Adriamycin, cyclophosphamide, ftorafur and tamoxifen (ACFT) in patients with advanced breast cancer

One hundred and six patients with advanced breast cancer were treated with chemoendocrine therapy consisting of adriamycin (40 mg/m2) i.v. on day 1 and cyclophosphamide (130 mg/m2) i.v. daily for 5 days every 3 weeks, ftorafur (500 mg/m2) and tamoxifen (40 mg) orally daily. Of 82 evaluable patients, 16 showed complete response (20%), 32 partial response (39%), 32 no change (39%), and two progressive disease (2%). The overall response rate was 59%, and the median duration of response was 16.3 (3.5-67+) months with a median survival time from the start of chemoendocrine therapy of 25.5 (3.5-67+) months. The median survival time of responders (32.5 months) was significantly longer than that of non-responders (15.3 months). The major toxicities were hair loss, G1 symptoms, and hematological toxicity, but these were clinically well tolerated. No serious cardiac, renal or liver damage was seen. These results indicated that the addition of tamoxifen to the ACF regimen increased the number of complete responses and prolonged the survival time of responders.     

Chemohormonal therapy for advanced breast cancer with tamoxifen, adriamycin, and cyclophosphamide (TAC)

Combined chemohormonal therapy is an attractive therapeutic strategy for the treatment of Stage IV breast cancer. Between 1977 and 1979, the authors evaluated a new chemohormonal therapy program in 63 evaluable women with advanced breast cancer who previously had not received cytotoxic chemotherapy or tamoxifen. The chemohormonal therapy consisted of 21- to 28-day cycles of tamoxifen (10 mg orally twice daily), Adriamycin (doxorubicin) (40 mg/m2 intravenously on day 1) and cyclophosphamide (200 mg/m2 orally on days 3-6) (TAC). Objective responses were observed in 82% of the patients (22% complete response, 60% partial response). With a median follow-up of 104 weeks (2 years), the median relapse-free survival for the 52 responding patients was 80 weeks. The median survival for the entire group of 63 patients was 118 weeks. Eleven pretreatment patient characteristics were evaluated via univariate and multivariate analysis to determine their effect on response and survival. Prognostic factors with a significant association with longer survivals were as follows: a lack of soft tissue involvement, a lack of pleural involvement, and a long disease-free interval (DFI). Estrogen receptor (ER)-unknown patients, being composed primarily of postmenopausal patients with a long DFI and single-organ involvement (primarily bone), comprised 62% of the patient population and achieved a survival similar to the smaller number of ER-positive patients and was superior to the survival of ER-negative patients. Toxicities were recorded on all patients and overall the treatment was well tolerated. Combined chemohormonal therapy with TAC resulted in a high objective response rate and a long median survival. This study would support additional trials of chemohormonal therapy in patients with ER-positive tumors or in those whose tumors are likely to be ER-positive (e.g., postmenopausal patients with long DFIs).     

Combined chemoendocrine therapy using adriamycin,cyclophosphamide and high dose toremifene in patients with recurrent breast cancer

We studied a new chemoendocrine therapy against recurrent breast cancer in order to evaluate its efficacy and toxicity. Sixteen eligible patients were treated with the therapy consisting of adriamycin/cyclophosphamide (AC) plus toremifene (TOR). Adriamycin (20 mg/m2) was administered intravenously on days 1 and 8, and cyclophosphamide (100 mg/body) was given orally on days 1 to 14 every 4 weeks. TOR (120 mg/day) was given orally daily. The median age of the patients was 52 years; 6 were premenopausal and 10 postmenopausal. As post-operative adjuvant therapy, anthracycline chemotherapy and tamoxifen were given to 4 and 9 patients, respectively. AC therapy was administered for 8.5 cycles (median). Four complete responses (25%), 8 partial responses (37.5%), 4 no change (25%) (including 2 long NC), and 2 progressive disease (12.5%) were obtained, for an overall response rate of 62.5%. The median duration of time to progression and survival were 13.2 months (0.7-30.4 months) and 22.8 months (13.7-44.8 + months), respectively. The frequent toxicities were leukopenia, nausea/vomiting, and alopecia, but these were clinically well tolerated. Our results suggest that the addition of high dose TOR to AC therapy is useful in the treatment of recurrent breast cancer.     

Adjuvant chemotherapy with adriamycin, fluorouracil, cyclophosphamide, methotrexate, with or without tamoxifen in operable breast cancer

Between January 1982 and February 1985, 70 breast cancer patients with histologically confirmed axillary node involvement and T1-3a were treated following surgery with a combination of adriamycin, fluorouracil, cyclophosphamide, methotrexate, with or without tamoxifen according to the estrogen and progesterone receptors state. At 60 months of study (median follow-up, 41 months), the estimated proportion remaining disease-free was 62%. The estimated survival rate was 81%. A comparison of the actuarial disease-free and overall survival with data reported in the literature indicates a similar positive effect of adjuvant systemic therapy as described in adjuvant studies using polychemotherapy regimens. Patient acception of chemotherapy regimen was generally good. This can be accounted for because of an adequate emesis control and real compliance of the patients with the oncologist.     

A combined chemo-endocrine therapy with tegafur, adriamycin, methotrexate and tamoxifen for advanced renal cell carcinoma

Six patients with advanced renal cell carcinoma was treated with a new chemo-endocrine regimen consisting of Tegafur, Adriamycin, Methotrexate and Tamoxifen. Estrogen receptor was measured in four cases from renal or metastatic tumors by DCC method, presenting 14.7, 9.7, 1.0 and 0 f moles/mg protein respectively. The patients were medicated with 800-1,200 mg of Tegafur and 20 mg of Tamoxifen daily po, and 20 mg of Adriamycin and 10 mg of Methotrexate intermittently for two weeks interval iv. According to a criteria of Japan Society for Cancer Therapy, two were regarded as CR, one as PR, one as NC and two as PD. The one out of two cases with and without estrogen receptor responded favourably to this therapy. Side effects observed in the treatment were mild gastrointestinal disorders including nausea and vomiting, slight degree of leukopenia, stomatitis, pigmentation and liver dysfunction. The patients were found to be in good quality of life during the treatment because of less toxicity. This therapy can be regarded as a good modality for a treatment of advanced renal cell carcinoma. This is a first report of combined chemo-endocrine therapy with Tegafur, Adriamycin, Methotrexate and Tamoxifen for renal cell carcinoma in the world.     

A patient with hepatic metastasis of breast cancer successfully treated with combined chemoendocrine therapy using epirubicin, tegafur and tamoxifen]

A solitary 1 cm sized metastatic lesion was found in the S5 region of the liver on a postoperative ultrasound screening of a 52-year-old breast cancer patient. It was confirmed by CT, MRI and hepatic angiography. At first, she was successfully treated with trans-arterial pirarubicin and lipiodol infusion but a metastatic lesion of similar size was found 6 months later in the same region. We then administered a triple 20 mg dose of epirubicin intravenously, and 450 mg of UFT and 30 mg of tamoxifen daily. Six months later the lesion had disappeared on US and CT scans and a complete remission has persisted for 18 months.     

A study on the efficacy of combination chemoendocrine therapy consisting of cyclophosphamide, adriamycin, UFT, and tamoxifen for advanced or recurrent breast cancer]

The efficacy of the combination chemoendocrine therapy CAUT against advanced and recurrent breast cancer was examined. One course of this therapy lasted 3 weeks and consisted of adriamycin (i.v.) at 30 mg/m2 on day 1, cyclophosphamide (p.o.) at 65 mg/m2 and UFT (p.o.) at 300 mg/m2 on days 1-14, and tamoxifen (p.o.) at 20 mg/body on days 1-21. Twenty patients were enrolled, of whom 19 were eligible including seven with advanced cancer and 12 with recurrent cancer. One patient achieved CR, ten PR, three NC, and five PD, for a response rate of 58% (95% CI: 29-87%). The response rates according to type of lesion were 73% (8/11) for the soft tissue, 38% (3/8) for the bone, 20% (1/5) for the lungs and pleura, and 50% (2/4) for the liver. Adverse events with a severity of grade 3 or more included a reduction in WBC in six patients (31.6%), a reduction in RBC in one (5.3%), alopecia in four (21.1%), and severe general fatigue in one (5.3%). One patient experiencing a grade 4 reduction in WBC, and one of five patients experiencing a grade 3 reduction with a fever, recovered after treatment with G-CSF. The other four patients recovered following suspension of administration. This therapy is considered useful, exhibiting a high response rate and relatively slight adverse effects.     

Vincristine, adriamycin, mitomycin-C and UFT (VAM-UFT) therapy in progressive or recurrent breast cancer

Since June 1984, 23 cases of progressive or recurrent breast cancers were treated with combination chemotherapy of VAM-UFT consisting of vincristine, adriamycin, mitomycin C and UFT. Clinical effects of VAM-UFT therapy were 3 CR, 12 PR, and the response rate was 65.2%. Its effective interval was 3 months. But the patients treated with over 4 cycles of VAM-UFT therapy showed an 85% response rate, with a 5-month effective interval. In each patient's background, a shorter disease free interval tended to be more highly effective, but other factors were not significant. Scirrhous carcinoma of pathology evidenced slightly high response rate. Compared with the survival time of patients treated with under 3 cycles and over 4 cycles of this therapy, the latter was significantly longer. Toxicity involved leukocytopenia (74%), thrombocytopenia (22%), anemia (30%), alopecia (91%), nausea and vomiting (87%) and stomatitis (35%), but cases in which the treatment was stopped were not observed. Therefore VAM-UFT therapy had a highly therapeutic effect, reflected in an 85% response rate, for progressive or recurrent breast cancers.     

Combination chemotherapy with adriamycin and cyclophosphamide for advanced breast cancer.

Fifty-five consecutive women with advanced breast cancer were treated with a combination of adriamycin (40 mg/m2 administered intravenously on day 1) and cyclophosphamide (200 mg/m2/day given orally in divided doses for 4 days on days 3-6). Courses were repeated at 21-28-day intervals. The mean age for the 55 patients was 55 years (range, 37-77 years); 20% of the patients were 65 years or older. All patients were evaluable. Objective response (at least a 50% decrease in the size of all measurable lesions lasting for at least 1 month) was noted in 40 (80%) of the 50 patients who received an adequate trial of chemotherapy (a minimum of two courses). Six of the 40 responses observed were complete. The median duration of response was 10 months. Actuarial survival for the entire group of 55 patients was 80% at 6 months after initiating chemotherapy and 70% at 12 months. Survival for the 40 responding patients was 95% at 6 months and 80% at 12 months. Response rates by site of involvement were: soft tissue, 20/25 (80%); lymph node, 15/19 (79%); bone, 21/25 (84%); lung, 15/18 (83%); pleural effusion, 6/8 (75%); and liver, 7/10 (70%). Eighty-three percent of the responses were apparent after two courses of treatment and 98% were apparent after four courses. Toxicity was acceptable and included nausea, myelosuppression, alopecia, and reversible congestive heart failure (in 2 patients who received 550 mg/m2 of adriamycin). Chemotherapy with adriamycin and cyclophosphamide proved to be safe and effective for out-patient treatment of advanced breast cancer.     

Ftorafur, adriamycin, cyclophosphamide and BCG in the treatment of metastatic breast cancer.

Ftorafur is a 5-fluorouracil analogue which is slowly metabolized to 5-FU, resulting in prolonged therapeutic levels of this latter drug. Ninety-one evaluable patients with metastatic breast cancer were treated with Ftorafur, Adriamycin, cyclophosphamide, and BCG (ACFTOR-BCG), in an attempt to increase the effectiveness of the program or decrease its myelosuppressive toxicity. The results of this trial were compared to those previously reported with the combination of 5-FU, Adriamycin, cyclophosphamide, and BCG (FAC-BCG). Overall objective response rates were 65% and 76% for ACFTOR-BCG and FAC-BCG, respectively. Durations of response were 12 months and 14 months for ACFTOR-BCG and FAC-BCG (p = 0.53). The median survival of responders was 22 and 23.9 months, respectively. Substantial toxicity was observed with Ftorafur: nausea and vomiting severe enough to cause weight loss was observed in a substantially higher fraction of the patients treated with this drug than with 5-FU. Other side-effects, which were not observed with the 5-FU combination, were somnolence, dizziness, personality changes, tremor, ataxia, and confusion. No differences in myelosuppressive toxicity were observed between the two combinations, and the incidence of infectious complications was identical. The combination of Ftorafur, Adriamycin, cyclophosphamide and BCG did not offer any advantages with respect to increased effectiveness or reduced toxicity over the FAC-BCG regimen in breast carcinoma.     

Combination chemo-endocrine therapy of metastatic and stage IV breast cancer with cyclophosphamide, adriamycin, prednisolone and tamoxifen (CAPT)--with special reference to management of brain and liver metastasis

Sixty-three evaluable patients with metastatic and stage IV breast cancer who had not previously undergone chemo-endocrine therapy were treated with a combination chemoendocrine therapy regimen consisting of cyclophosphamide 100 mg p.o. every day, adriamycin 10 mg i.v. on day 1 to 5, prednisolone 10 mg or 20 mg (20 mg was given on day 1 to 5) p.o. every day, and tamoxifen 20 mg p.o. every day. Adriamycin on day 1 to 5 was repeated three times every two weeks. After a total dose of 150 mg of adriamycin, the patients were changed to maintenance therapy consisting of cyclophosphamide 100 mg p.o., prednisolone 10 mg p.o. and tamoxifen 20 mg p.o. every day. After 72 months of the treatment there were 61 patients good for evaluation, 13 patients achieved a complete response (21.3%) with a median survival of 30.5 months and 18 patients had a partial response (29.5%) with a median survival of 21.0 months, and 30 patients failed to respond (49.2%) with a median survival of 8.5 months. There was a significant difference in survival time between responders (CR + PR) and non-responders (NC + PD) (p less than 0.001). Responses by site were seen in lung 10/18 (55.6%), liver 3/6 (50.0%), brain 2/4 (50.0%), bone 6/17 (35.3%) and soft tissue 14/24 (56.3%). A Satisfactory response for brain and liver metastasis, which are usually viewed as a sign of grim prognosis, was obtained similar to other sites of metastasis. Retreatment with CAPT, which was attempted in patients with secondary brain metastasis who responded to CAPT for initial brain metastasis, was uniformly effective. High ration of androgen to corticosteroid, positive estrogen receptors, long disease-free survival (over two years), premenopausal, high Broca' index (above 110) resulted from the chemo-endocrine therapy regimen CAPT. Toxicity was minimal and consisted of nausea, vomiting, alopecia and leucopenia.     

Long-term adjuvant tamoxifen therapy for breast cancer

Tamoxifen (ICI46,474) is a competitive inhibitor of estrogen action which has found ubiquitous application in the treatment of breast cancer. The drug is the front line endocrine therapy for breast cancer and is the proven treatment of choice for the adjuvant therapy of postmenopausal women with node-positive disease. Tamoxifen is available for the treatment of premenopausal patients with advanced disease, and is being evaluated in clinical trials as an adjuvant therapy for premenopausal patients with either node-positive or node-negative disease. Laboratory studies demonstrate that tamoxifen is a tumoristatic agent and long-term treatment strategies (chemosuppression) should be considered to apply the antiestrogen to its maximal therapeutic advantage. Optimal therapy with tamoxifen may also be achieved by treatment strategies to lower circulating estrogen levels in the premenopausal patient.Tamoxifen is a well tolerated drug, and long-term therapy does not appear to induce metabolic tolerance. Concerns about premature osteoporosis or cardiovascular disease appear to be unfounded because tamoxifen has an appropriate level of target site-directed estrogenic activity. Isolated reports about the growth or appearance of endometrial carcinoma during long-term adjuvant tamoxifen therapy must be balanced against the risks of withholding treatment to patients with a fatal disease.     

5-Fluorouracil, adriamycin and cyclophosphamide combined with high-dose medroxyprogesterone acetate in advanced breast cancer

Seventy-six patients with metastatic breast cancer were treated with fluorouracil, adriamycin (doxorubicin) and cyclophosphamide (FAC) plus high-dose medroxyprogesterone acetate (HD-MPA). MPA was given for 21 days at the dose of 500 mg/day i.m., then on a randomized basis, either 500 mg/week i.m. (FAC+HD-MPA i.m.) or 300 mg/day p.o. (FAC+HD-MPA p.o.). Objective response rates were 79% in 39 patients on FAC+HD-MPA i.m. and 73% in the 37 patients on FAC+HD-MPA p.o. There was no significant difference in the median duration of response and median survival for the 2 regimens (respectively, 17 months and 22 months, and 15 months and 21 months for FAC+HD-MPA i.m. and FAC+HD-MPA p.o.). Toxicity was mild and similar in both groups. Although FAC+HD-MPA was highly effective, at present it is difficult to select which regimen provides the best initial treatment for metastatic breast cancer.     

Combination chemoimmunotherapy of metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, and BCG.

One hundred and five patients with metastatic breast cancer were treated with 5-fluorouracil, Adriamycin, cyclophosphamide and BCG (FAC-BCG). The results were compared to those observed in a group of 44 patients treated with FAC chemotherapy alone. Although the overall response rates were similar (76% for FAC-BCG and 73% for FAC), the duration of remission was of 9 months for FAC and 14 months for FAC-BCG (p = 0.04). Similarly, survival or responding patients treated with FAC-BCG was significantly longer (24 months) than that observed in the chemotherapy alone treated group (15 months). There was no difference in survival or duration on study for non-responders. Response rates were not influenced by dominant site of disease, menopausal status or disease-free interval. The duration of remission and survival, however, were significantly longer for patients with bone and soft tissue involvement than for patients with visceral metastasis. Similarly patients with 1 or 2 metastatic sites survived significantly longer than those with more than 3 organ sites involved (p = 0.02). This chemotherapeutic combination is highly effective in inducing remissions. In addition, nonspecific immunotherapy with BCG appears to prolong duration of remission and survival for responding patients.     

A randomized trial of adriamycin,cyclophosphamide, ftorafur (ACF) and adriamycin,cyclophosphamide, ftorafur,methotrexate (ACFM) in patients with advanced breast cancer

Summary A prospective randomized trial was conducted comparing the clinical response of 60 patients with advanced breast cancer to a combination of adriamycin, cyclophosphamide, and oral ftorafur (ACF), or to a combination of ACF plus methotrexate (ACFM). The response rate was 12 of 28 (43%) in ACF and 18 of 30 (60%) in ACFM. Responses were seen more frequently in patients in whom fewer than two organs were involved, and responses at dominant metastatic sites were equal for the two arms. The response duration was 21+ (3.5–49.5+) months with ACF, as against 6.9 (1.9–30.8+) months with ACFM (P<0.05). The median survival time from start of therapy was 20.8+ months for ACF, while that for ACFM was 13+ months (statistically not significant). The major toxicities were hair loss, GI toxicity, and leukopenia. The response rate with ACFM was higher than that with ACF, but the addition of methotrexate to ACF did not increase the complete response rate or prolong response duration.