The combination of 4-epi doxorubicin (4-epi-DX) and 5-fluorouracil (5-FU) versus 5-FU alone was studied in previously untreated patients with metastatic gastric and rectosigmoid cancer. 5-FU alone was administered at the dose of 12mg/kg/day i.v. on days 1, 2, 3, 4 and 5 every 3–4 weeks. The combination regimen included 4-epi-DX 40 mg/m²/day i.v., on days 1 and 2 (80 mg/m²/cycle) and 5-FU administered as in the single-agent schedule, but at a somewhat lower dose (10 mg/m²/day i.v. on days 1, 2, 3, 4 and 5). Sixty-two patients with gastric cancer were evaluable, 30 in the 5-FU group and 32 in 4-epi-DX + 5-FU group. The results showed 6 partial remissions out of 30 patients treated with 5-FU alone (response rate 20%) with a median remission duration of 4 months. With 4-epi-DX + 5FU the response rate was 41% (13/32) with 1 complete and 12 partial remissions. The median remission duration was 8 months. The difference in treatment results was statistically significant (p <0.05). In rectosigmoid cancer the group on 5-FU included 26 patients who showed a response rate of 19% (5/26). 4-epi-DX + 5-FU resulted in 6 responses (2 complete remissions, 4 partial remissions) out of 27 patients treated (22%). Median remission duration in the 5-FU group was 3 months whereas it was 6 months in the 4-epi-DX + 5-FU group. Toxicity was mild and well tolerated in both treatment modalities. The results of the study in gastric cancer showed a clear-cut superiority of 4-epi-DX + 5-FU over 5-FU alone, while no difference in response rate was observed between the two approaches in rectosigmoid cancer. Nevertheless, rectal localization of primary tumors showed a slightly better response to 4-epi-DX + 5-FU (33 vs. 16%).

4'-Epi-doxorubicin, one of the analogs of doxorubicin, was shown in experimental animal tumor models to have a wide spectrum of antitumor activity. In comparison, its toxic side effects were less prominent than those of doxorubicin. Results of the first phase-I and II clinical trials in human tumors have confirmed experimental data. The aim of our study was to carry out a broad phase-II clinical trial mainly in various types of primarily chemoresistant solid tumors to obtain further information on the antitumor activity spectrum and toxicity of 4'-epi-doxorubicin. Ninety-two patients, 55 males and 37 females aged from 32 to 75 with an average age of 51 years, were available for the study. Karnofsky performance status was not less than 50. Previous chemotherapy was recorded in 33 patients. The drug was administered at doses of 40 mg/m2 i.v. daily for 2 days in the first 25 patients and, in all other patients, the dosage was increased to 50 mg/m2 i.v. daily for 2 days (100 mg/m2/cycle). The overall response was registered in 18 (seven complete, 11 partial remissions) out of 92 patients (20%). Regarding tumor types, the response was observed in 2/15 lung, 4/15 stomach, 3/14 colorectal, and 5/13 breast cancers. No response was observed in 11 patients with melanoma and five with hypernephroma. Toxicity was mild (myelosuppression, gastrointestinal toxicity, cardiotoxicity) and tolerable for the patients. On the basis of these results, we could conclude that 4'-epi-doxorubicin is an active antitumorigenic agent in breast cancer and in stomach, rectal, and small-cell lung tumors. These results justify further clinical investigation of this compound especially in combination chemotherapy treatment.

Forty-eight patients with metastatic breast cancer previously treated with cytostatics (except anthracyclines) underwent peroral treatment with 4-demethoxydaunorubicin (4-DMDR), a new daunorubicin analogue. Forty-three patients received >2 cycles and have been evaluated. The mean age was 54 years, with 10 premenopausal and 33 postmenopausal patients. All the patients showed progresssive disease. Performance status 0–2 (ECOG score) was recorded in 34, and 3 in 7 patients. Soft tissue metastases were recorded in 23, visceral in 10 and bone in 10 patients. 4-DMDR was administered in the dose of 15 mg/m2 perorally daily, on day 1, 2 and 3 (45 mg/m² per cycle). Since there was no severe toxicity, after 2 cycles the dosage was increased to 60 mg/m2 per cycle. The patients received 2–6 cycles (median 3) and the total cumulative dose ranged from 90 to 300 mg/m2 (median 140 mg/m²). Objective response was observed in 10 patients (1 complete remission, 9 partial remissions) with a response rate of 23% (10/43). Soft tissue metastases were most responsive (8/23–35%). Two responses were observed in visceral organs. Response lasted 2–6+ months (median 4 months). Toxic side effects have been mild with myelotoxicity (grade I–II) observed in 23% of patients. Alopecia (grade 1–15 patients, grade II and III = 4 patients) was moderate. Nausea and vomiting (grade I–II) was present in 60% of patients. In all the patients MUGA scans (left ventricular ejection fraction) were in normal range, however, reversible ECG changes have been recorded in 4 patients (grade 1 = 3, grade II = 1). All the changes appeared on the 3rd day of the cycle but became normal before starting a new cycle. In conclusion, it should be emphasized that 4-DMDR administered perorally (45 mg/m² per cycle) in previously treated (except anthracycline) metastatic breast cancer patients showed antitumor efficacy with a low incidence of toxic side effects. Further clinical studies, possibly with the dose escalation in the schedule we have used, will be needed in previously untreated breast cancer patients to determine exact antitumor activity of this new daunorubicin analogue.

Phase II studies of p.o. Idarubicin administration, a new daunorubicin analogue (4-demethoxy-daunorubicin), have shown antitumor activity in 23%-31% of previously treated metastatic breast cancer patients, while in untreated patients a response rate of 41% was observed. Our Phase II study has shown an overall response of 23% [1 complete response (CR), 9 partial response (PR), 10/43] with a daily dose of 15 mg/m2 p.o. on days 1,2,3. On the basis of these results we have recently included Idarubicin in combination chemotherapy of breast cancer, substituting Adriamycin by Idarubicin in an FAC schedule. Of 50 consecutive metastatic breast cancer patients who entered the study, 42 patients who received greater than 2 cycles were evaluable. There were 22 premenopausal and 20 postmenopausal patients (mean = 51 years). In 25 patients a performance status of 0-2 (ECOG) was registered and in 17 patients it was 3. Previous radiation had been administered in 34, hormonal therapy in 18, and adjuvant chemotherapy (CMF 5, CMFVP 3) in 8 patients; 22 patients had predominant metastatic sites in soft tissues, 18 in visceral organs, and 2 in the bones. The FIC schedule was administered as follows: 5-fluorouracil 500 mg/m2 i.v. days 1 and 8, Idarubicin 15 mg/m2 p.o. days 1, 2 and 3, and cyclophosphamide 500 mg/m2 i.v. day 1. An objective response was observed in 23 (5 CR, 18 PR) out of 42 patients (53%, CR 12%). Soft tissue metastases responded in 55% (12/22), visceral organs in 61% (11/18), and no response was observed in bone lesions (0/2). The median remission duration was 8 months (3-16+). Toxicity was mild, expressed mainly in the form of nausea/vomiting, grade I and II in 64% of the patients. Alopecia was very mild (grade I and II in 23% of the patients). Leukopenia grade I-II was observed in 21% of the patients. In 4 patients reversible ECG changes occurred. Left ventricular ejection fraction did not show any pathological changes. The Idarubicin-containing combination chemotherapy we have used has the following characteristics: easier administration (p.o. anthracycline, no risk of tissue extravasation), lower toxicity (cardiotoxicity, alopecia, and myelosuppression in particular), and a notable antitumor activity.

Based on favorable results we reported earlier with the CAP regimen in breast cancer (CAP vs CMFVP), the present study compared the CAP with the FAC regimen, which is so far one of the most active adriamycin containing chemotherapy regimens in breast cancer. The aim of the study was to find the optimal first line treatment and possibly evaluate the role of cis platinum in breast cancer chemotherapy. The CAP schedule consisted of cyclophosphamide 200 mg/m2 i.v. days 1, 3 and 5, adriamycin 40 mg/m2 i.v. day 1, and platinum 30 mg/m2 i.v. day 1, 3 and 5. The FAC schedule included 5-FU 500 mg/m2 days 1 and 8, adriamycin 50 mg/m2 day 1, and cyclophosphamide 500 mg/m2 day 1. One hundred and twenty-six previously untreated patients received greater than 2 cycles and were evaluated. In the CAP arm 15 complete (26%) and 24 partial remissions were observed, resulting in a 67% overall response rate (39/58). The response in soft tissue and visceral organs was notable (78% - 22/28, 71% - 15/21) with an important complete response rate (32%). In the FAC arm there was an overall response in 41% (28/68) of patients, with 8 complete (12%) and 20 partial responses. The difference in overall response, complete response, and response in soft tissue and visceral organs, was statistically significant in favor of the CAP arm (P less than 0.005). Concerning bone metastases there was no difference between the two schedules in response rate, nor in the median remission duration (CAP 11, FAC 10 months). In spite of a somewhat longer median survival in the CAP group, the difference (13 months vs 9 months) was not statistically significant (P = 0.10). Toxicity was moderate and tolerable in both regimens with more pronounced myelosuppression and vomiting in the CAP group. Compared with the FAC schedule the platinum containing combination chemotherapy (CAP) showed higher antitumor activity with no reflection on remission duration and survival.