John D. Cowan

Use of a human tumor cloning system to screen retinoids for antineoplastic activity

Retinoid analogs are being actively evaluated as antitumor agents in man. A human tumor cloning system was used to assess the antineoplastic activity of all‐trans‐retinoic acid, all‐trans‐retinol and 13‐cis‐retinoic acid. The effect of retinoids on the formation of tumor colony forming units (T‐CFU) was surveyed for 67 different human tumors. These analogs showed minor activity in a variety of neoplasms. The decrease in T‐CFU varied between histologic tumor types and between tumor of the same type. No significant difference between retinoid analogs was noted.

A randomized trial of doxorubicin, mitoxantrone and bisantrene in advanced breast cancer (A South West Oncology Group Study)

SummaryNew agents with increased activity and/or reduced toxicity are needed for the treatment of advanced breast cancer. The anthracene derivatives mitoxantrone and bisantrene had significant activity and acceptable toxicity in phase II trials. In an ongoing phase III trial we have now randomized 150 patients with advanced breast cancer to either doxorubicin (60 mg/m2), mitoxantrone (14 mg/m2) or bisantrene (260 mg/m2) i.v. q 3 weeks with re-randomization for cross-over at the time of progression to determine the relative efficacy and toxicity of these three agents. To be eligible, patients must have had only one previous chemotherapy regimen. ER positive patients must have failed endocrine therapy. Patients with CHF or severe cardiac disease were ineligible. In this preliminary evaluation, 117 patients are evaluable for response and 110 for toxicity. Median age for all patients is 58 years (range 26–78). The majority (86%) are postmenopausal. Fifty-nine percent of the patients have visceral dominant disease. Estrogen receptor is positive in 37%, negative in 39% and unknown in 24% of patients. Median performance status (SWOG) is 1, range 0–2. Objective responses have been observed on each arm (doxorubicin 9/35, mitoxantrone 6/38, bisantrene 6/44). Thirty-two patients are evaluable for cross-over response (doxorubicin 2/13, mitoxantrone 1/11, bisantrene 0/8). The predominant toxicity is leukopenia with a nadir WBC count <2000 in 45% of all courses administered. Leukopenia is similar with the three drugs. Significant nausea, vomiting and alopecia are common with doxorubicin and uncommon with the other agents. Congestive heart failure has been observed in one patient (doxorubicin). Definitive conclusions regarding the efficacy and toxicity of these agents await the completion of this trial.

Comparative cytotoxicity of adriamycin, mitoxantrone and bisantrene as measured by a human tumor cloning system.

SummaryA human tumor cloning system was used to assess the cytotoxicity of adriamycin, mitoxantrone and bisantrene at concentrations that are equitoxic in man. There were 989 specimens evaluable for drug sensitivity analysis. Overall, adriamycin showed in vitro cytotoxicity (≥ 50% decrease in tumor colony forming units) 14% of the time; mitoxantrone, 21% of the time; and bisantrene, 31% of the time. Three hundred ninety-nine of these evaluable specimens were simultaneously tested against more than one of the agents, providing 631 two-way drug comparisons. For these comparisons, there was lack of co-resistance 27–34% of the time, with mitoxantrone being more active than adriamycin (p < .05) and bisantrene being more active than adriamycin (p < .01) or mitoxantrone (p < .01). These data suggest that comparative and sequential clinical use of these agents should be investigated.

Phase II evaluation of bisantrene in acute leukemia. A Southwest Oncology Group Study.

Twenty-nine patients with heavily pretreated acute leukemia in relapse were treated with bisantrene (maximum dose 120 mg/m2/day X 5) in a phase II study. Twenty-seven of the 29 patients were evaluable for response, receiving a total of 53 courses of treatment. There were three complete remissions (11%) lasting 27, 107, and 115 days. One brief partial remission of 43 days was also seen for a total response rate of 15%. Toxicity was mainly limited to the expected myelotoxicity with minimal nonhematologic toxicity seen. Although the complete remission rate is low, an antileukemic effect was seen in the majority of the patients treated. Sixty-one percent of the patients had at least a 50% decrease in the circulating blast count and 32% had at least a 50% decrease in the number of bone marrow blasts. We conclude that bisantrene does have an antileukemic effect, but that the optimal starting dose is not yet established.

Phase II evaluation of bisantrene hydrochloride in refractory malignant melanoma - A southwest oncology group study

Patients with a pathologically proven diagnosis of malignant melanoma were entered into a phase II trial of bisantrene. Eligibility criteria included: measurable, metastatic disease; performance status 0–2 SWOG; and adriamycin total cumulative dose of < 400 mg/m2. The initial bisantrene dosing schedule was 260 mg/m2 every three weeks for good risk patients. Due to the absence of an objective response and the lack of severe toxicity in the first 25 bisantrene treated patients, the starting dose was increased to 300 mg/m2 for good risk patients. Fifty-one patients received a median of two bisantrene courses (range 1–11 courses). Leukopenia was the major toxicity. Fifteen (68%) of the 22 good risk, intermediate dose patients (260 mg/m2), and 8 (80%) of the 10 good risk, high dose patients (300 mg/m2) evaluable for toxicity experienced mild-severe leukopenia. None of the 51 patients experienced a complete or partial response to bisantrene. Median survival was 3.3 months. We conclude that bisantrene is ineffective in the treatment of metastatic melanoma.

A phase II study of bisantrene in malignant lymphomas. A Southwest Oncology Group Study.

SummaryForty evaluable patients with malignant lymphoma (ML) were treated with bisantrene at a dose of 260 mg/m2 every 3 weeks (18 patients) or 208 mg/m2 every 3 weeks (22 patients). The initial dose rate was determined on the basis of expected myelosuppression. Patients were heavily pretreated and had advanced disease (92% had stage IV). The overall response rate was 10% and included 1 partial response (PR) in 17 patients with Hodgkins disease (HD), 1 PR and 1 complete response (CR) in 5 patients with favorable histology in non-Hodgkins lymphoma (NHL), and 1 PR in 18 patients with unfavorable histology in NHL. Neutropenia (WBC≤3000 cells/μl) was the most common toxicity, occurring in 50% of patients. Phlebitis was a common side effect in patients treated with bisantrene administered by way of peripheral veins. Bisantrene has limited activity in heavily pretreated patients with HD or unfavorable histology in NHL. The role of bisantrene for treatment of NHL with favorable histology or for treatment at an earlier point in the natural history of ML is unknown.

Experimental Therapy: In Vitro Models

Cytotoxic agents have a key role in the treatment of cancer. Unfortunately, the effectiveness of these agents is limited, and their effect on an individual patient’s tumor is frequently difficult to predict. In an effort to improve the therapeutic results of cytotoxic chemical therapy, attempts have been made to develop an in vitro system to predict drug sensitivity in man, much as bacterial culture and sensitivity techniques are used to tailor antibiotic use. Such a system would allow (1) the rapid screening of potential antineoplastic agents, which would aid in the development of promising clinical trials; and (2) the selection of an appropriate chemotherapeutic agent or agents for an individual patient’s tumor.

The Human Tumor Cloning Assay: An In Vitro Assay for Antitumor Activity in Solid Tumors

It is desirable to develop an in vitro system to predict the activity of antineoplastic agents in man, much as bacterial culture and sensitivity techniques are used in the treatment of infectious disease. Such a test would allow the rapid screening of potential anticancer agents for activity and might allow the selection of appropriate chemotherapy for an individual patient’s tumor.