see chemo guide from MGH

Promising Survival for Patients With Newly Diagnosed Glioblastoma Multiforme Treated With Concomitant Radiation Plus Temozolomide Followed by Adjuvant Temozolomide

JCO Mar 1 2002: 1375-1382

Sixty-four patients were enrolled onto this open-label, phase II trial. Temozolomide (75 mg/m2/d x 7 d/wk for 6 weeks) was administered orally concomitant with fractionated radiotherapy (60 Gy total dose: 2 Gy x 5 d/wk for 6 weeks) followed by temozolomide monotherapy (200 mg/m2/d x 5 days, every 28 days for six cycles). Median survival was 16 months, and the 1- and 2-year survival rates were 58% and 31%, respectively. Patients younger than 50 years old and patients who underwent debulking surgery had the best survival outcome. Treatment volume generally included the contrast-enhancing lesion plus a 2- to 3-cm margin, depending on the location.

Concomitant radiochemotherapy with temozolomide in non-selected patients with newly diagnosed high-grade gliomas.

Department of Radiotherapy and Oncology, Johann Wolfgang Goethe-Universitat Frankfurt/Main, Frankfurt, Germany. Anticancer Res. 2006 Nov-Dec;26(6C):4959-64.

From 1999 to 2004, 104 patients with WHO grade III and IV gliomas underwent surgery and received concomitant radiotherapy combined with concomitant oral temozolomide. Patients with progressive disease received sequential 5-day cycles of temozolomide at 28-day intervals. RESULTS: The median overall survival was 19.7 and 15.0 months for patients with WHO grade III versus IV gliomas, respectively. Patient compliance was good and toxicity moderate. The overall survival was as long as 18.0 months in a subgroup of subjects with glioblastoma, performance status >60% and complete radiochemotherapy. CONCLUSION: Although our patients had more negative characteristics (age, performance, biopsy only), the results confirmed those from recently published optimistic phase III trial data and indeed surpassed them in some cases.

A prospective study on glioblastoma in the elderly. Elderly patients (age > 65 years) with glioblastoma multiforme frequently are excluded from clinical studies, and prospective trials for patients with this age group do not exist to date.The authors conducted a prospective trial in 79 consecutive elderly patients with glioblastoma who underwent surgery and received radiotherapy (59.44 grays in 33 fractions; Group A; n = 24 patients) or received the same radiotherapy plus adjuvant chemotherapy with procarbizine, lomustine, and vincristine (PCV; lomustine 110 mg/m2 on Day 1, procarbazine 60 mg/m2 on Days 8-21, and vincristine 1.4 mg/m2 on Days 8 and 29 every 42 days; Group B; n = 32 patients), or received the same radiotherapy plus adjuvant temozolomide (150 mg/m2 for 5 days every 28 days; Group C; n = 22 patients). The median time to disease progression (TTP) and median survival MST were 7.2 months (95% confidence interval [95%CI], 6.34-8.64) and 12.5 months (95%CI, 11.6-14.8), respectively. The TTP was significantly better for Group C compared with Groups A and B (10.7 months vs. 5.3 months and 6.9 months, respectively; P = 0.0002). Overall survival was better in Group C compared with Group A (14.9 months vs. 11.2 months; P = 0.002), but there were no statistical differences found between Groups A and B or between Groups B and C.   Cancer 2003;97:657-62 see graph.

FDA Approves Temodar For Refractory Anaplastic Astrocytoma

MADISON, NJ -- Aug. 12, 1999 - The United States Food and Drug Administration has granted accelerated approval to Schering-Plough Corp.’s Temodar(TM) (temozolomide) Capsules for the treatment of adult patients with refractory anaplastic astrocytoma, such as patients at first relapse with disease progression on a nitrosourea- and procarbazine-containing drug regimen. Temodar is the first new chemotherapy agent for this type of brain tumour approved in the U.S. in 20 years. It will be available nation-wide in early September. In addition, oral dosing with Temodar Capsules for five days in each 28-day treatment cycle is convenient for patients, enabling them to take medication in the comfort of their homes instead of at doctors' offices or hospitals where intravenous treatments are administered.” Temodar, an oral cytotoxic alkylating agent, is the lead compound in a new class of compounds known as imidazotetrazines. Cytotoxic agents are designed to prevent the replication of cells that divide rapidly, including those in tumours.

A single-arm, multicentre clinical study with Temodar Capsules was conducted in 162 patients who had anaplastic astrocytoma at first relapse. Patients had previously received radiation therapy and may also have previously received a nitrosourea with or without other chemotherapy. Of the 162 patients in the study, 54 patients had disease progression on prior therapy with both a nitrosourea and procarbazine and their malignancy was considered refractory to chemotherapy (refractory anaplastic astrocytoma population). Patients in the study were given Temodar for the first five days of a 28-day treatment cycle at a starting dose of 150 mg/m2 per day. In the refractory anaplastic astrocytoma population, the overall tumour response rate (complete response plus partial response) was 22 percent (12/54 patients) and the complete response rate was nine percent (five of 54 patients).The median duration of all responses was 50 weeks (range of 16 weeks to 114 weeks) and the median duration of complete responses was 64 weeks (range of 52 weeks to 114 weeks). Progression-free survival at six months was 45 percent (95 percent confidence interval of 31 percent to 58 percent), progression-free survival at 12 months was 29 percent (95 percent confidence interval of 16 percent to 42 percent), and median progression-free survival was 4.4 months. Overall survival at six months was 74 percent (95 percent confidence interval of 62 percent to 86 percent), overall survival at 12 months was 65 percent (95 percent confidence interval of 52 percent to 78 percent), and median overall survival was 15.9 months.

Semin Oncol 2000 Jun;27(3 Suppl 6):27-34

Temozolomide in malignant gliomas.

Yung WK

Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030-4009, USA.

Glioblastoma multiforme and anaplastic astrocytoma are the most common primary central nervous system malignancies and are the major cause of morbidity/ mortality despite combined modality approaches. Temozolomide (TMZ), a novel, oral, second-generation alkylating agent, has demonstrated antitumor activity against a broad range of solid tumors and highly resistant malignancies, including high-grade glioma Temozolomide does not require hepatic metabolism for activation, rapidly penetrates the cerebrospinal fluid, and consistently demonstrates reproducible linear pharmacokinetics with approximately 100% oral bioavailability. In preliminary clinical studies, TMZ has demonstrated meaningful efficacy and an acceptable safety profile in the treatment of patients with malignant glioma. These results have been recently confirmed in three open-label, multi-institutional studies that evaluated the use of TMZ in 525 malignant glioma patients. These studies represent the largest evaluation of a single agent in patients with recurrent malignant gliomas and were rigorously controlled with strict, prospectively defined criteria for assessment of tumor response, central review of histology, and validated instruments to assess health-related quality of life. Temozolomide was effective in delaying disease progression and maintaining health-related quality of life. Temozolomide represents a promising new agent in the treatment of malignant glioma.

Anticancer Res 2000 May-Jun;20(3B):1913-20

New drugs in recurrent high grade gliomas.

Brandes AA, Pasetto LM, Monfardini S

Divisione di Oncologia Medica, Azienda Ospedale, Universita, Padova, Italia. brandes@ux1.unipd.it

The most encouraging results to date come from studies of temozolomide, which is one of the most active and best tolerated drugs in recent years.

Journal of Clinical Oncology, Vol 21, Issue 8 (April), 2003: 1485-1491

Phase III Study Comparing Three Cycles of Infusional Carmustine and Cisplatin Followed by Radiation Therapy With Radiation Therapy and Concurrent Carmustine in Patients With Newly Diagnosed Supratentorial Glioblastoma Multiforme: Eastern Cooperative Oncology Group Trial 2394

Stuart A. Grossman,

Purpose: This phase III Eastern Cooperative Oncology Group-Southwest Oncology Group intergroup study was conducted to determine whether three 72-hour infusions of carmustine (BiCNU) and cisplatin administered monthly before external-beam radiotherapy would improve the survival of patients with newly diagnosed glioblastoma multiforme. The control arm consisted of radiation with standard adjuvant BiCNU.

Patients and Methods: A total of 223 patients were accrued from 1996 to 1999. Of these, 219 patients were eligible; 109 were randomly assigned to the experimental arm, and 110 were randomly assigned to the control arm. Randomization was stratified by age, performance status, and extent of resection.

Results: The median age of the patients was 55 years; 55% were male, 93% were white, 26% had a biopsy only, and 84% were ambulatory. Treatment arms were well balanced with respect to baseline characteristics. Median follow-up time of the 15 patients still alive at the time of analysis was 3.3 years (range, 2 to 5 years). Median survival times for the standard and experimental arms were 11.2 and 11.0 months (P = .33, two-sided log-rank test), and survival at 1 year was 45% versus 44%, respectively. Fifty-six percent of patients received all three cycles of BiCNU/cisplatin, 12% received two cycles, and 31% received only one cycle. Toxicity was primarily hematologic and was more common in the experimental arm (P < .01).

Conclusion: This study demonstrates that 72-hour infusions of BiCNU and cisplatin followed by radiation do not improve median survival, survival at 1 year, or time to progression. Furthermore, this treatment requires more time in the hospital and is associated with more serious toxicities than standard therapy.

Journal of Clinical Oncology, Vol 20, Issue 14 (July), 2002: 3149-3155

Survival of Patients With Newly Diagnosed Glioblastoma Multiforme Treated With RSR13 and Radiotherapy: Results of a Phase II New Approaches to Brain Tumor Therapy CNS Consortium Safety and Efficacy Study

By L. Kleinberg, S.A.

PURPOSE: The objectives of this phase II study were to determine survival, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 2,4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylpropionic acid (RSR13, efaproxiral) 100 mg/kg per day administered with standard cranial radiotherapy (RT) for the treatment of glioblastoma multiforme (GBM). RSR13, a synthetic allosteric modifier of hemoglobin, is a radiation-enhancing agent that noncovalently binds to hemoglobin, reduces oxygen-binding affinity, and increases oxygen unloading to hypoxic tissue.

PATIENTS AND METHODS: Fifty patients with newly diagnosed GBM (Karnofsky performance status >= 60) were enrolled onto this multicenter phase II study. Patients received daily RSR13 100 mg/kg intravenously infused for 30 minutes immediately before cranial RT (60 Gy in 30 fractions). Supplemental oxygen was given during RSR13 infusion and continued until after the RT treatment was completed. RT was given within 30 minutes of the end of RSR13 infusion. PK and PD determinations were performed.

RESULTS: The median survival for the RSR13-treated patients was 12.3 months with 1-year and 18-month survival rates of 54% and 24%, respectively. Twenty-four percent of patients had greater than grade 2 toxicity, which was generally transient and self-limited. A significant PD effect on hemoglobin-oxygen binding affinity was demonstrated for most patients.

CONCLUSION: RSR13 (100 mg/kg) administered immediately before cranial RT is well tolerated and is pharmacodynamically active. Median survival in excess of 1 year is favorable.