Charles D. Haas

The effects of delay in standard treatment due to induction chemotherapy in two randomized prospective studies

It is often suggested that tumors will respond to induction chemotherapy and result in improved survival for patients with squamous cell carcinoma of the head and neck. Two regimens of induction chemotherapy were studied in separate randomized, prospective trials over the last 6 years. Eighty‐three patients with advanced disease were entered into the first study (43/chemotherapy; 40/control), and 60 into the second (27/chemotherapy; 33/control). Patient randomization was stratified by stage (III/IV) and site (oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, paranasal sinuses). The first study utilized bleomycin, Cytoxan,® methotrexate and 5‐fluorouracil in two cycles (one cycle if no tumor response), followed by standard treatment which consisted of combined irradiation and surgery or, in some instances, primary irradiation alone. The second study utilized cisplatin and 5‐fluorouracil in three cycles prior to standard treatment. An objective tumor response to chemotherapy was observed in 68% in the first study and 85% in the second. The patient survival in both studies @ 24 months in the first; @ 19 in the second) was better in the control than that in the experimental groups (43% to 31%; 69% to 46%). In the second study, the average length of delay of standard treatment was longer than in the first study (95 days vs. 66 days; P<.02). Results combining the P‐values of both studies indicate that the relative risk of having persistent disease was 2.9 times greater for patients who received chemotherapy. While toxicity to chemotherapy was not a factor in survival, the number of patients who withdrew from the studies and those who did not comply with treatment were greater in the chemotherapy groups. Except for new drug regimens of exceptional promise, it is recommended that future studies be designed so that chemotherapy is given concurrent with, or following the completion of standard treatment.

Phase II evaluation of aclacinomycin-A in patients with adenocarcinoma and large cell carcinoma of the lung.

ACLACINOMYCIN-A (ACLA-A), the new anthracycline antibiotic that produces substantially less cardiotoxicity relative to doxorubicin, was evaluated in a phase II trial tor advanced large cell and adenocarcinoma of the lung patients. Twenty-three patients with measurable disease were entered into the trial and received ACLA-A in doses of a weekly infusion of 65 mg/m2 and 85 mg/m2 Eighteen patients were evaluable for response and toxicity. Two patients were evaluable for toxicity only, one died before completion of a full course of therapy, and two did not receive the drug. There were no complete or partial remissions in this study. Three patients had disease stabilization for a median of 10 weeks (range 6–17). Toxicity was mainly hematologic. Nausea and vomiting were moderate. ACLA-A, in the dose schedules used, appears to have no activity in large cell and adenocarcinoma of the lung.

Phase I and pharmacologic evaluation of nafazatrom in patients with cancer

SummaryNafazatrom was evaluated in escalating daily oral doses ranging from 0.25 to 8.0 g/m2 without producing significant toxicities. Malabsorption proved dose limiting at 8.0 g/m2 as a single daily dose, but splitting the same total dose into two or four doses circumvented this problem. Doses of 2.0 g/m2 at 6-h intervals or 4.0 g/m2 every 12 h are reasonable for Phase II and adjuvant trials. Pharmacologic evaluation of nafazatrom confirmed malabsorption at the highest single daily dose level tested and suggests that absorption was impaired in patients with extensive liver metastases.

Treatment of Metastatic Breast Cancer with AZQ: A Phase II Trial

Seventeen patients with metastatic breast cancer who had failed prior chemotherapy were treated with intravenous AZQ at a dose of 15-20 mg/m2 weekly for four consecutive weeks followed by a two-week rest period. No responses were observed. Myelosuppression was the dose-limiting toxicity. One patient experienced massive liver infarction possibly related to AZQ. Our data suggest that this agent at the schedule and dosage used is of no benefit in pretreated breast cancer patients.

Dibromodulcitol (DBD), DTIC, and actinomycin-D in disseminated malignant melanoma A phase I-II clinical trial

THIRTY-SEVEN FULLY ASSESSABLE PATIENTS with metastatic malignant melanoma were administered DTIC, actinomycin-D, and dibromodulcitol (DBD) on a q 3-to 4-week schedule. Doses of actinomycin-D and DTIC were 1.25 mg/m2 and 750 mg/m2, respectively, on day 1. DBD was progressively escalated in five dose levels in succeeding patients from an initial 90 mg/m2 daily, days 3–7, to a dose-limiting 230 rag/ m2 Two complete and nine partial responses were observed for an overall response rate of 30%. Median duration of response was 18 weeks. Major toxicities observed were hematologic and gastrointestinal. Median survival of all patients was 30 weeks and did not differ significantly from our earlier trials of DTIC and actinomycin-D ± chlorozotocin. Although the observed objective response rate was higher than our previous efforts in this disease, the addition of DBD failed to significantly impact on the survival of the entire treatment group. Further investigation of this chemotherapy combination does not appear warranted.

Phase II clinical evaluation of AZQ in adenocarcinoma of the lung.

TWENTY PATIENTS WITH ADVANCED MEASURABLE adenocarcinoma of the lung were treated with AZQ 20 mg/m2 weekly for 4 weeks, followed by a 2-week rest. No complete or partial responses were observed. Stabilization was observed in seven individuals, lasting 6–32+ weeks, with a median of 6 weeks. Toxicity was limited to reversible myelosuppression. We conclude that AZQ administered at this dose and schedule has no significant activity against advanced adenocarcinoma of the lung.

Vindesine in head and neck cancer

SummaryVindesine was tested in 23 fully evaluable patients with advanced carcinomas of the head and neck. All had received previous chemotherapy. No complete or partial responses resulted after one or more courses of 1.5 mg/m2 i.v. bolus daily × 2 days. Leukopenia was noted in 46% and peripheral neuropathy was reported in 29%. This dose-schedule of vindesine is inactive in previously treated patients with squamous carcinomas of the head and neck.

Phase II evaluation of 1-(2-chloroethyl)-3-(2,6-dioxo-(piperidyl)-1 nitrosourea (PCNU NSC-95466) in patients with advanced carcinoma of the lung

Sixty-one assessable patients with advanced small cell and non-small cell carcinoma of the lung were given PCNU on an intermittent every 6-week schedule. Starting doses ranged from 75 mg/m2 for poor-risk patients to 100 mg/m2 for good-risk patients, depending on the bone marrow, liver, and renal status. Six partial responses (two small cell carcinoma, two adenocarcinoma, two large cell carcinoma) of short duration were documented. The major toxic effects were thrombocytopenia (35%) and leukopenia (16%). PCNU does not appear to have sufficient antitumor activity to warrant further investigation in advanced lung cancer.

Nafazatrom: clonogenic in-vitro assessment of activity against human malignancies

SummaryNafazatrom was tested against a variety of human malignancies with the human tumor stem cell assay at one or more of the following concentrations: 1, 10, 25, and 100 μg/ml × 1 h or 0.05, 0.5, or 5 μg/ml by continuous exposure. Major (≧70%) inhibition was noted in 7/52 adenocarcinomas, in 0/9 squamous carcinomas, and 1/17 other malignancies. Intermediate levels of inhibition (50 to 69%) were noted in 7/52, 4/9, and 6/17 of these respective subtypes. No clear trend toward superiority of any dose-schedule was noted. Since nafazatrom has proven non-toxic in our nearly completed Phase I study, and since this study suggests activity against several human cancers, Phase II level testing is warranted.

Chlorozotocin: results in colorectal carcinoma treated with high and low doses

SummaryClorozotocin was evaluated in patients with advanced colorectal cancer at 225 mg/m2 every six weeks in 14 patients with no prior treatment, at 200 mg/m2 in 43 patients with normal tolerance of prior chemotherapy, and at 100 mg/m2 in 38 patients with extensive or poorly tolerated prior therapy. Median survival for the respective groups was 192, 107 and 79 days; these differences are best explained as a function of performance status. Partial response was reported for one patient, 15 had disease stabilization and two had improvement short of partial remission. Myelotoxicity was acceptable at all doses, with thrombocytopenia being dose limiting at 225 mg/m2. Four patients developed azotemia during or after Chlorozotocin treatment. Chlorozotocin has minimal activity against colorectal carcinomas and no dose-response relationship is evident.