John E. Byfield

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.

Intra-arterial chemotherapy using an implantable infusion pump and liver irradiation for the treatment of hepatic metastases.

Liver metastases are a common cause of death in colon carcinoma. The dual blood supply of the liver permits regional perfusion while hepatic catabolism of 5‐fluorouracil (FU), floxuridine (FUdR) permit higher drug exposures than systemic (IV) administration. We have studied the effect of continuous intraarterial chemotherapy (FU: 5–10 mg/kg/day and FUdR: 0.2 mg/kg/day) and whole liver irradiation (1000 rad every 4 weeks, total dose of 3000 rad) for metastatic colon carcinoma to liver. Eighteen patients with metastases to liver only are reported using this combination therapy. Seven patients had percutaneous placement of a catheter via the brachial artery, two had operative placement of a catheter via the gastroduodenal artery, all of which were connected to the Cormed infusor system, nine had operative placement of the Infusaid implantable pump with catheter placement into the hepatic artery via the gastroduodenal artery. The median survival for the entire group was 241 days. In those patients whose liver function tests (bilirubin and alkaline phosphatase) were less than two times normal, the median survival was 770 days. The median survival of the patients with greater than two times normal LFTs was 178 days. Two patients died of complications of the treatment. One who developed irreversible radiation hepatitis but at autopsy had only two areas of microscopic tumor foci in the liver and another who had received only 15 days of infusion and 1000 rad to liver. This patient developed irreversible chemical enteritis secondary to chemotherapy infusion into the superior mesenteric artery. Three patients have undergone abdominal reexploration and one at autopsy, who were found to have no gross evidence of tumor in the liver despite previous pathologic confirmation. It appears that some patients with minimal tumor burdens can have sterilization of their tumors. There were three cases of reversible liver function abnormalities. Complications associated with conventional intra‐arterial chemotherapy (artery thrombosis, catheter sepsis and dislodgement, pump infusion variation and pump failure) were not seen with the Infusaid delivery system. The pump is refilled every 2–3 weeks via percutaneous puncture. All therapy was given on an outpatient basis. Pump acceptance and tolerance was 100%. Intra‐arterial chemotherapy can now be accomplished without the morbidity associated with it in the past. The combination of chemotherapy and liver irradiation may offer improved survival in selected patients.

Phase I and pharmacologic study of 72-hour infused 5-fluorouracil and hyperfractionated cyclical radiation

We have studied 21 patients infused for 72 hours with 5-Fluorouracil (5-FU) at progressive doses combined with hyperfractionated radiation. The schedule was chosen as being one capable of inducing 5-FU radiosensitization (RS). All patients were started at a daily 5-FU dose of 40 mg/kg/24 hours; doses were then escalated with each subsequent treatment cycle to limiting toxicity or until taken off study. Patients received between one and six infusion cycles. Every treatment cycle included coincident hyperfractionated radiation to various body areas including the abdomen, chest, and head and neck region. Radiation fractionation was invariant; 1,000 rad were delivered in four equal fractions. Two fractions of 250 rad each were given on days 1 and 2 of each three day 5-FU cycle, i.e. at approximately 0, 8, 24, and 32 hours into the drug infusion. Patients were followed for toxicity; serum 5-FU concentrations were determined using a high pressure liquid chromatographic assay. 5-FU clearances were calculated from the mean serum drug levels and the infused drug dose. The toxicity spectrum was not found to be significantly different from infused drug alone in this dose range save when the head and neck region received coincident irradiation. In that region the two anticipated toxicities combined in what appears to be a synergistic fashion to enhance mucositis. Most toxicities including gastrointestinal and bone marrow appeared dependent on the mean serum 5-FU level as did mucositis itself. 5-FU clearance was found to be non-linear in this dose region but did not appear influenced by radiation to any part of the body. This study shows that 72-hour infused 5-FU can be combined with external beam radiation and will produce reasonably predictable toxicity patterns which depend on the region of the body being irradiated. 5-FU toxicity correlates with mean serum drug level which is itself dependent on 5-FU clearance. Minor variations in 5-FU clearance therefore probably contribute to the natural range found in the dose-response relationship for infused 5-FU toxicities. Future studies should integrate this understanding of 5-FU pharmacokinetics into treatment regimens. The combination of infused 5-FU and coincident radiation appears useful in treating several tumor types, particularly squamous and squamous-like cancers. However, further scheduling and radiation fractionation studies are desirable to optimize 5-FU RS in man and to quantify late effects.

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.

Treatment of locally advanced squamous cell carcinoma of the head and neck with concurrent bleomycin and external beam radiation therapy

Abstract Nineteen patients with advanced head and neck cancer were treated with bleomycin (15u BM and irradiation (180 rad, 5d/week, 5040 rad) and have analyzed the effects. Most patients went on to further radical treatment. Both epithelial toxicity and tumor regression seemed enhanced. Approaching 1 year minimum follow-up (2 years maximum) crude survival is 68% and disease-free survival is 57%. Late complications do not seem to be enhanced. Regression in advanced nodal disease was less impressive.

Phase I and pharmacologic study of oral ftorafur and X ray therapy in advanced gastrointestinal cancer

We have treated 15 patients with advanced gastrointestinal carcinoma with a cyclical regimen of combined Ftorafur (N1-((2-furanidyl-))-5-Fluorouracil, a 5-FU pro-drug) and external beam radiation. The Ftorafur (FT) was administered orally in daily doses of between 1.0 and 2.5 g/m2/day in 3 divided doses in a Phase I format. The drug was given daily for 5 days along with conventional X ray treatment portals and daily radiation doses of 250 rad on each of the first 4 days of each treatment cycle. The patients were then rested for a minimum of 10 days or until all significant side effects had passed. The total number of 1,000 rad cycles and radiation dose were dictated by tolerance and by normal organ dose limitations. The most common toxicity in general, and the most common limiting toxicity was nausea and vomiting, in contrast to oral FT alone where diarrhea is more prominent. Stomatitis was seen only once and no other form of serious toxicity was encountered. Two-thirds of the patients responded in subjective terms (pain relief). There was 1 partial response to FT alone (pulmonary metastases outside the treatment field). The sole patient whose treatment field was outside the abdomen (chest portals for esophageal carcinoma) developed pneumonitis which contributed to his death. No other delayed effects were noted. Serum FT levels were related to the ingested dose and in the microgram range while serum 5-FU levels were in the nanogram range indicating slow decomposition of FT into 5-FU. The therapy was reasonably well tolerated at doses of 2.0 g/m2/day or lower with abdominal radiation. FT offers the potential for replacing intra-venous infused 5-FU as a clinical radiosensitizer.

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.

Enhanced accumulation of 5-Fluorouracil in human tumors in athymic mice by co-administration of Ftorafur and Uracil

Human colonic tumors grown in athymic mice were tested for the effect of coincident uracil (U) and Ftorafur (FT) exposure versus FT alone on 5-Fluorouracil (5-FU) metabolism. Serum and tumor FT and 5-FU levels were studied as a function of time after FT +/- U injections. The combination of U + FT led to significantly higher tumor/serum 5-FU ratios than FT alone. The data indicate that the metabolism of 5-FU released from FT can be modulated by coincident U exposure in human tumor cells in vivo. Such combinations may be of use in the development of oral 5-FU pro-drugs for applications using 5-FU as an out-patient non-invasive radiosensitizer.

Radiotherapy plus razoxane for advanced limited extent carcinoma of the lung

Forty‐four patients with limited extent American Joint Committee on Cancer Stage II‐III non‐small cell carcinoma of the lung were randomly assigned to potentially curative radiation therapy plus one of two schedules of razoxane. The weekly schedule was 1 gram per square meter body surface area (BSA) every 8 hours for two doses per week, and the daily schedule was a fixed dose of 250 mg per day. The 50% Kaplan‐Meier survival estimate for both groups combined was 9 months. There was no survival difference between the two dose‐schedules. Toxicity was formidable with an 82% incidence of esophagitis, and a 20% incidence of grade III‐IV esophagitis. Fifty‐nine percent of patients developed hematologic toxicity. This was greater with the weekly dose‐schedule (P = 0.01). Forty‐one percent of patients developed radiographic or symptomatic pneumonitis. One patient developed a fatal myelitis. This program is no more effective than irradiation alone, and has substantial morbidity.

Antibody-dependent cellular cytotoxicity-mediated serotherapy against murine neuroblastoma

SummaryHuman peripheral lymphocytes (HLc) have been studied in vitro as possible effector cells in an antibody-dependent cellular cytotoxicity (ADCC) reaction. HLc were found to be active against murine neuroblastoma cells (MNB) inoculated into the flank of syngeneic mice. Both the time of onset of tumor appearance and the mean survival time of tumor-bearing host mice were beneficially influenced. Occasional animals could be cured of up to 105 tumor cells (1–10 cells of MNB are lethal). This level of tumor cytotoxicity approaches that of tolerance-dose chemotherapy and is without demonstrable side-effects. HLc from patients who had just received = 3,000 rads fractionated therapeutic X-irradiation were equally effective as HLc from control non-irradiated donors when assayed at equivalent HLc : tumor cell ratios. HLc could also inhibit MNB tumor cell growth in the ascitic form, confirming in vivo activity. Overall, HLc appeared almost as active as rat spleen cells in mediating a useful anti-tumor ADCC. This approach may ultimately prove useful in man, especially in the peritoneal cavity, and is currently limited only by the need to develop appropriate antisera. It is proposed and emphasized that such antisera need not necessarily be directed at tumor-specific antigens. Organ-specific antibodies such are already known to develop spontaneously in some human auto-immune diseases might be equally useful and are a naturally occurring potential source of appropriately expressed genetic material.