Phase I trial of the hypoxic cell cytotoxin tirapazamine with concurrent radiation therapy in the treatment of refractory solid tumors.

PURPOSE: Patients with refractory solid tumors were treated with the combination of fractionated radiation therapy and multiple-dose intravenous tirapazamine to determine the toxicities and maximum tolerated dose of tirapazamine when given concurrently with radiation therapy. METHODS: Patients received radiation therapy in accordance with standard treatment practice in relation to fraction size and number of fractions for their particular cancer. In all cases, the course of radiation therapy exceeded the time of tirapazamine administration. Initially, tirapazamine was administered 5 days per week for 2 weeks for a total of 10 doses. After the first 8 patients, the schedule was changed to 3 times per week (Monday, Wednesday, Friday) for 4 weeks for a total of 12 doses. Between 3 and 6 patients were treated at each dose level. RESULTS: A total of 43 patients were treated in the study between 1991 and 1995. All patients were 18 years old or older, had a Karnofsky performance status of > or = 60% and had adequate hematologic, hepatic, and renal function. Dose escalation began at 9 mg/m(2)/dose and was increased using a modified Fibonacci schema. The maximum tolerated dose was not reached and dose escalation was stopped at 260 mg/m(2) because of other data that became available suggesting 330 mg/m(2) was associated with dose-limiting toxicity (1, 2). CONCLUSION: Tirapazamine in doses of up to 260 mg/m(2) times 12 doses can be given safely with fractionated radiation therapy. This dose appears to result in adequate plasma exposure (2) for radiation sensitization, and this schedule is being tested in a Phase II trial by the Radiation Therapy Oncology Group to determine if tirapazamine is a radiation enhancer in the clinic.

Survival results from a phase I study of etanidazole (SR2508) and radiotherapy in patients with malignant glioma.

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 > or = 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 x 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 x 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 (< or = 49 or > 49 years), KPS (< or = 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 < or = 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.

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 study of etanidazole and radiotherapy in malignant glioma.

PURPOSE: To determine the maximum tolerable total dose (MTD) of etanidazole (ETA) when administered with external beam radiotherapy (XRT) and as a continuous infusion during stereotactic brachytherapy for patients with malignant glioma (anaplastic astrocytoma or glioblastoma multiforme or mixed cell tumors). METHODS AND MATERIALS: Seventy previously untreated patients were entered in a Phase I study. Prior to initiation of treatment, patients were stratified according to whether or not they were candidates for interstitial implantation. The implant patients (IMP, n = 17 pt) received accelerated fractionation XRT 20 Gy BID (6 h apart) to 40 Gy in 2 weeks with ETA 2 gm/m2 x 6 doses, a 2 week break and then interstitial implant to 50 Gy (4-7 days) with a continuous infusion of ETA over 90-96 h. The two sequentially conducted nonimplant arms started with accelerated fractionation XRT 2 Gy BID (6 h apart) to 40 Gy in 2 weeks with ETA 2 gm/m2 x 4-5 doses/week. NonIMP 1 arm (n = 38) received a 2-week break before standard fractionated boost XRT of 20 Gy/day for 2 weeks to a total dose of 60 Gy with ETA. NonIMP 2 arm (n = 14) did not have the 2-week break. All patients had plasma pharmacokinetic monitoring of ETA. RESULTS: The dose-limiting toxicity (DLT) in the IMP group was the cramping/arthralgia syndrome (4) and the cumulative MTD was 26 gm/m2. For both nonIMP 1 and 2 the DLTs were peripheral neuropathy and the cramping-arthralgia syndrome. The MTD for nonIMP 1 was 34 gm/m2 and nonIMP 2, 30 gm/m2. CONCLUSION: The clinical efficacy and radiation-related toxicity of these regimens are being evaluated. The doses of ETA that can be used with accelerated fractionation and with external beam irradiation plus brachytherapy have been established.

Long term results of stereotactic brachytherapy used in the initial treatment of patients with glioblastomas.

BACKGROUND: Despite optimal therapy with surgery and radiotherapy, the prognosis of patients with glioblastomas remains poor. Stereotactic brachytherapy involves the accurate placement of radioactive isotopes within brain tumors, significantly increasing the dose of radiation that can be delivered to the tumor bed without substantial risk to surrounding normal tissue, potentially improving local tumor control and patient survival. METHODS: Between February 1987 and July 1993, the authors treated 56 patients with glioblastomas with stereotactic brachytherapy as part of their initial therapy. Patients underwent surgery, limited field external beam radiotherapy, and brachytherapy with temporary high-activity iodine 125 sources, giving an additional 50 Gy to the tumor bed. RESULTS: Median survival for patients undergoing brachytherapy was 18 months compared with 11 months for a matched brachytherapy control group with similar clinical and radiologic features (P < 0.0007). Survival rates at 1, 2, and 3 years after diagnosis of 83%, 34%, and 27%, respectively, for patients receiving brachytherapy were significantly increased compared with survival rates of 40%, 12.5%, and 9%, respectively, for control subjects. Thirty-six patients (64%) underwent reoperation for symptomatic radiation necrosis from 3 to 42 months (median, 11 months) after brachytherapy. The median survival of patients undergoing reoperation was 22 months compared with 13 months for those who did not have further surgery (P < 0.02). Thirty-five percent of patients relapsed locally within the brachytherapy target volume, whereas 65% had marginal or distant relapses. CONCLUSIONS: Brachytherapy may improve local tumor control and prolong survival when used in the initial treatment of selected patients with glioblastomas.

Pharmacodynamics of prolonged treatment with L,S-buthionine sulfoximine.

PURPOSE: To develop dosing criteria for the use of L-buthionine-S-sulfoximine (active diastereoisomer) as a glutathione depletor in the clinic, using a pharmacodynamic and pharmacokinetic in vitro-in vivo approach. METHODS AND MATERIALS: In vitro: L-buthionine-S-sulfoximine uptake was determined in human glioblastoma cells (T98G) and NIH-3T3 cells using 35S-labeled drug. Dose response relationships were derived for inhibition of glutathione synthesis in CHO cells, and for depletion of glutathione in exponentially growing T98G and CHO cells, as a function of extracellular L-buthionine-S-sulfoximine concentration. Steady-state glutathione levels for CHO and NIH-3T3 cells were measured using an enzymatic assay, while glutathione synthesis rates in CHO cells were determined using a flow cytometric assay. In vivo: L-buthionine-S-sulfoximine biodistribution was determined in male nude mice carrying human glioblastomas (T98G) intracranially, using 35S-labeled drug infused subcutaneously by osmotic pump. Tissue glutathione levels were measured using an enzymatic assay. RESULTS AND CONCLUSION: The observed cellular uptake t1/2 of approximately 55 min, coupled with a previously reported, rapid in vivo clearance of buthionine sulfoximine, suggest that continuous infusion would be preferable to bolus dosing. Effective concentrations of L-buthionine-S-sulfoximine (24 h exposure), required to lower cellular glutathione content to 50% of control (EC50), were under 1 mM for both cell lines. The amount of L-buthionine-S-sulfoximine in tissues (estimated from 35S drug disposition) reached steady state within 8 h and was proportional to the rate of infusion. Brain tumors were depleted to approximately 50% of control glutathione by a infusion rate of 0.25 mumoles/h (25 g mice). At lower infusion rates an increase in glutathione content was noted in certain nude mouse tissues including brain tumor xenografts.

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.

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 of 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/m2, 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 less than 40 mM-hr. Sufficient efficacy data are not yet available. The use of drug dose modification has reduced the incidence of neurotoxicity from (a) unmodified: 17/26 = 65% (1 grade II); (b) schedule adjustment: 5/9 = 55% (no grade II); and (c) individualized dose modification: 1/19 (no grade II) = 6%. The minimum number of time points needed to accurately assess the AUC will be determined. Pharmacokinetic monitoring will be important in the use of ETA so that drug underdosing can be avoided while minimizing the risk of serious neurotoxicity.

Final report of the phase I trial of continuous infusion etanidazole (SR 2508): a Radiation Therapy Oncology Group study.

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.

Distribution of etanidazole into human brain tumors: implications for treating high grade gliomas.

Etanidazole was developed as an oxygen-mimetic radiosensitizer less lipophilic than misonidazole. Sensitization depends on an adequate concentration of drug in the tumor at the time of irradiation. Therefore, due to the presence of the blood-brain barrier, brain tumors may theoretically be difficult to radiosensitize due to the hydrophilic characteristics of etanidazole. Based on previous reports of loss of BBB integrity in brain tumors, we investigated the ability of etanidazole to penetrate into malignant gliomas of patients receiving etanidazole as part of a Phase I continuous infusion protocol. The patients had completed previous external beam irradiation. Twenty-two patients were studied and their etanidazole plasma and biopsy data were compared to the 2-compartment model derived from a second group of 19 patients with bolus etanidazole. Etanidazole concentration in brain tumor biopsies varied widely and appeared to be clustered into a higher and a lower pharmacokinetic group having mean tumor to well-perfused second compartment ratios of 1 and 0.25, respectively. Both high and low etanidazole concentrations were evident in different biopsies obtained from the same patient. Correlations between histology and tissue concentrations suggested that the higher level correspond to malignant tissue. These data indicate that the blood brain barrier is disrupted to varying degrees by the brain tumor and/or prior irradiation and that etanidazole penetrates into brain tumors.

Results of stereotactic brachytherapy used in the initial management of patients with glioblastoma.

Recent studies have shown a survival benefit for patients with recurrent glioblastomas treated with stereotactic brachytherapy. On the basis of these encouraging results, we began a prospective study in 1987 to evaluate the use of brachytherapy in patients with newly diagnosed glioblastoma. Patients were considered eligible for this study if they met the following criteria: Karnofsky performance status 70% or greater; tumor size not greater than 5 cm in any dimension; a radiographically well delineated, supratentorial lesion not involving the ependymal surfaces; and pathologically confirmed glioblastoma. We treated 35 such patients between 1987 and 1990 with stereotactic brachytherapy as part of their initial therapy. The treatment protocol involved surgery, partial brain external-beam radiotherapy (59.4 Gy in 33 fractions), and stereotactic brachytherapy with temporary high-activity iodine 125 sources giving an additional 50 Gy to the tumor bed. Chemotherapy was not used in the initial management of these 35 patients. To compare our results with those obtained in a matched control group, we identified 40 patients with glioblastoma treated with surgery and external radiotherapy, with or without chemotherapy, between 1977 and 1986 at our institution. These patients had clinical and radiographic characteristics that would have made them eligible for the brachytherapy protocol. Survival rates at 1 and 2 years after diagnosis were 87% and 57%, respectively, for patients receiving brachytherapy versus 40% and 12.5%, respectively, for the controls (P less than .001). We conclude that stereotactic brachytherapy improves the survival of patients with glioblastoma when it can be incorporated into the initial treatment approach. Unfortunately, only about one in four patients with glioblastoma are suitable candidates for brachytherapy at the time of initial presentation.