Fatal hematologic toxicity with prolonged continuous administration of temozolomide (TMZ) during radiation therapy (RT) in the treatment of newly-diagnosed glioblastoma multiforme (GBM): Report of a Phase II trial

Abstract

1546 Background: A Phase III trial demonstrated superior survival in GBM patients (pts) treated with postoperative RT and concomitant and adjuvant TMZ. Hematologic toxicity was acceptable; only 7% of pts experienced grade 3/4 toxicity (Stupp et al, ASCO Proc 2004, No. 2). The current phase II trial studied the same regimen. Methods: Pts age ≥ 18 with newly diagnosed histologically-proven GBM and KPS ≥ 60 with normal hematologic, hepatic and renal function were enrolled from 1/2001–10/2002. RT (60 Gy in 30 daily fractions of 2 Gy) and concomitant TMZ 75mg/m2 for up to 42 days were administered. Adjuvant TMZ 200mg/m2 day 1–5 every 28 days for up to 12 cycles was given following RT. Survival and toxicity were primary endpoints. Prophylactic trimethoprim-sulfamethoxazole (TMP-SMZ) 160mg/800mg 3 times weekly was given to those taking dexamethasone. Results: 16 pts were registered and all included in the analysis. The table describes survival and hematologic toxicity of all 16 pts. 3 (3/16, 19%) died from toxicity of TMZ given with RT. These are detailed in the lower part of the table. 1 pt had bone marrow (BM) biopsies (day 46 and 67) showing aplasia. Another pts day 38 BM biopsy showed 5% cellularity. Grade 3/4 thrombocytopenia preceded grade 3/4 neutropenia. Conclusions: 3/16 pts experienced fatal hematologic toxicity following daily TMZ 75mg/m2 during RT. 2 pts had BM examinations; 1 had aplastic anemia, the other only 5% cellularity. Due to routine use of TMP-SMZ prophylaxis, a drug interaction with TMZ cannot be excluded as a cause of hematologic toxicity. Further investigation is warranted. Caution is advised when using this regimen. N (pts) 16 Age, median/range 56/35–72 KPS 90–100/60–80 7/9 Survival, median (days)/1 yr/2 yr 393/38%/19% Grade 4 neutropenia 3/16 Grade 4 thrombocytopenia 3/16 Grade 5 hematologic toxicity 3/16 Aplastic BM 2/16 Patients with fatal toxicity: Age 57 61 63 Days of TMZ during RT 33 22 29 Days† to grade 3/4 neutropenia ANC nadir 35/39 0 -/27 0 35/36 0 Days† to grade 3/4 thrombocytopenia Platlet nadir k/uL 28/31 5* 24/-28* 32/34 13* Survival (days) 155 103 51 * pt given platelet transfusion-true nadir unknown † from day 1 TMZ Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering Schering