Robert W. Talley

Phase II evaluation of adriamycin in human neoplasia

Four hundred and seventy‐two patients with disseminated neoplasia were treated with two or more doses of adriamycin. The initial dose for “good risk” patients was 75 mg/m2 every 3 weeks, and for “poor risk” patients was 60 mg/m2 every 3 weeks. Objective remissions were seen in 118/472 patients, with best results noted in lymphomas (21/48), sarcomas (21/64), and carcinoma of the breast (16/50). Eighty‐nine per cent of remissions occurred within three courses. Hematopoietic toxic effects were seen in 73% of patients; nausea, vomiting, and/or stomatitis were observed in 43%. Changes in electrocardiograms were seen in 42/472 patients after cumulative doses of adriamycin ranging from 45 mg/m2 to 600+mg/m2. Irreversible congestive heart failure occurred in two patients after cumulative doses of 555 mg/m2 and 825 mg/m2, respectively. It is concluded that adriamycin is an active agent, most remissions occur promptly, and significant cardiotoxic reactions appear to be cumulative.

Aggressive Versus Conservative Management of Stage IV Renal Cell Carcinoma

Improved modalities to treat metastatic renal cell carcinoma will require an aggressive surgical and chemotherapeutic approach. Nephrectomy with hormonal and non-hormonal chemotherapy does improve median survival and 3-year survival significantly. The use of xenogeneic specific immune ribonucleic acid and Bacillus Calmette-Guerin offers promising immunotherapeutic modalities that may be combined with surgical and chemotherapeutic regimens. Early diagnosis of metastatic disease is important to evaluate properly the results of various modalities of treatment and possibly to improve the efficiency of these modalities. The management of solitary metastatic nodules should involve aggressive resection of the primary and metastatic nodule. Adjuvant hormonal and non-hormonal chemotherapy should be considered in all stages of the disease.

Phase II evaluation of bleomycin. A Southwest Oncology Group study

Bleomycin given intravenously (i.v.) or intramuscularly (i.m.) in twice‐weekly doses of 10 mg/m2 was evaluated for efficacy and toxicity in 382 patients. Responses were observed in 11/27 Hodgkins diseases, 10/30 lymphomas, 9/22 squamous cell cancers of ectodermal origin, 12/26 germinal cancers, and 3/8 renal adenocarcinomas. The i.m. route is less, likely to cause pulmonary toxicity or hypotension than the i.v. route. Advanced age and total doses exceeding 200 mg were Associated with a higher risk of lung toxicity. All responders had shown at least improvement upon receiving 200 mg; higher total doses should be used only in responding patients.

Chemotherapy of adenocarcinoma of the kidney

Despite the development of many new cancer chemotherapeutic programs, metastatic renal carcinomas have remained unresponsive either to single agents or combinations of agents. Extensive review of the literature and personal experience at Henry Ford Hospital have failed to find either a single agent or a combination of agents which produces consistent response rates. Single available agents which have been employed include; (a) A variety of alkylating agents—no response in 22 patients; (b) antimetabolites, including 5‐fluorouracil, hydroxyurea, methotrexate, 6‐mercaptopurine, and cytosine arabinoside—no significant response in 31 patients; (c) the antibiotics, including actinomycin D, mithramycin, adriamycin, and others—no response in 20 patients; (d) the periwinkle alkaloid antimitotic, Vincaleukoblastine—2 objective regressions in 15 patients. Newer investigative agents also have been unrewarding, with no objective remissions observed in 3 patients treated with dimethyl imidazole carboxamide, 3 patients treated with adriamycin, and 3 patients treated with 5‐azacytidine. No responses were observed in 10 patients treated with the nitrosoureas. A review of the literature yields only occasional well‐documented objective remissions with a variety of agents, primarily cyclophosphamide and hydroxyurea.

CCNU (1‐[2‐chloroethyl]‐3‐cyclohexyl‐1‐nitrosourea, NSC‐79037) in the treatment of cancer. Phase II study

CCNU (1‐[2‐chloroethyl]‐3‐cyclohexyl‐1‐nitrosourea, NSC‐79037), was used to treat 141 evaluable patients with a variety of advanced malignancies, 56% of whom had not received prior chemotherapy. Patients with an adequate bone marrow reserve received 130 mg/m2 as the initial dose and those with an impaired reserve received 100 mg/m2. Therapy was repeated every 6 weeks and the dosage modified according to the hematologic toxicity. Responses greater than 50% reduction in tumor size were noted in 26 patients; stable disease or reduction in tumor size of less than 50% was observed in 21 patients. The well‐differentiated adenocarcinomas and squamous cell tumors appeared to be least sensitive to CCNU. Bone marrow depression was the major dose‐limiting factor. Without adequate antiemetic therapy, all patients would have had nausea and vomiting. Hepatocellular toxicity was noted in two patients.

Improved complete remission rates and survival for patients with large cell lymphoma treated with chemoimmunotherapy: A southwest oncology group study

Between 1974 and 1977, 652 patients with non‐Hodgkins lymphoma without prior chemotherapy were randomized to 1 of 3 combination chemotherapy programs designed to induce complete remission (CR): COP‐bleomycin (180 patients), CHOP‐bleomycin (232 patients) or CHOP plus immunotherapy with Bacillus Calmette Guerin (BCG) (240 patients). With mature follow‐up, the major effect of BCG immunotherapy was observed in patients with large cell lymphomas (diffuse or nodular “histiocytic”) and not in other common lymphoma subtypes. CR rate for 65 patients with large cell lymphoma treated with CHOP‐BCG was 68% compared to 48% in 61 patients treated with CHOP‐bleomycin (P = 0.02) (two‐tailed test) or 44% for 45 patients treated with COP‐bleomycin (P = 0.02). CR duration for both CHOP‐based regimens was similar and superior to that produced by COP‐bleomycin (P = 0.03). Survival of patients with large cell lymphoma treated with CHOP‐BCG was better than that observed with CHOP‐bleomycin (P = 0.02) or COP‐Bleomycin (P = 0.002). Although the explanation for the favorable effect of BCG remains unclear, further clinical trials to evaluate the combination of chemotherapy and other “biologic response modifiers” is warranted for patients with lymphoma.

Infusion of fluorinated pyrimidines into hepatic artery for treatment of metastatic carcinoma of liver

Hepatic artery infusion of 5‐fluorouracil via transbrachial artery catheter by repeated acute monthly courses has been used in 101 patients. Objective regressions were seen in 39 of 68 patients (59%) with gastrointestinal malignancies; however, only rare regressions were observed in 41 neoplasms of other primary sites. Twenty patients were treated adequately by prolonged continuous infusion of 5‐fluoro‐2′‐deoxyuridine. Five of these patients obtained objective regressions. This was not a randomized comparative study of the two methods but comprised two separate studies. The acute intermittent program appeared superior to prolonged chronic infusion; however, with the latter method, he‐matopoietic toxicity was less severe. The use of hepatic artery catheters positioned via the brachial artery has been a practical and effective method of pursuing this form of therapy with the major significant complication, irreversible ischemic changes of the fingers and hand, occurring in only two patients.

Comparison of cyclophosphamide and 5‐fluorouracil in the treatment of patients with metastatic breast cancer

Sixty‐two patients with metastatic breast cancer were treated randomly with either cyclophosphamide or 5‐fluorouracil. The patients were classified as haVing either an objective remission or a failure of treatment by accepted techniques. Eleven of 30 patients responded to 5‐fluorouracil, and 7 of 32 responded to cyclophosphamide. These differences are not significant. Subsequently, each patient was treated with the other agent, and 4 of 32 responded to 5‐fluorouracil, and 7 of 30 responded to cyclophosphamide. Thus, a total of 14 patients experienced clinical remissions of their disease with cyclophosphamide, and 15 had remissions with 5‐fluorouracil. Of the 18 patients responding to the first agent, 7 experienced objective regressions with the second agent, whereas only 4 of the 44 patients failing to respond to the first agent experienced objective remissions with the second agent. This difference was significant at p < 0.02. Factors such as menopausal age of patient, site of the dominant lesion, and response to prior hormonal therapy were of no value in predicting response to these two agents. Survival of the patients after the start of chemotherapy was 14.7 ± 10.2 months for patients responding to both agents, 10.5 ± 9.0 months for patients responding to the first agent only, 6.2 ± 12.8 months for patients responding to the second agent only, and 5.2 ± 4.5 months for patients responding to neither agent. Subjective improvement correlated well with objective improvement, but some patients failing to respond to therapy experienced temporary subjective improvement.

The value of serial carcinoembryonic antigen (CEA) in predicting response rate and survival of patients with gastrointestinal cancer treated with chemotherapy. A Southwest oncology group study

Elevated serum levels of carcinoembryonic antigen (CEA) were found in 70% of 141 patients with advanced gastrointestinal (GI) cancers. Serial CEA measurements were performed on 70 patients before and during chemotherapy. The majority were treated with 5‐FU and Methyl‐CCNU (33 patients), 5‐FU (19 patients), or 5‐FU and mitomycin‐C (8 patients). In 49 patients with colorectal carcinoma who had elevated serum CEA prior to chemotherapy, 18 had objective partial tumor remission, 16/18 (89%) showed definite decrease in CEA level, one had no change, and one had an increase CEA titer. Thirty‐one patients had either stable disease (10 patients) or increasing disease (21 patients) while on chemotherapy. Of these patients four showed decrease in CEA, eight had no change, and 19 had increase in CEA levels as compared to pretreatment value. The survival of patients with a decrease in CEA during chemotherapy was statistically significant (p = .03) as compared to survival of those with no change or increasing CEA levels. In 21 patients with other GI cancers, the correlation between the clinical response and change in CEA level observed was not as definite as in patients with colorectal carcinoma.

A dose-response evaluation of androgens in the treatment of metastatic breast cancer

A comparative double‐blind clinical trial of two androgens, one at two dose levels the other at three dose levels, in the treatment of metastatic breast cancer, was conducted by 10 members of the Cooperative Breast Cancer Group. The two androgens studied were dromostanolone propionate at 100 mg and 200 mg three times weekly and 7α‐methyl‐19‐nortestosterone acetate at 10 mg, 33 mg, and 100 mg weekly. The latter compound is a much more potent androgen and the hypothesis to be tested was whether or not a much more potent an androgen could induce a greater incidence of regressions. The rates of regression observed in this study were as follows: dromostanolone propionate at 100 mg, 22%, at 200 mg, 16% (the p value for the difference is 0.325); 7α‐methyl 19‐nortestosterone acetate at 10 mg, 15%, at 33 mg, 22%, and at 100 mg, 28% (the difference between the lowest and highest dose‐response rates being 0.05%). This study suggests that at least a log dose increase of a potent androgen is required to obtain an increased objective remission rate, whereas a one tenth of a log dose increase of a weaker androgen is not associated with an increased response rate. Abnormalities occurring during therapy with 7α‐methyl‐19‐ndrtestosterone acetate, whether drug‐and/ or disease‐related, decreased with increasing doses. The reason for this is not clear. No difference in total survival was observed between any of the treatment groups, but patients who had regressions had longer median survival than those who were classified as failures to therapy.