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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
T. J. Doyle, T.
Mikkelsen, D. Croteau, H. Ali, J.
Anderson, R. Beasse, L. Rogers, M.
Rosenblum and S. Ryu
Henry Ford Hosp, Detroit, MI;
NeoPharm Inc, Lake Forest, IL
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
|
