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Fifty-two patients with locally advanced primary breast cancer (T3, T4, N2, N3) but no evidence of distant metastases were treated with three cycles of combination chemotherapy. The regimen consisted of 5-fluorouracil, Adriamycin, cyclophosphamide, and Bacillus Calmette-Guerin (FAC-BCG), followed by local therapy (simple mastectomy and/or radiotherapy to the breast/chest wall and the regional lymphatic system) and adjuvant chemotherapy for two full years. The results were compared with those in an historical control group of 52 patients matched for initial stage of disease who were treated by a simple mastectomy and postoperative radiotherapy only. Forty-nine (94%) of 52 FAC-treated patients and 48 (92%) of the control patients became free of clinically detectable disease. At the median follow-up time of 56 months, 37.5% of the FAC-treated patients and 19.5% of the control patients had remained free of disease. FAC-treated patients who completed 2 years of therapy and in whom adjuvant chemotherapy was started promptly after local treatment had a 48% disease-free survival rate of 4 years. In those in whom the initial manifestation was supraclavicular involvement, the estimated 5-year disease-free survival rate was 42% for patients treated with FAC and 9% for control patients. There were local recurrences in 25% of FAC-treated patients and 23% of control patients (not significant). Distant metastases developed in 50% of FAC-treated patients and 77% of control patients (p less than 0.01). The median disease-free interval was 25 months in the FAC-treated group and 11 months in the control group (p = 0.025). The greatest improvement in prognosis was in patients with supraclavicular involvement; the median disease-free survival was 26 months in FAC-treated patients and 6 months in the control group (p = 0.007). This multimodal approach effectively renders the majority of patients with locoregionally advanced breast cancer free of disease and prolongs the disease-free survival period.

The method of administering BCG by scarification is described in detail. A system of classifying the intensity of local reactions is proposed to standardize administration. The experience of the M.D. Anderson Hospital involving over 2700 patients is reviewed. Administration of BCG by scarification has been accomplished with safety and has been well tolerated and accepted. The most commonly observed side effects are discussed as well as their management.

Forty-five patients with disseminated breast cancer were given a trial of combination chemotherapy consisting of fluorouracil, adriamycin, and cyclophosphamide (FAC) and immunotherapy with BCG given by scarification. The results were compared with those in a comparable group of 44 patients treated with FAC alone immediately before the chemoimmunotherapy study. The remission rates (73% and 76% for FAC and FAC-BCG respectively) were similar in both studies. The durations of remission for patients on FAC-BCG (medium 12 months) were longer than remissions achieved for patients given FAC alone (median 8 months) (P = 0.068). The most notable effect of BCG was on survival. Thus 21 out of 34 patients achieving remission on FAC-BCG were alive at the time of the last follow-up examination (median over 22 months) compared with 11 out of 32 patients achieving remission on FAC (median 15 months) (P = 0.01). Twenty-six of the 45 patients given FAC-BCG were alive at the time of the last follow-up examination (median over 22 months) compared with 12 of the 44 patients given FAC (median 15 months) (P = 0.005). Although the apparent benefit of BCG could be explained by a maldistribution of some prognostic factors, the data suggest that further trial of chemoimmunotherapy of breast cancer should be carried out.

Between May 1977 and April 1980, 238 patients with operable breast cancer were treated with adjuvant fluorouracil, doxorubicin, and cyclophosphamide (FAC) chemotherapy. All patients were randomized to receive FAC alone or FAC with nonspecific immunotherapy with Bacillus Calmette-Guerin (BCG) vaccine. A randomization for routine postoperative irradiation was included in the study in May 1978. At the median follow-up of 33 months, 53 patients had developed recurrent disease. Up to the present time, there have been no significant differences in the disease-free survival of patients treated with FAC alone from those treated with FAC + BCG (P = 0.21). The disease-free survival for patients treated with and without routine postoperative irradiation was similar (P = 0.99). Disease-free survival of premenopausal and postmenopausal women was similar. The overall estimate of disease-free survival was 72% at 3 years.

In an attempt to prolong the durations of remission and survival of patients with advanced breast cancer treated with the FAC-BCG protocol, we modified the CMF maintenance combination by increasing the dose of all three drugs and administering them intravenously. Eighty-five evaluable patients treated with this new regimen were compared with a recent historical control group of 105 evaluable patients treated with FAC-BCG and a lower-dose, oral CMF maintenance program. The overall (70% and 76%) and complete (16% and 19%) response rates were identical in these two groups. The median times to progression for all patients entered were similar too (13 months for both groups.). The durations of response were 17 months (PO-CMF) and 14 months (IV-CMF), not significantly different (P = .16). The durations of survival of the two treated groups were also very similar. After the administration of intensive FAC induction therapy, a high-dose, intravenous CMF maintenance program appears no better than a low-dose oral regimen. Other drug combinations consisting entirely of drugs not used in the induction regimen might be better choices for maintenance treatment

Fifty-two patients with locally advanced primary breast cancer (T3, T4/N2, N3) without distant metastases were treated with three cycles of combination chemotherapy consisting of 5-FU, Adriamycin and cyclophosphamide (FAC) and immunotherapy with Bacillus Calmette-Guerin (BCG) followed by local therapy (simple mastectomy and/or radiotherapy to breast/chest wall and regional lymphatics) and adjuvant chemotherapy to complete two years of treatment. Forty-nine of 52 (94%) patients were rendered free of clinically detectable disease. The median disease-free interval was 24 months. At a median follow-up time of 60 months, 40% of patients remained free of disease, off all therapy. Those patients who completed two years of therapy and started adjuvant chemotherapy promptly after local treatment had a 48% disease-free survival at five years. Local recurrences were observed in 21% of patients. Distant metastases developed in 40% of patients. Despite good tolerance, treatment compliance was poor. The complete remission rate with this multimodal approach is high and long-term disease-free survival is achieved in a considerable number of patients.

One hundred fifty-six evaluable patients with metastatic breast cancer were treated with vincristine, Adriamycin and cyclophosphamide alternating at fixed intervals with 5-FU and methotrexate. Immunotherapy with BCG or MER-BCG was administered to all patients in two consecutive treatment programs. Overall objective response rate and complete response rate were 67% and 20%, respectively. These were not significantly different between the two immunotherapeutic groups. The median time to progression was sixteen-and-a-half months from initiation of therapy. The median survival of all patients was 21 months and that of responders was 26 months. Response rates, time to progression, and survival showed no significant advantage over a recent historical control group treated with FAC-BCG. Toxicity related to the gastrointestinal tract and bone marrow was considerably higher in this protocol than in the FAC combinations. MER at the dose, route, and schedule administered in this protocol caused excessive local and systemic toxic reactions. The alternate use of these noncross-resistant combinations in advanced breast cancer is not superior to combination chemotherapy used in the traditional manner.

One hundred and fourteen evaluable patients with metastatic breast cancer were treated with a program consisting of 5-FU, Adriamycin, cyclophosphamide (FAC) and nonspecific immunotherapy with Levamisole. The results of this treatment program were compared to those observed with FAC and Bacillus Calmette Guerin (BCG) and FAC chemotherapy alone, both groups treated prior to the study reported in this paper. The overall response rates and complete response rates for all three treatment regimens were identical. The duration of remission, survival of all patients and survival of responders was similar for both chemoimmunotherapy regimens, being superior to the FAC chemotherapy alone group. Immunotherapy with Levamisole was well tolerated and side-effects were experienced by less than one-fourth of the patients. Overall, Levamisole was better tolerated than BCG and was easier to administer than the latter drug. These results suggest than nonspecific immunotherapy with Levamisole might prolong remission and survival of patients with metastatic breast cancer. Since the results achieved with BCG and Levamisole appear similar, the therapeutic ratio favors the use of Levamisole.

Thirty-two patients with a diagnosis of primary inflammatory breast carcinoma were treated with combination chemoimmunotherapy consisting of 5-fluorouracil, doxorubicin hydrochloride (Adriamycin), and cyclophosphamide (FAC) plus BCG followed by radiation therapy. This group of patients was compared to a group of 32 consecutive historical controls treated with radiation therapy alone. The estimated mean disease-free interval for the FAC-BCG group was 16 months, compared to 9 months for the radiation therapy alone group (P less than 0.01). The estimated median survival for the FAC-BCG treated group was 24 months, compared to 18 months for the radiation therapy alone group (P = less than 0.03). The combined modality approach consisting of chemoimmunotherapy and radiation therapy significantly improved the disease-free interval and survival of patients with inflammatory breast carcinoma.

One hundred and fourteen evaluable patients with measurable metastatic breast cancer were treated with a combination chemoimmunotherapy program (5-fluorouracil, adriamycin, and cyclophosphamide [FAC-levamisole [LSM]). An additional 117 patients with similar characteristics were treated with the same program with the addition of bacillus Calmette-Guérin (BCG) by scarification (FAC-BCG-LMS). The results were compared to those observed in 44 evaluable patients treated with FAC chemotherapy alone. Overall remission rates were identical in the three studies (72%, 73%, and 72%). The median duration of remission was 9 months for FAC, 13 months for FAC-LMS (P = 0.07), and 14 months for FAC-BCG-LMS (P = 0.05). The median duration of survival was 17 months for FAC and 28.6 months for FAC-LMS (P = 0.01). Although the median survival for the FAC-BCG-LMS group has not been reached, it is significantly superior to FAC alone (P = 0.009). These three sequential studies suggest that the addition of nonspecific immunotherapy with LMS or the combination of BCG and LMS prolongs the duration of remission and survival of responding patients treated with chemotherapy. Combination immunotherapy with BCG and LMS did not seem superior to LMS alone in this study.

One hundred 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 = 0.008). Similarly, survival of 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 nonresponders. Analysis of response rates by known prognostic factors was unrewarding. The duration of remission and survival, however, were significantly longer for patients with bone 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 combination of 5-fluorouracil, Adriamycin, cyclophosphamide, and BCG (FAC-BCG) was evaluated as adjuvant treatment in breast cancer patients following surgical excision and/or radiation of first site of recurrent disease. In a group of 68 patients treated with FAC-BCG, the estimated proportion remaining free of disease at 2 years from first recurrence was 69%, compared to 24% in 60 historical control patients (P less than 0.01). Estimated 2-year survival rate from first recurrence was 85% for the FAC-BCG patients and 78% for the controls (P = 0.07). This regimen has significantly prolonged the disease-free interval from the first recurrence, but additional follow-up is needed to determine its effect on long-term survival.

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.

Thirty-nine patients with 40 refractory malignant effusions (26 pleural and 14 peritoneal) were treated locally with a nonviable mycobacterial vaccine. The vaccine was administered into the effusion and consisted of BCG cell wall skeleton and trehalose dimycolate attached to oil microdroplets. A dose range of 150--3000 microgram was tested. The overall response rate was 44.0% (complete response [CR] plus partial response [PR]) and was not clearly dose-related. The response rates for each site were 13.6% (CR) and 31.8% (PR) for pleural effusions and 33.3% (CR) and 8.3% (PR) for peritoneal effusions. Toxic effects consisted of fever (40%), serosal pain (37.5%), and increased effusion (27.5%) and were not clearly dose-related. Gastrointestinal toxic effects were seen in 50% of patients treated for peritoneal effusions. Response correlated with prior exposure to BCG vaccine or tuberculosis, and with a febrile response to vaccine administration. This vaccine has a therapeutic effect on both pleural and peritoneal effusions.

Thirty-two patients with inflammatory breast cancer were treated with a combined modality approach consisting of combination chemotherapy with fluorouracil, doxorubicin hydrochloride, and cyclophosphamide, followed by radiation therapy. The disease-free interval and survival of this group were compared with 32 patients with inflammatory breast cancer treated with irradiation without systemic therapy at our institution in the past. In the actuarial median follow-up of 62 months (range 42+ to 76+ months) of study, 11 patients in combined modality group and three patients in the irradiation group were free of disease. Overall median disease-free interval was 22.8 months for the combined modality group and nine months for the irradiation group, and 30.1 months and 18 months, respectively. The median disease-free interval of patients less than 50 years of age was 19 months for the combined modality group and nine months for the irradiation group; median survival was 24 months for both subgroups. Forty percent of the patients under 50 years of age in the combined modality group and 7% in the irradiation group had recurrence of central nervous system disease. Of the patients greater than of equal to 50 years of age, the median disease-free interval was 32.1 months for the combined modality group and nine months for irradiation group; median survival was 42 months and 18 months, respectively. The combined modality approach has resulted in improved disease-free interval of patients less than 50 years of age, but survival of this subgroup was not significantly improved possibly because of the high incidence of central nervous system disease recurrence. This treatment was effective in prolonging the disease-free interval and survival of patients greater than or equal to 50 years of age, with an estimated 45% of the patients surviving free of disease beyond 42 months.