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Aims and Background Rarely are conclusions from clinical trials summarized in international consensus conferences and promptly transferred to patient care. The adjuvant therapy for colorectal cancer used in daily clinical practice in Italy is described and compared with the recommendations of the 1990 NIH Consensus Conference.Patients and Methods We audited prescriptions of adjuvant systemic therapies for Italian colorectal cancer patients in 82 centers during a fixed one-week period.Results Among 434 patients receiving adjuvant chemotherapy there were 139 (42.5%) colon cancer patients with N- and 169 (51.7%) with N+ regional nodal involvement. Treatment at academic centers, a young age, T4 and a low total number of lymph nodes removed at surgery were the factors potentially justifying the decision for adjuvant chemotherapy in stage II colon cancer patients. The most common chemotherapy used was a bolus of 5-fluorouracil/folinic acid for 6 months (75.8%). Adjuvant radiotherapy was not administered to 37 (38.5%) of 96 patients with stage II and III rectal cancer.Conclusions The study shows that a substantial proportion of patients on adjuvant treatment at a certain time point in a large enough sample of Italian centers are stage II (potential over-treatment) and that an under-treatment of stage II and III rectal cancer patients (lack of radiotherapy) occurs too often in daily clinical practice in this country.

Human recombinant interleukin-3 (IL-3; Sandoz AG, Basel, Switzerland) was administered for 7 days to patients with neoplastic disease and normal hematopoiesis. The purpose of the study was to assess IL-3 toxicity, to identify target cells, to define their kinetics of response at different dose levels, and to determine if IL-3 in vivo increased the sensitivity of bone marrow (BM) progenitors to the action of other hematopoietic growth factors. A total of 21 patients entered the study; the dosage ranged from 0.25 to 10 micrograms/kg/d. The effect on peripheral blood cells during treatment showed no significant changes in the number of platelets, erythrocytes, neutrophils, or lymphocytes (and their subsets). A mild monocytosis and basophilia occurred. Eosinopenia, present in the first hours of treatment, was followed by a dose-and time-dependent eosinophilia. IL-3 treatment affected BM cell proliferation by increasing the percentage of BM progenitors engaged in the S-phase of the cell cycle. The effect was dose dependent, with the various progenitors showing different degrees of sensitivity. The most sensitive progenitors were the megakaryocyte progenitors (colony-forming unit-megakaryocyte), then the erythroid progenitors (burst-forming unit-erythroid), and finally the granulo- monocyte progenitors (colony-forming unit-granulocyte-macrophage) whose proliferative activity was stimulated at the higher doses of IL-3. Only a slight increase in the proliferative activity of myeloblasts, promyelocytes, and myelocytes was observed, whereas the activity of erythroblasts was unchanged. The priming effect was such that BM progenitors, purified from patients treated with IL-3, produced more colonies in vitro in the presence of granulocyte colony-stimulating factor (G-CSF; granulocyte colonies), IL-5 (eosinophil colonies), and granulocyte-macrophage CSF (GM-CSF; predominantly eosinophil colonies). These data indicate that even in vivo IL-3 acts essentially as a primer for the action of other cytokines. Therefore, optimum stimulus of myelopoiesis will require either endogenous or exogenous late-acting cytokines such as G-CSF, erythropoietin, GM-CSF, and IL-6 for achieving fully mature cells in peripheral blood. If exogenous cytokines are used with IL-3, it is likely that G-CSF will yield more neutrophils, whereas GM-CSF may enhance eosinophils, monocytes, and neutrophils. Attention to the clinical relevance of each cell type will be necessary and should determine the selection of the combination of cytokines.

The monoclonal antibody-defined CARS antigen is a new carcinoma associated marker which is expressed on a mucin-like molecule. Serum concentrations of CARS were assayed in 181 patients with carcinomas of different organs, 20 patients with non-carcinomatous malignancies, 123 patients with inflammatory diseases and 150 healthy controls. Serum levels of CARS were significantly increased in 51% of the patients with pancreatic carcinomas, in 60% of patients with biliary tract carcinomas and in about 15% of the patients with carcinomas of the digestive apparatus. Sera from patients with breast carcinomas were negative, as well as sera from patients with melanomas or sarcomas. CAR-3 values in samples from patients with chronic pancreatitis were constantly negative, as were samples from healthy donors. Significant concentrations of CAR-3 were detected in 20% of the sera from patients with acute pancreatitis and in 15% of the sera from patients with cirrhosis. Because of its high specificity for pancreatic carcinomas compared to chronic pancreatitis, CARS seems a promising marker for distinguishing between neoplastic and chronic inflammatory diseases of the pancreas, whose differential diagnosis is difficult.

Ifosfamide, an oxazophosphorin compound, active in mesenchimal tumours has recently been used at high doses (14–18 g/sqm) in order to increase the number of responses. Continuous infusion (C.L) of Ifosfamide probably decreases toxicity and increases the therapeutic window of the drug. Bone marrow and renal toxicities seem to be modified greatly by C.L.. Aim of our study has been to characterize the pharmacokinetic drug profile during C.L high dose-fosfamide (HD-IFO). From April to December 1994, 9 patients (pts) with advanced soft tissue sarcomas, 5 pts with osteosarcomas and I pts with Ewing's sarcoma with normal liver and renal function, treated with C.I. HD-IFO (14g/sqm. over 4 days) and Mesna contemporary infusion, entered into the study. 33 chemotherapy courses were administered (range 1–4, mean 2.2). Pts were submitted to blood sampling previous starting of infusion, and 12, 24,48,72,96, 100, 104, 114, and 120 hours after treatment beginning. Plasma samples were stored at 0°C. Chemical analysis was perfonned using HPLC. Maximum concentration of the drug was observed at 24th hour (C24: 61.5±21.9/μg/ml) while decreased pseudo-steady rate levels were reached after 70–80 hours (Css: 28.3 ± 11.5 μg/ml). Tenninal half life was 3.2±0.4 hours; AVC (following trapezoidal rule) was 3654±1222mg/l. × hour. Median Clearances (total dose/AVC) was 7.14±3.31/h. At the second or following cycles a relevant reduction of Tl/2 and AVC (–20% and –25%) due to enzymatic auto induction was observed. In confront with Ifosfamide administration at the same doses but in 1 hour infusion we observed that C.I. leads to a higher AUC (3650 vs. 1230) to a shorter Tl/2 (3.2 h. vs. 5.9 h.) and to a relevant increase of total clearance (7.14 vs. 3.9).This significant difference in pharmacokinetic profile can explain the different spectrum of activity between the two manners of administration.

From June 1992 to March 1995,28 patients (pts) with advanced bladder cancer were treated with CMV cytostatic regimen (14 pts; day 1: methotrexate 40 mg/m2e.v., vinblastine 4 mg/m2e.v.; day 2: cisplatin 90 mg/m2e.v.; day 8 =day 1; every 21 days) or with CaMV schedule, if serum creatinine was1. 5 mg/dl (14 pts; cisplatin substituted by carboplatin, according to renal function, following Calvert formula; every 28 days).Pts’ characteristics were: 23 males, 5 females; median age: 62.5 (range 49–76) median performance status (ECOG): 1 (range 0–2). Sites of disease involvement: locoregional spreading in 13 pts; nodal metastases (mts) in 15 pts; pulmonary mts in 4 pts; hepatic mts in 3 pts; bone mts in 1 patient (pt).Total number of administered cycles was 107 (median number of cycles per pt: 4; range 1–8). Grade 3 toxicity was: nausea and vomiting in 2 pts; anemia in 5 pts; leukopenia in 3 pts; thrombocytopenia in 2 pts; stomatitis in 3 pts. No grade 4 toxicity was reported.25 pts were evaluable for the response; we observed: 3 (12%) complete remissions (CR), 8 (32%) partial remissions (PR), 4 (16%) stable diseases and 10 (40%) prog ressive diseases.Overall response rate was good (CR+PR=44%) and toxicity was manageable and reversible.