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Biomedical subjects

D C Shrieve

Publications and source records attributed to D C Shrieve.

At least 37 records · Page 2Linked to original sources
PubMed1995

Radiation pneumonitis following combined modality therapy for lung cancer: analysis of prognostic factors.

PURPOSE: To identify factors associated with radiation pneumonitis (RP) resulting from combined modality therapy (CMT) for lung cancer. MATERIALS AND METHODS: Series published before 1994 that used CMT for the treatment of lung cancer and explicitly reported the incidence of RP are the basis for this analysis. Factors evaluated included the radiation dose per fraction (Fx), total radiation dose, fractionation scheme (split v continuous), type of chemotherapy and intended dose-intensity, overall treatment time, histology (small-cell lung cancer [SCLC] v non-small-cell lung cancer [NSCLC]), and treatment schedule (concurrent v induction, sequential, or alternating CMT). RESULTS: Twenty-four series, including 27 treatment groups and 1,911 assessable patients, met our criteria for inclusion in this analysis. The median total dose of radiation used in the trials analyzed was 50 Gy (range, 25 to 63 Gy). The median daily Fx used was 2.0 Gy (range, 1.5 to 4.0 Gy). Nineteen series included 22 treatment groups and 1,745 patients treated with single daily fractions. Among these patients, 136 received a daily Fx greater than 2.67 Gy. Five series used twice-daily radiotherapy and included 166 patients (Fx, 1.5 to 1.7 Gy). The incidence of RP was 7.8%. In a multivariate analysis, only daily Fx, number of daily fractions, and total dose were associated with the risk of RP (P < .0001, P < .018, and P < .003, respectively). CONCLUSION: In this analysis, the use of Fx greater than 2.67 Gy was the most significant factor associated with an increased risk of RP. High total dose also appears to be associated with an increased risk, but twice-daily irradiation seems to reduce the risk expected if the same total daily dose is given as a single fraction. High-Fx radiotherapy should be avoided in patients who receive CMT with curative intent.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme.

The purpose of this study was to compare the efficacy of stereotactic radiosurgery (SRS) and brachytherapy in the treatment of recurrent glioblastoma multiforme (GBM). The patients had either progressive GBM or pathologically proven GBM at recurrence after previous treatment for a lower grade astrocytoma. Thirty-two patients were treated with interstitial brachytherapy, and 86 received treatment with stereotactic radiosurgery (SRS). The patient characteristics were similar in the two groups. Those patients treated with SRS had a median tumor volume of 10.1 cm3 and received a median peripheral tumor dose of 13 Gy. Patients treated with brachytherapy had a median tumor volume of 29 cm3. Median dose to the periphery of the tumor volume was 50 Gy delivered at a median dose rate of 43 cGy/hour. Twenty-one patients (24%) treated with SRS were alive, with a median follow-up of 17.5 months. Median actuarial survival, measured from the time of treatment for recurrence, for all patients treated with SRS was 10.2 months, with survivals of 12 and 24 months being 45 and 19%, respectively. A younger age and a smaller tumor volume were predictive of better outcome. The tumor dose, the interval from initial diagnosis, and the need for reoperation were not predictive of outcome after SRS. Five patients (16%) treated with brachytherapy were alive, with a median follow-up of 43.3 months. The median actuarial survival for all patients treated with brachytherapy was 11.5 months. Survivals of 12 and 24 months were 44 and 17%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Advances in radiation therapy for brain tumors.

Despite important advances in surgery and chemotherapy, much of the recent progress that has been achieved in the treatment of brain tumors has resulted from developments in radiation therapy. This article reviews some of the recent advances in radiotherapeutic strategies being used in the treatment of brain tumors in adults. The overall management of each specific tumor type is discussed.

Adult↗
PubMed1995

High-grade astrocytomas.

Despite intense research, progress in the treatment of patients with HGA has remained slow. New therapeutic strategies are emerging, however, based on technologic advances in surgery and radiotherapy, improved understanding of the molecular, cellular, and immunobiology of astrocytomas, and advances in gene therapy, It is likely that these new strategies will result in significant progress in the treatment of HGA in the next decade.

Adult↗
PubMed1994

Radiation therapy with concomitant continuous infusion cisplatin for unresectable nonsmall cell lung carcinoma.

PURPOSE: This pilot study was designed to test the tolerance and effectiveness of concurrent continuous infusion cisplatin and radiotherapy in the treatment of unresectable nonsmall cell lung (NSCL) cancer. METHODS AND MATERIALS: Between July 1989 and July 1991, 92 consecutive patients with either medically or technically inoperable NSCL cancer were treated with thoracic radiotherapy and concomitant chemotherapy. Radiotherapy consisted of a total dose of 70 Gy delivered in 2 Gy daily fractions over 9 weeks with a planned 2-week break after 40 Gy. During the second week of each cycle of radiotherapy, cisplatin was administered, 20 mg/m2/day for 5 days as a continuous infusion. Eighty-five patients were evaluable. RESULTS: Overall response rate was 81.7% (65.9% complete response). Medically operable patients were considered for curative surgical resection following 40 Gy and one cycle of chemotherapy; 11 patients underwent resection with 3/11 having no pathologic evidence of tumor. Median survival for all 85 patients was 11.4 months with a median follow-up of 27 months. Overall survival was 48.2%, 27.5%, and 25% at 12, 24, and 36 months, respectively. Survival was independent of tumor stage, histology and grade, and patient age and gender. Patients having a complete response (n = 54) had a 2-year survival of 42.1% compared to 3.2% for partial-responders and nonresponders (n = 31; p < 0.0001). Patients undergoing surgical resection (n = 11) had a 2-year survival of 75.8% compared to 20.6% for those treated with chemoradiotherapy alone (n = 74). Forty-eight patients have died of their disease. There were two treatment-related deaths, seven deaths of intercurrent disease and three of unknown causes. Eighteen of 25 patients alive at the time of analysis were without evidence of disease. Actuarial local control was 50.6% at 1 year, and 33.3% at 2 years. The distant failure rate was 47.8% at 2 years. Major acute toxicities, mainly hematologic or gastrointestinal, occurred in less than 10% of patients. Esophagitis was mild and infrequent (8.4%). Severe late pulmonary fibrosis occurred in 5.2% of patients and resulted in two treatment-related deaths. CONCLUSION: Concomitant chemoradiotherapy was well tolerated, resulted in a high rate of local control, and in a survival benefit for patients demonstrating a complete response or going on to surgical resection. The incidence of distant metastases continues to be high and future strategies should be directed at improving systemic therapy.

Adult↗
PubMed1994

Stereotactic radiotherapy: a technique for dose optimization and escalation for intracranial tumors.

Stereotactic radiosurgery offers the ability to treat relatively small volume intracranial lesions with single fraction, high dose radiotherapy while sparing surrounding tissue due to rapid fall off of dose outside of the treatment volume. Conventional radiotherapy takes advantage of the sparing effects of dose fractionation, but includes relatively large amounts of normal brain in the treatment volume the tolerance of which is dose-limiting. For some intracranial lesions it may not be optimal to treat with large single fractions due to tumor location or size. Conventional fractionated radiotherapy may not be optimum in all cases due to the necessary inclusion of normal structures. Through the development of relocatable head frames, the precision of stereotactic techniques and the biologic advantages of fractionation may be combined in stereotactic radiotherapy (SRT). We report on the treatment of 68 patients with intracranial lesions using a dedicated stereotactic linear accelerator to deliver SRT between June 1992 and June 1993. SRT was used either in order to optimize dose distribution and spare normal tissues in patients with excellent prognosis or in order to increase the dose to tumor while keeping doses to normal tissues below tolerance levels in patients with poorer prognosis (dose escalation). Histologies treated included meningioma, low grade astrocytoma, pituitary adenoma and acoustic neuroma. The most common treatment sites were the parasellar region and cavernous sinuses. Most patients (79%) had surgical debulking prior to SRT. 10-12 patients were treated daily. Patient positioning using relocatable stereotactic frames was highly precise. Acute and subacute side effects were minimal and radiographic responses have been similar to those expected with conventional radiotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Hyperfractionated radiation therapy for gliomas of the brainstem in children and in adults.

Between February 1984 and September 1990, 60 patients with brainstem gliomas were treated with hyperfractionated radiotherapy in the Department of Radiation Oncology at the University of California, San Francisco. Forty-one children (< or = 18 years) and 19 adults were treated with 100 cGy twice daily with 4-8 hr between doses. Thirty-one patients (21 children and 10 adults) received total doses of 66-72 Gy and 29 patients (20 children and nine adults) received 74-78 Gy. Median follow-up was 208 weeks for all patients (214 weeks for children, 157 weeks for adults). Twenty-three patients (14 children and nine adults) were alive at the time of analysis, surviving 59-359 weeks following treatment. Median actuarial survival was 73.6 weeks overall (72 weeks for children, 190 weeks for adults; p = 0.43). Survival at 12 and 24 months was 65% and 38%, respectively (63% and 32%, for children; 68% and 53% for adults). All patients had pretreatment magnetic resonance imaging by which tumors were classified as either focal or diffuse. No significant pretreatment prognostic factors for adults were identified. In children, significant favorable prognostic factors on univariate analysis were older age (p = 0.001), tumor location in thalamus or midbrain (p = 0.002), focal appearance on MRI scan (p < 0.001) and duration of symptoms > 2 months prior to treatment (p < 0.001). Thirty-five patients had tumor biopsies, leading to a diagnosis in 33 (22 children and 11 adults). Children with moderately anaplastic astrocytomas survived significantly longer than those with glioblastoma multiforme or unbiopsied tumors (p < 0.001). Only duration of symptoms > 2 months remained significant as a favorable prognostic indicator for children on multivariate analysis (p < 0.001). Survival was not significantly different for patients receiving < or = 72 Gy and those receiving > 72 Gy (p = 0.18). No subgroup of patients showed significantly better survival with the higher dose. These findings indicate that hyperfractionated radiotherapy is effective treatment for adults and a subgroup of better prognosis children with brainstem gliomas. There is a subgroup of pediatric patients with extremely poor prognosis for whom even this aggressive treatment does little to extend survival. We conclude that there is no benefit to increasing total dose above 72 Gy for any of the groups analyzed.

Adolescent↗
PubMed1988

Heterogeneity of cellular glutathione among cells derived from a murine fibrosarcoma or a human renal cell carcinoma detected by flow cytometric analysis.

Monochlorobimane (syn-(ClCH2, CH3)-1,5-diazabicyclo-[3.3.0]-octa-3,6-dione-2,8-dione; mBCl) forms a fluorescent adduct with glutathione (GSH), which has been used as a basis for flow cytometric analysis. While mBCl will react nonspecifically with many different thiols, preferential derivatization of GSH can be achieved by using a low concentration of mBCl, since the reaction with GSH is catalyzed by GSH S-transferase, and the nonenzymatic reaction is very slow (k = 3.3 x 10(-1) M-1 s-1 at 37 degrees C, pH 7.5). The rate of derivatization of cellular GSH can be 1000 times greater than predicted from the nonenzymatic reaction rate, although this factor can vary among cell lines. GSH values obtained by flow cytometry (FCM) agree well with those obtained by an enzymatic assay, over a wide range of GSH values, for EMT6/SF cells treated with L-buthionine sulfoximine to vary GSH content. FCM analysis of the GSH content of cells obtained by disaggregation of EMT6/SF tumors, grown in BALB/c mice, revealed a wide variation in single-cell GSH content. The data suggest that there are distinct subpopulations within these tumors, which can be partially characterized by GSH content, but may also have other distinguishing characteristics, such as enhanced sensitivity or resistance to cytotoxic agents. Heterogeneity in single-cell GSH content was also observed by FCM analysis of cells obtained by disaggregation of a biopsy of a human renal cell carcinoma. This result points to the potential value of FCM analysis of GSH in the identification and characterization of human tumor subpopulations which may be of clinical significance in the treatment of cancer by radiation or chemotherapeutic agents.

Animals↗
PubMed1988

Repair of radiation induced damage--dependence on oxygen and energy status.

Repair of radiation-induced sublethal damage by Chinese hamster V-79 cells is studied under conditions of different pO2 (15 ppm to 21%) and cellular energy status. Cellular ATP content and energy charge are drastically reduced when cells are deprived of both oxygen and nutrient. Both indices are within normal range when cells are provided with nutrients or trace levels of oxygen (300 ppm). When deprived of nutrient, hypoxic (15 ppm O2) cells do not repair SLD, while cells in 300 ppm O2 do. Thus, cellular SLD repair appears to be dependent on cellular energy status which in turn is sensitive to oxygen concentration. Relatedly, nutrient deprived hypoxic cells are sensitized to radiation with storage under 23 degrees C, a phenomenon which may stem from a decrease of endogenous glutathione content.

Animals↗
PubMed1987

Effect of glutathione depletion by L-buthionine sulfoximine on the cytotoxicity of cyclophosphamide in single and fractionated doses to EMT6/SF mouse tumors and bone marrow.

The combined cytotoxicity of cyclophosphamide [(CYC) CAS: 50-18-0] and glutathione [(GSH) CAS: 70-18-8] depletion by buthionine sulfoximine (BSO) toward EMT6/SF tumors and mouse bone marrow was studied in male BALB/c mice. Tumor GSH was depleted to 28.7 and 7.8% of control by 1 or 2 doses of BSO (5 mmol/kg), respectively, administered ip at 12-hour intervals prior to assay. Tumor GSH could be maintained at a level 8% of control by daily dosing with BSO for 3 days. The same BSO administration schedule lowered bone marrow cell GSH to 31% of control for the 3-day period studied. Tumor growth and bone marrow cell counts were unaffected by all BSO treatments studied. However, BSO pretreatment enhanced the cytotoxicity of CYC to tumor cells, as measured by an in vitro colony-forming assay, but it did not enhance the depletion of bone marrow cells in CYC-treated mice. The magnitude of the enhancement of CYC cytotoxicity by BSO depended on the extent of GSH depletion, tumor size, and the CYC dosing schedule: Single and double doses of BSO enhanced the cytotoxicity of a single dose of CYC by factors of 1.5 and 2.0, respectively, in 7-day-old tumors, based on the dose of CYC required to produce a surviving fraction of 4 X 10(-3). The response of 9-day-old tumors to CYC suggested the presence of a subpopulation of cells that were relatively resistant to CYC. There was no evidence for this subpopulation in BSO-pretreated tumors. Multiple doses of BSO and CYC also combined to give enhanced (1.65-fold) tumor cell killing compared to tumors treated with CYC alone. The data suggest a possible role for BSO as a clinical chemosensitizer, which could be combined with fractionated doses of CYC and may be effective on small cancerous lesions.

Animals↗
PubMed1986

Effects of glutathione depletion by buthionine sulfoximine on the sensitivity of EMT6/SF cells to chemotherapy agents or X radiation.

The effects of depletion of cellular glutathione (GSH) on the sensitivity of cultured EMT6/SF cells to chemotherapy agents or x rays under hypoxic and aerated conditions were investigated. Buthionine sulfoximine (BSO), a potent inhibitor of the enzyme gamma-glutamyl-cysteine synthetase, was used to deplete cellular GSH. Addition of BSO (50 microM) to EMT6/SF cultures depleted cellular GSH with a half-time of approximately 2 hr. Cellular GSH reached very low levels within hours of addition of BSO. After removal of BSO, cellular GSH recovered with approximately the same kinetics as was seen for depletion. Incubation of EMT6/SF cells with BSO concentrations of up to 1 mM did not reduce the viability or inhibit growth when exposure was limited to times less than 24 hr. However, for longer exposure times, toxicity and growth inhibition were demonstrated in a dose dependent fashion. EMT6/SF cells were treated with chemotherapy agents under either aerated or extremely hypoxic conditions. Cells were more sensitive to cis-dichlorodiammino Pt(II) (DDP), mitomycin C (MitC), L-phenylalanine mustard (L-PAM), and nitrogen mustard (HN2) when treatment was under hypoxic conditions. The magnitude of this sensitization under hypoxic conditions ranged from a dose modifying factor (DMF) of 1.4 (HN2) to 4.1 (MitC), measured at the 0.1 level of cell survival. Hypoxic EMT6/SF cells were more resistant to the cytotoxic effects of actinomycin D (ActD) under hypoxic conditions (DMF = 10 at SF = 0.3). When cellular GSH was depleted to less than 5% of control by treatment with 50 microM BSO for 12-14 hr, cells were sensitized to DDP, L-PAM and HN2 under both aerated and hypoxic conditions. DMF's ranged from 1.4-6.5, depending on the agent. Hypoxic cell sensitization was never significantly greater than that seen in aerated cells, as was the case for X radiation (DMF = 1.3 for hypoxic cells only). GSH depletion also sensitized to MitC, but only under aerated conditions (DMF = 2.1). Hypoxic EMT6/SF cells were not sensitized to MitC by depletion of GSH. GSH depletion afforded slight protection against ActD toxicity under both aerated and hypoxic conditions. These studies suggest that cellular GSH plays an important role in modifying cellular response to cytotoxic drugs. GSH depletion may sensitize tumor cells to some chemotherapy agents, but differential sensitization of tumors compared to normal tissues, based on hypoxic tumor cells as targets, would not be expected based on these in vitro experiments.

Animals↗
PubMed1986

Enhancement of EMT6/SF tumor cell killing by mitomycin C and cyclophosphamide following in vivo administration of buthionine sulfoximine.

We have examined the effect of L-buthionine sulfoximine (BSO) treatment on the subsequent cytotoxicity of mitomycin C (Mit C) and cyclophosphamide (CYC) in EMT6/SF tumors growing in Balb/c mice. GSH content in tumors decreased to a minimum level (less than 30% of control) 12 hr after a single injection of 5 mmole/kg of BSO. The recovery of tumor GSH was protracted and did not reach control levels up to 24 hr following BSO administration. Mit C and CYC were administered 12 hr after BSO injection. Tumor cell survival reached almost the same minimum level (SF = 0.050-0.06%) 1 hour after Mit C (10 mg/kg) treatment with or without BSO. However, 24 hr after Mit C treatment, survival had increased 36-fold (SF = 1.9%) in non-BSO-treated tumors compared to only 4-fold (SF = 0.3%) in the BSO-treated tumors. A dose modifying factor (DMF) of 1.4-1.8 was observed for BSO-pretreated tumors assayed 24 hr after Mit C administration. In CYC-treated tumors, minimum surviving fractions were found 4 hr after CYC treatment with or without BSO treatment. These minimum survival levels were almost the same in BSO-treated tumors following 100 mg/kg CYC (SF = 0.03%) as in control tumors treated with 150 mg/kg CYC (SF = 0.04%). The same increase in cell survival was observed when tumor excision and assay were delayed 24 hr following CYC administration with or without prior BSO treatment. BSO treatment enhanced the cytotoxicity of CYC by DMFs of 1.6-1.9 based on the 24 hr excision assay. Depletion of tumor GSH by BSO caused enhancement of tumor cell killing by the two chemotherapy agents studied, either by increasing cytotoxicity, in the case of CYC or by decreasing PLD recovery following Mit C.

Animals↗
PubMed1986

The radiosensitizing effects of misonidazole (MISO) in combination with diethyl maleate (DEM) in mouse mammary tumors.

Large radiosensitization of C3H/He mouse mammary tumors was obtained with the combination of a non-protein sulfhydryl (NPSH) depletor, diethyl maleate (DEM), and misonidazole (MISO), compared with MISO alone over a range of MISO dose. The difference in enhancement ratios (ER's) for these two treatments was especially prominent at small MISO doses. ER's of 2.06 and 1.44 were obtained, respectively, by combined treatment with DEM (760 mg/kg) and MISO (100 mg/kg) or treatment with MISO alone. Radiosensitization of tumors by DEM alone was observed for doses over 600 mg/kg. When DEM was combined with MISO (100 mg/kg), ER's of the combination were larger than that of MISO alone, for doses over 400 mg/kg of DEM. Similarly, in case of DEM plus MISO (300 mg/kg), the ER's became larger than MISO alone, for doses over 200 mg/kg of DEM. The NPSH content in untreated tumors was 1.08 mmole/kg on the average and no changes in NPSH content was observed after MISO treatment. DEM treatment markedly reduced the NPSH content of tumors as a function of DEM dose and this decrease in NPSH was not significantly affected by MISO treatment. Tumor NPSH was reduced to 24% or less of control by administration of 760 mg/kg of DEM with or without MISO. These results are consistent with competition theory of NPSH and electron affinic radiosensitizers.

Animals↗