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Previous analyses of the GIM (Gruppo Italiano Mammella) 2 study showed that addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel in patients with node-positive early breast cancer does not improve outcome, whereas dose-dense chemotherapy induces a significant improvement in both disease-free survival and overall survival as compared with a standard schedule. Here, we present long-term results of the study.In this 2 × 2 factorial, open-label, randomised, phase 3 trial, we enrolled patients aged 18-70 years with operable, node-positive, breast cancer with Eastern Cooperative Oncology Group performance status of 0-1 from 81 hospitals in Italy. Eligible patients were randomly allocated (1:1:1:1) to one of the four following study groups: four cycles of standard-interval intravenous EC (epirubicin 90 mg/mBetween April 24, 2003, and July 3, 2006, 2091 patients were randomly assigned to treatment: 545 to q3EC-P, 544 to q3FEC-P, 502 to q2EC-P, and 500 to q2FEC-P. 88 patients were enrolled in centres providing only standard interval schedule and were assigned only to q3FEC-P and q3EC-P; thus, 2091 patients were included in the intention-to-treat analysis for the comparison of EC-P (1047 patients) versus FEC-P (1044 patients) and 2003 patients were included in the intention-to-treat analysis for the comparison of dose-dense (1002 patients) versus standard interval analysis (1001 patients). After a median follow-up of 15·1 years (IQR 8·4-16·3), median disease-free survival was not significantly different between FEC-P and EC-P groups (17·09 years [95% CI 15·51-not reached] vs not reached [17·54-not reached]; unadjusted hazard ratio 1·12 [95% CI 0·98-1·29]; log-rank p=0·11). Median disease-free survival was significantly higher in the dose-dense interval group than the standard-interval group (not reached [95% CI 17·45-not reached] vs 16·52 [14·24-17·54]; 0·77 [95% CI 0·67-0·89]; p=0·0004). The most common grade 3-4 adverse events were neutropenia (200 [37%] of 536 patients in the q3EC-P group vs 257 [48%] of 533 in the q3FEC-P group vs 50 [10%] of 496 q2EC-P vs 97 [20%] of 492) and alopecia (238 [44%] vs 249 [47%] vs 228 [46%] vs 235 [48%]). During extended follow-up, no further grade 3-4 adverse events or deaths related to toxic-effects were reported. Treatment-related serious adverse events were reported in nine (2%) patients in the q3EC-P group, seven (1%) in the q3FEC-P group, nine (2%) in the q2EC-P group, and nine (2%) in the q2FEC-P group. No treatment-related deaths occurred.Updated results from the GIM2 study support that optimal adjuvant chemotherapy for patients with high-risk early breast cancer should not include fluorouracil and should use a dose-dense schedule.Bristol-Myers Squibb, Pharmacia, Dompè Biotec Italy, Italian Ministry of Health, Fondazione Italiana per la Ricerca sul Cancro, and Alliance Against Cancer.

Since 1983, a series of experimental and clinical studies have been carried out on the possibility of enhancing the chemotherapy effectiveness in breast cancer by expanding the fraction of cycling cells. Theoretically estrogens should recruit breast cancer cells and this fact should result in a higher killing efficiency of antiproliferative drugs. Actually it has been clearly shown, by means of the thymidine labeling index and primer-dependent α-DNA polymerase assay, that low doses of diethylstilbesterol are able to increase the tumor proliferative activity of human breast cancer in vivo (estrogenic recruitment). Three randomized trials have been carried out (one in locally advanced and two in metastatic breast cancer) comparing conventional polichemotherapy vs chemotherapy with estrogenic recruitment. Only limited advantages have been observed in these trials. Searching for new modalities of kinetic manipulation of tumors, recombinant human growth hormone has been employed in a pilot study: the preliminary results indicate that it largely enhances tumor proliferative activity, suggesting the possibility of employing a growth factor system to increase chemosensitivity.

Objective: To compare the nutritional habits among six Mediterranean countries and also with the various official recommendations and the ‘Mediterranean diet’ as originally described. Design: Cross-sectional study. Settings: Three centres in Greece, two in Italy and one in Algeria, Bulgaria, Egypt and Yugoslavia. Subjects: Randomly selected non-diabetic subjects from the general population, of age 35 - 60, not on diet for at least 3 months before the study. Interventions: A dietary questionnaire validated against the 3-Day Diet Diary was used. Demographic data were collected and anthropometrical measurements done. Results: All results were age adjusted. Energy intake varied in men, from 1825 kcal/day in Italy-Rome to 3322 kcal/day in Bulgaria and in women, from 1561 kcal/day in Italy-Rome to 2550 kcal/day in Algeria. Protein contribution (%) to the energy intake varied little, ranging from 13.4% in Greece to 18.5% in Italy-Rome, while fat ranged from 25.3% in Egypt to 40.2% in Bulgaria and carbohydrates from 41.5% in Bulgaria to 58.6% in Egypt. Fibre intake, g/1000 kcal, ranged from 6.8 in Bulgaria to 13.3 in Egypt and the ratio of plant to animal fat from 1.2 in Bulgaria to 2.8 in Greece. The proportion of subjects following the WHO and the Diabetes and Nutrition Study Group (DNSG) of the EASD recommendations for carbohydrates, fat and protein ranged from 4.2% in Bulgaria to 75.7% in Egypt. Comparison with the Mediterranean diet, as defined in the seven Country Study, showed significant differences especially for fruit, 123 - 377 vs 464g/day of the Mediterranean diet, meat, 72 - 193 vs 35g/day, cheese, 15 - 79 vs 13g/day, bread, 126 - 367 vs 380g/day. Conclusions: (a) Dietary habits of the ‘normal’ population vary greatly among the Mediterranean countries studied. (b) Egypt is closest to the DNSG recommendations. (c) Significant differences from the originally described Mediterranean diet are documented in most Mediterranean countries, showing a Westernization of the dietary habits.

Summary Background: This phase HI study was carried out to verify whether a kinetic recruitment induced with low doses of diethylstilbestrol (DES) could increase the antitumor activity of chemotherapy in patients with advanced breast cancer. Patients and methods: Two hundred fifty-eight women with metastatic breast cancer were randomized to receive chemotherapy consisting of cyclophosphamide 600 mg/sqm i.v., epidoxorubicin 60 mg/sqm i.v. and fluorouracil 600 mg/ sqm i.v. (CEF) on day 1 or DES-CEF (diethylstilbestrol 1 mg orally days 1-3 CEF on day 4) every 21 days. Patients were treated until progression or, if responsive, for a maximum of 10 courses. Results: There were no significant differences between the two treatment arms in response rates (51.3% to CEF and 49.6% for DES-CEF); median progression-free survival (9.4 months for CEF and 11 months for DES-CEF group) or median overall survival (17.3 and 20 months for CEF and DES-CEF arms, respectively). Non-hematological toxicities were superimposable in the two arms, while DES-chemotherapy was more myelotoxic. Conclusions: This trial confirms that chemotherapy preceded by estrogenic recruitment is still in an experimental phase and that, at present, it has no role in clinical practice. Further research is needed to test the possibility of combining different mitogens in the light of new information about breast cancer cell growth.

To evaluate cost-effectiveness and response predictors of treatment with recombinant interferon alpha-2a in chronic non-A, non-B hepatitis, 263 consecutive patients were enrolled in a multicenter long-term study. A pre-planned analysis aimed at identifying predictors of early response was carried out when all patients had completed the initial 3 months of treatment with 6 MU thrice weekly. Sixty-three percent of the patients enrolled were classified as responders. At multivariate logistic regression analysis, baseline gamma-glutamyltranspeptidase levels and cirrhosis were the only independent variables significantly associated with response. The risk of no response after 3 months of treatment was 3.9 times higher (95% confidence interval, 1.6 to 7.2) in patients with high baseline levels of gamma-glutamyltranspeptidase as compared with patients showing low baseline levels, and it was 2.0 times higher (1.1 to 3.8) in patients with cirrhosis as compared with those without it. We expect that results from this and other studies on large patient populations may help to select those patients who are more likely to benefit from interferon administration.

148 patients with advanced untreated colorectal cancer were randomised to receive a weekly bolus of 5-fluorouracil (5-FU) 600 mg/m2 alone, with or without leucovorin (LV) 500 mg/m2. 5-FU plus LV produced a higher response rate than 5-FU alone: 23% (5 complete response, 11 partial response) vs. 8% (2 complete response, 4 partial response) (P = 0.03) out of 70 and 72 evaluable patients, respectively. Median survival was 11 months in both groups and median time to progression was not significantly different (P = 0.08). The combined regimen was more toxic than 5-FU alone, as evidenced by (a) a higher percentage of grade 3-4 diarrhoea, 19.5% vs. 8.5% (P = 0.045) and conjunctivitis, 26.5% vs. 5.6% (P = 0.0025); (b) the recording of one toxic death in the combined arm; and (c) the reduction of the median dose intensity of 5-FU actually delivered during the first 2 months of treatment. We conclude that 5-FU plus LV at a price of a higher toxicity is more active than 5-FU alone without improving survival and progression-free survival.

Serum CA 125 was measured in 100 patients with ovarian epithelial carcinoma at diagnosis and in follow-up. Levels over 35 U/ml were found in 43 (75.4%) of 57 cases at diagnosis and in 21 (48.8%) of 43 cases in follow-up. A correlation was found between tumor burden and marker positivity: advanced Stages (III and IV) and recurrences had 84.2 and 91% of positivity, compared to 59.1% in early disease (Stages I and II). Analysis by histotype and FIGO grade revealed a difference between the mucinous type and the others and a positive association with less differentiated tumors. In the 30 patients submitted to second-look laparotomy a correlation was found between CA 125 levels and pathological response in 86.7% of cases. This ovarian cancer marker may thus be more useful in monitoring the response to treatment and in long-term follow-up than in diagnosis.

Combination of Cisplatin (CDDP) and 5-Fluorouracil (5-FU) has been shown to have an encouraging activity both in rodent tumor systems (1), and in the treatment of various solid tumors (2), particularly in head and neck carcinoma, testicular and ovarian cancer, and more recently, in bladder carcinoma.

In the last decade the chemotherapy of metastatic breast cancer has reached a plateau in terms of response rate and survival [1]. The knowledge of hormone dependency of at least a proportion of breast tumors has stimulated investigation into the possibility of improving results by combining chemo-hormonotherapy. Unfortunately many randomized clinical trials fail to demonstrate any clear advantage of such combinations [2]. One reason for this lack of potentiation could be due to the fact that tamoxifen drives cancer cells into a resting state that is a kinetic sanctuary from cytotoxic agents. On the other hand, a large amount of experimental data* has demonstrated that low levels of estrogens are able to induce kinetic recruitment of breast cancer cells [3]. Therefore, the new era of clinical studies are based on a more rational approach: estrogens are given to stimulate tumor growth so that subsequent chemotherapy can act on a larger proportion of cycling cells.

The hypothesis that the results o fsecond line hormonotherapy for breast cancer may be ameliorated with continuation of the first line has been explored in a randomized trial. Patients progressing under tamoxifen were randomly allocated to aminoglutethimide and hydrocortisone acetate with or without tamoxifen continuation. No difference has been observed between the two arms in terms of response rate and progression-free or overall survival