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© 2000 American Society for Clinical Oncology Single-Arm, Open-Label Phase II Study of Intravenously Administered Tirapazamine and Radiation Therapy for Glioblastoma MultiformeFrom the Department of Radiation Oncology, Montefiore Medical Center, Bronx, NY; Radiation Therapy Oncology Group Statistical Unit; Departments of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA; Notre Dame Hospital, Montreal, Quebec; Cross Cancer Institute, Edmonton, Alberta; and London Regional Cancer Facility, London, Ontario, Canada. Address reprint requests to John Del Rowe, MD, Department of Radiation Oncology, Montefiore Medical Center, 111 E 210th St, Bronx, NY 10467; email jdelrowe{at}montefiore.org
PURPOSE: This phase II study tested the efficacy and safety of tirapazamine (Sanofi Synthelabo Research, Malvern, PA), a bioreductive agent, in glioblastoma multiforme (GBM) patients. The patients were staged according to a model constructed by a recursive partitioning analysis (RPA) of glioma patients in prior Radiation Therapy Oncology Group (RTOG) trials and compared with a matched standard population, as predicted by the model. PATIENTS AND METHODS: A total of 124 patients diagnosed with a GBM were treated with radiation therapy and intravenous tirapazamine between January 27,1995, and April 25,1997. All patients received 60 Gy in 2-Gy fractions. Tirapazamine was delivered three times a week for 12 treatments during radiotherapy. Fifty-five patients received tirapazamine at 159 mg/m2. A second dose level, 260 mg/m2, was opened, and 69 patients were entered. RESULTS: There was no significant survival advantage to the drug in any RPA class at either dose level. The median survival time was 10.8 months for the patient population treated with the 159-mg/m2 dose of tirapazamine and 9.5 months for the group treated with the 260-mg/m 2 dose of tirapazamine. Survival times by RPA class for patients receiving tirapazamine at 159 mg/m2 were 27.4 months (class III), 10.8 months (class IV), 7.9 months (class V), and 3.8 months (class VI). Survival times by RPA class for patients receiving tirapazamine at 260 mg/m2 were 16.2 months (class III), 10.3 months (class IV), 5.1 months (class V), and 1.3 months (class VI). Patients in RPA class III treated in the 159 mg/m2 dose arm had a notably longer survival than patients in the RTOG database RPA class III, but the difference did not reach statistical significance. There were no fatal toxicities. Grade 3/4 toxicities were more frequent at the higher dose level. CONCLUSION: Survival in the population treated with radiation and tirapazamine was equivalent to the control population. Patients in RPA class III treated with radiation and tirapazamine at the 159-mg/m2 dose had a longer survival when compared with the historical controls. The improvement in survival did not reach statistical significance. Toxicity was acceptable in both treatment arms, but grade 3/4 toxicities were more frequent in the higher dose regimen.
GLIOBLASTOMA MULTIFORME (GBM) is a highly malignant brain tumor that is resistant to standard therapy. Surgery followed by radiation therapy and chemotherapy offers the patient the best chance for survival, but results are dismal.1,2 Approaches to improve survival need to identify obstacles that limit the effectiveness of current therapy. One such obstacle is hypoxia.3 An estimated 12% to 20% of the cells in human tumors may be hypoxic, with some cells cycling between aerobic and hypoxic states.3,4 Hypoxic tumor cells are resistant to chemotherapy5,6 and radiotherapy.7,8 They require two to three times higher radiation doses to produce the same level of cell killing as do normally oxygenated cells.9 To date, strategies to overcome the radio-resistance of hypoxic tumor cells have achieved only limited success. Hyperbaric oxygen has provided modest improvement in local control of some tumors,10,11 and treatments using particle beams with high linear energy transfer12 are less oxygen-dependent. However, high linear energy transfer radiation lacks selectivity for tumor tissue.13-15 A third method uses electron-affinic radiosensitizers,16 such as nitroimidazoles (eg, misonidazole). Such agents are effective in some trials17 but may also cause dose-limiting neurotoxicity.18,19 Second generation nitroimidazoles (eg, etanidazole) only partially overcame the radio-protective effects of hypoxia at clinically achievable doses. Agents with greater differential toxicity for hypoxic cells and an improved therapeutic index are needed. Tirapazamine (Sanofi Synthelabo Research, Malvern, PA) is a benzotriazine compound exhibiting substantial differential toxicity for hypoxic cells.20,21 In preclinical studies, the addition of tirapazamine to radiotherapy may result in greater than additive hypoxic cell kill.22 It also shows a substantial margin of safety between the low levels required for significant toxicity to hypoxic tumor cells and doses that are toxic to normally oxygenated tissues. A number of factors, patient and tumor characteristics and treatment-related variables, have been reported to affect survival in the malignant glioma patient population. Curran et al23 used a nonparametric statistical technique to examine the associations of both pretreatment patient and tumor characteristics and treatment-related variables with survival duration. Using data from the Radiation Therapy Oncology Group (RTOG) database of over 1,500 patients, a model was constructed to better classify patients. Patients were assigned to six classes; each class identifies a more homogeneous patient population with regard to survival. In our investigation of tirapazamine and radiotherapy, we staged patients according to the model and compared them with a matched standard population, as predicted by the model. (Median survival times of RTOG database patients are listed in Table 1.) Many of the patients in the standard population received combined-modality therapy, which included 1 year of chemotherapy. This study assessed the efficacy and safety of a regimen combining tirapazamine with radiotherapy in the treatment of patients with GBM.
Eligibility Patients were eligible for the study if they had histologically confirmed supratentorial GBM, a Karnofsky performance status of at least 60, and a neurologic functional status of 0, 1, or 2.24 Surgical biopsy or excision confirmed the diagnosis. Therapy had to begin within 5 weeks of surgery. Patients were ineligible if the histology was anaplastic astrocytoma or if the diagnosis was multifocal glioma or recurrent GBM. Patients were also excluded if they received prior radiotherapy or chemotherapy or if they were candidates for RTOG 93–05, which investigated the role of radiosurgery in patients with GBM  40 mm in diameter. Patients had to be at least 18 years of age, hemoglobin had to be  10 g/L, and have a platelet count of at least 100,000/µL. Pretreatment evaluation included a complete medical history, a physical examination, and a detailed neurologic examination. The Mini-Mental State Examination was included in the neurologic examination. Laboratory tests included complete blood count with platelet count and blood chemistry. Computed tomography (CT) with contrast or magnetic resonance imaging scan with and without gadolinium was performed preoperatively and postoperatively before the initiation of radiotherapy. The protocol was approved by the ethics and human investigation committee of each participating institution. Written informed consent was obtained from all patients before entry onto the study.
Protocol Treatment Radiation therapy was delivered with megavoltage machines of energy equal to at least 4 MV. Adequate immobilization was required to ensure reproducibility. The treatment volume for both the initial fields and the cone-down fields was determined by the preoperative CT and magnetic resonance imaging scan. The initial treatment volume included the contrast-enhancing lesion and surrounding edema plus a 2-cm margin. This volume received a dose of 46 Gy in 2-Gy fractions. The boost volume included the contrast enhancing lesion without edema plus a 2.5-cm margin. An additional 14 Gy in 2-Gy fractions was delivered to this volume. Systemic chemotherapy was not part of the initial treatment protocol. The therapeutic management at time of recurrence was left up to the individual investigator. The Cooperative Group common toxicity criteria were used for grading side effects to both tirapazamine and radiotherapy. If grade 3 or grade 4 tirapazamine-related toxicity was observed in any patient and was not controlled acutely by symptomatic measures, tirapazamine administration was stopped until resolution of the toxicity by two grade levels. The drug could be restarted at a dose reduced by 25%. If tirapazamine had to be withheld again because of drug-related toxicity, the drug was to be discontinued. Patients were assessed for toxicity daily during radiation therapy. Hematologic evaluation was performed weekly. Serum chemistries, including creatinine, were taken every 2 weeks during therapy. Follow-up was performed 3 months after the start of radiotherapy and continued every 3 months. At each follow-up, the evaluation included neurologic examination, hemoglobin and platelet counts, and serum chemistries including creatinine. Repeat scans were performed at first follow-up and repeated if there was evidence of neurologic deterioration.
Statistical Methods
Patient Characteristics Between January 1995 and April 1997, 124 patients from 14 institutions were entered onto the protocol. Three patients were excluded. Two were ineligible because pretreatment evaluations were incomplete. One patient refused all treatment, and one patient’s forms were not received. Fifty-three assessable patients received 159 mg/m2, and 68 received 260 mg/m2. Table 2 lists the pretreatment characteristics by treatment arm. Patients in the 159-mg/m2 group had a mean age of 53.8 years (range, 23 to 76 years). In the 260-mg/m2 group, the mean age was 55.4 years (range, 19 to 76 years). Forty-two percent of the patients in the 159-mg/m2 group and 32% of the patients in the 260-mg/m2 group were less than 50 years old. The majority of the patients, 66% and 59% in the 159 mg/m2 and 260 mg/m2 groups, respectively, had a partial resection of the tumor.
Toxicity Acute toxicity data were available on all the patients in both arms. Fifty of 53 patients completed therapy according to the protocol. Fifty-three of 54 patients completed the entire course of radiotherapy. One case discontinued all treatment after 42 Gy. One patient completed the 12 courses of tirapazamine during the radiotherapy but not within the first 4 weeks of treatment. One patient, mentioned above, received less than 12 courses, and tirapazamine therapy was discontinued. Only one patient in the group discontinued treatment secondary to toxicity. The patient had a grade 3 neutropenia. Fifty-two of 68 patients who received the higher dose completed the protocol with regard to tirapazamine. Sixteen patients who did not complete treatment included six patients who refused to continue treatment, one patient whose therapy was discontinued by the treating physician, and one patient with disease progression. Four patients had therapy discontinued because of toxicity during treatment. One patient suffered from seizures secondary to tumor, one had a grade 2 skin rash, one developed an allergy to penicillin, and one had grade 2 nausea and vomiting and incontinence. Eight patients in this arm did not complete the radiation therapy course. As noted above, six patients refused treatment, and one patient’s physician cancelled treatment. One patient discontinued treatment because of progressive disease. No fatal toxicities have been observed. The incidence of acute grade 3 and grade 4 toxicities by dose schedule is listed in Table 3.
Overall the most common toxicities of tirapazamine were nausea, vomiting, muscle pain, and skin reactions. Of the patients receiving the 159-mg/m2 dose, one patient experienced a grade 4 acute toxicity, and 13 patients experienced a grade 3 toxicity as their most severe acute toxicity. In comparison, of the patients receiving the 260-mg/m2 dose, seven patients experienced a grade 4 acute toxicity, and 27 patients experienced, at most, a grade 3 toxicity. The single grade 4 toxicity in the lower dose arm was muscle pain that resolved in 6 days. In the higher dose arm, tirapazamine caused or contributed to the six grade 4 toxicities. Four of the six cases resolved in 1 day. They included two cases of hyperglycemia, a case of muscle pain, and a pulmonary toxicity. One patient had a generalized skin rash that lasted 2 months. This patient was also on phenytoin. One patient with an occipital/parietal tumor presented with bilateral visual field defects and showed deterioration of visual acuity and bilateral visual loss on day 13 of treatment past the fifth dose of tirapazamine. Brain CT scan showed a slight increase in edema but no change in tumor size. This grade 4 toxicity never resolved. Muscle cramps were a common grade 3 toxicity in both groups. The amount of tirapazamine received that precipitated muscle pain varied from 318 mg/m2 to 1,113 mg/m2. The dose of radiation when muscle pain was first appreciated was 2 to 20 Gy. Late toxicities are listed in Table 4. The number of assessable patients was less than the original patient number because some patients died of their disease or were lost to follow-up. There was only one grade 3 late toxicity reported at each dose level. No late grade 4 toxicities have been observed.
Overall Survival The median survival time of the entire patient population treated at 159 mg/m2 was 10.8 months. For patients treated at 260 mg/m2, the survival was 9.5 months. The median survival time by recursive partitioning analysis (RPA) class is listed in Table 2. The survival times by RPA class for patients receiving tirapazamine at 159 mg/m2 were 27.4 months (class III),10.8 months (class IV), 7.9 months (class V), and 3.8 months (class VI). The survival times by RPA class for patients receiving tirapazamine at 260 mg/m 2 were 16.2 months (class III),10.3 months (class IV), 5.1 months (class V), and 1.3 months (class VI). There was no significant difference in median survival time for patients treated with either dose level of tirapazamine when compared with the RTOG database population. The median survival time of patients in RPA class III treated on the lower dose arm (159 mg/m2) is notably longer than the RTOG historical controls but did not reach statistical significance.
The primary objective of this study was to determine whether survival for patients with GBM treated with tirapazamine and radiotherapy was significantly better than standard therapy. A secondary end point was to determine whether toxicity was acceptable. Patients in the current study were staged according to the RPA class model proposed by Curran et al23 and then compared with a matched standard population, as predicted by the model. Grade 3/4 toxicities were higher in the patients who received 260 mg/m2. Only one grade 4 toxicity was reported in the lower dose arm compared with six in the higher dose arm. Most toxicities were reversible. Seven patients refused to continue treatment in the higher dose arm, whereas no patients refused to continue in the lower dose arm. The drug was better tolerated at the lower dose level. There was no significant difference in survival for patients treated with tirapazamine when compared with the standard population (RTOG database). The median survival time for RPA class III patients treated with the 159-mg/m2 dose schedule had a notably longer survival than RPA historical controls, but the difference did not reach statistical significance. No chemotherapy was administered in this study. Although most patients did not achieve a significantly improved survival compared with historical controls, it is worth noting that patients treated with a short course of a radiation sensitizer, tirapazamine, during radiotherapy achieved similar survivals to a matched patient population that received 1 year of carmustine. Patients who belong to RPA class III potentially benefited from this treatment. A phase III study aimed at this population would be required to confirm efficacy. Nevertheless, new therapies are needed to improve the survival in this patient population. Tirapazamine was designed to target hypoxic cells in tumors. GBM was a good choice to test the drug because areas of necrosis are known to exist in GBM. This study has shown a potential benefit from treatment with tirapazamine, given at a dose of 159 mg/m2, and radiotherapy in GBM patients who are RPA class III. Survival for patients in other RPA classes did not significantly improve when compared with the control population. Toxicities from tirapazamine were more frequent for patients receiving the drug at a dose of 260 mg/m2 than a dose of 159 mg/m2, a dose at which the drug was well tolerated.
Supported in part by Public Health Service grants no. U10 CA21661, CCOP U10 CA37422, and Stat U10 CA32115 from the National Cancer Institute, Bethesda, MD. Also supported in part by Sanofi Pharmaceutical, Inc, Malvern, PA.
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
