Endocrinopathy following radiation to the head and neck.
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Biomedical subjects
Publications and source records attributed to J J Fischer.
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Delivery of continuous low-dose-rate radiation at a constant rate using an after-loading plastic helmet system can achieve the local cure of the BA1112 rat sarcoma. Complete dose response curves for local tumor cure have been obtained at 170 rad (1.7 Gy) and 130 rad (1.3 Gy) per hour. The results are consistent with the known radiobiological properties of the BA1112 tumor.
Short-course, high fractional dose radiation therapy was compared with the conventional protracted radiation schedule in the treatment of advanced (stages III and IV) head and neck cancer. Sixty-four patients with surgically unresectable squamous cell carcinoma were randomized to receive either 6,000 to 7,000 rad in six to seven weeks or 4,000 to 4,800 rad in two to three weeks. The palliative benefits of irradiation were comparable in the two treatment arms, and complete tumor regression was observed in the majority of patients in both groups. There was no difference between the groups with regard to either short-term normal tissue radiation reaction or long-term complications. High fractional dose irradiation appears to yield results equivalent to those of conventionally fractionated radiation therapy in advanced head and neck cancer and deserves further study both as primary treatment and in combination with surgery.
A method has been developed for the in vitro assay of the survival of BA1112 rat sarcoma cells following treatment in vivo. The BA1112 tumor was not adapted for growth in culture and was maintained by serial transplantation in vivo. The assay used a feeder layer of heavily irradiated cells to eliminate any changes in plating efficiency caused by the large number of dying cells which must be plated when assaying cell survival after intensive treatments. The plating efficiency of the tumor cells was not affected significantly by the age of the feeder layer (between 1 and 4 days), the density at which the experimental cells were plated or the interval between preparation of the cell suspension and plating (up to 4 hr). Using the in vitro assay a survival curve was determined for cells from tumors irradiated in air-breathing animals. This curve was similar to that determined previously for BA1112 tumor cells using an in vivo assay to measure cell survival.
Dose response curves were established for local control of the rat rhabdomyosarcoma BA1112 for radiation alone and for radiation following a cytoreductive operation. Removal of one-half of the tumor prior to irradiation did not significantly alter the dose of radiation necessary to cure 50 per cent of the tumors. This experimental result confirms the theoretic predictions and suggests that, to be useful in combination with radiation, surgical treatment must remove in excess of 90 per cent of the tumor.
Blood rickettsial titers, skin biopsy results, and circulating endotoxin measurements were correlated with the clinical course of disease in patients with Rocky Mountain spotted fever (RMSF). Nine of 11 patients with documented RMSF had Rickettsia rickettsii isolated from plasma samples. Of the eight patients in whom rickettsial titers were measured, seven had 10(0.7) to 10(1.2) median tissue culture infective doses (TCID50) per milliliter; all seven had mild to moderately severe disease. One patient with fulminant, fatal untreated RMSF had 10(3) TCID50/mL of postmortem plasma. Two patients from whom rickettsiae were not isolated had positive direct immunofluorescent stains of skin biopsy material for R rickettsii. Circulating endotoxin was present in two patients, one with documented rickettsemia and one with a positive skin biopsy alone. Only low levels of circulating rickettsiae are present in patients with moderately severe disease. Measurement of plasma endotoxin is not useful in the early diagnosis of RMSF.
The effect of cycloheximide (CHM) on skin and renal radiation tolerance in the rat has been studied. When administered 24 hr prior to a range of single radiation doses to the hind limbs, the drug protected against skin damage. When administered at intervals of 45 min to 100 hr prior to single-dose irradiation of the kidneys, no protection against renal injury, as manifested by blood pressure, urine creatinine level, and lethality, was observed. CHM-induced alteration in the cell cycle may confer radioprotection to a rapidly proliferating cell renewal system such as the skin and exert no radioprotective action in slowly proliferative tissue such as kidney.
Malignant melanoma is considered unresponsive to conventional radiation therapy when it is delivered at a daily dose rate of 130--300 rad/fraction. Previous studies have suggested that this is in part due to a large shoulder on the radiation survival curve and that higher dose fractions might be beneficial. High-dose fraction therapy is effective for local control of cutaneous, lymph node, and soft-tissue metastases. Results in 46 patients treated with high- or low-dose fractions for intracranial metastases over the last decade in the Melanoma Unit and Department of Radiotherapy at Yale have been examined. Twenty-six patients received high-dose fraction therapy, generally 600 rad/fraction/week to 2400--3600 rad; 20 patients received low-dose fraction radiotherapy with 125--400 rad/fraction daily. All patients were given steroids, and most received chemotherapy. Results in both groups were similar. Comparison of high- and low-dose fraction patients revealed: improvement in 38 and 35%, respectively, stability in 23 and 25%, and deterioration in 38 and 40%. Median survival was three months in the high-dose fraction group and 2 1/2 months in the low-dose fraction group. Presence of hepatic metastases had no significant influence upon median survival in patients who received high-dose fraction radiotherapy. In patients receiving low-dose fraction, survival was 2 1/4 months with and three months without hepatic metastases. Death in most patients resulted from progression of central nervous system disease. Side effects, especially headache, were more prominent in the high-dose fraction group. However, in no instance did side effects require discontinuation of therapy. The greater ease of delivery for weekly high-dose fraction radiotherapy outweighed any other difference between the regimens.
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A prospectively randomized clinical trial was undertaken to compare conventionally fractionated radiation therapy and high fractional dose irradiation in the treatment of advanced, surgically unresectable head and neck squamous cell carcinoma. Sixty-four patients were entered into the study between 1973 and 1979 and were randomized to receive either 200 rad daily to total tumor doses of 6000-7000 rad in 6-7 weeks, or 400 rad daily to a total of approximately 4400 rad in 2-3 weeks. The distribution of patients between the two fractionation schedules was comparable regarding site of the primary tumor, extent of disease, degree of histologic differentiation and performance status. Twenty-nine of 31 (94%) patients in the 200 rad group and 29 of 33 (88%) in the 400 rad group has Stage IV disease. Twenty-six in the former group and 30 in the latter completed radiation therapy as planned. Acute skin and mucosal reactions occurred earlier in patients treated with 400 rad daily, but were of equivalent intensity and well within acceptable levels in both groups. No increase in late adverse effects was seen with high daily doses. Palliation of tumor-related symptoms and extent of tumor control were comparable in the two groups. Actuarial five year disease-free survival rates were approximately 10% in both treatment groups with a mean follow-up period of 5 1/2 years. We conclude that high fractional dose irradiation is equivalent to conventionally fractionated radiation therapy in the treatment of advanced head and neck cancer.
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The rat rhabdomyosarcoma BA1112 has a number of features which make it a useful model for the study of tumour response to radiation therapy. It is a transplantable tumour, isologous to an inbred line of WAG/Rij rats and it elicits no demonstrable host immune response. The tumour grows locally at the implantation site and rarely metastasizes. It is known to contain hypoxic cells which reoxygenate during a prolonged course of fractionated radiation therapy. The growth and radiation response characteristics of the tumour have remained stable for over 15 years. A newly developed in vitro assay for tumour cell clonogenicity greatly facilitates the measurement of radiation dose-response curves and the monitoring of cell response following in vivo treatment. The in vivo response of the tumour to fractionated radiation therapy is analysed in terms of cellular response, reoxygenation and cell proliferation.
Fatal invasive pulmonary aspergillosis may follow viral influenza infections. Two cases with verified influenza A infection were followed by fatal necrotizing pneumonia due to Aspergillus fumigatus. Both patients demonstrated cutaneous anergy and lymphocytopenia. Influenza and perhaps other viruses that depress T-cell function may result in increased susceptibility to infections in which T cells are important in host defenses.