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Norman C Coleman - One of the best experts on this subject based on the ideXlab platform.

  • survival results from a phase i study of Etanidazole sr2508 and radiotherapy in patients with malignant glioma
    International Journal of Radiation Oncology Biology Physics, 1998
    Co-Authors: L Eric M D Chang, S Jay M D Loeffler, M Nancy P H E Riese, Y Patrick M D Wen, Eben Alexander, Peter Mcl Black, Norman C Coleman
    Abstract:

    Purpose: To report the survival results from a previous Phase I study of Etanidazole (ETA) and radiotherapy in patients with glioblastoma multiforme (GBM n = 50) or anaplastic astrocytoma (AA n = 19) and examine survival according to age, Karnofsky performance status (KPS), and implant status. Patients and Methods: In a previous Phase I study, 70 previously untreated patients (median age 49) with malignant gliomas were accrued. One patient was excluded from analysis because pathology was unverifiable. All had KPS ≥ 70. Prior to initiation of treatment, patients were stratified according to whether they were candidates for interstitial implantation. The implant patients (IMP n = 14) received accelerated fractionation radiotherapy (XRT) 2 Gy BID (6 hours apart) to 40 Gy in 2 weeks with ETA 2 gm/m2 × 6 doses, a 2 week break, and then interstitial implant for an additional 50 Gy (4–7 days) with a continuous infusion of ETA over 90–96 hours. There were 55 patients treated on two sequentially conducted non-implant arms. These patients started with accelerated fractionation XRT 2 Gy BID (6 hours apart) to 40 Gy in 2 weeks with ETA 2 gm/m2 × 4–5 doses/week. Non-IMP1 arm (n = 41) received a 2-week break before standard fractionated boost XRT of 2 Gy/day for 2 weeks to a total dose of 60 Gy with ETA. Non-IMP2 arm (n = 14) did not have the 2-week break. All patients had plasma pharmacokinetic monitoring of ETA. Subsequent follow-up study provided information regarding long-term survival status of this group of patients. The Phase I toxicity evaluation was conducted according to the RTOG toxicity scale and was found well tolerated in both groups. Overall actuarial survival was plotted for all patients, by histologic group, and by implant status. Subset analyses of GBM patients by age (≤ 49 or > 49 years), KPS (≤ 80 or > 80) and implant versus non-implant were also performed. Results: Median survival of GBM patients was 1.1 years and that of anaplastic astrocytoma patients was 3.1 years (p = 0.0001). In GBM patients, KPS > 80, implanted patients, and age ≤ 49 were factors found not to be associated with a statistically improved survival. Conclusion: The results of survival in this Phase I Etanidazole study of patients with anaplastic astrocytoma are comparable to the results from other studies using bromodeoxyuridine, iododeoxyuridine, or procarbazine, lomustine (CCNU), and vincristine. The use of Etanidazole with accelerated radiotherapy does not appear to improve survival in patients with glioblastoma multiforme compared to those treated with conventional therapies.

  • pharmacokinetic monitoring and dose modification of Etanidazole in the rtog 85 27 phase iii head and neck trial
    International Journal of Radiation Oncology Biology Physics, 1997
    Co-Authors: Nancy Riese, Lori Buswell, Lisa Noll, Thomas F Pajak, Jo Ann Stetz, D J Lee, Norman C Coleman
    Abstract:

    Purpose: To prospectively evaluate the pharmacokinetic monitoring and drug dose adjustment of Etanidazole (Eta) in patients treated on the RTOG randomized trial for Stage III and IV head and neck cancer. Methods and Materials: From June, 1986 to October, 1991, 521 patients were randomized to conventional RT alone or RT plus Eta. The primary goal was to determine whether the addition of Eta to conventional radiation therapy improves local-regional control and tumor-free survival. Of the 264 patients who received Eta, 233 had their drug exposure calculated and the Eta dose and schedule adjusted accordingly to prevent the occurrence of serious peripheral neuropathy. Drug exposure was assessed using the area under the curve (AUC) for a single treatment that was calculated by the integral over time of the serum concentration of Eta. The total drug exposure (total-AUC) was estimated by multiplying the AUC by the number of drug administrations. Results: Eighteen percent of patients developed Grade I and 6% developed Grade II peripheral neuropathy. There was no Grade 3 or 4 peripheral neuropathy. There is a trend for an increased risk of neuropathy by single dose AUC. The minimal difference in incidence of neuropathy by single-dose AUC was due to the use of dose and schedule modification for patients with the higher values. Conclusions: The pharmacokinetics investigated in this study confirm previous work that monitoring Eta levels, with dose adjustment, allows it to be used safely in the clinic. In a subset analysis there was a statistically significant improvement in local-regional control and survival rates for patients with N0 and N1 disease, that will require confirmation (14). However, the clinical efficacy of Eta in this trial proved to be of little overall benefit.

  • a phase i trial of Etanidazole and hyperfractionated radiotherapy in children with diffuse brainstem glioma
    International Journal of Radiation Oncology Biology Physics, 1997
    Co-Authors: Norman C Coleman, Karen J Marcus, S C Dutton, Patrick D Barnes, Scott L Pomeroy, Liliana Goumnerova
    Abstract:

    Abstract Purpose To determine the toxicity and maximum tolerated dose of Etanidazole administered concurrently with hyperfractionated radiation therapy (HRT) for children with brainstem glioma. Methods and materials Eighteen patients with brainstem glioma were treated with Etanidazole and HRT on a dose escalation protocol (Phase I trial) between 1990 and 1996. All patients had MRI confirmation of diffuse pontine glioma and signs/symptoms of cranial nerve deficit, ataxia, or long tract signs of 2 × 17 doses (30.6 g/m 2 ) at Step 1 to a maximum of 2.4 g/m 2 × 21 doses (50.4 g/m 2 ) at Step 8. Dose escalation was planned with 3 patients at each of the 8 levels. Results Three patients were treated at each dose level except Level 2, on which only 1 patient was treated. The highest dose level achieved was Level 7, which delivered a total Etanidazole dose of 46.2 g/m 2 . Two patients were treated at this level, and both patients experienced Grade 3 toxicity in the form of a diffuse cutaneous rash. Three patients received a lower dose of 42 g/m 2 (dose Level 6) without significant toxicity, and this represents the maximum tolerated dose (MTD). There were 23 cases of Grade 1 toxicity (10 vomiting, 5 peripheral neuropathy, 2 rash, 2 constipation, 1 weight loss, 3 others), 11 cases of Grade 2 toxicity (4 vomiting, 2 skin erythema, 2 constipation, 1 arthralgia, 1 urinary retention, 1 hematologic), and 4 Grade 3 toxicities (2 rash, 1 vomiting, 1 skin desquamation). Grade 2 or 3 peripheral neuropathy was not seen at any dose level. The median survival from the start of treatment was 8.5 months (range: 3–58 months). Conclusion The MTD of Etanidazole in children receiving HRT for brainstem glioma is 42 g/m 2 , with cutaneous rash as the dose-limiting toxicity. This is in contrast to the adult experience, which demonstrates a 24% lower MTD of 34 g/m 2 limited by peripheral neuropathy.

  • results of a phase ii trial of external beam radiation with Etanidazole sr 2508 for the treatment of locally advanced prostate cancer rtog protocol 90 20
    International Journal of Radiation Oncology Biology Physics, 1996
    Co-Authors: Colleen A Lawton, Victor A. Marcial, Norman C Coleman, Jan W Buzydlowski, Jeffrey D Forman, John Delrowe, Marvin Rotman
    Abstract:

    Purpose: RTOG Protocol 90-20 was designed to evaluated the effect of the hypoxic cell sensitizer Etanidazole (SR-2508) on locally advanced adenocarcinoma of the prostate treated with concurrent external beam irradiation. Methods and Materials: Patients with biopsy-proven adenocarcinoma of the prostate with locally advanced T2b, T3, and T4 tumors were eligible for this study. No patients with disease beyond the pelvis were eligible. Serum prostate specific antigen (PSA) was mandatory. All patients received definitive external beam irradiation using standard four-field whole pelvis treatment to 45–50 Gy, followed by a cone down with a minimum total dose to the prostate of 66 Gy at 1.8–2.0 Gy/fraction over 6.5–7.5 weeks. Etanidazole was delivered 1.8 g/m2 given 3 times a week to a total of 34.2 g/m2 or 19 doses. Results:Thirty-nine patients were entered onto the study.Three patients refused treatment; therefore, 36 patients were eligible for further evaluation. Median follow-up was 36.9 months from treatment end. All patients had elevated initial PSA levels, adn 18 patients had PSAs of > 20 ng/ml. Tumor classification was T2, 12 patients (33.3%); T3, 22 patients (61.1%); and T4, 2 patients (5.6%). Complete clinical response, defined as PSA < 4 ng/ml and complete clinical disappearance, was attained in 17.9% of (5/28 pts) with information at 90 days and 56% of patients by 12 months following treatment. Relapse-free survival was 13% at 3 years with PSA < 4 ng/ml. There were no Grade 4 or 5 toxicities, either acute (during treatment) or in follow-up. Conclusions: Results of this trial regarding PSA response and clinical disappearance of disease are similar to historical controls and do not warrant further investigation of Etanidazole as was done in this trial. Drug toxicity that, in the past, has been unacceptably high with other hypoxic cell sensitizers does not appear to be a significant problem with this drug.

  • results of an rtog phase iii trial rtog 85 27 comparing radiotherapy plus Etanidazole with radiotherapy alone for locally advanced head and neck carcinomas
    International Journal of Radiation Oncology Biology Physics, 1995
    Co-Authors: Ding Jen Lee, Dennis Cosmatos, Victor A. Marcial, Walter J Curran, Marvin Rotman, Jay S Cooper, H Ortiz, Jonathan J Beitler, Ross A Abrams, Norman C Coleman
    Abstract:

    Purpose : The objectives of this study were to determine the efficacy and toxicity of Etanidazole (ETA), a hypoxic cell sensitizer, when combined with conventional radiotherapy (RT) in the management of advanced head and neck carcinomas. Methods and Materials : From March 1988 to September 1991, 521 patients who had Stage III or IV head and neck carcinomas were randomized to receive conventional RT alone (66 Gy in 33 fractions to 74 Gy in 37 fractions, 5 fractions per week) or RT+ETA (2.0 g/m 2 thrice weekly for 17 doses), of whom 504 were eligible and analyzable. Treatment assignments were stratified before randomization according to the primary site (oral cavity + hypopharynx vs. supraglottic larynx + oropharynx + nasopharynx), T-stage (T1-3 vs. T4), and N-stage (N0-2 vs. N3). Pretreatment characteristics were balanced. In the RT-alone arm, 39% of patients had T3 and 34% had T4 disease, whereas in the RT+ETA arm, 42% of patients had T3 and 33% had T4 disease. Thirty-eight percent of the RT-alone patients and 37% of the RT+ETA patients had N3 disease. The median follow-up of surviving patients was 3.38 years, with a range between 0.96 and 5.63 years. Results : One hundred and ninety-four of the 252 (77%) RT+ETA patients received at least 14 doses of the drug. Overall RT protocol compliance rate was 82% in the RT-alone arm and 86% in the RT+ETA arm. No Grade 3 or 4 central nervous system or peripheral neuropathy was observed in the RT+ETA arm. Eighteen percent of the patients developed Grade 1 and 5% developed Grade 2 peripheral neuropathy. Other drug related toxicities included nausea/vomiting (27%), low blood counts (15%), and allergy (9%). Most of these toxicities were Grade 1 and 2. The incidence of severe acute and late radiation effects were similar between the two arms. The 2-year actuarial local-regional control rate (LCR) was 40% for the RT-alone arm and 40% for the RT+ETA arm. Two-year actuarial survival was 41% for the RT-alone arm and 43% for the RT+ETA arm (p = 0.65). Multivariate analyses were performed to investigate the influence of covariates on treatment effects. A strong treatment interaction with N-stage was revealed : LCR (50% vs. 40% at 2 years), RT+ETA improved for patients with N0-2 disease but not for N3 patients (22% for RT+ETA and 40% for RT). Further analyses showed that RT+ETA was more advantageous in N0-1 patients, with a 2-year LCR of 55% for RT+ETA vs. 37% for RT only (p = 0.03). A similar phenomenon was observed when using survival as the end point. Conclusion : The results showed that adding Etanidazole to conventional RT produced no global benefit for patients who had advanced head and neck carcinomas. There was a suggested benefit for patients who had N0-1 disease, and that needs to be confirmed by another study.

Chihwa Wang - One of the best experts on this subject based on the ideXlab platform.

  • in vivo performance of implantable biodegradable preparations delivering paclitaxel and Etanidazole for the treatment of glioma
    Biomaterials, 2007
    Co-Authors: Pavan Kumar Naraharisetti, Chihwa Wang, Benjamin Yung Sheng Ong, Jingwei Xie, Timothy Kam Yiu Lee, Nikolaos V Sahinidis
    Abstract:

    Drug-releasing implants delivering chemotherapeutic and radio-sensitizing agents are beginning to play a major role in the post-surgical eradication of residual glioma in the brain. Benefits from early arresting of tumor growth and tumor recovery dynamics stress the impact of drug release profiles of the implants on the efficacy of the treatment. This paper examines responses of BALB/c nude mice, bearing C6 glioma tumors subcutaneously, to treatments by PLGA microspheres, microparticles and discs-delivering Paclitaxel and Etanidazole. The experimental results are used to correlate the efficacy of treatment to in vitro release profiles from the various formulations. Our study demonstrates that radio-sensitizing effects during irradiation could be achieved by double burst profiles from Etanidazole-loaded discs, when compared to controls 17 days after implantation despite the short half-life of Etanidazole (1.4h) in vivo. These results also showed inhibited tumor growth on tumor volumes of 59%, 65% and 70% over the blank placebo groups after 21 days of tumor growth for spray-dried microspheres, electrohydrodynamic atomization microparticles and spray-dried discs, respectively.

  • subcutaneous study on the controlled release of Etanidazole and taxol for the treatment of glioma
    2005
    Co-Authors: Pavan Kumar Naraharisetti, Timothy Kam Yiu Lee, Chihwa Wang
    Abstract:

    BALB/c nude mice 6 weeks old were inoculated with glioma C6 cell-line and the efficacy of the different amount of Etanidazole-discs and Taxol-microspheres was investigated. Poly (D,L-lactic-co-glycolic acid) (PLGA) was used as the main encapsulating polymer and polyethylene glycol was added to increase the porosity. The 1% drug loading microspheres of each drug were produced by spray drying and the discs were obtained by compressing the Etanidazole-microspheres. Intra-tumoral injection followed by irradiation resulted in high systemic dosage and thus systemic toxicity. Tumors grown for 6 days, 9 days and 16 days were implanted with 0.5 mg or 1.0 mg or 1.5 mg of the drug. A radiation dosage of 2 Gy each time for a number of times was given for animals implanted with Etanidazole and no irradiation was given for animals implanted with Taxol. Increasing the number of doses clearly decreased the rate of tumor growth. The increase in the amount of drug on smaller sized tumors controlled the tumor better and there was agglomeration of the microspheres resulting in deviation of release profile of the drug as compared to the in vitro studies. It was observed that 1.0 mg of Taxol given to a tumor grown for 6 days was able to suppress the tumor for a total period of approximately two months and no tumor resurrection was observed during the second month.

  • delivery of Etanidazole to brain tumor from plga wafers
    2004
    Co-Authors: Wilson Hor Keong Tan, Timothy C Lee, Chihwa Wang
    Abstract:

    This paper presents the computer simulation results on the delivery of Etanidazole (radiosensitiser) to the brain tumor and examines several factors affecting the delivery. The simulation consists of a 3D model of tumor with poly (lactide-co-glycolide) (PLGA) wafers of 1% Etanidzole loading implanted in the resected cavity. A zeroorder release device will produce a concentration profile in the tumor which increases with time until the drug in the carrier is depleted. This causes toxicity complications during the later stages of drug treatment. However, for wafers of similar loading, such release results in a higher drug penetration depth and therapeutic index as compared to the double drug burst profile. The numerical accuracy of the model was verified by the similar results obtained in the twodimensional and three-dimensional models. [Full Text Not Available]

  • computer simulation of the delivery of Etanidazole to brain tumor from plga wafers comparison between linear and double burst release systems
    Biotechnology and Bioengineering, 2003
    Co-Authors: Wilson Hor Keong Tan, Timothy C Lee, Chihwa Wang, Fangjing Wang
    Abstract:

    This paper presents the computer simulation results on the delivery of Etanidazole (radiosensitizer) to the brain tumor and examines several factors affecting the delivery. The simulation consists of a 3D model of tumor with poly(lactide-co-glycolide) (PLGA) wafers with 1% Etanidazole loading implanted in the resected cavity. A zero-order release device will produce a concentration profile in the tumor which increases with time until the drug in the carrier is depleted. This causes toxicity complications during the later stages of drug treatment. However, for wafers of similar loading, such release results in a higher drug penetration depth and therapeutic index as compared to the double drug burst profile. The numerical accuracy of the model was verified by the similar results obtained in the two-dimensional and three-dimensional models.

  • sustained release system for highly water soluble radiosensitizer drug Etanidazole irradiation and degradation studies
    Biomaterials, 2003
    Co-Authors: Ee Ying Yip, Jianjun Wang, Chihwa Wang
    Abstract:

    Etanidazole (one nitro-imidazole hypoxic radiosensitizer) is formulated as polymer matrix type controlled release devices in this study. A novel double polymer drug carrier, unlike the double wall microparticles, is fabricated for the purpose of drug delivery, with the following objectives in mind: (1) to have a high encapsulation efficiency, (2) to achieve a pusatile release profile suitable for the radiation schedule of radiotherapy, (3) to elucidate the degradation profile of these microparticles. Irradiation of the microparticles were also studied to investigate effects on release and degradation. At a dosage of 50 Gy (total dosage during a radiotherapy treatment period) showed no apparent effects on the tri-phase release profile. It consists of an initial burst in the first 72 h, followed by a slow and steady drug release phase, and finally a faster degradation controlled phase corresponding to the degradation state of the different microparticles. At 25 kGy (sterilization dosage), the release profiles of the drug carrier were drastically modified. The faster erosion of the polymer with high dosage irradiation hastened the drug release and shortened the release time span, accompanied by decreases in the polymer molecular weight and glass transition temperatures, which was not apparent from SEM imaging. Degradation studies suggested a heterogeneous degradation process, with the outer layer and inner matrix degrading at different rates. The modifiable tri-phase release profile using microparticles of different polymer blends implies that the release properties of the drug carriers can be modified for different treatment regimes.

Lori Buswell - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetic monitoring and dose modification of Etanidazole in the rtog 85 27 phase iii head and neck trial
    International Journal of Radiation Oncology Biology Physics, 1997
    Co-Authors: Nancy Riese, Lori Buswell, Lisa Noll, Thomas F Pajak, Jo Ann Stetz, D J Lee, Norman C Coleman
    Abstract:

    Purpose: To prospectively evaluate the pharmacokinetic monitoring and drug dose adjustment of Etanidazole (Eta) in patients treated on the RTOG randomized trial for Stage III and IV head and neck cancer. Methods and Materials: From June, 1986 to October, 1991, 521 patients were randomized to conventional RT alone or RT plus Eta. The primary goal was to determine whether the addition of Eta to conventional radiation therapy improves local-regional control and tumor-free survival. Of the 264 patients who received Eta, 233 had their drug exposure calculated and the Eta dose and schedule adjusted accordingly to prevent the occurrence of serious peripheral neuropathy. Drug exposure was assessed using the area under the curve (AUC) for a single treatment that was calculated by the integral over time of the serum concentration of Eta. The total drug exposure (total-AUC) was estimated by multiplying the AUC by the number of drug administrations. Results: Eighteen percent of patients developed Grade I and 6% developed Grade II peripheral neuropathy. There was no Grade 3 or 4 peripheral neuropathy. There is a trend for an increased risk of neuropathy by single dose AUC. The minimal difference in incidence of neuropathy by single-dose AUC was due to the use of dose and schedule modification for patients with the higher values. Conclusions: The pharmacokinetics investigated in this study confirm previous work that monitoring Eta levels, with dose adjustment, allows it to be used safely in the clinic. In a subset analysis there was a statistically significant improvement in local-regional control and survival rates for patients with N0 and N1 disease, that will require confirmation (14). However, the clinical efficacy of Eta in this trial proved to be of little overall benefit.

  • pilot study of local hyperthermia radiation therapy Etanidazole and cisplatin for advanced superficial tumours
    International Journal of Hyperthermia, 1995
    Co-Authors: Bruce A Bornstein, Beverly A Teicher, Terence S Herman, Lori Buswell, Jorgen L Hansen, Pamela Scott Zouranjian, Suzette M Fraser, Goran K Svensson, C. N. Coleman
    Abstract:

    Five patients (six hyperthermia sites) with advanced superficial tumours were treated with combined Etanidazole, cisplatin, local hyperthermia, and radiation therapy as part of a Phase I pilot study. Treatment was given once weekly and consisted of Etanidazole 3 gm/m2 IV bolus, cisplatin 50 mg/m2 IV bolus, hyperthermia for 60 min with a target temperature of 43°C, and radiation therapy 500 cGy/fraction (median total dose 3000 cGy) for a total of six weeks. Blood levels of Etanidazole were taken during treatment at week 1 and week 4. Etanidazole drug exposure was calculated using the trapezoidal rule and expressed as the area under the curve (AUC) of plasma concentration X time. Five of six treatment sites had received prior irradiation. Prior chemotherapy had been given in three patients and tamoxifen therapy given in the other two patients. The median follow-up time is 34 months; 3/5 patients have died of disease. The most significant toxicity was grade I or II nausea and vomiting associated with 19/32 t...

  • phase i pharmacokinetic study of the hypoxic cell sensitizer Etanidazole with carboplatin and cyclophosphamide in the treatment of advanced ovarian cancer
    International Journal of Radiation Oncology Biology Physics, 1994
    Co-Authors: Lawrence N Shulman, Beverly A Teicher, T. Kusumoto, Selwyn J Hurwitz, Lori Buswell, Howard M Goodman, Michael G Muto, Ross S Berkowitz, Leslie A Kalish, Norman C Coleman
    Abstract:

    Abstract Purpose: A Phase I study was undertaken to determine the maximum tolerated dose of the hypoxic cell sensitizer Etanidazole which could be administered with carboplatin and cyclophosphamide, to determine whether adequate serum levels of Etanidazole were achieved to allow for alkylating agent sensitization, and whether pretreatment with Etanidazole altered carboplatin pharmacokinetics. Methods and Materials Patients received 2 g/m 2 of intravenous Etanidazole followed by a second dose of 4 g/m 2 90 min later, followed by intravenous carboplatin (300 mg/m 2 ) and cyclophosphamide (600 mg/m 2 ) for four treatment cycles. Patients received an additional two cycles of carboplatin and cyclophosphamide without Etanidazole. Results: Two patients who received a total of 24 g/m 2 of Etanidazole developed Grade 1 neurotoxicity, and therefore Etanidazole doses were not escalated further. The grade of granulocytopenia was worse after cycles with Etanidazole than after those without ( p = 0.03), but clinical outcome was not different. Etanidazole levels were adequate for alkylating agent sensitization (> 70 ug/ml) in all patients for the majority of the 7 h of testing. Pharmacokinetic data suggested t12α and t12β for carboplatin were prolonged after pretreatment with Etanidazole. Conclusion: Etanidazole, 2 g/m 2 followed by 4 g/m 2 90 min later, is safe and results in adequate serum levels for alkylating agent sensitization. Neurotoxicity appears to prevent dose escalation of Etanidazole, and an interaction between Etanidazole and carboplatin may have enhanced neurotoxicity in these patients.

  • use of the hypoxic cell sensitizer Etanidazole sr 2508 with intravenous melphalan and prednisone in the treatment of multiple myeloma a pharmacokinetic study
    International Journal of Radiation Oncology Biology Physics, 1994
    Co-Authors: Lawrence N Shulman, Lori Buswell, Leslie A Kalish, Norman C Coleman
    Abstract:

    Abstract Purpose: A study was undertaken adding the alkylating agent sensitizer Etanidazole to intravenous melphalan and oral prednisone for patients with multiple myeloma. This study explored the toxicity profile of these agents when given together and assessed the ability to attain adequate serum levels of Etanidazole to permit sensitization to occur. Methods and Materials: Etanidazole was administered intravenously in two doses of 3 g/m 2 and 5 g/m 2 90 min apart immediately prior to the administration of intravenous melphalan and oral prednisone for three consecutive cycles (total dose 24 g/m 2 ). Patients received three additional cycles without Etanidazole, allowing a comparison of hematologic toxicity from melphalan with and without Etanidazole. Results: Hematologic toxicity was moderate (Grade 3 or 4), but severity was similar during cycles with and without Etanidazole. Only one Etanidazole. Only one patient developed a Grade 1 peripheral neuropathy questionably related to Etanidazole. Most patients had Etanidazole levels of ≥ 70 ug/ml for 7 h, a level felt to be necessary for sensitization to occur. Conclusion: Etanidazole, administered as described, results in adequate serum levels for potential alkylating agent sensitization, without significant toxicity.

  • combined modality therapy of esophageal cancer with radiotherapy Etanidazole and cisplatin fluorouracil with or without surgery neurotoxicity other toxicities and outcome
    International Journal of Radiation Oncology Biology Physics, 1994
    Co-Authors: Lori Buswell, Abram Recht, John I Clark, Thanjuvar Ravikumar, Paul M Busse, Norman C Coleman
    Abstract:

    Abstract Purpose: To investigate whether Etanidazole and cisplatin can be given safely together and to evaluate the relationship between incidence of peripheral neuropathy and cumulative exposure to Etanidazole and cisplatin, as well as other toxicities and treatment outcome. Methods and Materials: Thirty-two previously untreated patients with locally advanced esophageal cancer were entered on a Phase I study of Etanidazole combined with radiation therapy and chemotherapy. Cisplatin/5-FU (two cycles, weeks 1 and 4) and Etanidazole (weeks 2, 3 and 5) were given concurrently with radiation therapy. Eligible patients then underwent surgical resection. All patients were scheduled to receive two additional cycles of cisplatin/ 5-FU chemotherapy after completion of radiation therapy (definitive arm) or surgery (preoperative arm). Results: Of 19 fully evaluable patients, nine (47%) developed peripheral neuropathy. Six of six patients, 65 years or older, experienced peripheral neuropathy, compared with three of 13 patients less than 65 years old ( p = .003). For patients younger than 65 years, two of the two patients with single dose area under the curve (AUC) > 4.0 mMhr experienced peripheral neuropathy, compared with one of 11 patients with single-dose AUC p = .03). Grade 4 toxicity included neutropenia (23%) and thrombocytopenia (26%). No other Grade 4 toxicity was observed. The pathologic complete response rate in patients who underwent surgical resection was 29%. Conclusion: This regime of chemotherapy, radiotherapy, and Etanidazole had acceptable toxicity. However, combining Etanidazole and cisplatin appears to increase the risk of developing peripheral neuropathy for at least some categories of patients. Further studies of these interactions are needed.

Lisa Noll - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetic monitoring and dose modification of Etanidazole in the rtog 85 27 phase iii head and neck trial
    International Journal of Radiation Oncology Biology Physics, 1997
    Co-Authors: Nancy Riese, Lori Buswell, Lisa Noll, Thomas F Pajak, Jo Ann Stetz, D J Lee, Norman C Coleman
    Abstract:

    Purpose: To prospectively evaluate the pharmacokinetic monitoring and drug dose adjustment of Etanidazole (Eta) in patients treated on the RTOG randomized trial for Stage III and IV head and neck cancer. Methods and Materials: From June, 1986 to October, 1991, 521 patients were randomized to conventional RT alone or RT plus Eta. The primary goal was to determine whether the addition of Eta to conventional radiation therapy improves local-regional control and tumor-free survival. Of the 264 patients who received Eta, 233 had their drug exposure calculated and the Eta dose and schedule adjusted accordingly to prevent the occurrence of serious peripheral neuropathy. Drug exposure was assessed using the area under the curve (AUC) for a single treatment that was calculated by the integral over time of the serum concentration of Eta. The total drug exposure (total-AUC) was estimated by multiplying the AUC by the number of drug administrations. Results: Eighteen percent of patients developed Grade I and 6% developed Grade II peripheral neuropathy. There was no Grade 3 or 4 peripheral neuropathy. There is a trend for an increased risk of neuropathy by single dose AUC. The minimal difference in incidence of neuropathy by single-dose AUC was due to the use of dose and schedule modification for patients with the higher values. Conclusions: The pharmacokinetics investigated in this study confirm previous work that monitoring Eta levels, with dose adjustment, allows it to be used safely in the clinic. In a subset analysis there was a statistically significant improvement in local-regional control and survival rates for patients with N0 and N1 disease, that will require confirmation (14). However, the clinical efficacy of Eta in this trial proved to be of little overall benefit.

  • phase ii trial of external beam radiation with Etanidazole sr 2508 for the treatment of locally advanced prostate cancer
    International Journal of Radiation Oncology Biology Physics, 1994
    Co-Authors: Clair J Beard, Lori Buswell, Mary Ann Rose, Lisa Noll, Douglas E Johnson, C. N. Coleman
    Abstract:

    Abstract Purpose: To evaluate the efficacy and toxicity of the addition of Etanidazole (ETA) to external beam radiation. Methods and Materials: Fifty eight previously untreated patients with locally advanced adenocarcinoma of the prostate were entered on a Phase II trial of Etanidazole (ETA) combined with standard external beam radiation therapy. ETA was given concurrently with irradiation. Four patients received less than 25% of the intended dose of ETA and were ineligible for further analysis. The stage of the remaining patients were T 2c-11 , T 3–39 , T 4-1 , bulky local recurrence after prostatectomy-1, and T 3 , N 1–2 . Results: Forty-five of 54 patients (83.3%) achieved a clinical complete response (CCR) in the prostate and seminal vesicles as judged by digital rectal exam (DRE). Responses were rapid with a median time to CCR of 3.4 months, range 0–22.8 months. Local control was maintained in 82% of the patients who achieved a CCR. Fifteen of 32 eligible patients with a normal DRE underwent prostate biopsies from 12–20 months after treatment, seven had negative biopsies (46.6%). Distant metastases occurred in 18 patients (33.3%). Pretreatment prostatic specific antigen (PSA), Gleason score, and stage were not associated with treatment outcome in a univariate analysis. Conclusion: While ETA plus radiation was associated with a rapid CCR, the overall treatment outcome of these patients appeared to be similar to published reports of patients receiving RT alone. The rapid response rate may imply biologic activity of the ETA. In future trials, it may be reasonable to focus on patients at lower risk for the subsequent development of distant disease.

  • final report of the phase i trial of continuous infusion Etanidazole sr 2508 a radiation therapy oncology group study
    International Journal of Radiation Oncology Biology Physics, 1992
    Co-Authors: Norman C Coleman, Lori Buswell, Lisa Noll, Nancy Riese, Anthony E Howes
    Abstract:

    Seventy-eight patients have been treated on a Phase I trial using continuous infusion Etanidazole while undergoing brachytherapy for locally advanced tumors. There were two sequential schemata, the first treated 63 patients with doses ranging from 8-23 g/m2 over 48 hr and the second treated 15 patients with doses ranging from 20-23 g/m2 over 96 hr. The tumor sites were: brain (n = 42), cervix (n = 22), and breast (n = 14). Patients received a loading dose of Etanidazole of 2 g/m2 followed by a continuous infusion for a total of 48 or 96 hr while radioactive implants were in place. Of the 63 patients in the 48-hr study, 52 were entered at doses of less than or equal to 21 g/m2 and there were no definite neuropathies but two patients with the cramping/arthralgia syndrome. Of the 11 patients entered at 22-23 g/m2, 1 patient had symptoms of peripheral neuropathy (Grade II) and 6 had the cramping/arthralgia syndrome. This is a new syndrome, distinct from the peripheral neuropathy, characterized by transient alterations in sensations consisting of cramping, arthralgias, or tingling that resolved completely at intervals varying from a few hours to about 1 week post-treatment. The cramping/arthralgia syndrome limited dose escalation; therefore, the maximum tolerated dose over 48 hr was determined to be 20-21 g/m2. The 96-hr infusion was limited to patients with recurrent gliomas undergoing stereotactic implantation. To date, 15 patients have been treated with doses of 20-23 g/m2. No toxicity was encountered at doses less than or equal to 22 g/m2. At 23 g/m2, one patient developed Grade III neuropathy and three patients had mild cramping/arthralgia syndrome, for whom the drug was discontinued. Therefore, it appears the maximum tolerated dose at 96 hr will be approximately 23 g/m2, which is 10-15% higher than for the 48-hr infusion.

  • the efficacy of pharmacokinetic monitoring and dose modification of Etanidazole on the incidence of neurotoxicity results from a phase ii trial of Etanidazole and radiation therapy in locally advanced prostate cancer
    International Journal of Radiation Oncology Biology Physics, 1992
    Co-Authors: Norman C Coleman, Lori Buswell, Lisa Noll, Nancy Riese, Mary Ann Rose
    Abstract:

    Abstract Fifty-four patients have been entered on a Phase II trial to study the efficacy of Etanidazole (ETA) for locally advanced prostate cancer. The primary goal was to study the incidence of and time to a complete response for patients receiving ETA and radiation therapy. The secondary goal was to prospectively evaluate the utility of pharmacokinetic monitoring and dose-modification on the incidence and severity of the dose-limiting peripheral neurotoxicity. Within a constant radiation therapy regimen, the dose of ETA was either (a) unmodified (2 g/m 2 , 3 times weekly for 17 doses); (b) altered by a schedule modification of either number of doses or dose adjustment; or (c) individualization of single dose size so that the total number of doses (19 doses) were maintained but the single dose size was adjusted to keep the total AUC of plasma concentration versus time to

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  • pilot study of local hyperthermia radiation therapy Etanidazole and cisplatin for advanced superficial tumours
    International Journal of Hyperthermia, 1995
    Co-Authors: Bruce A Bornstein, Beverly A Teicher, Terence S Herman, Lori Buswell, Jorgen L Hansen, Pamela Scott Zouranjian, Suzette M Fraser, Goran K Svensson, C. N. Coleman
    Abstract:

    Five patients (six hyperthermia sites) with advanced superficial tumours were treated with combined Etanidazole, cisplatin, local hyperthermia, and radiation therapy as part of a Phase I pilot study. Treatment was given once weekly and consisted of Etanidazole 3 gm/m2 IV bolus, cisplatin 50 mg/m2 IV bolus, hyperthermia for 60 min with a target temperature of 43°C, and radiation therapy 500 cGy/fraction (median total dose 3000 cGy) for a total of six weeks. Blood levels of Etanidazole were taken during treatment at week 1 and week 4. Etanidazole drug exposure was calculated using the trapezoidal rule and expressed as the area under the curve (AUC) of plasma concentration X time. Five of six treatment sites had received prior irradiation. Prior chemotherapy had been given in three patients and tamoxifen therapy given in the other two patients. The median follow-up time is 34 months; 3/5 patients have died of disease. The most significant toxicity was grade I or II nausea and vomiting associated with 19/32 t...

  • cytotoxicity of antitumor platinum complexes with l buthionine r s sulfoximine and or Etanidazole in human carcinoma cell lines sensitive and resistant to cisplatin
    Cancer Chemotherapy and Pharmacology, 1995
    Co-Authors: Sandra E Brooks, Sylvia A. Holden, Timothy Korbut, Norman P Dupuis, Beverly A Teicher
    Abstract:

    Human 2008 ovarian carcinoma cells and the C13 CDDP-resistant subline and human MCF-7 breast carcinoma cells and the MCF-7/CDDP CDDP-resistant subline were exposed tol-buthionine-(S, R)-sulfoximine (50 μM) for 48 h prior to and during exposure for 1 h to the antitumor platinum complexes,cis-diamminedichloroplatinum(II), carboplatin or D,L-tetraplatin and/or to Etanidazole (1 mM) for 2 h prior to and during exposure for 1 to the antitumor platinum complexes. These modulators alone did not significantly alter the cytotoxicity of CDDP toward either parental line. A twofold enhancement in cytotoxicity was observed with carboplatin in the 2008 cells and with D,L-tetraplatin in both parental lines with the single modulators. The modulator combination (buthionine sulfoximine/Etanidazole) was very effective along with D,L-tetraplatin in both the MCF-7 parent and MCF-7/CDDP cell lines where at the higher platinum complex concentrations there was 1.5 to 3 logs increased killing of cells by the drug plus the modulators compared with the drug alone. Similarly, when C13 cells were exposed to CDDP (100 μM) or D,L-tetraplatin (100 μM) along with buthionine sulfoximine and Etanidazole there was a 2-log increase in cell killing compared with exposure to the platinum complex alone. Treatment of each of the four cell lines with buthionine sulfoximine decreased both the non-protein and total sulfhydryl content of the cells. Treatment with the combination of modulators did not produce a further decrease in cellular sulfhydryl content compared with buthionine sulfoximine alone. The total sulfhydryl content in MCF-7 cells and 2008 cells exposed to buthionine sulfoximine and Etanidazole was 58% and 31% of normal and the total sulfhydryl content of MCF-7/CDDP cells and C13 cells treated the same way was 54% and 23% of normal, respectively. DNA alkaline elution was used to assess the impact of exposure to the modulators, buthionine sulfoximine and Etanidazole, alone and in combination on the cross linking of DNA by the antitumor platinum complexes in the MCF-7 and MCF-7/CDDP cell lines. Overall, the increases in DNA cross linking factors were greater in the MCF-7 cells than in the MCF-7/CDDP cells. These results indicate a possible clinical potential for this modulator combination.

  • phase i pharmacokinetic study of the hypoxic cell sensitizer Etanidazole with carboplatin and cyclophosphamide in the treatment of advanced ovarian cancer
    International Journal of Radiation Oncology Biology Physics, 1994
    Co-Authors: Lawrence N Shulman, Beverly A Teicher, T. Kusumoto, Selwyn J Hurwitz, Lori Buswell, Howard M Goodman, Michael G Muto, Ross S Berkowitz, Leslie A Kalish, Norman C Coleman
    Abstract:

    Abstract Purpose: A Phase I study was undertaken to determine the maximum tolerated dose of the hypoxic cell sensitizer Etanidazole which could be administered with carboplatin and cyclophosphamide, to determine whether adequate serum levels of Etanidazole were achieved to allow for alkylating agent sensitization, and whether pretreatment with Etanidazole altered carboplatin pharmacokinetics. Methods and Materials Patients received 2 g/m 2 of intravenous Etanidazole followed by a second dose of 4 g/m 2 90 min later, followed by intravenous carboplatin (300 mg/m 2 ) and cyclophosphamide (600 mg/m 2 ) for four treatment cycles. Patients received an additional two cycles of carboplatin and cyclophosphamide without Etanidazole. Results: Two patients who received a total of 24 g/m 2 of Etanidazole developed Grade 1 neurotoxicity, and therefore Etanidazole doses were not escalated further. The grade of granulocytopenia was worse after cycles with Etanidazole than after those without ( p = 0.03), but clinical outcome was not different. Etanidazole levels were adequate for alkylating agent sensitization (> 70 ug/ml) in all patients for the majority of the 7 h of testing. Pharmacokinetic data suggested t12α and t12β for carboplatin were prolonged after pretreatment with Etanidazole. Conclusion: Etanidazole, 2 g/m 2 followed by 4 g/m 2 90 min later, is safe and results in adequate serum levels for alkylating agent sensitization. Neurotoxicity appears to prevent dose escalation of Etanidazole, and an interaction between Etanidazole and carboplatin may have enhanced neurotoxicity in these patients.

  • whole body hyperthermia as an adjuvant to treatment with platinum complexes with or without Etanidazole in mice bearing the lewis lung carcinoma or the fsall fibrosarcoma
    International Journal of Hyperthermia, 1992
    Co-Authors: Beverly A Teicher, Terence S Herman, Krishna Menon, Timothy Korbut
    Abstract:

    The response of s.c. primary and metastatic Lewis lung carcinoma to five antitumour platinum complexes with or without tolerable whole-body hyperthermia (60 min to reach temperature then 60 min at 42 degrees C) was examined. The whole-body hyperthermia treatment produced about 2.8 days of tumour growth delay in the s.c. tumours. The addition of whole-body hyperthermia to treatment with each of the platinum complexes was well tolerated by the animals and increases of 1.6-2.0-fold in tumour growth delay resulted with the combined treatment compared with the platinum complexes alone. The combination of Etanidazole (1 g/kg) and the platinum complexes followed by whole-body hyperthermia produced marked increases in tumour growth delay ranging from 2.5- to 3.6-fold over the growth delays obtained with the platinum complexes alone. FSaLLC tumour cell survival and bone marrow CFU-GM experiments indicated that local hyperthermia (43 degrees C, 30 min) produced greater potentiation of the cytotoxicity of three platinum complexes than did whole-body hyperthermia (42 degrees C, 60 min). Only the complete treatments including whole-body hyperthermia/Etanidazole and the platinum complexes were effective in significantly reducing the numbers of lung metastases formed from s.c. primary tumours. Serum urea nitrogen and creatinine levels were monitored over a time-course post-treatment. Although some treatment combinations caused elevations in these normal tissue parameters by day 12 post-treatment both serum urea nitrogen and serum creatinine returned to the levels of the untreated control animals.

  • schedule dependent tumour growth delay dna cross linking and pharmacokinetic parameters in target tissues with cis diamminedichloroplatinum ii and Etanidazole with or without hyperthermia or radiation
    International Journal of Hyperthermia, 1991
    Co-Authors: Beverly A Teicher, M R Pfeffer, Alvarez E Sotomayor, Terence S Herman
    Abstract:

    It has been reported previously that striking increases in tumour growth delay and cytotoxicity are seen when cis-diamminedichloroplatinum(II) (CDDP) is combined with mild local hyperthermia (43 degrees C, 30 min) and/or Etanidazole (ETA). This paper reports a study of CDDP pharmacology and the in vivo tumour DNA cross-linking produced by these combinations. In C3H mice bearing the FSaIIC murine fibrosarcoma, Pt plasma pharmacokinetics were not significantly altered by any of the combination of treatments. Although ETA caused no significant change in CDDP tissue pharmacokinetics, treatment of the tumour-bearing limb with hyperthermia immediately following an i.p. injection of CDDP (10 mg/kg) resulted in an increased peak Pt concentration (3.5 versus 2.8 micrograms Pt/g tumour wet weight) and doubled the t1/2 elimination of Pt (15 to 30 h) from the tumour. Similar heat-induced changes were observed in the Pt pharmacokinetics in skin. There was about a three-fold increase in the Pt area under the curve (AUC) for the tumour, a 1.5-fold increase in the AUC for skin and little change in the AUC for muscle with hyperthermia. When the tumour DNA cross-linking factor (CLF) was determined, it was found that local hyperthermia treatment (43 degrees C, 30 min) increased the CLF of CDDP from 1.7 to 2.7 and hyperthermia (43 degrees C, 1 h) further increased the CLF to 6.1. Misonidazole (MISO) (1 g/kg) increased the CDDP CLF to 2.0, 6.3 and 15.1 in conjunction with 37, 43 (30 min) and 43 degrees C (1 h), respectively. ETA (1 g/kg) was more effective than MISO at increasing the CDDP CLF, producing CLFs of 2.8, 9.1 and 21.5 at 37, 43 (30 min) and 43 degrees C (1 h), respectively. These changes in CLF were reflected in an increased tumour growth delay in the FSaIIC murine fibrosarcoma with CDDP (5 mg/kg) alone from 4.4 to 5.9 days with 43 degrees C (30 min) and then to 11.9 days with ETA (1 g/kg) and 20.9 days with both ETA and local hyperthermia (43 degrees C, 30 min). When CDDP, ETA and hyperthermia were added to a radiation schedule of 300 cGy daily for five days, it was found that giving ETA (1 g/kg), CDDP (5 mg/kg) and hyperthermia (43 degrees C, 30 min) together on day 1 produced the largest tumour growth delay (43 days) and that other schedules which divided the dose of ETA over the other days of the radiation treatment (including one schedule with a second heat treatment on day 4) were significantly inferior.(ABSTRACT TRUNCATED AT 400 WORDS)