Phase II study of weekly oxaliplatin and high-dose infusional 5-fluorouracil plus leucovorin in pretreated patients with metastatic colorectal cancer.

BACKGROUND: Chemotherapy with oxaliplatin, fluorouracil (5-FU) and leucovorin (LV) has proven efficacy in patients with advanced colorectal carcinoma (CRC), although the optimal dosage and administration schedule are still unclear. This phase II trial investigated the tolerability and activity of weekly oxaliplatin, high-dose infusional 5-FU and LV in pretreated patients with metastatic CRC. MATERIALS AND METHODS: Patients received weekly courses of i.v. oxaliplatin 50 mg/m2 (1-h infusion), LV 100 mg/m2 (1-h infusion) and 5-FU 2100 mg/m2 (24-h infusion) until disease progression or unacceptable toxicity. NCI-CTC criteria were used for assessment of side-effects (at each cycle) and WHO criteria for assessment of tumour response (every 8 cycles). For descriptive purposes, time to progression, overall survival and duration of objective response were also calculated. RESULTS: Forty-four patients were enrolled and received a total of 606 cycles (median 13/patient, range 4-33), and 70% of courses (421/606) were delivered at 100% of the planned dose. The most frequent side-effects were gastrointestinal and neurological and incidence rates were: diarrhoea 66% (grade III: 29%), nausea/vomiting 54%, neurotoxicity 34% (grade III: 2%), fatigue 27%, mucositis 22%, leucopenia 14%. No grade IV toxicity was observed. Objective response rates were: partial response 23% (10 patients), stable disease 59% (26) and progressive disease 11% (5). Median time to progression was 7 months, overall survival 13 months and the duration of partial response and stable disease were 9 and 6 months, respectively. CONCLUSION: The study demonstrated that this regimen has a favourable tolerability profile and is an active combination in the pretreated metastatic CRC patient, deserving further evaluation in phase III trials.

Selective lymph node dissection in patients with intermediate thickness melanoma: our experience.

The role of elective lymph node dissection (ELND) for the treatment of cutaneous melanoma has been debated for many years. Actually, the value of ELND is seriously questioned because an increasing of overall survival rates has not been demonstrated. The lymphatic mapping technique, initially performed by an intradermic injection of vital blue dye, subsequently improved by the use of radioguided surgery (RGS), proved effective for the detection of clinical occult lymph node metastasis. We performed a sentinel node biopsy on 71 patients with stage pT2/T3N0M0 melanoma. Vital blue dye mapping alone was performed on 39 patients; the remaining 32 patients had a combined lymphatic mapping with both blue dye and RGS. The sentinel node (SN) was complexively identified in 69/71 (97.2%) patients. Sixteen patients (23.2%) were found to have metastatic melanoma cells in their SN(s); all these patients underwent lymph node dissection of the affected basin. Our experience confirmed that the intraoperative detection of sentinel nodes using both blue dye and radio-guided surgery is an effective and reliable technique for selecting patients to be submitted to lymph node dissection.

Activity of high dose 24 hour 5-fluorouracil infusion plus L-leucovorin in advanced colorectal cancer.

BACKGROUND: Modulation of 5-fluorouracil (5-FU) by leucovorin (L-LV) in patients (pts) with advanced colorectal cancer has been demonstrated to produce a highly significant benefit over single-agent 5-FU in terms of tumor response rate, but this advantage does not translate into an evident improvement of overall survival. To improve the clinical efficacy of the 5-FU plus L-LV regimen a phase II study of weekly 24-hour high-dose 5-FU infusion with L-LV was undertaken. PATIENTS AND METHODS: Seventy advanced colorectal patients were enrolled and treated by a weekly outpatient combination regimen according to the following schedule: L-LV 100 mg/sqm by 4 hours i.v. infusion followed by 5-FU 2600 mg/sqm over a 24 hours infusion combined with a fixed dose of oral L-LV (50 mg) every 4 hours for 5 times. Forty-four pts did not receive any previous CT and 26 pts were pretreated with fluoropyrimidines. RESULTS: The overall objective response rate (OR) was 35.3%; 7 CR and 11 PR (42.8% OR) were observed in the group of untreated pts, and 6 PR (23% OR) were reported among previously treated pts. Major side effects were represented by diarrhoea (grade III: 26%, grade IV: 1%), hand-foot syndrome (grade III: 4%, grade IV: 1%) and mucositis (grade III: 4%); however, this did not significantly influence the therapeutic programme. Median 5-FU dose intensity was 100% and 80% at 4 weeks, 87% and 75% at 8 weeks in untreated and pretreated pts, respectively. CONCLUSIONS: L-Leucovorin modulation of weekly short-term continuous infusion of high-dose 5-fluorouracil appeared a well-tolerated outpatient regimen; it demonstrated a high activity in advanced colorectal cancer, both in untreated pts and in pts resistant to 5-FU-based chemotherapy.

Liver and tumor uptake and plasma pharmacokinetic of arterial cisplatin administered with and without starch microspheres in patients with liver metastases.

Arterial chemoembolization of liver tumors should improve regional treatment by reducing native blood flow of the whole organ and redistributing residual flow toward hypovascular masses. Plasma cisplatin pharmacokinetics and its tissue uptake and relative tumor and liver vascularity were studied during surgical placement of arterial catheters in four patients and in four patients with colorectal metastases given intraoperative arterial cisplatin (DDP, 25 mg/m2), with an without coadministration of 600 mg degradable starch microspheres (DSM). Mean (+/- standard deviation) filterable plasma platinum levels peaked later (2 minutes) and were significantly lower after DDP with DSM (1.23 +/- 0.69 micrograms/ml) than after DDP alone (2.13 +/- 0.43 micrograms/ml, P less than 0.05), with the area under the curve (AUC0-30 min) values of 15.8 +/- 5.5 and 25.1 +/- 3.8 micrograms x min/ml (P less than 0.05), respectively. No differences in urine excretion, total body clearance, or plasma protein binding of platinum were observed. Tissue biopsies were started 15 minutes after DDP administration and completed in all cases within 5 minutes. Tumor platinum concentrations were significantly higher after DDP with DSM (3.03 +/- 1.60 micrograms/g) than after DDP alone (0.67 +/- 0.49 micrograms/ml, P less than 0.05). Liver concentrations and tumor-liver ratios of platinum also were higher, although not significantly, after DDP with DSM. Preoperative vascularization, studied with arterial perfusion scan, influenced individual tissue drug uptake in cases given DDP alone, with the lowest tumor levels in cold masses. Very high and almost superimposable liver and tumor concentrations were measured in those receiving DDP and DSM. The latter phenomenon was irrespective of native vascularization, indicating that DSM administration induced both an increased whole-liver extraction of the drug and a redistribution of blood flow and flow-dependent tissue uptake of platinum.

A phase I study of recombinant interleukin-2 intraperitoneal infusion in patients with neoplastic ascites: toxic effects and immunologic results.

A phase I study to evaluate the use of i.p. infusion of recombinant interleukin-2 (rIL-2) was planned. The following dose levels were calculated: 0.1, 0.3, 1.0, 3.0 and 10 mg/m2/day for 14 days, but only the second levels were reached. In this trial the acute toxic effects at this dosage included cardiac ischemia, transient liver impairment and septic peritonitis. The maximum tolerated dose (MTD) was 0.3 mg/m2/day for 14 days. In addition, two patients developed peritoneal fibrosis. No objective responses were observed. Therefore, in order to explore the biological activity of low (nontoxic) doses, three patients (one untreated and two previously treated with rIL-2) were infused with 0.01 and 0.03 mg/m2/day for 7 days. Potentiation of cytolytic activities in peritoneal lymphocytes and activation of a lymphokine cascade in the ascitic fluid were observed at doses ranging from 0.03 mg/m2/day to 0.3 mg/m2/day. These findings in association with the toxic effects observed at the MTD suggest the use of the minimum effective dose for future locoregional immunotherapeutic protocols.

[Extended and palliative surgery in the treatment of gastric cancer in advanced stage]. / Chirurgia allargata e palliativa nel trattamento del cancro gastrico in fase avanzata.

Five hundred and fifty patients operated between 1965 and 1983 for stomach carcinoma were included in the study. Of these, 244 (44.4%) underwent extended (54 patients) or palliative surgery (190 patients) due to the extragastric diffusion of the neoplasia. Global postoperative mortality for patients undergoing extended surgery was 16.7% and the five-year survival rate was 18.5%; in the case of those undergoing palliative surgery the postoperative mortality rate was 30.5% and the two-year survival rate was 14% for resection and 4% for derivatives. Patients who underwent a derivative operation showed an easing of symptoms and an improved quality of life. On the basis of these results the Authors consider that the possibility of extended surgery should still be carefully evaluated in patients in whom a stomach tumour has exceeded the gastric boundary, irrespective of its extent, since the limit of radical surgery is not related to the extension of surgical demolition but to the entity of the extragastric diffusion of the neoplasia. In addition, surgical abstention is not always justified even in patients in whom surgery cannot be curative since a 10% five-year survival rate was observed in patients undergoing palliative resection.

Phenotypic and functional characteristics of tumor-associated lymphocytes in patients with malignant ascites receiving intraperitoneal infusions of recombinant interleukin-2 (rIL-2).

In the course of a phase I trial, in which recombinant IL-2 (rIL-2) was infused intraperitoneally (i.p.) in patients with peritoneal carcinomatosis, we evaluated the effect on "tumor-associated lymphocytes" (TAL) isolated from the ascitic fluid. No major changes in the percentages of cells expressing the CD3, CD4, CD8, Leu-7, OKM1 and WT-31 antigens were detected either in TAL or in peripheral blood lymphocytes (PBL) after 7 days of rIL-2 infusion. In contrast the percentages of TAL (but not PBL) expressing surface IL-2 receptor (Tac), or LAK-1 antigen were sharply increased. Analysis of cytolytic functions showed a potentiation of the lytic activity against natural-killer (NK) sensitive K562 target cells and the de novo appearance of lytic activity against fresh melanoma cells. In one patient IFN-gamma was detected in the ascitic fluid following rIL-2 infusion. T-cell clones derived from the patient were analyzed for the IFN-gamma production. While only approximately 40% of PB-derived control clones produced medium to low amounts of IFN-gamma, all of the TAL-derived clones produced medium to high amounts of the lymphokine.

Factors influencing survival in 242 cases of primary gastric carcinoma.

Two hundred and forty-two patients who underwent curative surgery for primary gastric cancer between 1965 and 1979 were reviewed, and the influence on survival of the type of surgical treatment, primary tumor location, operative mortality, and stage of disease was analyzed. Operative mortality was significantly increased in patients with multicentric primaries compared to all other sites (P less than .001) and in patients undergoing total gastrectomy versus subtotal gastric resection (P less than 0.001). Stage III-IV lesions had a significantly worse prognosis than stage I-II tumors (P less than .001). Our data confirm that early diagnosis could lead to increased survival.

[Comparison of the performance of a totally implantable pump and conventional access systems in regional arterial chemotherapy of liver tumors]. / Paragone di affidabilità tra pompa totalmente impiantabile e sistemi tradizionali di accesso per la chemioterapia arteriosa regionale dei tumori epatici.

Forty-nine patients with liver tumors have been submitted to regional arterial chemotherapy by means of either totally implantable Infusaid 400 pumps (29 casse) or implantable ports (20 cases). The latter were subsequently perfused with external pumps. There was one single major operative complication and no operative deaths. Most patients underwent continuous FUDR infusion. Access related complications in the Pump and Port groups respectively included 1 and 0 malfunctions, 7 and 2 seromas, 2 and 0 pocket necroses, 8 and 10 thromboses, 2 and 4 catheter dislocations, 0 and 2 portal breakages. Treatment was stopped for access related complications in 5 and 5 patients respectively. In most of those cases, however, more than 6 cycles of chemotherapy have been performed. The Infusaid 400 pumps showed a 12-month duration of 58.4% with a 13 month median versus 17% and 9 month median of the Ports. The difference was not significant. The new implantable systems give better results in comparison with traditional regional methods; the performance of the Port systems appear very similar to the totally implantable pumps, with an obvious advantage, however, for the pumps as far as quality of life is concerned.

Colorectal cancer: relationship of histologic grading to disease prognosis.

Ninety patients underwent curative surgery for colorectal adenocarcinoma and they were followed for a period of 3 years. The aim of this retrospective study was to relate the cell differentiation (grading) and TNM classification of the UICC (1978) with the disease evaluation and patient survival. The results showed a consistent relation between grading and lymph node metastasis in patients with moderately and poorly differentiated adenocarcinoma, whereas no relationship was found between grading and local invasion of the tumor. Therefore, histocytologic grading of colorectal cancer appears to significantly influence survival grading parameters, and it may be a good method for monitoring the disease and follow-up of the patients.

[Degree of parietal penetration of gastric cancer in relation to medium- and long-term survival]. / Il grado di penetrazione parietale del cancro gastrico in relazione alla sopravvivenza a medio e lungo termine.

The Authors analysed their experience about gastric carcinoma, with particular reference to short, middle and long time survival in relation to the degree of parietal penetration. In the patients without remote metastases, the survival till 5 years depends mainly on this factor, whereas the lymphonodal spreading plays a secundary rôle, especially in the cases where the tumour deeply infiltrated the gastric wall. Lymphoadenectomy, therefore, seems essential in cases of neoplasm with low degree of parietal penetration, whereas in those with high degree it does not seem determinant on the remote results.

[Validity of distal subtotal gastroresection in the treatment of tumors of the lower 1/3 of the stomach]. / Validità della gastroresezione sub-totale distale nel trattamento dei tumori del 1/3 inferiore dello stomaco.

The Authors analysed the results of a casuistry of 75 patients subjected to radical subtotal gastroresection for carcinoma of the distal third of stomach, with the purpose to verify the validity of such operation, as compared to the total gastrectomy on principle. The postoperative mortality reached 8% and morbidity 8.7%. The survival after 5 years reached 42%. 85% of the patients, at checkings, resulted in good or excellent conditions (Visik 1-2). On the basis of these data, the Authors conclude the distal subtotal gastric resection should be considered the choice treatment for tumours of the lower third of stomach.

[Surgery of biliary lithiasis. I. Physiopathology and diagnosis]. / La chirurgia della litiasi biliare. Nota I. Fisiopatologia e diagnostica.

Experimental studies and clinical observations are referred to in stressing the frequent correlation between duodenal, biliary and pancreatic disturbances, and the importance of the role of spontaneous or iatrogenic impairment of Oddi's sphincter in the origin of this pathology. These physiopathological concepts are regarded as fundamental in the correct surgical management of cholelithiasis. A pre- and postoperative diagnostic protocol designed to investigate the anatomofunctional aspects of the duodenum and pancreas as well as bile duct morphology and Oddi sphincter function is described. Its employment enabled 633 cases to be divided six well-defined groups for diversified treatment.