Adjuvant chemotherapy in gastric cancer: 5-year results of a randomised study by the Italian Trials in Medical Oncology (ITMO) Group.

BACKGROUND: The aim of this study was to determine the efficacy of the EAP regimen (etoposide, adriamycin and cisplatin) followed by the Machover schedule (fluorouracil and folinic acid) given as adjuvant treatment to patients with poor prognostic factors (N+ or T3/4). PATIENTS AND METHODS: Before randomisation, the subjects were stratified on the basis of node involvement (N+ or N-) and the time from surgery to randomisation (< or = 21 days or > 22 days). The surgical procedures for sub-total or total gastrectomy with D2 dissection were standardised among the participating centres. RESULTS: Between December 1992 and December 1997, 274 patients were enrolled: 137 in the treatment arm and 137 in the control arm. The majority of the patients (90%) were N+. After a median follow up of 66 months (range 2-83), the 5-year overall survival (OS) was 52% in the treatment arm and 48% in the control arm [hazard ratio (HR) 0.93; 95% confidence interval (CI) 0.65-1.34]; the 5-year disease-free survival (DFS) was 49% and 44%, respectively (HR: 0.83; 95% CI 0.59-1.17). Among the patients with N-/N+ (1-6), the 5-year OS was 61% in the treatment group and 60% in the control group; in those with N+ (1-6), it was 42% and 22%. The treatment was completed by 87% of patients. Drug-related grade 3/4 WHO toxicities included leukopenia (21%), nausea and vomiting (14%), mucositis (9%), neutropenia (3%) and thrombocytopenia (2%). There were two deaths due to sepsis. CONCLUSIONS: Although our results are not statistically significant, there was a limited relative risk reduction in the patients receiving adjuvant therapy (17% in DFS and 7% in OS). The data suggest that D2 surgery may have a favourable impact on OS.

Docetaxel neuropathy: a distal axonopathy.

Docetaxel has been implicated as a causative agent in peripheral neuropathy, but pathological changes in peripheral nerve have not been described. During docetaxel treatment a 54-year-old man developed a sensorimotor polyneuropathy when the overall docetaxel dosage was 540 mg/m(2). Neurophysiological investigation revealed a sensorimotor axonal neuropathy. Fascicular sural nerve biopsy showed an axonal neuropathy with a preferentially loss of large myelinated fibers. There was evidence of considerable fiber regeneration. Sensory and motor symptoms progressively improved after docetaxel withdrawal.

Randomized phase II noncomparative trial of oral and intravenous doxifluridine plus levo-leucovorin in untreated patients with advanced colorectal carcinoma.

BACKGROUND: Doxifluridine (5-dFUR) is a fluoropyrimidine derivative that has been shown to be active on a variety of solid tumors. The clinical use of intravenous (i.v.) 5-dFUR as a bolus injection or short term infusion has been limited because of its unpredictable severe neurotoxicity. Unlike fluorouracil (5-FU), 5-dFUR is effective when administered orally. METHODS: This randomized, parallel-group, Phase II trial of two schedules of 5-dFUR was conducted between April 1993 and September 1994. A total of 130 previously untreated patients with locally advanced or metastatic colorectal carcinoma were randomized to receive oral levo-leucovorin (1-leucovorin) 25 mg/dose followed by oral 5-dFUR 750 mg/m2 twice daily for 4 days every 12 days (arm A) or i.v. 1-leucovorin 25 mg/dose followed by i.v. 5-dFUR 3000 mg/m2 for 5 days every 21 days (arm B). RESULTS: The two treatment arms were well balanced in terms of age, sex, and disease extension. Metastases were present in more than 90% of the total population, with the liver being the most common site. A median of 7 oral courses (range, 1-15) and 5 intravenous courses (range, 1-9) were administered. Intent-to-treat analysis rate of the randomized patients revealed a response rate of 15% (95% confidence interval [CI], 7-26) in arm A and 41% (95% CI, 29-54) in arm B. However, 7 cases in arm A and 12 in arm B were inadequately treated, and the response rates, according to standard analysis, were respectively 17% (95% CI, 8-28) and 51% (95% CI, 37-65). The median time to treatment failure was 4 months (range, 1-23) and 7 months (range, 1-9), respectively, for the two groups; median survival was 11 months (range, 1-24) in both groups. National Cancer Institute Grade 3 and 4 diarrhea were observed in 25% of the orally treated patients and in 18% of those receiving i.v. treatment. Stomatitis was reported mainly in arm B (15%). Mild and moderate neurotoxicity was observed in 6% of the patients in both arms; no severe neurotoxicity was reported. CONCLUSIONS: 5-dFUR with l-leucovorin, administered either orally or intravenously, produces response rates that are similar to those offered by the regimens containing 5-FU that are usually used to treat advanced colorectal carcinoma. This study documents the good tolerance of the i.v. schedule administered as a 1-hour infusion; furthermore, oral administration seems to be promising and feasible as a home treatment.

The role of intraoperative therapy by electron beam and combination of adjuvant chemotherapy and external radiotherapy in carcinoma of the pancreas.

AIMS AND BACKGROUND: In the treatment of pancreatic carcinomas, one modality is intraoperative radiotherapy (IORT). A study was carried out to assess the feasibility of IORT alone or in a multimodality approach with postoperative adjuvant chemotherapy and external radiotherapy and to compare local control and survival of patients. Another objective of this retrospective study was to verify prognostic factors in resected patients treated with IORT. METHODS: From January 1985 through September 1992, 54 adenocarcinomas of the pancreas (unresectable and resected patients) were treated with IORT by electron beam at the San Raffaele Hospital and then analyzed. Comparison was also carried out between IORT-treated resected patients and a non-randomized control group of resected patients treated without IORT in the same period. RESULTS: In unresectable patients treated by laparotomy bypass and IORT, overall median survival was 6 months and 8 months in non-metastatic patients. Relief of severe pain present in 14 patients was observed in 85% within 12 days of IORT. As regards resected patients, the most important finding was that significantly better local control resulted from IORT. In fact, overall, local relapses were 25% in the IORT group and 55.8% in the non-IORT group (control group); instead, survival of the IORT group was not significantly longer than that of the control group. From a statistical analysis of resected patients treated with IORT and performed on prognostic factors on the basis of available data, survival was significantly influenced by tumor pathologic grading and diameter; postoperative adjuvant therapy was not a significant prognosis factor. CONCLUSIONS: IORT has a role in local control of unresectable pancreatic carcinomas and in control of resultant severe pain. In resected patients, IORT is effective in decreasing local recurrences but has little impact on survival. To obtain more satisfactory results, new and more effective adjuvant therapies and better abdominal prophylaxis should be tested.

Intraoperative radiation therapy adjuvant to resection in the treatment of pancreatic cancer.

BACKGROUND: Local recurrence is the most frequent site of failure after resection for pancreatic cancer. Tolerance, local control, and survival obtained by the association of resection and intraoperative radiation therapy (IORT) were reported. METHODS: Between June 1985 and March 1993, 90 resections for pancreatic cancer were performed at the authors' institution. For 43 patients, IORT was added to resection (Group 1), whereas the other 47 patients underwent resection alone (Group 2), because of either the unavailability of linear accelerator or the patient's refusal. In Group 1, radiation doses from 12.5 to 20 Gy, with electron beam energies between 6 and 12 MeV, were delivered. Extension of the disease was similar in the two groups of patients: mean diameter of the tumor was 3.2 cm in Group 1 and 3.4 cm in Group 2; percentage of third degree stage disease (International Union Against Cancer classification) was 65.1% in Group 1 and 57.4% in Group 2; and tumor clearance was incomplete in 39.5% of patients in Group 1 and in 34.0% in Group 2. RESULTS: Operative mortality and overall early post-operative complications were respectively 2.3% and 23.2% in Group 1 and 2.1% and 23.4% in Group 2. One-year, 2-year, and 3-year survival rates were respectively 71%, 24%, and 7% in Group 1 and 49%, 16%, and 10% in Group 2 (P was not significant). Median disease free survival was 13 months in Group 1 and 8 months in Group 2 (P was not significant). A local recurrence was detected in 27.0% of patients in Group 1 and in 56.4% of patients in Group 2 (P < 0.01). CONCLUSIONS: The results suggest a better local control in patients with pancreatic cancer undergoing adjuvant IORT.