Charles K. Tashima

Pulmonary toxicity of mitomycin

Six patients with breast cancer developed pulmonary toxicity following mitomycin therapy. The presenting symptoms were shortness of breath and a dry cough. The radiological pictures varied from a normal chest x‐ray to extensive bilateral pneumonitis. The histological findings consisted of diffuse alveolar damage progressing to interstitial pulmonary fibrosis. Corticosteroid therapy resulted in complete resolution of pneumonia in one patient. Respiratory symptoms improved in 3 patients following discontinuation of the drug. Two patients with extensive bilateral pneumonitis, who were not treated with steriods, died of respiratory failure. Mitomycin‐induced lung toxicity appears to be reversible with the discontinuation of drug and the administration of corticosteroids. Lung biopsy is necessary in order to rule out other diagnoses.

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 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. 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.

Intensive postoperative chemoimmunotherapy for patients with stage II and stage III breast cancer

For the past 34 months, a combination of 5‐fluorouracil, adriamycin, cyclophosphamide, and BCG (FAC‐BCG) was evaluated as adjuvant treatment in stage II and III breast cancer patients with positive axillary nodes. In the group of 131 patients receiving FAC‐BCG, the estimated proportion remaining disease‐free at 2 years from surgery was 91% compared to an estimated 69% in a group of 151 historical control patients (p < 0.01). This advantage was statistically significant in all subgroups except for patients with primary tumor less than 3 cm and for patients with less than 4 positive nodes. Estimated 2‐year survival rates were 96% for FAC‐BCG patients and 86% for control (p = 0.02). Treatment was well tolerated. Adjuvant FAC‐BCG seems effective in prolonging disease‐free interval and early survival in patients with stage II and III breast cancer. Its long term efficacy will require longer follow‐ups.

Electrocardiographic changes after adriamycin chemotherapy

The electrocardiograms of 146 patients with metastatic carcinoma of the breast were reviewed before, during, and after the patients received Adriamycin (Doxorubicin) chemotherapy (AD). The most significant electrocardiographic change occurred in the amplitude of the QRS voltage. Seven patients developed cardiomyopathy after AD and showed a significant decrease in QRS voltage. This decrease, however, was more severe at the onset of congestive heart failure than at conclusion of Adriamycin. In 35 patients with pleural effusion, there was an inverse relation between the extent of the effusion and the amplitude of QRS voltage in the absence of congestive heart failure. These results indicate that 1) the sudden and relatively severe decrease in QRS voltage with the onset of CHF limits the value of this ECG criterion for predicting early Adriamycin toxicity, and 2) caution should be exercised in the interpretation of QRS voltage changes in patients with significant pleural effusion. Cancer 43:465–471, 1979.

Mitomycin-C and megestrol acetate in treatment of breast cancer refractory to hormonal and combination chemotherapy.

Fifty patients with breast cancer refractory to endocrine manipulation and/or combination chemotherapy were treated with mitomycin‐C 20 mg/m2 I.V. every 4–6 weeks and megestrol acetate 160 mg daily. Of 48 evaluable patients, 4% achieved complete remission (CR), 23% had partial remission (PR). Median duration of response for CR and PR was 7 months. Non‐responders had a median survival of 2 months. The difference in survival of responders (both CR and PR) and non‐responders was statistically significant at p<0.01 level. Attenuated doses of mitomycin‐C were administered at increasing intervals due to cumulative myelosuppressive toxicity.

Alternating noncross‐resistant combination chemotherapy and active nonspecific immunotherapy with BCG or MER‐BCG for advanced breast carcinoma

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. Cancer 45:742‐749, 1980.

Combined chemoimmunotherapy for advanced breast cancer: a comparison of BCG and levamisole.

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 that 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. Cancer 43:1112–1122, 1979.

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. Cancer 44:398‐405, 1979.

Adriamycin and 1-(2-chlorethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in the treatment of metastatic breast cancer.

Adriamycin every three weeks and CCNU every six weeks were given to thirty patients with metastatic breast carcinoma. Most patients had received prior chemotherapy. The overall response rate was 40%, with three patients obtaining complete remission. Survival was significantly prolonged in responders versus nonresponders. Three patients developed CNS metastasis while on treatment. Prior chemotherapy was a major factor in determining response rate; all patients without prior chemotherapy responded. The combination appears to be inferior to adriamycin alone in patients who have received prior chemotherapy.

Severe hypoglycemia associated with terminal lymphomas: Report of five cases

Five patients with lymphoma developed severe hypoglycemia in the terminal stages of the disease. There were several possible causes for the hypoglycemia in these patients, including severe liver disease, malabsorption, inanition and gastro‐intestinal ulceration. Characteristics were present which were similar to nonpancreatic tumors associated with hypoglycemia. The authors suggest that hypoglycemia may be more frequent than commonly is recognized and should be searched for in patients with lymphomatous disease.