Richard J.R. Johnson
New York State Department of Health
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International Journal of Radiation Oncology Biology Physics | 1979
Todd H. Wasserman; Theodore L. Phillips; Richard J.R. Johnson; Charles J. Gomer; Gilbert Lawrence; Wolfgang Sadée; Roberto A. Marques; Victor A. Levin; Gretchen Vanraalte
Abstract The hypoxic cell radiosensitizer, misonidazole, is in a Phase I clinical pharmacology and toxicology trial. Forty patients were evaluated on a weekly dose schedule. Misonidazole was given on the dose schedule of a single oral dose weekly for 3 or 6 weeks in separate patient groups. Radiation therapy, of a palliative nature, was given 4–6 hr after drug administration to allow for maximal tumor levels. The initial dose level was 1 gm/m 2 and escalated to 3 gm/m 2 weekly × 6 weeks and 5 gm/m 2 weekly × 3 weeks. Toxicologic evaluation included serial clinical and laboratory evaluations. The principle toxicities observed were nausea and vomiting and neurotoxicity. The nausea and vomiting were acute, and dose limiting at 5 gm/m 2 . The neurotoxicity was primarily a peripheral sensory polyneuropathy, either seen on objective exam only or with mild to moderate paresthesias. Three patients manifested motor neuropathy with moderate weakness. Some ototoxicity and encephalopathy was observed. All patients had reversible, non-progressive neuropathy. The development of neuropathy was not related to the pharmacologic parameters of serum level or half-life. The incidence of neuropathy was related to total drug dose. Patients receiving less than or equal to 10 gms/m 2 had an incidence of 4 of 19 (21%) compared to patients receiving more than 10 gms/m 2 who had an incidence of 15 of 19 (79%). Pharmacologic evaluation included ultraviolet (UV) or high pressure liquid chromatography (HPLC) measurements of blood, urine, stool, and tumor biopsies. The HPLC identified Ro-05-9963, the desmethylated compound, as the principal metabolite in both blood and urine. Comparison of sera levels at the time of radiation (4–6 hr) with oral drug dose showed a good correlation, with maximum oral drug absorption not reached. Clinically significant blood level of 100 μg/ml could be achieved by a dose of about 2.5 gm/m 2 or 65–80 mg/kg. The pharmacology yielded peak sera levels at 2–4 hr with a mean half life of 15 hr and median of 14 hr; the half life was not related to drug dose. Urinary excretion was principally of the active metabolite (9963); total per cent excretion of both compounds in 24 hr ranged from 12–65% with a mean of 28% and a median of 23%. Tumor levels in 2 patients were 80 and 90% of peak sera levels. No increased toxicity of normal tissues in the radiation field was observed. Some interesting patient responses were observed. Further toxicologic, pharmacologic, and efficacy studies are underway.
International Journal of Radiation Oncology Biology Physics | 1984
Ronald S. Scott; Richard J.R. Johnson; Katherine Story; Laverne Clay
Fifty-nine patients with superficial malignancies appropriate for treatment with definitive radiotherapy and technically suitable for application of local microwave hyperthermia were available for at least 6 months follow-up. Thirty-one of these patients presented with two lesions, only one of which was heated, the other serving as internal control. The responses of the lesions which were heated were compared with those receiving only radiation. The heated lesions responded more quickly, reconfirming observations previously made. However, at subsequent 6 months, 1 year, 18 months and 2 years follow-ups, tumor clearance was shown to be significantly more complete as compared with the internal controls. At 6 months follow-up complete response with combined therapy was observed in 27 of 31 lesions (87%) in contrast to complete response in 12 of 31 (39%) lesions treated with radiotherapy alone. At one year combined modality treatment produced complete response in 19 of 19 lesions (100%) while radiotherapy alone yielded complete response in 10 of 19 lesions (53%). At 18 months, 8 of 9 lesions (89%) treated with combined therapy remained controlled, 1 having recurred. Seven of 9 (78%) treated by radiotherapy alone were controlled, 2 having recurred. At 2 years, 6 patients were available for follow-up and 6 of 6 (100%) of lesions treated with combined modality remained controlled. Among those treated by radiotherapy alone, 5 of 6 (83%) remained controlled, while 1 recurred. The rate of tumor recurrence among the heated lesions was significantly lower than was found among the controls. The recurrence rate among the controls was similar to that expected in a similar group of patients treated with definitive radiotherapy. Therefore, in addition to its established capability to shrink tumors, hyperthermia in combination with radiotherapy has been shown to increase the rate of overall tumor clearance and reduce recurrences compared with that obtained from radiotherapy alone.
International Journal of Radiation Oncology Biology Physics | 1981
Ronald S. Scott; Richard J.R. Johnson; Henry S. Kowal; R. Murty Krishnamsetty; Katherine Story; Lawerne Clay
Facilities for regional tumor hyperthermia has been in use at RPMI since 1976, and have been routinely used to treat patients according to protocol since 1977. Hyperthermia delivery has been exclusively by microwave using 434 MHz, 915 MHz and 2450 MHz. Greatest success at reaching tumor temperatures of 43-44 degrees C with minimal skin heating was obtained using 915 MHz. The majority of the patients were treated with this frequency. Approximately 125 patients have been treated and 70 have achieved completion of therapy and follow-up. Follow-up has been at least one month and several patients have been followed for one to two years. Initially, for entry into the hyperthermia protocol, patients were required to have three or more lesions. One lesion on each patient was treated with 800 rad fractions repeated three times on a 72 hour schedule. The second lesion was treated with 700 rad fractions and the third with 500 rad plus hyperthermia on the same schedule. Twelve patients with multiple melanoma lesions completed this study. One of 12 patients showed no response to the combination of hyperthermia plus radiotherapy, while four showed no response to radiotherapy alone. Of eight patients who survived three months, all lesions treated by hyperthermia plus radiotherapy responded completely, while only five lesions treated by radiotherapy alone so responded. In a second study, 58 patients with superficial tumors were treated by a protocol where hyperthermia was added to optimal conventional radiotherapy. Of the total, 43 patients had complete tumor response at follow-up varying from one month to 18 months. A subgroup of 24 of these patients had two lesions, one of which was treated with hyperthermia in addition to radiotherapy while the other served as control, receiving radiotherapy only. Nineteen lesions demonstrated complete response to hyperthermia plus radiotherapy, while only 14 of the controls had complete response. None of the lesions treated with hyperthermia responded less well than those treated by radiotherapy alone. Morbidity, as measured by skin reaction, was rarely increased in the heated field.
Cancer | 1981
Theodore L. Phillips; Todd H. Wasserman; Richard J.R. Johnson; Victor A. Levin; Gretchen Vanraalte
The hypoxic cell sensitizer misonidazole began phase I evaluation in the United States in July 1977. One hundred two patients received 104 individual courses of drug. Drug was administered from once to five times per week over time spans from one to six weeks. The individual doses ranged 1–5 g/m2, and 411 mean 4–6 hour serum levels were determined. The mean 4–6 hour serum level ranged from 30 μg/ml at 1 g/m2 to 183 μg/ml at 5 g/m2. The major toxicity noted was neurologic; 49% of evaluable courses showed peripheral neuropathy, and 9% of evaluable courses showed central nervous system effects and/or ototoxicity. In addition, 48 of 102 patients exhibited some degree of nausea and vomiting. The concomitant administration of dexamethasone and phenytoin sodium appeared to lower the incidence of neuropathy. Observations of efficacy were made comparatively in five patients who had multiple lesions treated with and without misonidazole. All five showed increased response in the lesions treated with misonidazole. It is concluded that misonidazole is a reasonably safe and potentially effective hypoxic cell sensitizer whose dose‐limiting toxicity is neurologic.
International Journal of Radiation Oncology Biology Physics | 1984
Kenneth H. Luk; Mildred E. Francis; Carlos A. Perez; Richard J.R. Johnson
A registry established by the Radiation Therapy Oncology Group provides data for assessing the impact of clinical heating in a set of non-randomized patients treated with hyperthermia in participating member institutions from 1/77 to 6/81. This analysis focuses on tumor response when localized hyperthermia is produced by microwave and applied pursuant to two distinctly different treatment schedules. Hyperthermia treatments were biweekly and combined with daily radiation treatments in one patient group, and combined with biweekly radiation treatment in another. Sample X consists of 65 patients who received a course of therapy using combined hyperthermia and radiation in consecutive treatment sessions each separated by at least 48 hours, but no more than 96 hours. Sample Y consists of 34 patients who received further radiation after the start of a course of combined therapy--either between or at the end of a series of combined treatment sessions. The average length of heat treatment was 72 minutes for Sample X and 32 minutes for Sample Y patients. None of the patients received concurrent chemotherapy; all received between 3 and 13 hyperthermia treatments; all had superficial, measurable tumors. On the average, Sample X patients received 704 total minutes of heat compared to Sample Y patients who received 233 total minutes of heat. Total tumor radiation doses ranged from 17.0 Gy to 44.0 Gy among Sample X patients with 92.3% receiving radiation at either 3 Gy or 4 Gy per fraction. In Sample Y the range for total tumor dose was 16.0 Gy to 70.2 Gy with 73.4% of the patients receiving radiation at 2.5 Gy or less per fraction. Generally, the two treatment schedules achieved similar levels of tumor response. Among treated tumors in Sample X and Sample Y, complete regression rates were 52.4 and 61.8%, respectively, and partial regression rates were 16.9 and 14.7%. Adenocarcinoma and squamous cell carcinoma in both samples responded well to these combined treatments. Only in Sample X was there a statistically significant trend of decreasing complete regression rate when the treated tumor sizes increased. Best responses to treatment generally occurred between 28 and 84 days after completion of the combined therapy course. There were no differences between the two samples with respect to median days to best response or response duration. Blister, ulcer or wet desquamation were reported in 47.7% of Sample X as the maximum skin reaction. In contrast, only 20.6% of Sample Y had these complications.(ABSTRACT TRUNCATED AT 400 WORDS)
International Journal of Radiation Oncology Biology Physics | 1976
Richard J.R. Johnson
Abstract A thermodynamic method to assess human and animal tumor blood flow was developed at the Massachusetts Institute of Technology. Blood flow is assessed by measuring the thermal flux occurring when a beat sink is positioned over the tumor and maintained at either a constant hyperthermic or a hypothermic temperature. The concept of the adenosine autoregulatory control of cellular oxygen tension was utilized to interpret the quality of the flow. The preliminary results obtained in human tumors using the thermodynamic method to assess blood flow has shown that: 1. (1)| Blood flow in some human tumors will increase during the first few days following a single dose of 400 to 800 rad. 2. (2)| Fractionated radiation (5000 rad in 5 weeks) causes a gradual increase in both normal and tumor tissue blood flow during treatment and inhibits the normal tissue hypothermic vasoconsriction. 3. (3)| The presence of hypothermic vasoconstriction in normal tissue and in some tumors suggests that constant vasomotion (cycles of vasoconstriction and vasodilation) may induce cycling hypoxia sufficient to affect the radiation response. It is suggested that this cycling hypoxia may account for the presence of some biologically hypoxic epithelial cells m normal skin and that inhibiton of the vasoconstrictive response by radiation may be a contributing factor towards reoxygenation in tumors which exhibit microvascular control.
International Journal of Radiation Oncology Biology Physics | 1979
Richard J.R. Johnson; Taljit S. Sandhu; Frederick W. Hetzel; Seung-Yil Song; Haim I. Bicher; John R. Subjeck; Henry S. Kowal
This article reports the clinical results of the combined treatment of radiation and localized microwave hyperthermia to treat multiple metastatic melanoma tumors. The response of normal skin to the treatment was measured by evaluating the degree of erythema using a numerical scoring system. Tumor response to the treatment was assessed by measuring tumor diameter at follow-up visits. Whenever possible, thermal enhancement ratios for normal skin and tumor tissue were evaluated. The manuscript discusses problems associated with obtaining useful clinical data.
International Journal of Radiation Oncology Biology Physics | 1978
Taljit S. Sandhu; Henry S. Kowal; Richard J.R. Johnson
Abstract Two direct-contact microwave (915 MHz and 2450 MHz) applicators were designed and fabricated for localized hyperthermia treatments of solid tumors. The 2.45 GHz applicator can be attached to an X-ray machine head and used as a cone to deliver X-rays and microwaves simultaneously. The 915 MHz applicator has the capability of cooling the skin surface by circulating a dielectric liquid through a bag attached to the application end of the applicator. The temperature and the flow of the liquid can be controlled to achieve the desired skin temperature. The temperatures of the incoming and outgoing liquid through the bag were measured to determine the energy lost. Temperature distributions were obtained using a pig in vivo system with liquid crystal and thermocouple probes. Using the 2.45 GHz applicator the skin surface remained at the highest temperature and a very steep temperature drop was observed (3.5°C drop at a depth of 3 cm). Temperature distribution improved when the 915 MHz applicator was employed. The skin surface remained at a temperature 0.5° C lower than that of the tissue at 1 cm depth. A temperature drop of only 1°C was observed at a depth of 3 cm. An even better distribution was obtained when skin surface was cooled. Skin surface and tissue at a depth of 3 cm were elevated to the same temperature while the tissue at depth of 2 cm was raised to a temperature 1°C higher.
Radiation Research | 1983
B. W. Henderson; H. I. Bicher; Richard J.R. Johnson
The vascular fibrinolytic activity, known to originate from the endothelium, was studied histochemically by fibrinolysis autography in liver samples from beagles exposed to radiation treatment. Eighteen to thirty months prior to sacrifice, six dogs received X irradiation (4600 rad in 5 weeks) and three dogs received X irradiation plus aspirin (1 g/kg). Two dogs served as untreated controls. Control livers showed extensive fibrinolytic activity related to large and small vascular structures. The vascular fibrinolytic activity had been lost from all vessels except the major portal branches in five irradiated livers and was severely diminished in three. One irradiated liver appeared to possess normal fibrinolytic activity.
Radiation Research | 1979
Charles Gomer; Richard J.R. Johnson
A single intraperitoneal injection of the radiation sensitizer misonidazole at doses greater than 0.5 mg/g was found to produce a transient hypothermic response in C3H mice. An increase in the acute toxicity of this drug was demonstrated when the animal core temperature was maintained at a normal 35 to 370C by placing the mice in a warmed environment immediately following injection of the drug. The LDs0/3 day, dose of misonidazole was determined to be 1.48 mg/g for mice allowed to become hypothermic following injection but 0.77 mg/g for mice maintained at a normal core temperature following injection.