Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial.

From February 1983 to January 1985, 497 patients with advanced breast cancer were randomly allocated to receive either epirubicin or doxorubicin in the following combination chemotherapy regimen: fluorouracil (5-FU) 500 mg/m2 intravenous (IV) on days 1 and 8; epirubicin or doxorubicin 50 mg/m2 IV on day 1; cyclophosphamide 500 mg/m2 IV on day 1 (FEC or FAC). Cycles were repeated every 21 days until progression or to cumulative doses of 700 mg/m2 for epirubicin and 550 mg/m2 for doxorubicin. Dose reductions were applied according to the standard criteria. Activity was evaluated in 443 patients (222 in the FEC arm and 221 in the FAC arm). The two experimental groups were comparable in age, performance status, menopausal status, histology, previous treatments, and site of the disease. The overall response rate (complete response and partial response [CR + PR]) was not significantly different: 53.6% for FEC and 56.5% for FAC. The median time to progression was 273 days for FEC and 314 days for FAC; the median survival time was 591 and 613 days, respectively. Leukopenia, anemia, nausea, and vomiting were significantly lower in patients treated with FEC. As for cardiotoxicity, four cases of congestive heart failure (CHF) were recorded among patients treated with FAC while only one was observed in the FEC group. These results indicate that epirubicin in a combination chemotherapy regimen is as active as doxorubicin and is significantly less toxic.

Epidoxorubicin plus ifosfamide in advanced and/or metastatic soft-tissue sarcomas.

We undertook this phase II study to evaluate the efficacy and toxicity of epidoxorubicin and ifosfamide in the treatment of locally advanced and/or metastatic soft-tissue sarcomas. We used escalating doses of epidoxorubicin (from 60 to 75 mg/m2) on day 1 and 1.2 g/m2 ifosfamide on days 1-5. Chemotherapy courses were repeated every 3-4 weeks. A total of 16 patients--13 who had not previously been treated and 3 who had undergone prior therapy with anthracyclines--entered the study. In all, 15 patients were evaluable for response and 16, for toxicity. At least two courses of chemotherapy were given. A complete remission (CR) was seen in 1 patient, a partial remission (PR) in 5, and a minor response (MR) in 1, for an objective response rate (CR + PR) of 40% (6/15); this value reached 50% in non-pretreated patients (6/12). Stable disease (SD) was observed in 40% (6/15) of patients. The relative dose intensity of epidoxorubicin ranged from 10 to 23.3 mg/m2 (median, 16.6 mg/m2). The time to objective response ranged from 4 to 12 weeks (median, 8.5 weeks). The duration of response was 4 months for the single CR, and that for the five PRs was 6+ months (range, 4-18 months). Toxicity was evaluated according to WHO criteria in 16 patients; it was mild and consisted mainly of alopecia, nausea and vomiting, and leucopenia. In only three patients did we observe grade 3 leucopenia. In one case an ifosfamide-associated encephalopathy occurred, but it regressed after 24 h. Neither chronic nor acute cardiac toxicity was reported. In this preliminary analysis, the response rate obtained with the combination of epidoxorubicin and ifosfamide was encouraging and the toxicity was acceptable.

[Function test of renal excretion of water and sodium after water loading in liver cirrhosis]. / Esplorazione funzionale della capacità escretoria renale di acqua e sodio dopo carico idrico nella cirrosi epatica.

Water loading was used as a diagnostic test in the study of renal excretion of water and sodium during the clinical stages of cirrhosis of the liver in 25 patients free from clinical and instrumental signs of ascites, 26 with treatable ascites, and 14 with intractable ascites. The water load consisted of 20 cc/kg water administered i.v. as a 5% glucose solution. Examination of diuresis in the ensuring 5 hr showed that: 1) clearance of free water is the most sensitive parameter for the detection of patients at short-term risk for the onset of ascites; 2) very low urinary sodium is an indicator of refractory ascites, whereas values are virtually the same and higher in subjects without ascites or with treatable forms; 3) chloruresis in only reduced significantly in cirrhosis with refractory ascites.

[Ferritin, CEA and TPA as tumor markers in breast neoplasms]. / Ferritina-CEA-TPA come markers neoplastici nelle neoplasie mammarie.

In order to assess the sensitivity and specificity of Ferritin, CEA and TPA as neoplastic markers in breast carcinomas, 91 patients all classified according to the TNM-UICC system were studied in a cancer clinic. The results of the analyses indicate that ferritin is apparently only influenced by the presence of metastatic neoplasias and that greater sensitivity is obtained if all three markers are employed simultaneously.

[The renin-angiotensin-aldosterone system in liver cirrhosis]. / Il sistema renina-angiotensina-aldosterone nella cirrosi epatica.

The role of the RAA system in the genesis of ascites in liver cirrhosis patients is not yet perfectly clear. The present study was conducted on 176 cirrhosis patients in order to investigate RAA system function, to assess the changes taking place in the various stages of the disease and to correlate such changes with the various kidney function parameters. The patients were divided into 3 groups as follows: Group I: patients without ascites on admission and with no history of the condition; Group 2: patients with ascites of recent onset and/or response to diuretic treatment; Group 3: patients with ascites not responsive to diuretic treatment. In Group 1, 19 patients (38%) reveal a significant reduction in renin activity together with portal hypertension and increased hydrosaline retention. In Group 2 renin activity was reduced in 4 patients (6%), aldosterone activity in 3 (4%). Progressive deterioration in liver function parameters and progressive activation of the RAA system combined with reduced sodiuria content were found in over 50% of these patients. The presence or absence of portal hypertension in this group was not related to significant changes in diuresis or sodiuria. In Group 3 renin was activated in 54 patients (89%), aldosterone in 58 (95%) and there was also a distinct reduction in sodiuria (96% of patients) and chloruria (100%). A substantial increase was also noted in the incidence of low blood sodium (53%) while portal hypertension was found in 97% of patients. On the basis of those data it may be hypothesised that high pressure inside the liver creates the stimulus for primary sodium retention. The decrease in effective blood volume after vasodilation, accentuated by low blood albumin and splanchnic venous stagnation may the stimulate the sympathetic nervous system and RAA system. Hyperaldosteronism only becomes the dominant factor in renal imbalance when the cirrhosis reaches the resistant ascites phase.

[Changes in antidiuretic hormone (ADH) in liver cirrhosis with resistant ascites]. / Modificazioni dell'ormone antidiuretico (ADH) nella cirrosi epatica con ascite resistente.

The pathogenetic role of ADH in determining hyponatremia in patients with liver cirrhosis is still much debated. Osmotic stimuli are not able to inhibit secretion of ADH in refractory ascites and under such conditions the reduction in effective plasma volume has been put forward as the main cause. Twenty patients with liver cirrhosis and refractory ascites were studied before and during extraction-concentration-reinfusion (ECR) of ascitic fluid by means of Rhodiascit. ADH, renin, aldosterone, blood and urine osmolarity, plasma and urinary concentration of sodium, potassium, chlorine, and the clearance of free water were evaluated. All patients presented high renin values (15.4 +/- 11.7 ng/ml), aldosterone (341 +/- 172 ng/ml), ADH (6.3 +/- 5.2 pg/ml). During ECR, a significant drop was observed in renin (p less than 0.001), aldosterone (p less than 0.001) urinary osmolarity (p less than 0.001) and an equality significant increase in diuresis (p less than 0.001), natriuria (p less than 0.005), kaliuria (p less than 0.001) while ADH presented an irregular course: in 11 cases it remained unchanged, in 3 it fell and in 6 it presented a constant increase. To conclude, data suggest that the diminished filtrate reaching the distal tubule constitutes the greatest cause of the inability to dilute urine in many patients with cirrhosis and that ADH is a permissive rather than a primary factor.

[Study of blood ferritin in cancer patients and its possible use as an indicator of an unfavorable prognosis]. / Studio della ferritinemia in pazienti neoplastici e sua possibile utilizzazione come indice prognostico sfavorevole.

Ferritinaemia levels were measured in 97 neoplastic patients and compared with the levels found in a healthy control group, in order to discover whether ferritinaemia had any significance as a neoplastic marker. Higher levels were encountered in all neoplastic patients (P less than 0.005) than in the control group. Levels were particularly high in the patients with metastasised tumours (especially breast cancer: P less than 0.001). The highest ferritinaemia levels were found in terminal patients (P less than 0.001).

Bi-weekly docetaxel and gemcitabine regimen in her-2-negative and anthracycline-pretreated metastatic breast cancer patients: a multicenter phase II trial.

PURPOSE: Bi-weekly gemcitabine (G) in combination with docetaxel (D) is an effective treatment for metastatic breast cancer (MBC) previously treated with adjuvant/neoadjuvant anthracyclines containing regimens with a good toxicity profile. In the present phase II study, we investigated the activity of the same regimen as first-line treatment. METHODS: Women with breast cancer pretreated in adjuvant/neoadjuvant setting with anthracyclines received bi-weekly G (1,250 mg/m² days 1, 15) and D (50 mg/m² days 1, 15) every 28 days with restaging after 3 and 6 cycles. RESULTS: Overall 42 patients were enrolled. Median age is 48 years (range, 31-71 years). Eight patients (19%) achieved complete responses, 18 (43%) partial responses for an overall response rate (ORR) of 62%; five patients (12%) obtained stable disease (SD), and 8 (19%) patients had progressive disease (PD). After a median 17-month follow-up, the median time to disease progression was 12 months (95% CI, 3-26 months) and the median survival time was 27 months (95% CI, 4-57 months). No grade 4 toxicity was seen except in one patient who developed a grade 4 neutropenia. Grade 3 toxicities were leukopenia (2%), neutropenia (14%), anemia (2%), nausea and vomiting (2%), diarrhea (2%), asthenia (2%), and skin toxicity (12%). CONCLUSION: The GD bi-weekly regimen is well tolerated and active as first line in anthracyclines-pretreated women with MBC. It appears as an interesting alternative compared to a 3-week schedule whenever hematological toxicity is the main clinical concern.

Megestrol acetate plus alpha 2a interferon as second line therapy for postmenopausal patients with advanced breast cancer: results of a multicentric phase II trial.

This phase II study was aimed to evaluate the activity of a combination of megestrol acetate (MA) and alpha 2a interferon (IFN) in a group of tamoxifen-responsive breast cancer patients. Thirty patients with metastatic breast cancer either previously treated with adjuvant tamoxifen for at least 24 months or treated with tamoxifen for metastatic disease and showing an objective response or stability of disease, were given MA (single daily dose of 160 mg per os) and alpha 2a IFN (3 million units-MU-three times per week intramuscularly-i.m.-). Of the 29 evaluable patients, 2 (6.8%) achieved a complete response and 4 (13.8%) a partial response for an overall response rate of 20.6% (95% confidence limits = 5.9%-35.4%). Treatment toxicity was mild and no patient had to discontinue or delay the treatment due to IFN side effects. Our results seem to rule out that alpha 2a IFN is able to improve the activity of MA as second-line therapy in tamoxifen-responsive patients.

Adjuvant chemotherapy in the treatment of colon cancer: randomized multicenter trial of the Italian National Intergroup of Adjuvant Chemotherapy in Colon Cancer (INTACC).

BACKGROUND: To determine whether the addition of leucovorin to the combination 5-fluorouracil plus levamisole prolongs disease-free survival and overall survival in patients with radically resected colon cancer (Dukes' B(2-3) and C). PATIENTS AND METHODS: Patients (1703) were accrued between March 1992 and February 1995 in a large-scale clinical trial within five Italian cooperative groups. After stratification for center, patients were randomized as follows: arm A, 5-fluorouracil [450 mg/m(2) intravenous (i.v.) bolus on days 1-5] and levamisole (150 mg orally for 3 days, every 14 days for 6 months) versus arm B, 6-S-leucovorin (100 mg/m(2) i.v. bolus on days 1-5) followed by 5-fluorouracil (370 mg/m(2) i.v. bolus on days 1-5), plus levamisole (as arm A), every 4 weeks for six cycles. RESULTS: After a median follow-up of 6.4 years no significant difference was seen for either disease-free survival (58% versus 60%, not significant) or 5-year overall survival (68% versus 71%, not significant), respectively. Gastrointestinal toxicity (World Health Organization grade 3/4) was more frequent in arm B (8% versus 18%, not significant). CONCLUSIONS: In this trial the schedules used showed no statistically significant differences in terms of disease-free survival or overall survival in the treatment of colorectal cancer.