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R C Urtasun

Publications and source records attributed to R C Urtasun.

At least 19 recordsLinked to original sources
PubMed1992

Comparison of prognostic factors and survival among black patients and white patients treated with irradiation for non-small-cell lung cancer.

BACKGROUND: Many studies have reported differences in cancer incidence and survival between populations of Blacks and Whites. A 45% higher death rate from lung cancer for Black men and a survival duration for Black patients with lung cancer that is generally shorter than that for White patients have also been reported. PURPOSE: The purpose of this study was to evaluate whether race affects known prognostic factors for non-small-cell lung cancer in Black versus White patients. This analysis attempts to determine which prognostic factors may contribute to the reported differences in disease outcome. METHODS: We used data from 1565 patients with non-small-cell lung cancer treated in four randomized prospective trials conducted by the Radiation Therapy Oncology Group (RTOG). The data were pooled for a retrospective analysis of survival and prognostic factors by race. RESULTS: Univariate analysis showed significant differences between Blacks and Whites with regard to sex, weight loss, histology, and RTOG T stage (P < .05), but the only clinically significant difference (P < or = .01) was weight loss. Despite these findings, overall survival for Blacks and Whites did not differ significantly (P = .67). Median survival for Blacks and Whites with a Karnofsky performance status (KPS) of 90 or more was 12.1 and 11.3 months, respectively (P = .45). Survival for Blacks and Whites with a KPS of less than 90 was 7.8 and 6.8 months, respectively. Cause of death did not differ between the two races. For both races, KPS, age, sex, weight loss, and RTOG T and N stages were significant prognostic factors for survival (P < .01), but race was not a significant prognostic factor. CONCLUSION: Further studies of the differential in cancer survival for Blacks and Whites may be indicated, but greater impact may be achieved by addressing socioeconomic factors, lifestyle and occupational risk factors, health education, and access to adequate health care.

Black People↗
PubMed1992

Increasing radiation dose intensity using hyperfractionation in patients with malignant glioma. Final report of a prospective phase I-II dose response study.

We attempted to show a dose effect relationship for radiation therapy by treating patients harbouring malignant glioma with increasing doses of radiation in a step-wise fashion. We postulated that no increase in delayed toxicity would be seen because we used hyperfractionation technique. Between January 1981 and December 1988 we treated 280 patients three times daily at 4 hour intervals. 100 patients received a total dose of 6141 cGy, 73 patients received 7120 cGy, and 107 patients received 8000 cGy. CCNU was given at the time of tumor progression following radiotherapy. Median time to tumor progression was 28 weeks for patients who received 6141 cGy, 27 weeks for patients who received 7120 cGy and 36 weeks for patients who received 8000 cGy. Median survival was 46 weeks for patients who received 6141 cGy, 38 weeks for patients who received 7120 cGy and 45 weeks for patients who received 8000 cGy. There was no statistically significant difference in either time to tumor progression or survival among the three treatment arms and no dose response effect was seen. There was no increase in delayed radiation toxicity when the total radiation dose was increased up to 8000 cGy.

Adolescent↗
PubMed1992

Does improved depth dose characteristics and treatment planning correlate with a gain in therapeutic results? Evidence from past clinical experience using conventional radiation sources.

Experience with the use of external beam conventional radiation over a period of several decades has shown that in every instance where there has been a major advance in the physical delivery of radiation to the tumor (beam energy and characteristics and precise tumor dose delivery) there has been a corresponding major improvement in the treatment results. The advent of megavoltage sources following the invention and use of Cobalt 60 and medical linear accelerator units during the late 1940's and early 1950's and their major impact on tumor control and patient survival in solid tumors such as carcinoma of the prostate, Hodgkin's Disease, head and neck tumors and cancer of the cervix are being discussed. Most recently, the use of computerized tomography and computer systems for treatment planning is likely to show a further improvement in the therapeutic results.

Humans↗
PubMed1992

Heterogeneity in response to treatment with buthionine sulfoximine or interferon in human malignant glioma cells.

Two tumor cell lines were established from each of three human malignant glioma biopsy specimens (M059, M067, M071) and sensitivity to treatment with radiation or chemotherapeutic agents (BCNU, nitrogen mustard) was determined. The effects of recombinant human interferon-alpha (rIFN) on the radiation response and of buthionine sulfoximine (BSO) on the drug response were investigated as well. For tumor M059, two cell lines that differed significantly in radiosensitivity were isolated (surviving fractions at 2 Gy = 0.02 and 0.64). The chemosensitivity and response to chemical modification differed as well. Cell lines established from tumor M071 differed in their response to rIFN only and were not sensitized by BSO. M067 cell lines showed little difference and were not sensitized by either agent. These results suggest that differences may exist both within and among human malignant gliomas with regard to their sensitivity to drugs, radiation, and the ability of chemical agents to modify treatment responses.

Buthionine Sulfoximine↗
PubMed1992

Radiosensitivity testing of human primary brain tumor specimens.

The inherent radiosensitivity of early passage cells derived from 22 patients with tumors of glial origin has been determined using a clonogenic assay system. The mean (+/- SD) surviving fraction at 2 Gy was 0.37 +/- 0.22 (range = 0.02-0.87). No correlation between inherent radiosensitivity and tumor cell plating efficiency or intracellular glutathione was observed. Tumor cells that were both resistant to nitrosoureas and expressed the Mer+ phenotype did not differ significantly in their radiosensitivity as compared to cells that were repair deficient (Mer-) and sensitive to nitrosoureas. Initial clinical follow-up suggests that factors in addition to inherent tumor cell radiosensitivity, such as performance status and age, continue to be the most important determinants of the response of patients with primary brain tumors to radiotherapy.

Astrocytoma↗
PubMed1992

Non-invasive assessment of human tumour hypoxia with 123I-iodoazomycin arabinoside: preliminary report of a clinical study.

Non-invasive predictive assays which can confirm the presence or absence of hypoxic cells in human tumours show promise for understanding the natural history of tumour oxygenation, and improving the selection of patient subsets for novel radiotherapeutic strategies. Sensitiser adducts have been proposed as markers for hypoxic cells. Misonidazole analogues radiolabelled with iodine-123 have been developed for the detection of tumour hypoxia using conventional nuclear medicine techniques. In this pilot study, we have investigated one such potential marker, 123I-iodoazomycin arabinoside (123I-IAZA). Patients with advanced malignancies have undergone planar and single-photon emission computed tomographic (SPECT) imaging after intravenous administration of 123I-IAZA. We have observed radiotracer avidity in three out of ten tumours studied to date. Normal tissue activity of variable extent was also seen in the thyroid and salivary glands, upper aerodigestive tract, liver, intestine, and urinary bladder. Quantitative analysis of those images showing radiotracer avidity revealed tumour/normal tissue (T/N) ratios of 2.3 (primary small cell lung carcinoma), 1.9 (primary malignant fibrous histiocytoma) and 3.2 (brain metastasis from small cell lung carcinoma) at 18-24 h post injection. These preliminary data suggest that the use of gamma-emitter labelled 2-nitroimidazoles as diagnostic radiopharmaceuticals is feasible and safe, and that metabolic binding of 123I-IAZA is observed in some, but not all tumours. The inference that tumour 123I-IAZA avidity could be a non-invasive measure of tumour hypoxia deserves independent confirmation with needle oximetry.

Adult↗
PubMed1991

Glutathione levels and chemosensitizing effects of buthionine sulfoximine in human malignant glioma cells.

Biopsy samples and cultured cells derived from them were obtained from 39 patients with malignant glioma and were analyzed for 1) glutathione (GSH) content; 2) sensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and/or nitrogen mustard (HN2) treatment and 3) the effect of buthionine sulfoximine (BSO) treatment on BCNU and/or HN2 cytotoxicity. The average GSH concentration of biopsy specimens was lower than those of cultured cells (2.36 +/- 0.44 vs. 11.42 +/- 2.32 nmol/10(6) cells). While some of the tumor specimens were sensitive to either BCNU or HN2, the majority were resistant to both. However, 8 of 23 tumors tested showed enhanced sensitivity to BCNU following treatment with BSO. Five of 17 tumors were similarly sensitized to HN2 by BSO. These results suggest that BSO chemosensitization may be of value for certain patients and that screening assays may help identify treatment-sensitive individuals.

Adolescent↗
PubMed1990

Final report of the phase I trial of the hypoxic cell radiosensitizer SR 2508 (etanidazole) Radiation Therapy Oncology Group 83-03.

In a Phase I trial SR 2508 was administered by rapid intravenous infusion to 102 patients receiving radiation therapy. The dose-limiting toxicity was peripheral sensory neuropathy (PN) which was related to the cumulative dose administered. The highest single daily dose, 3.7 g/m2, was tolerated without toxicity. The lowest cumulative toxic dose was 21.6 g/m2, and the highest non-toxic dose was 40.8 g/m2. Grade 1 neuropathies were mild and self-limited; grade 2 neuropathies were long-lasting and debilitating. In a retrospective analysis, the risk of developing neurotoxicity was related to the cumulative drug exposure calculated by the area-under-the-curve (AUC) of plasma concentration versus time. There was an increased incidence of neuropathy in patients with a cumulative AUC of greater than or equal to 36 mM-hr. At a total dose of 34 g/m2 over 6 weeks, the incidence of Grade 1 neuropathy was approximately 30%; no grade 2 neuropathy occurred at this dose and schedule. Additional toxicities observed included nausea and vomiting (6%), skin rash (4%), and transient arthralgias (3%). One patient had transient abnormalities in liver function tests of unknown etiology. (In a more recent Phase II trial neutropenia has been observed which may be related to SR2508). Approximately three times more SR 2508 is tolerable compared to misonidazole, and it appears that severe neuropathy can be avoided by monitoring individual patient pharmacokinetic parameters. Evaluation of the efficacy of this hypoxic cell sensitizer is in progress.

Adult↗
PubMed1989

Hyperfractionated radiation therapy for brain-stem glioma: a phase I-II trial.

Fifty-three patients (19 adults and 34 children) harboring brain-stem glioma were treated with hyperfractionated radiation therapy (100 cGy twice a day, 5 days/wk, to a total dose of 7200 cGy). For the entire group, the median time to tumor progression (TTP) was 59 weeks (adults 66 weeks, children 44 weeks) and the median survival time was 74 weeks (adults 92 weeks, children 64 weeks). Statistically significant prognostic factors associated with a decrease in TTP and median survival times (adults less than children) were: patient's age, a clinical history of less than 2 months, widespread brain-stem dysfunction, and a diffuse tumor as seen on magnetic resonance imaging. A finding of glioblastoma multiforme at histological analysis was associated with a statistical trend toward poorer survival, but in general tumor histology was not predictive of outcome. No evidence of an increase in acute or delayed radiation toxicity was seen with this fractionation schedule and total dose. This study suggests that hyperfractionation prolongs the TTP and survival time for many patients with brain-stem glioma. However, there remains a group of patients who are only moderately helped by this technique and for whom more aggressive treatment is warranted.

Adult↗
PubMed1988

Final report on phase I trial of WR-2721 before protracted fractionated radiation therapy.

This is the final report of the Phase I Protocol for the initial clinical study of Multiple Dose WR-2721 with radiotherapy (RTOG 80-02). The essential object of the study was to determine the highest dose of WR-2721 that could be given daily for the greatest number of weeks 15 to 30 minutes before conventional radiation treatment schedules. Eighty-four patients were entered into various dose levels. The major and dose-limiting toxicities were emesis, hypotension and malaise. The latter symptom was characterized by increasing weakness, fatigability, and ill-feeling. The maximum tolerated dose (MTD) established by this study is 340 mg/m2 given 4 days a week (excepting Wednesday) for 5 weeks. The drug is delivered intravenously in 7 minutes. There were no long-term blood chemistry changes. There were no deaths due to the administration of the radioprotector.

Adolescent↗
PubMed1988

Use of hemibody irradiation as a non-cross-resistant agent in combination with systematic chemotherapy in small cell lung cancer.

Previously, investigators at this institute have studied the use of upper hemibody irradiation as a consolidation agent following combination chemotherapy for small cell lung cancer. There was no improvement in survival compared to that in the group treated with chemotherapy alone. In our present pilot study, we are investigating the toxicity and efficacy of using hemibody irradiation (HBI) as a non-cross-resistant agent early in a program of alternating chemotherapy consisting of six treatment cycles. Toxicity due to the combined effects of chemotherapy (cisplatin and etoposide plus cyclophosphamide, doxorubicin, and vincristine) plus HBI is reported. The HBI was given at a dose of 1,000 cGy in four fractions for limited disease or as a single 800-cGy dose for extensive disease. Bone marrow suppression following HBI necessitated a subsequent delay in the chemotherapy cycle or dose reduction in 55% of the 33 patients. Six patients developed diffuse interstitial pneumonitis following chemotherapy and HBI; 3 have died, and in 2 of these, the etiology was opportunistic infection. In our previous studies utilizing HBI either alone or as consolidation therapy after induction chemotherapy, a low incidence of lung toxicity occurred. This increased incidence suggests a possible drug-radiation interaction when HBI is used as an alternating agent with doxorubicin and cisplatin.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Relationship between the neurotoxicity of the hypoxic cell radiosensitizer SR 2508 and the pharmacokinetic profile.

Complete pharmacological data from 71 patients treated on the phase I trial of SR 2508 were analyzed to see if the dose-limiting toxicity of peripheral neuropathy is related to the individual patient's pharmacokinetic profile. In a retrospective analysis, the risk of toxicity was best predicted by using the bivariate model of total drug exposure and the time over which the treatment course was given. Drug exposure [area under the curve (AUC)] for a single treatment was calculated by the integral over time of the serum concentration of SR 2508. Since the AUC was constant during the course of a patient's treatment, the total drug exposure (total-AUC) was estimated by the product of the AUC times the number of drug administrations. While the clinical efficacy of hypoxic cell sensitizers remains to be proven, SR 2508 is better tolerated than its predecessors, misonidazole and desmethylmisonidazole, as three times the amount of SR 2508 can be given. If this model is confirmed in the current phase II and III trials, the probability of developing neuropathy would be predictable for an individual patient from measurements made at the time of the first drug dose, allowing for the adjustment of drug schedule to avoid all but minor toxicity.

Dose-Response Relationship, Drug↗
PubMed1987

Misonidazole and CCNU chemotherapy for recurrent primary brain tumor.

CCNU chemotherapy prolongs survival of patients with primary brain tumor when given at the time of tumor progression following radiation therapy. Used as single agent, response rates of 30 to 80 per cent have been reported with median response durations of five to six months. Experimentally, tumor cytotoxicity is enhanced using the combination of misonidazole and CCNU, without increasing myelotoxicity. In this phase I/II study, 23 patients with primary brain tumor which progressed following radiation therapy were treated with combined CCNU and misonidazole. In all patients either the diagnosis of high grade glioma was made at the time of initial diagnosis prior to radiation therapy or the tumor transformed from low grade to high grade glioma at the time of progression following radiation therapy. CCNU 120 mg/M2 was given four hours following misonidazole 3.5 g/M2 every six weeks, with dosage adjustments for myelotoxicity. Treatment was continued for one year or until tumor progression. Of the 17 patients in the study for one year or more, 11 (65 per cent) survived for one year, and six (35 per cent) remained free of tumor progression for one year. Median time to tumor progression from start of CCNU plus misonidazole chemotherapy was 27 weeks and median survival was 80 weeks. No severe complications resulted from myelotoxicity. One patient developed mild peripheral neuropathy which disappeared following discontinuation of misonidazole.

Adult↗
PubMed1987

Eastern Cooperative Oncology Group: a comparison of adjuvant doxorubicin and observation for patients with localized soft tissue sarcoma.

Forty-seven patients with stage I, II, or III soft tissue sarcoma were entered into a prospective randomized Eastern Cooperative Oncology Group (ECOG) adjuvant protocol. Eligibility included conservative or radical primary treatment for local cure. Patients were then randomized to control or Adriamycin (Adria Laboratories, Columbus, OH). Adriamycin was administered at 70 mg/m2 (slow push, every 3 weeks for seven courses for a maximum of 550 mg/m2). To date, 32 patients, 17 males and 15 females, with an age range of 17 to 75 years (median, 44 years) have been followed sufficiently long to be included in this analysis. Nine patients have died. The median follow-up of the remaining 23 patients is 30 months (range, 2 to 50 months). Survival was not significantly different between Adriamycin or control. However, the disease-free interval was slightly different in favor of observation. This preliminary report does not support the hypothesis that Adriamycin is an effective adjuvant therapy for soft tissue sarcoma. Due to the small numbers, these results must be interpreted in relation to our ability to detect a difference, if in fact one existed. These preliminary data suggest that adjuvant Adriamycin not be used outside the confines of a clinical trial such as the current intergroup adjuvant sarcoma study.

Adult↗
PubMed1986

Phase I trial of the hypoxic cell radiosensitizer SR-2508: the results of the five to six week drug schedule.

Sixty-five patients were entered on the long schedule of the Phase I trial of SR-2508. The planned total doses ranged from 30 to 40.8 g/m2 using various treatment schema including daily, split course, and every-other-day schedules. The individual dose size was 2 g/m2 for 56 patients and 1.7 g/m2 for nine. In contrast to misonidazole and desmethylmisonidazole, more SR-2508 can be administered as the duration of therapy is lengthened. All six patients on the 30 g/m2 step tolerated the drug without toxicity. This total dose was not achievable in the three week schedule. Additionally, a number of patients did not develop neuropathy at a cumulative dose of 40.8 g/m2. Although the analysis is not yet complete, a given patient's drug exposure as measured by their total AUC (mMxhr), defined as the area-under-the-curve of serum concentration of SR-2508 vs. time for a single dose times the number of doses given, is useful in predicting toxicity for that patient. The recommended starting schedule for the Phase II and III trials is 34 g/m2 over a 6 week period (2 g/m2 every other day). A total AUC of approximately 39 mMxhr should be tolerable. The drug regimen must be altered for patients who have a high AUC. Therefore, it is mandatory to have an accurate and rapid pharmacokinetic analysis for each patient. The clinical efficacy of the hypoxic cell sensitizers remains to be proven. However, using the guidelines derived from the Phase I trial, SR-2508 should be a relatively safe drug, producing minor or no toxicity.

Drug Administration Schedule↗
PubMed1986

Binding of 3H-misonidazole to solid human tumors as a measure of tumor hypoxia.

Treatment-resistant, chronically hypoxic tumor cells have been assumed to exist in some solid human tumors, limiting their curability. To date, six patients with different types of tumors have been studied using radioactive labelled electron affinic compounds that bind to hypoxic cells. Although the gross clinical appearance of the tumors in all six patients was of a large and fixed mass which might on clinical grounds be expected to contain hypoxic cells, we have observed drug binding to hypoxic regions in only two, a rapidly growing small cell lung cancer (SCLC) and a malignant melanoma. The hypoxic fraction of the malignant melanoma was found to be 6% and the SCLC tumor approximately 10%. We have observed that areas of maximum adduct formation can be found in tumor cells immediately adjacent to blood vessels, suggesting that blood flow over the labelling interval was restricted. These preliminary studies suggest that sensitizer adduct formation in human tumor tissue may be a useful measure of tissue pO2 at the cellular level and that tumor hypoxia might be more related to the rate of tumor growth and histological grading than to tumor size.

Autoradiography↗
PubMed1986

A novel technique for measuring human tissue pO2 at the cellular level.

Some electron-affinic drugs, developed as hypoxic cell radiosensitizers, become selectively bound to the molecules of hypoxic cells by metabolism. This technique has been used to identify zones of chronically hypoxic cells in multicellular spheroids and animal tumours. Tritiated-misonidazole was administered to a patient with advanced melanoma 22 h prior to the surgical resection of a large metastatic s.c. lesion growing on the face. Autoradiographic analysis of histological sections revealed zones of intense labelling by the radioactive drug, indicative of tumour cells which were chronically hypoxic. This technique appears to provide an indirect measurement of tissue pO2 at the cellular level from which estimates of the tumour hypoxic fraction can be made. These data are encouraging as regards the development of 'sensitizer-adduct' procedures for the invasive and non-invasive measurement of hypoxia in both tumours and normal tissues.

Adult↗