Thomas R. Sharp

Infusional 5‐fluorouracil and x‐ray therapy for non‐resectable esophageal cancer

Six patients with unresectable carcinoma of the esophagus received a combined course of external radiation therapy (1000 rads in four fractions in four days commencing on day 2) combined with constant infusional 5‐fluorouracil (20 mg/kg every 24 hours for five days beginning on day 1). This program was repeated every other week to give a total x‐ray dose of 6000 rads. This regimen has been well‐tolerated by the majority of the patients and resulted in a complete response rate within the x‐ray treatment field of 83% (5/6). All patients who showed a demonstrable systemic response to 5‐fluorouracil reached complete response. The median survival has not yet been reached at six months with post‐treatment survivors alive and without disease (four patients) at one, six, nine, and 22 months. Our previous median survival by x‐ray therapy alone was 4 1/2 months. Toxicity consists primarily of hematologic suppression at a subclinical level. Although the length of therapy is substantial (11 weeks), the program appears tolerable and is capable of inducing long‐term remissions. The program is currently being studied for dose escalation because neither local nor systemic side effects of a doselimiting nature have been observed at 20 mg/kg 5‐FU. Cancer 45:703‐708, 1980.

Treatment with combined intra-arterial 5-FUdR infusion and whole-liver radiation for colon carcinoma metastatic to the liver. Preliminary results.

TWENTY-EIGHT PATIENTS WITH COLON CARCINOMA metastatic to the liver were treated with continuously infused intra-arterial 5-fluorouracil deoxyriboside (5-FUdR) and cyclical whole-liver radiation (2000–3000 rad). Survivorship ranged from 25 days to almost 4 years and was a clear function of the extent of liver dysfunction at the time of initiation of this treatment. Difficulties in establishing the objective complete response rates in patients with minor imaging abnormalities were frequently noted. Both extracorporeal and permanently implanted arterial infusion devices have been employed, the results favoring the internal infusion units. Under ideal circumstances (early treatment, disease limited to the liver, and a permanent indwelling pump), a median survivorship of approximately 2 years can be projected with a significant number of patients rendered free of progressive cancer in the liver for months to years. The dose-limiting feature of this approach is treatment-related to hepatitis, which proved lethal in one of 28 patients thus far treated. Preclinical studies on the original and reduction of drug- and x-ray-induced liver toxicity should have high research priority.

Phase I and pharmacologic study of 72-hour infused 5-fluorouracil in man

THE RELATIONSHIPS BETWEEN THE ADMINISTERED DOSE, clearance, and the toxicity spectrum of 5-fluorouracil (5-FU) administered as 72-hour constant infusion have been studied in 21 patients with advanced cancer. This was done as a pilot study for possible future combination using 5-FU as a radiosensitizer. Individual patients tolerated up to 65 mg/kg/24 hours, but serious toxicity appeared once as low as 35 mg/kg. Limiting toxicity proved to be “mixed” with upper intestinal symptoms (nausea and vomiting), stomatitis, and central nervous system signs all occurring in various patients. Central nervous system effects (both cerebellar and vomiting) proved as troublesome as stomatitis. There was only a general link between the administered dose and the subsequent toxicity grade, but a reasonably quantitative relationship emerged when the serum 5-Fu levels obtained and the degree of patient toxicity were compared.The clearance of 5-FU was confirmed to be nonlinear over the entire dose range studied (25–65 mg/ kg/24 hours), consistent with a two-compartment model of drug metabolism. One compartment appears to be systemic (extra-hepatic) metabolism (probably anabolic removal) which is saturated at just below 15 mg/kg/day. Doses above that level lead to drug accumulation. No steady state was reached, contrary to previous reports. At the higher infusion rates, clearance progressively approaches that predicted by the assumption that the second compartment is splanchnic blood flow and catabo-lism. While 5-FU can be administered as a 72-hour infusion as one possible schedule for use as a single agent or for combined modality studies, CNS effects are quite troublesome in comparison to longer infusions to toxicity.

Surgical adjuvant therapy in colon carcinoma: a human tumor spheroid model for evaluating radiation sensitizing agents.

HT‐29 human colon tumor cells growing as spheroids have been evaluated as a model system for measuring the response of human colon tumor cell to antineoplastic agents. HT‐29 cells have the capacity to form spheroids up to 1 mm or more in diameter when grown in spinner culture. The multicellular HT‐29 spheroids develop hypoxic centers reflecting the cellular conditions found in human cancer treatment, i.e., nutritionally deficient hypoxic cells that are felt to be a significant source of both radiation and chemotherapy clinical treatment failures. Spheroids of increasing size were radiated and then dispersed into single cells for colony survival assay. Compared with irradiated single cell suspensions, the spheroid cells demonstrated a significant increase in radioresistance. Growing spheroids developed a complex radiation survival curve which was variable with respect to size of the spheroid. The drug 5‐FU was studied to examine in a preliminary fashion its interaction with these resistant cell fractions. In direct cytotoxicity assay, 5‐fluorouracil (5‐FU) exhibited both cytotoxic and cytostatic effects when the drug was present at a concentration greater than 0.4 μg/ml. The interaction of 5‐FU with x‐rays in the HT‐29 spheroids was complex and dependent on the type of assay employed (spheroid size versus clonogenicity). The effect of allopurinol, an agent that protects cells from 5‐FU toxicity was also examined. Allopurinol at a concentration of 100 μg/ml was found to protect these human colonic carcinoma cells from the cytotoxic effects of 5‐FU under conditions resembling those found in vivo. Overall, this HT‐29 spheroid system appears to be an interesting model for studying a variety of drug/x‐ray interactions in vitro and may prove capable of answering specific questions of preclinical and clinical relevance.

Bleomycin, cyclophosphamide and radiotherapy in regionally advanced epidermoid carcinoma of the head and neck

We have treated 24 patients with squamous carcinoma of the head and neck and advanced regional (N2-3) disease. The regimen consisted of 3 cycles, each of 28 days. Cyclophosphamide (1 gm/m2 I.V.) was given on day 1, bleomycin (15 u I.M.) on days 2, 4, 9 and 11, and ionizing radiation (60Co, 180 rad/fraction) days 1-5, and 8-12. No therapy was given on days 13-28. After three cycles of therapy, 13 patients had a complete response; following further therapy (surgery, interstitial or external beam radiation), 16 patients were free of disease. However, remissions were not durable and 11/16 patients recurred loco-regionally with a median time to recurrence of 5 months; most (7/11 also developed distant metastases. These patients have biologically aggressive disease and may have a worse prognosis than patients who are Stage IV based on a T4 primary lesion only.