Tumori, 92: 98-103, 2006
TREATMENT OF GLIOBLASTOMA MULTIFORME IN ELDERLY PATIENTS. CLINICO-THERAPEUTIC REMARKS IN 22 PATIENTS OLDER THAN 80 YEARS Manolo Piccirilli1, Simona Bistazzoni2, Franco Maria Gagliardi1, Alessandro Landi1, Antonio Santoro1, Felice Giangaspero3, and Maurizio Salvati2 1 Neurosurgery, Department of Neurological Sciences, University “La Sapienza”, Rome; 2Department of Neurosurgery and 3Department of Neuropathology INM Neuromed, Pozzilli (IS), Italy
We report our remarks on 22 patients, 80 years of age and older, who were treated for glioblastoma multiforme. The 16 patients who underwent a multimodality treatment (surgery + radiotherapy + chemotherapy) had an average survival of 16.7 months versus the 5.8 months of the 8 patients treated with biopsy followed by radiotherapy and/or chemotherapy (logrank test, P 60) should be treated in the same way as younger patients.
Key words: chemotherapy, elderly cancer patients, glioblastoma multiforme, long-term follow-up, multimodality treatment, radiotherapy, surgery.
Introduction
In 1914, Mallory first used the term spongioblastoma multiforme1, which was changed in 1926 by Bailey and Cushing to glioblastoma multiforme2. Glioblastoma multiforme is the most malignant astrocytic tumor and corresponds to WHO grade IV3. It is the most frequent primitive brain tumor, representing 12-15% of all intracranial neoplasms and 50-60% of all astrocytic tumors. In Europe and North America, the incidence is about 2-3 new cases per 100,000 population per year 3 . Glioblastoma typically affects adults and is most often located in the subcortical white matter of the cerebral hemispheres3. Treatment of the neoplasm, which even nowadays has a poor prognosis, has a multimodality nature and is based on cytoreductive surgery followed by adjuvant radiotherapy and chemotherapy. Median survival is about 50 weeks4. The benefit of glioblastoma standard treatment in elderly patients is still debated. Several studies have pointed out that the tumor in the elderly has a poor response to multimodality treatment5,6. Elderly patients affected by glioblastoma multiforme are thus often untreated or excluded from therapeutic trials specific for younger patients. Otherwise, we have to consider that in the last decades there has been a constant and important increase in the age of the general population. Moreover, several studies have confirmed that the incidence of primary brain tumors, and in particular high grade
gliomas, is increasing in elderly patients7-9. For these reasons glioblastoma multiforme treatment in the elderly is important. The present study analyzed a series of 22 patients, all over the age of 80, with pathologically confirmed glioblastoma multiforme. Materials and methods
Between April 2000 and October 2003, 22 patients, all over the age of 80 and with a histologically proven diagnosis of glioblastoma multiforme were treated in the Department of Neurosurgery of the University “La Sapienza” and in the Department of Neurosurgery of Pozzilli (Table 1). Average patient age was 83.6 years (range, 81-89). There were 14 female and 8 male patients (F:M ratio, 1.7:1). All the patients were assessed for history, neurologic examination and a contrast-enhanced MRI of the brain. Sixteen patients underwent surgical removal, and in 6 patients a cerebral biopsy was performed. Cytoreductive surgery was obtained by the use of microsurgical methods and tools, and the extent of surgical resection was defined by the neurosurgeon’s impression and, above all, by an MRI performed within 72 h of surgery. Of the 16 patients who underwent surgical removal, 14 had a gross total removal and 2 had a subtotal removal. In 8 patients who had gross total removal, a new surgical removal was performed: 6 patients had partial removal and 2 a new gross total removal. The 2 patients
Correspondence to: Dr Maurizio Salvati, Via Cardinal Agliardi 15, 00165 Rome, Italy. Tel +39-06-49979119; fax +39-06-4940941; e-mail
[email protected] Received July 13, 2005; accepted October 14, 2005.
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GLIOBLASTOMA MULTIFORME OVER 80 Table 1 - Glioblastoma multiforme (GBM) over 80 Patients GBM location
Age
Surgery RT 1 2
Right temporal 81 lobe Right frontal lobe 83
3
Left frontal lobe
85
4
Right occipital lobe Left frontal lobe
85
5 6 7 8 9 10 11 12
81
Right parietal 82 lobe Right frontal lobe 84 Left temporal lobe Right temporal lobe Left temporal lobe Left occipital lobe
89 82 83 85
13
Right occipital 82 lobe Right temporal lobe 83
14
Left parietal lobe 85
15
Left occipital lobe Left frontal lobe
16 17 18 19 20 21 22
86 80
Right temporal 83 lobe Right frontal lobe 83 Left parietal lobe Right frontal lobe Left frontal lobe Right frontal lobe
84 81 88 86
Relapse 2nd-treatment Relapse 3rd-treatment Relapse Exitus Overall survival
Treatment CT
TR
64 TMZ No at Gy 9 mth TR 64 – 11 mth Gy Biopsy 64 _ 5 mth Gy TR 64 _ 9 mth Gy Biopsy _ _ _ TR
64 _ 10 mth Gy TR 64 TMZ 12 mth Gy Biopsy 64 PCV 6 mth Gy TR 64 TMZ 12 mth Gy SR _ _ 4 mth TR
64 _ 10 mth Gy TR 64 TMZ No at Gy 8 mth TR 64 – 11 mth Gy Biopsy 64 _ 5 mth Gy TR 64 _ 9 mth Gy Biopsy _ _ _ TR
64 _ 10 mth Gy TR 64 TMZ 12 mth Gy Biopsy 64 PCV 6 mth Gy TR 64 TMZ 12 mth Gy SR _ _ 4 mth TR
64 Gy
_
10 mth
Surgery
CT
–
–
SR
KPS
MGMT hypermetilation
Surgery
CT
–
–
–
–
–
Alive
100
Yes
PCV
8 mth
_
_
_
2 mth
21 mth
Yes
_
_
_
_
_
_
1 mth
6 mth
>70 till 21 mth 60
_
_
_
_
_
_
4 mth
>70 for
Yes
_
_
_
_
_
_
_
>60 for
No
SR
_
5 mth
_
_
_
1 mth
>70 for
No
_
_
_
_
_
_
3 mth
>70 for
No
_
_
_
_
_
_
2 mth
50 for
No
TR
PCV
9 mth
SR
_
70 for
Yes
_
_
_
_
_
_
2 mth
50 for
No
SR
_
4 mth
_
_
_
2 mth
>70 for
Yes
–
–
–
–
–
–
–
13 mth 13 mth 3 mth 2 mth 16 mth 14 mth 15 mth 13 mth 8 mth 6 mth 27 mth 27 mth 6 mth 4 mth 16 mth 16 mth Alive
100
Yes
SR
PCV
8 mth
_
_
_
3 mth
22 mth
Yes
_
_
_
_
_
_
2 mth
7 mth
>70 till 20 mth 60
_
_
_
_
_
_
5 mth
14 mth
Yes
_
_
_
_
_
_
_
3 mth
SR
_
4 mth
_
_
_
1 mth
15 mth
_
_
_
_
_
_
3 mth
15 mth
_
_
_
_
_
_
2 mth
8 mth
TR
PCV
9 mth
SR
_
5 mth 2 mth
28 mth
_
_
_
_
_
_
2 mth
6 mth
SR
_
5 mth
_
_
_
2 mth
17 mth
>80 for 13 mth >70 for 2 mth >80 for 15 mth >80 for 13 mth 60 for 6 mth 80 for 27 mth 60 for 4 mth >80 for 16 mth
5 mth 1 mth
No
No
No Yes Yes Yes Yes No Yes
TMZ, temozolomide; TR, total removal; SR, subtotal removal; PCV, procarbazine, lomustine, vincristine; RT, radiotherapy; CT, chemotherapy; MGMT, O6-methylguanine-DNA methyltransferase.
underwent a new surgical operation with partial removal. Eighteen patients received adjuvant radiotherapy. Radiotherapy was administered in all patients using Linac. Treatment fields were confined to the tumor plus a 2 cm margin over the neoplastic edema, as documented by T2 sequences on preoperative MRI. The average duration of the radiotherapy was 6 weeks, for a total average dose of 64 Gy. Ten patients received adjuvant chemotherapy: 6 patients received temozolomide concomitantly (1 h before radiotherapy, 75 mg/m2 daily x 5 days/week) and sequentially after radiotherapy (200 mg/m 2 daily x 5, every 28 days). Six patients were treated using a PCV schedule (procarbazine, 75 mg/m2/per os days 8-21; lomustine, 130 mg/m2 per os day 1; vincristine, 1.4 mg/m2 iv days 8-29, for a cycle of 6 weeks). Two patients were
first treated using temozolomide until progression of the disease and after a new surgical treatment received the PCV chemotherapy. Ondansetron (4 mg/die for 5 days) was used as a prophylactic antiemetic in all patients before chemotherapy. The median interval between completion of radiotherapy and commencement of adjuvant chemotherapy was 15 days (range, 10-18). Tumor tissues were placed in 10% formalin and submitted for histopathologic examination. Other tumor tissues were frozen immediately after removal and stored at -80 °C until the isolation of genomic DNA. Genomic DNA from the frozen tumors was isolated by proteinase-K digestion and phenolchloroform extraction. The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter in each tumor was analyzed with the methylation-specific polymerase chain reaction (PCR) assay in two steps: modification of DNA by sodium
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M PICCIRILLI, S BISTAZZONI, FM GAGLIARDI ET AL
bisulfite and PCR amplification. Normal human lymphocyte DNA was used as a negative control and normal human lymphocyte DNA treated with Sss I methylase (New England Biolabs, Beverly, MA, USA) as a positive control. After PCR, 10 µl of the reaction product was separated by electrophoresis on 3% agarose gels and stained with 0.5 µg/ml ethidium bromide under ultraviolet illumination. Survival curves were generated by the Kaplan-Meier method, and the logrank test was used to estimate differences between survival curves. We considered statistically significant P
