5-Fluorouracil radiation sensitization--a brief review.

5-Fluorouracil (FUra) has emerged as the most promising clinical radiosensitizer now available. FUra's capacity to render human cells more sensitive to x-rays was established soon after its synthesis. However, the recognition that the drug's unusual pharmacology dictated explicit scheduling requirements in man was not realized until recently when work in the author's laboratory identified the extra-cellular drug concentration X time factors necessary to create the intra-cellular radiosensitive state. Subsequent clinico-pharmacologic investigations led to the realization that only prolonged continuous infusions combined with appropriately fractionated, cyclical radiation therapy would maximize the clinical utility of this approach. Infused FUra radiation-sensitization therapy reaches its maximum efficacy against the squamous-transitional cancers. This group of human malignancies comprises about 15% of all human cancers. Preliminary data also suggests substantial promise in the local/regional control of rectal and breast cancers. Infused FUra used as a radiosensitizer has the potential to eliminate the need for about 90% of all radical cancer surgery.

Exclusion of an interactive effect of combined x-irradiation and activated cyclophosphamide in tissue culture.

The effect of Cyclophosphamide (CY) on the X ray survival of clonogenic tumor cells has been studied in vitro. Two activated derivatives of the drug, Peroxycyclophosphamide and Hydroperoxycyclophosphamide, were employed. Two cell lines, repair-competent human HeLa cells and the repair-deficient rat REQ line, were investigated. Neither form of CY had any effect on the X ray survival curve of either cell line, indicating that any interaction anticipated in vivo could be expected to be additive.

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 catabolism. 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.

Relevance of the pharmacology of oral tegafur to its use as a 5-FU pro-drug.

We have studied the pharmacology of iv and oral tegafur (FT) and compared the results with similar studies using continuously infused 5-FU. All patients received daily abdominal irradiation as well as FT. In eight patients receiving 1.0 g/m2 of iv FT, serum FT levels were essentially the same as those in five patients receiving the same dose of oral FT. Oral FT appeared well-absorbed, even with abdominal irradiation. The mean serum FT achieved on a daily basis was a linear function of the oral FT dose between 1.0 and 2.5 g/m2 and was consistently about 1000-fold higher than the resultant 5-FU level. The major FT metabolite, dehydro-FT (DHFT), was persistently present at about ten times the 5-FU level. Because of their long half-lives, both FT and DHFT accumulate during continuous therapy. When the mean serum 5-FU levels with oral FT were compared to those found during continuous 5-FU infusions, we found that oral FT was the equivalent of low-level 5-FU infusion. Oral FT at 1.0 g/m2 was the equivalent of about 11.5 mg/kg/24 hours of 5-FU, increasing to about 17.5 mg/kg of 5-FU for oral FT at 2.5 g/m2. The pharmacologic properties of FT appear to dictate its most useful schedule (continuous oral dosing in multiple doses) and explain why FT alone is not ideal as a 5-FU pro-drug. In addition, insight into the pharmacokinetic limitations of FT also suggests means by which its usage may be improved, including its potential application as a radiosensitizer.

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.

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.

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.

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.

Hematologic parameters in the adjustment of chemotherapy doses in combined modality treatments involving radiation.

The differential white blood cell count of a group of patients with Stages I and II infiltrating ductal carcinoma who underwent treatment in the preadjuvant chemotherapy era have been evaluated. All patients received a modified radical mastectomy followed by postoperative radiation therapy to the chest wall and draining regional lymph node chains (ipsilateral internal mammary, axillary,and supraclavicular regions). When the levels of circulating neutrophils, band cells, and lymphocytes were compared for the period beginning prior to surgery and ending 1 year after the completion of radiotherapy, it was found that radiation induced a significant lymphopenia. However, all patients maintained a neutrophil count at least twice that needed for full-dose conventional chemotherapy. Based on these observations and related preclinical and clinical information, it is proposed that future clinical trials utilizing even local radiotherapy as a component of therapy must have their chemotherapy doses based on appropriate hematologic parameters (neutrophil + band count) in order to avoid spurious and quite possibly erroneous results.

Thermal marrow expansion: effect of temperature on bone marrow distribution.

The distribution of bone marrow in adult mammals is limited mainly to those bones deeply embedded in the body and subject to the higher core body temperature. Active marrow is much less prevalent in the limbs. In the past this was attributed to the lower temperature of the peripheral bone marrow. We have studied the possibility of stimulating hematopoiesis in the limbs (and tails) by increasing the limb temperature. This has been done by elevating the ambient temperature of mice and by tail implantation techniques. Mice incubated at ambient temperature of 22 degrees C can be "expanded" to have markedly enhanced marrow activity in the limbs by either incubation for seven days or more at 34 degrees C, or by implantation of the bone into core temperature areas (peritoneal implantation). The increase in marrow activity is shown both histologically and by 59Fe uptake techniques. Anemia does not enhance this effect, indicating a local phenomenon. A variety of experiments suggest that temperature per se and not temperature-induced increase in blood flow is involved. The increase in marrow activity is accompanied by a modest local increase in clonogenic marrow stem cells but it cannot be shown for certainty whether the phenomenon of Thermal Marrow Expansion (TME) is due to the local effect of elevated temperature on stem or stromal cells. The erythrocytes produced by TME appear normal by in vivo fragility testing. TME may have clinical usefulness in man if the phenomenon occurs in the same fashion as rodents.

Phase I and II trial of five-day infused 5-fluorouracil and radiation in advanced cancer of the head and neck.

Eighteen patients with advanced epithelial cancers of the head and neck region were studied for their tolerance and response to combined cycles of 120-hour infused 5-fluorouracil (5-FU) and external-beam radiation therapy. 5-FU infusions were given under conditions where radiosensitization would be expected at the higher infusion doses. Coincident radiation treatments were given as four sequential daily fractions of 250 rad each administered during days 1 through 4 of each five-day infusion cycle. The patients were rested for at least nine days after each cycle or longer until toxicity was resolved. The regimen was then repeated in each patient for a total of five treatment cycles. Thereafter therapy was consolidated, usually by boost radiation without drug. In sequential patient subsets the infusion load was progressively escalated in a phase I format. The complete response rate for stage IV patients was 75% with survival benefit compared to prior results. 5-FU dose-dependent combined modality loco-regional toxicity was demonstrated without significant enhancement of systemic toxicity of any form; 5-FU dose-dependent enhanced responsiveness and survival benefit is also suggested. Further scheduling and response studies of 5-FU under radiosensitizing conditions appear warranted.

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.

Phase I-II study of 120-hour infused 5-FU and split-course radiation therapy in localized non-small cell lung cancer.

Thirty patients with locally advanced nonresectable non-small cell bronchogenic carcinoma were studied for tolerance and response to 120-hour continuously infused 5-FU (IFU) combined with chest x-ray therapy. The IFU was escalated in patient groups from 20 to 35 mg/kg/24 hours. Radiation was also escalated in patient subsets from 200 to 400 rads/fraction using a split-course technique to a total dose of 5000 rads. Tolerance was exceeded by IFU doses of 35 mg/kg/day. The complete response rate was ten of 28 patients (36%); a complete response was associated with a significantly prolonged survival. Radiosensitization of lung cancer by IFU appears clinically feasible in man.

Conservative management without alkylating agents of squamous cell anal cancer using cyclical 5-FU alone and x-ray therapy.

We have treated 11 patients with squamous cell anal carcinoma using a regimen of repeated cycles of 120-hour infused 5-FU (25 mg/kg/24 hours) and x-rays. Total radiation doses were between 3000 (palliative) and 4750 (curative) rads. Unlike all other equivalent combined-modality studies, no alkylating agent or drug other than 5-FU was used. With follow-up between 1 and 4 years, there has been only one local recurrence (coincident with terminal disseminated disease in a stage III patient treated palliatively). All other patients have maintained local control. Inclusion of alkylating agents (eg, mitomycin) in this approach can be questioned if the patient is willing to accept somewhat greater acute but reversible toxic effects.

Antibody-dependent cellular cytotoxicity-mediated serotherapy against murine neuroblastoma. II. In vitro and in vivo treatment using effector cells from normal and X-irradiated humans.

Human 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 10(5) 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.

Prognostic factors in the management of metastatic epidural spinal cord compression.

The results of 51 patients with metastatic spinal cord compression were analyzed. There were seven paralyzed patients, three received radiotherapy (RT) alone and four received laminectomy (L) + RT. No patient regained any motor function. Of six ambulatory patients, half received RT and half L + RT. All remained ambulatory after the treatment. Of 38 paraparetic patients, 20 underwent L + RT. Their complete, partial and nonresponse (CR, PR, NR respectively) rates were 25%, 60% and 15%, respectively. This result was clearly better than 18 other patients treated by RT alone of which only 22% regained ambulation (CR = 22%) while 67% were NR and 11% had a PR. In this series combined modality therapy appears better in paraparetic patients. Five patients with radiosensitive tumors all had CR/PR whether treated by RT or L + RT. Patients with epithelial tumors treated by L + RT had a PR (CR + PR) of 71% while RT alone gave only 25%. On the basis of this analysis we conclude: (1) ambulatory patients respond satisfactorily to RT alone; (2) paraparetic patients with radiosensitive tumors do well with RT alone while such patients with epithelial tumors merit L + RT; but (3) paraplegic patients rarely benefit from either modality; (4) pain control appears a useful measure of minimally adequate radiation dose in individual patients.