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Biomedical subjects

T H Wasserman

Publications and source records attributed to T H Wasserman.

At least 73 records · Page 4Linked to original sources
PubMed1984

Neuropathy of nitroimidazole radiosensitizers: clinical and pathological description.

The dose limiting toxicity of the nitroimidazole radiosensitizers is peripherial neuropathy. Improved pharmacology of newer drugs has eliminated the encephalopathy. Peripheral neuropathies are predominently mild to moderate paresthesias of both hands and feet. Subjective changes occur with or without minimal objective changes on neurologic exam. All of the neuropathies occurred within 30 days of the last drug dose and are of variable duration. Sural nerve biopsies from patients indicate progressive axonal degeneration affecting both large and small caliber myelinated fibers. Axonal damage appears to be more severe in the distal portion of the nerves. More data are needed for correlation of clinical and pathological changes.

Etanidazole↗
PubMed1984

Initial report of the phase I trial of the hypoxic cell radiosensitizer SR-2508.

From March 15, through August 31, 1983, 37 patients have been entered on the RTOG Phase I trial of SR-2508. The drug was given intravenously three times weekly for three weeks. The starting total dose was 11.7 g/m2 and the highest total dose given was 32 g/m2. The lower lipophilicity of SR-2508 has produced the expected decrease in terminal half-life (5.4 hrs) of drug excretion and increase in total drug excreted unchanged in the urine (71%) compared to misonidazole or desmethylmisonidazole. The maximum single dose (3.7 g/m2) administered was well tolerated. With multiple doses peripheral neuropathy is the dose-limiting toxicity. The lowest cumulative dose producing toxicity was 21.6 g/m2, the highest non-toxic dose was 29.7 g/m2. The use of an individual patient's drug exposure as measured by the area under the curve of drug concentration vs time may be an excellent predictor of toxicity. This may eventually permit individualization of dose and prevention of serious toxicity. A single dose of 2 g/m2 will produce a tumor concentration of drug (approx. 100 micrograms/ml) that will yield a sensitizer enhancement ratio of 1.5 to 1.7. Using a starting dose of 2 g/m2 three times weekly, patients are now being studied on a five week drug schedule to further evaluate predictability of drug toxicity in preparation for clinical trials of drug efficacy.

Drug Evaluation↗
PubMed1984

Promise of radiosensitizers and radioprotectors in the treatment of human cancer.

Over the past 30 years, as an understanding of radiation chemistry has developed, it has been possible to develop compounds which modify the initial radiochemical event. In addition, certain physiologic means such as hyperbaric oxygen or blood flow restriction have also been developed as methods to modify radiation response through the radiochemical processes. Following the success of certain hyperbaric trials, a great effort was made to develop chemical agents which would mimic oxygen in their sensitization of hypoxic cells. A large series of compounds have now been identified with such properties and several of these have entered clinical trial. The first compound to receive widespread testing, misonidazole, has proven too toxic to be used in adequate doses for clinically relevant sensitization. Two new nitroimidazole analogs, which are excluded from the central nervous system, promise to allow much higher degrees of sensitization in planned clinical trials and new non-nitro drugs are under development. Radioprotection can be achieved through various methods, including restriction in blood flow and the use of sulfhydryl-containing compounds which again modify the initial radiochemical events. To be successful in tumor therapy, such agents must be selective in protecting the normal tissues. One class of compounds, the thiophosphates, show differential protection of normal tissue vis-à-vis tumor through several mechanisms. After extensive animal testing, one of these compounds, WR 2721, is now in phase I clinical testing, with phase II evaluation planned for the near future. Other potential sensitizers with varying degrees of differential activity in tumor versus normal tissue are also discussed.

Clinical Trials as Topic↗
PubMed1983

Palliative radiation treatment of cutaneous mycosis fungoides--a dose response.

Between 1966 and 1981, 20 patients (191 lesions) underwent palliative radiation therapy for control of biopsy-proven cutaneous mycosis fungoides. Six patients (47 lesions) and an additional 34 lesions from the remaining 14 patients with complete response to treatment were excluded from the study because of follow-up of less than one year. Included in the remaining 110 lesions were all recurrences and all partial responses. The modalities for treatment included superficial X rays, Cobalt-60 or electron beam irradiation. The total tumor doses employed ranged from 600-4000 cGy. The 110 lesions (14 patients) were retrospectively analyzed to determine the dose required for local control of the lesions. Fifty-three percent of the lesions were classified as plaques, 20% as tumors less than or equal to 3 cm in diameter, and 27% as tumors greater than 3 cm in diameter. Complete response to treatment was observed in 95% of the plaque lesions, 95% of the tumors less than or equal to 3 cm in diameter and 93% of tumor greater than 3 cm in diameter. A complete response to treatment was noted in all lesions receiving greater than 2000 cGy. In the total population of lesions having a complete response, a local infield recurrence rate of 42% was noted in the group receiving less than or equal to 1000 cGy, 32% in those receiving 1001-2000 cGy, 21% in those receiving 2001-3000 cGy, and 0% in the group receiving greater than 3000 cGy. No infield recurrence was seen when the treated lesion received a total tumor dose greater than or equal to TDF of 49. Of those lesions which recurred, the mean time to recurrence for the first three dose ranges above were 5 months, 10 months and 16 months respectively. Eighty-three percent of the 30 recurrences were seen within one year of treatment; 100% of the recurrences occurred within two years of treatment. The data from this study indicate that tumor doses equivalent to at least 3000 cGy at 200 cGy per fraction, five fractions per week (TDF greater than or equal to 49) are needed for adequate local control of cutaneous mycosis fungoides lesions.

Cobalt Radioisotopes↗
PubMed1983

Misonidazole combined with large-fraction pelvic irradiation in the treatment of patients with advanced pelvic malignancies. Preliminary report of an ongoing RTOG phase I-II study.

Between October 1979 and January 1982, a total of 39 cases were entered on a nonrandomized phase I-II protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with advanced pelvic malignancies of multiple gynecological and gastrointestinal origin. Patients were treated with pelvic irradiation using a dose of 1000 rad in one fraction every 4 weeks for a total of three treatments. Oral misonidazole at a dose of 4 g/m2, was administered 4-6 hours prior to the radiation treatment (total dose, 12 g/m2). Of the 39 patients entered, 25 have completed the three doses of radiation and have had at least one follow-up after the third treatment. Eight patients have had insufficient follow-up information for evaluation and five patients did not complete three doses of radiation but have follow-up. One patient was excluded from the study. Among the 30 patients with follow-up, there were four complete responses (13.3%) and seven partial responses (23.3%). Two patients showed no response, and 17 experienced progression of disease. Follow-up time ranged from 2 to 16 months. The most frequent toxicity in the study has been nausea and vomiting. There were eight cases of neurotoxicity reported: ototoxicity grade 1 (one patient), peripheral neuropathy grades 1 and 2 (six patients), and C.N.S. toxicity grade 2 (one patient). Toxicity from radiation was difficult to separate from the presenting symptomatology. In the 30 patients with follow-up information, eight cases of abdominal sequelae were seen with five of them major complications (perforation, obstruction, and abscess). Early information from the study indicates the following: The most frequent morbidity at this point is acute nausea and vomiting. This level of nausea is consistent with the protocol dose of misonidazole. From the evaluable patients, 5/30 (17%) have developed major bowel problems requiring surgery. At the time of this report, this protocol remains open for case accession.

Adolescent↗
PubMed1983

Non-Hodgkin's lymphoma of the stomach.

Thirty-seven patients with non-Hodgkin's lymphoma of the stomach were treated with curative intent by several single and combined modality regimens. Twenty-two patients presented with stage IE and 15 with stage IIE disease. All but three patients underwent laparotomy. Of all diagnostic procedures used, x-ray of the upper gastrointestinal tract proved to be most helpful in diagnosing malignant lesions (87%). Gastric cytology was suspicious or diagnostic of malignancy in 35% of the patients. Twelve of 34 evaluable patients (35%) developed recurrence. Distant metastases (75%) was the most common mode of failure. The recurrence rates varied by the type of therapy and also the extent of initial disease. Four of 12 patients (33%) were salvaged with retreatment. The 5-year actuarial no evidence of disease survival for the entire group was 61% (stage IE-57%; stage IIE-67%). Patients receiving combined modality therapy had significantly (p = less than 0.05) higher survival than patients treated with single modality treatment. Three of 29 patients (10%) died of surgical complications after gastrectomy. Radiation treatment was well tolerated. Our data and a critical review of the literature do not support the reportedly high incidence of gastric perforation after radiation treatment. We recommend the use of adjuvant radiation for stage IE and adjuvant radiation plus chemotherapy for stage IIE gastric lymphoma.

Adult↗
PubMed1982

Evaluation of the bioavailability of misonidazole (NSC#261037) in capsule and tablet form and pharmacologic effects of daily dosage.

A total of 34 patients were studied in order to evaluate capsule vs. tablet form of misonidazole and intermittent vs. daily administration. These patients were given drug formulation of tablets for one week and capsules for one week on either an intermittent (1, 2, or 3 times per week) or daily schedule. Total doses ranged from 5-15 gm/m2. There was no significant difference seen in mean serum levels or half-lives between capsules and tablets. Daily misonidazole resulted in slight build-up of serum levels in the latter part of the week. There was no difference in toxicities seen with drug daily vs. intermittent administration.

Adult↗
PubMed1982

Cutaneous Hodgkin's disease.

Involvement of the skin in advanced Hodgkin's disease is well known. However, Hodgkin's disease initially seen in the skin is extremely rare. A patient had Hodgkin's disease that was initially seen as a cutaneous lesion on the buttock. Lymphadenopathy developed two months after completion of local radiotherapy to the cutaneous lesion and seven months after initial diagnosis. The histologic changes in both instances were those of Hodgkin's disease. We discuss problems in the diagnosis and treatment of skin involvement with Hodgkin's disease.

Biopsy↗
PubMed1981

Primary radiation treatment of colloid carcinoma of the breast: a case report.

A case report is presented of a patient with a colloid carcinoma of the breast, stage T3 N0 M0, treated definitively with external and interstitial radiation. Three-year follow-up has shown no local recurrence, with complete regression and no development of regional or distant metastases. The prognostic significance of colloid carcinoma and the use of radiation in its treatment are discussed.

Adenocarcinoma, Mucinous↗
PubMed1981

Final report on the United States Phase I Clinical Trial of the hypoxic cell radiosensitizer, misonidazole (Ro-07-0582; NSC #261037).

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 micrograms/ml at 1 g/m2 to 183 micrograms/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.

Adolescent↗
PubMed1981

The potential for radiation sensitizers and radiation protectors combined with radiation therapy in gynecologic cancer.

Radiation sensitizers are agents which can increase the lethal properties of ionizing radiation when administered in conjunction with radiation therapy. They increase radiosensitivity without being innately toxic and give rise to significant increase in the radiation sensitivity of neoplasm over normal tissues. Much laboratory work, mostly in vitro, has shown that many chemical compounds can act as radiation sensitizers. The practicality depends upon the exploitation of the differences between normal and malignant cells when radiation sensitizers are used. Many tumors contain hypoxic cells which are relatively resistant to the lethal effects of ionizing radiation. In human tumors, these hypoxic cells present a potential barrier to successful treatment. The application of chemical radiosensitizers active against hypoxic cells offers great potential for improvement in cancer management using radiation therapy. Data is presented to illustrate the usefulness of these agents in gynecologic cancer.

Amifostine↗
PubMed1981

Radiation Therapy Oncology Group clinical trials with misonidazole.

This paper presents a review of the progressive clinical trials of the hypoxic cell radiosensitizer, misonidazole, in the Radiation Therapy Oncology Group (RTOG). Presentation is made of all the schemas of the recently completed and currently active RTOG Phase II and Phase III studies. Detailed information is provided on the clinical toxicity of the Phase II trials, specifically regarding neurotoxicity. With limitations in drug total dose, a variety of dose schedules have proven to be tolerable, with a moderate incidence of nausea and vomiting and mild peripheral neuropathy, and a low incidence of more severe peripheral neuropathy or central neuropathy. No other organ toxicity has been seen, specifically no liver, renal or bone marrow toxicities. The clinical pharmacologic monitoring of misonidazole blood levels has been satisfactory with good correlation between the group-wide (Phase II) UV values and the HPLC values from the Phase I study. The patient accrual of the trials has been rapidly increasing and an early analysis suggests efficacy better than previous radiation experience. A series of eight Phase III trials are currently underway or proposed in the RTOG and the results of these are pending. An additional Phase III malignant glioma trial in the Brain tumor Study Group is described.

Brain Neoplasms↗
PubMed1981

Differential protection against cytotoxic chemotherapeutic effects on bone marrow CFUs by Wr-2721.

This paper reports on the ability of the radioprotector WR-2721 to protect bone marrow colony forming units from the cell kill of various cytotoxic chemotherapy agents including nitrogen mustard, cyclophosphamide, BCNU, cis-platinum, and 5-fluorouracil. The dose-modifying factors seen with these compounds ranged from 1.5 to 4.6. Protection by WR-2721 seems to be selective for the bone marrow endpoint, in that similar protection against EMT6/SF tumor cell kill was not seen with the same combination of the cytotoxic chemotherapy agents and WR-2721 as measured by regrowth delay. The implications of these data are discussed in the paper.

Amifostine↗
PubMed1981

Clinical trials of misonidazole in the United States.

This paper presents a review of the progressive clinical trials of the hypoxic cell radiosensitizer, misonidazole, in the United States. Presentation is made of all of the schemata of the recently completed and currently active Radiation Therapy Oncology Group (RTOG) phase II and phase III studies. Detailed information is presented on the clinical toxicity of the phase I and II trials, specifically regarding neurotoxicity. With limitations in drug total dose, a variety of dose schedules have proven to be tolerable, with a moderate incidence of nausea and vomiting and mild peripheral neuropathy, and a low incidence of more severe peripheral neuropathy or central neuropathy. No other organ toxicity has been seen, specifically no liver, renal, or bone marrow toxicities. The clinical pharmacologic monitoring of misonidazole blood levels has been satisfactory with good correlation between the group-wide (phase II) UV values and the HPLC values from the phase I study. The patient accrual of the trials has been rapidly increasing and an early analysis suggests efficacy which is at least comparable to previous radiation experience. A series of the five phase III trials are currently underway in the RTOG and the results of these are pending. An additional malignant glioma trial in the Brain Tumor Study Group is described.

Drug Evaluation↗
PubMed1980

Therapy of hepatocellular cancer with combined intrahepatic arterial chemotherapy and whole liver irradiation.

Hepatocellular cancer provides an ideal model for studying combined modality chemotherapy and radiation interactions. We have treated 20 evaluable patients. All patients received intrahepatic arterial (IA) 5 FU (10 mg/kg/d continuous infusion times 5 minus 9 d) + Adriamycin (3-5 mg/m(2)/d bolus times 5 minus 7 d), and 1,500 and 2,100 rads whole liver radiation (300 rads/day). Additionally, 3 patients have received IA Mitomycin C (8 mg/m(2)). After this "induction" therapy patients usually received IV Adriamycin + 5FU +/- Mitomycin monthly. Objective regressions occurred in 9/20 (45%) and another 9/20 (45%) and stable disease. Median duration of response is 5+ months (range 1+ to 8 months). Improvement in liver function tests occurred in 11/19, and local symptomatic relief in 12/15. Median WBC nadir = 4,000; platelet nadir = 115,000. Mild anorexia, fever, and nausea were frequent, but no radiation hepatitis has been detected. This program seems to result in significant clinical benefit (subjective and objective) in this refractory neoplasm.

Adult↗