneal pelviscopy showed 13 pN1 patients and NMR imaging ten tumours of 6 cm or larger in diameter. Treatment started with concommitant pelvic irradiation (44 Gy) and one conommitant cycle of 5 Fu-CDDP, followed by a short course of high dose rate upper vagina brachytherapy (4 Gy). Four weeks later a radical Wertheim operation was performed together with IORT on the lateral pelvis. RESULTS: 1) RUC: overall survival (Kaplan Meier) at 4 years is 32% (+/- 8). Local relapse in the fiedl of IORT was observed in six patients. Grade 2-3 complications: six patients (radiation proctitis, neuritis, vertebral collapse, ureteral stenosis); 2) ACC: the median follow up is hort (18 months). Four cases of pelvic relapse, no postoperative death. The first line radio chemotherapy was associated with two G3 early complications. Postoperative radiation complication was less than 10% G3. DISCUSSION: promising results of IORT in RUC have been observed especially if no irradiation is given during the primary treatment. Good feasibility of the pilot study of IORT in ACC was also observed. It could be followed by a multicentric feasibility trial.

[Effect of fibrin glue on lymphostasis during lymph node excisions. Prospective randomized study in 40 patients]. / Efficacité d'une colle de fibrine sur la lymphostase au cours des curages ganglionnaires. Etude prospective randomisée sur 40 patients.

To evaluate the efficacy of fibrin glue for lymphostasis during axillary and inguinal lymph node removal, we conducted a prospective randomized study including 40 patients. Post-operative mortality and morbidity rates were not different throughout the 2 groups. However they were significant decreasement in drainage duration, in drainage quantity and in hospital duration in the group "with" fibrin when compared with the group "without".

Intraoperative chemohyperthermia in the management of digestive cancers. A general review of literature.

Intraoperative chemohyperthermia is a new method in the treatment of peritoneal seedings from digestive cancers, which combines surgery, intraperitoneal chemotherapy (mitomycin C and/or cisplatyl) and peritoneal hyperthermia. After a brief reminder on the general principles concerning high temperature action, a review of literature is made: 5 teams have performed this technique. We differentiate the indications, design features and results of each team. The results show a mean survival after 2 years of 35% (in peritoneal carcinomatosis) up to 78% (in gastric serosal invasion, peritoneal seeding free). The best result of the method is the drying up of cancerous ascites, allowing a more comfortable survival.

A new device for the treatment of pleural malignancies: intrapleural chemohyperthermia preliminary report.

The prognosis of malignant pleural tumors remains extremely unfavorable. The aim of this study is to evaluate the combination of intrathoracic intrapleural chemotherapy and intrapleural hyperthermia (ITCH) in these diseases. Under anesthesia, 5 men were studied. After pleurectomy for mesothelioma (3/5) or adenocarcinoma (2/5), ITCH is carried out for over 60 min, either with mitomycin C (4/5) or cisplatin (1/5). No pre- or postoperative death occurred. The maximal pleural temperature is 42.6 degrees C. The blood level of mitomycin C never reached the systemic toxic level. All the patients were discharged from the surgical ward, 3 are still alive 15 months later. Therefore, ITCH appears to be a safe and reliable therapy.

Biochemical modifications in the blood and the heated fluids during intraperitoneal chemohyperthermia.

The biochemical changes in blood during intraperitoneal chemohyperthermia (IPCH) were examined by carrying out complete assessments before and after the operation. These assessments were made up of 23 parameters: Na, K, Cl, CO2, urea, creatinine, proteins, glucose, calcium, phosphates, magnesium, bilirubin, uric acid, lactic acid, CRP, ASAT, ALAT, CK, LDH, gamma-GT, ALP, lipase, and amylase. Only 5 of these parameters showed significant changes: proteins, urea, ALP, gamma-GT, lactic acid. The protein and urea levels decreased due to hemodilution induced by the perfusion of fluids. ALP and gamma-GT levels decreased, possibly due to localized inhibition of secretion. Lactic acid levels increased due to the movement of lactates from the heated fluid into the blood. The study of biochemical changes within the heated fluids was made using the following parameters: CA 125, CA 19-9, CEA, ASAT, ALAT, CK, LDH, gamma-GT, ALP, lipase, uric acid, phosphates, proteins, Na, K, Cl, urea, creatinine, and magnesium. Between the beginning and the end of IPCH, significant increases were found in the levels of CA 125 (+173%), proteins (+190%), ASAT (+130%), LDH (+103%), K+ (+232%), PO4 (+134%), and uric acid (+99%). These increases indicate the existence of a significant degree of cellular lysis.

Cytokine production during intraperitoneal chemohyperthermia.

The aim of the present work is to investigate in vivo cytokine production during chemohyperthermia. 11 patients suffering from gastric adenocarcinoma (n = 6), ovarian adenocarcinoma (n = 4) or malignant mesothelioma (n = 1) were studied. Patients received 60 mg mitomycin or 100 mg cisplatin per square meter during 2 h in 6 liters of a heating solution (temperature 42 degrees C, flow rate 200 ml/min in a closed circuit) after previous surgical resection. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured at 0, 30, 45, 60 and 90 min, both in the blood stream and in the heating solution circulating intraperitoneally. We observed a slight increase in plasma IL-6 occurring as soon as 30 min, a dramatic rise in IL-6 in the heating solution. TNF-alpha values were only slightly augmented. In addition, the importance of various factors in the induction of IL-6 and TNF-alpha production during chemohyperthermia (temperature, mitomycin C, cisplatin) were studied using a whole blood ex vivo model.

[Cancers of the stomach and peritoneal carcinoses: will hyperthermia be a new therapeutic approach?]. / Cancers de l'estomac avec carcinoses péritonéales: l'hyperthermie sera-t-elle une nouvelle voie thérapeutique?

Overall survival rate of gastric adenocarcinoma is poor whatever the therapeutic is. Main reasons for this poor prognosis are regional failure and local recurrences. Using hyperthermia could be of interest in peritoneal carcinomatosis during gastric carcinoma: in vitro cytotoxic effect of hyperthermia is well known. Using hyperthermia in combination with intra peritoneal chemotherapy could improve local control. Preliminary results of pilot studies treating peritoneal carcinomatosis with intra peritoneal chemohyperthermia are reported.

[Intraoperative radiotherapy in gastric adenocarcinomas. Apropos of 45 cases]. / Radiothérapie per-opératoire dans les adénocarcinomes gastriques. A propos de quarante-cinq cas.

Intra-operative radiation therapy (IORT) is a multidisciplinary approach in which residual tumors or tumor beds are directly irradiated during a surgical procedure. To evaluate its efficacy we conducted since 1985 a prospective study including non metastatic gastric adenocarcinoma treated by surgery, IORT (15 Gy) and post-operative external beam radiotherapy (44 Gy). Up to now, 45 gastric adenocarcinomas (18 pNO and 27 pN1N2) have been included in the study. Mortality and morbidity rates were not different from those of surgery alone. Overall 5 year survival rate is 59.1% and pN1N2 5 years survival rate is 50.6%. These promising results are comparable with those of asian randomized studies which demonstrate the possible value of IORT in the treatment of gastric adenocarcinoma.

[Intraperitoneal chemo-hyperthermia in the treatment of peritoneal carcinomatosis of ovarian origin. Initial cases, physiopathologic data]. / Chimio-hyperthermie intrapéritonéale dans le traitement des carcinoses péritonéales d'origine ovarienne. Premières observations, données physiopathologiques.

The authors report the first results using intraperitoneal hyperthermic chemotherapy with mitomycin C or cisplatinum with protective hypothermia up to 32 degrees C in four cases of peritoneal carcinomatosis secondary to cancer of the ovary which was resistant to conventional treatment. They were stage III and IV in the FIGO classification. There were no post-operative complications. Two patients are still alive 4 and 6 months after intraperitoneal hyper-chemotherapy. Hypothermia has its own action of destroying tumour cells and potentiates the effects of chemotherapy. We have, following the work of the japanese, devised a therapeutic regime combining chemotherapy and intraperitoneal hyperthermia.

[Intraperitoneal chemo-hyperthermia with mitomycin C. Development and in vivo study of tolerability in dogs]. / Chimio-hyperthermie intra-péritonéale (CHIP) avec mitomycine C (MMC). Mise au point et étude in vivo de la tolérance chez le chien.

Peritoneal carcinosis is relatively frequent in the clinical course of digestive cancers (48% in cases with invasion of the serous membrane). Despite various therapeutic strategies, prognosis is almost always unfavourable, survival after 6 months is extremely rare. Because of the known in vitro anti-tumour effect of hyperthermia and its chemosensitizing effect during Mitomycine C therapy, we decided to develop a technique based on these two anticancer effects: intraperitoneal hyperthermia and intraperitoneal chemotherapy. Termed CHIP, or chemo-hyperthermia intraperitoneal, this new method could be used for the treatment of peritoneal carcinosis. We report here results of the necessary animal experimentation before such a method could be proposed for human anticancer therapy.

Tolerance of intraperitoneal chemohyperthermia with mitomycin C: in vivo study in dogs.

Tolerance of intraperitoneal chemohyperthermia (IPCH) with mitomycin C (2 mg/kg) by irrigation of the peritoneal cavity via a closed circuit system was evaluated in Beagle dogs for possible use in the management of human peritoneal carcinomatosis. Of dogs, 24 underwent three digestive anastomoses each. They were randomized into three groups: control (n = 6), intraperitoneal hyperthermia (n = 8) and IPCH (n = 10). Peritoneal temperatures were maintained between 41-43 degrees C for 60 min. Tolerance was evaluated through clinical follow-up, biological samples (serum electrolytes, blood counts and serum enzymes), histological examinations and post-mortem macro- and microscopic controls of anastomosis. Mortality and morbidity rates were not different in the three groups. No anastomotic leakage occurred. Evidence of biological toxicity was minimal. Histological examinations showed no definitive tissue damage. IPCH appears to be a safe and reliable device in dogs. Plans to combine IPCH with MMC in surgical resection of patients with peritoneal carcinomatosis are underway.