Stephen K. Carter

A clinical review of bleomycin—a new antineoplastic agent

Bleomycin, a new antibiotic antineoplastic agent, has undergone extensive clinical trial. Data from 1,174 patients were reviewed and summarized by cell type. The most commonly used dose schedule was 15 mg/m2 twice a week intravenously. Significant response rates were achieved in patients with squamous cell carcinoma of various anatomical sites, lymphomas, and testicular carcinoma. Most responses were of 1 to 2 months duration. Drug toxicities included significant skin and pulmonary complications and some degree of drug‐induced pyrexia and nausea with vomiting. Rare insignificant bone marrow depression was encountered. The limitations of a retrospective clinical review of this type using uncontrolled pooled data from various patient populations were discussed. In conclusion, however, bleomycin appeared to be useful in the treatment of patients with specific tumors refractory to standard treatment and/or whose bone marrow status precluded the use of conventional chemotherapy. The final role of bleomycin in cancer chemotherapy awaits the results of controlled prospective clinical trials.

Hexamethylmelamine—A new drug with activity in solid tumors

Abstract Hexamethylmelamine (NSC 13875) is a iriazine that has completed phase I–II trials under the sponsorship of the Division of Cancer Treatment, National Cancer Institute. It was selected for clinical trial based on superior activity against the Walker 256 carcinosarcoma. In the clinical trials reported, the dose schedules used were 4–15 mg/kd/d for 21–90 days. Dose limiting toxicity was gastrointestinal. Also seen were leukopenia, thrombocylopenia, and central nervous system toxicity. The overall response rate in 784 evaluable patients was 17%. Greater than 20% response rates were seen in the following tumor types: small cell (oat) carcinoma of the lung, ovarian adenocarcinoma, lymphoma, and breast cancer. Further controlled clinical trials in certain tumor types are warranted.

Adjuvant chemotherapy in lung cancer. Review and prospects

The results of trials testing combined surgery and chemotherapy in lung cancer are reviewed. Fifteen adjuvant trials using various chemotherapeutic agents were analyzed to determine reasons for their lack of success. Current trials with adjuvant therapy in lung cancer are briefly outlined. In addition, analysis of the activity of chemotherapeutic agents in advanced lung cancer and its implications in the design of future adjuvant studies are detailed.

Some thoughts on experimental models and their clinical correlations

Abstract In a field as complex as cancer chemotherapy, where a very large number of antitumor agents may be candidates for clinical studies, clinicians must have the help of experimentalists in developing model tumor systems that will select the drugs having the greatest potential for clinical success. Consideration of experimental systems and their clinical correlations is particularly critical in view of the increasing importance of rationally designed combination drug regimens and the emphasis being placed on chemotherapy combined with other modalities in the treatment of solid tumors. This paper reviews the clinical experience with data obtained in the leukemia L1210 system, which has been the major screening tool in the drug development program of the National Cancer Institute, and its relationship to selecting new model systems for predicting drugs active against solid tumors. Within this context, some of the correlations between drug activity in the L1210 and B-16 melanoma systems and activity in human solid tumors are discussed.

Immunotherapy of cancer in man: current status and prospectus.

The long-term goal of any cancer treatment program is the achievement of normal life expectancy among cancer patients, with the least possible morbidity. The basic assumption in cancer treatment is that cure requires the destruction or removal of all malignant cells, or at least a reduction of these cells to an “effective zero” level that can be controlled by the host’s defense mechanisms. Five widely used therapeutic modalities have the potential of accomplishing this end: surgery, radiotherapy, chemotherapy, endocrinotherapy, and immunotherapy. Some of these modalities are more successful than others, but all are incompletely understood, and important improvements in their research concept and widespread application are needed. Surgery is the most frequently used and most effective approach currently available, curing more patients than any other therapy. For example, advances in surgical techniques have increased the 5-year survival, although not necessarily achieving cure, in at least 85% of patients with skin cancer, in about 60% of women with breast cancer and 70% with uterine cancer, and in about 40% of colon cancer cases. However, the significant improvements in managing cancer by surgery alone have become fewer during the past decade. Radiotherapy is second in importance to surgery as a means of controlling a wide variety of solid tumors. Radiation therapy aims to destroy malignant cells with a minimum of danger to the normal surrounding tissue and, when successful, produces good functional cosmetic results in most cases. Radiotherapy has extended survival to 5 years or more in at least 90% of patients with seminoma of the testis, at least 80% of children with retinobiastoma, about 75% of cases of early Hodgkin’s disease, and about 50% of patients with squarnous cancer of the cervix and nasopharynx. While neither surgery nor radiotherapy can be curative unless the tumor is locally or regionally confined, each decreases the tumor burden of the patient, so that, hopefully, the systemic modalities of chemotherapy and immunotherapy may become more effective. Chemotherapy has been practiced in cancer since early recorded history, but its modern application began after World War 11, when it became clear that a variety of drugs could kill or significantly inhibit transformed cells without unreasonable toxic effects on the patients. Drug research has produced at least 40 clinically effective compounds,1 and drug therapy alone can bring about cure in a significant number of patients with choriocarcinoma and Burkitt’s lymphoma. In eight other forms of cancer (acute lymphocytic leukemia, Hodgkin’s disease, histiocytic lymphomas, Ewing’s tumor, Wilms’ tumor, em-

4′-Demethyl-epipodophyllotoxin-β-d-thenylidene glucoside (VM-26)—A brief review

Abstract 4 ′-Demethyl-epipodophyllotoxin-β-d-thenylidene-glucoside is as emisynthetic derivative of podophyllotoxin, a natural product from the May apple plant (Podophyllum peltatum) . The drug is highly water insoluble and requires a lipid solvent for i.v. administration. The mode of action is at least two-fold, i.e., immediate metaphase arrest of dividing cells and subsequent prevention of cells from entering mitosis which is related to inhibition of DNA synthesis. In the L 1210 system the drug is highly active, the best schedule being every three hours on days 1 and 9 or days 1, 5 , and 9 . VM- 26 also has activity in intracerebrally inoculated L 1210 mice. Phase I studies have arrived at a maximum tolerated dose (MTD), on a weekly schedule, of 67 mg/m 2 . Other schedules employed include a twice weekly schedule of 1–3 mg/kg ( 40–120 mg/m 2 ), a weekly regimen at 100–130 mg/m 2 , and a schedule of 30 mg/m 2 daily × 5 repeated every 10–15 days. All schedules require drug administration by i.v. infusion over 30–60 min. Human toxicity includes leukopenia (dose related), hypotension on rapid administration, alopecia, occasional GI distress, and one episode of anaphylaxis. Early clinical studies indicate that VM- 26 may have activity in Hodgkins and non-Hodgkins lymphomas, brain tumors and carcinoma of the bladder.

New drugs on the horizon in bronchogenic carcinoma.

The Chemotherapy Program of the National Cancer Institute in its drug development function sponsors for clinical trial a wide range of new antiplastic drugs. All of these drugs are tested in lung cancer which is considered one of the Programs “signal” tumor types. Among the new drugs sponsored for trial, which have shown evidence of activity against lung cancer, are the nitrosoureas of which three are in various stages of clinical evaluation. BCNU has shown activity in 9/83 (11%) while CCNU has shown activity in 11/52 (21%). The newest analogue, Methyl CCNU, is of great interest because of its superior activity against the advanced Lewis lung tumor. Other new agents which have shown some evidence of activity include adriamycin (30/147 = 20%), hexamethylmelamine (42/202 = 21%), and bleomycin (5/62 = 8%). Among the new drugs just completing Phase I evaluation and awaiting trial in lung cancer are: Iphosphamide (NSC 109724) an analogue of cyclophosphamide, ICRF‐159 (NSC 129943), 5‐azacytidine (NSC 102816), and Cis‐platinum (II) Diamminodichloride (NSC 119875).

A Chemotherapeutic Perspective on Clinical Trials with Corynebacterium parvum

Cancer is one of the oldest diseases afflicting mankind, and the efforts at treatment have been recorded as long ago as the use of arsenic pastes in ancient Egypt. Today, cancer is second only to cardiovascular disease as the major cause of death in the United States. Each year, an estimated 650,000 new cases are diagnosed, and over 1 million known patients continue treatment. The major difficulties in mounting a rapid scientific assault on cancer are that it encompasses more than 100 clinically distinct diseases and is inextricably linked to fundamental life processes which still are not completely understood.

Corynebacterium parvum Outlook and Future

Now that I have listened to all of the speakers, I am still not certain that I have answers to all the questions that I raised earlier, but I do have some. I am particularly intrigued by the data on the administration of intravenous Corynebacterium parvum. Three separate studies have been presented, each utilizing a different schedule. Professor Woodruff’s group may have reached the single dose MTD at 10–15 mg/m2, as a single dose appears to be about as much as can be tolerated. I wonder whether the M. D. Anderson group, which is now up to 10 mg/m2 and is trying to repeat their dose once or twice monthly, may not be pretty close to their limit, based on the amount that can be well tolerated as a single dose.