Published in Am J Clin Oncol. 2008 Improvement, Clinical Course and Quality of Life after Palliative Radiotherapy for Recurrent Glioblastoma

CARSTEN NIEDER, MD1, SABRINA T. ASTNER, MD2, MINESH P. MEHTA, MD3, ANCA L. GROSU, MD4, and MICHAEL MOLLS, MD2 1

Department of Internal Medicine - Oncology and Radiation Oncology Units, Nordlandssykehuset HF, Bodø, Norway 2 Department of Radiation Oncology, Klinikum rechts der Isar der Technischen Universität Mûnchen, Munich, Germany 3 Department of Human Oncology, University of Wisconsin Hospital Medical School, Madison, WI, USA 4 Francis H. Burr Proton Therapy Center, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA

Correspondence to: Carsten Nieder, MD, Department of Internal Medicine – Oncology and Radiation Oncology Units, Nordlandssykehuset HF, 8092 Bodø, Norway, Tel: +47 755 78449, FAX: +47 755 34742, e-mail: [email protected]

1

1. 2.

Abstract The purpose of this review is to assess the palliative effect of re-irradiation in adult patients with recurrent supratentorial glioblastoma (GBM) previously treated with adjuvant or primary radiation therapy, with or without chemotherapy. From a comprehensive literature search, studies were identified reporting on survival, progression and quality of life endpoints including, but not limited to, EORTC QLQ-C30 questionnaire, clinical symptoms and ability to reduce dexamethasone. Data from more than 300 GBM patients (Grade 3 anaplastic gliomas were excluded) demonstrates that re-irradiation yields 6-months PFS of 28-39% and 1-year overall survival of 18-48%, without additional chemotherapy (median value 26%). Patients with Karnofsky performance status (KPS) <70 appeared to be at higher risk of early progression and apparently had lesser benefit from re-irradiation. Clinical improvement was observed in 24-45% of the patients. Most studies suggest that stabilisation of the performance status is a realistic aim. In the studies reporting on corticosteroid usage during and after re-irradiation, 20-60% of the patients achieved a reduction in steroid dependency. Serious late toxicity was uncommon, especially after conventional treatment and fractionated stereotactic radiotherapy (FSRT). In light of recent technological advances such as FSRT and intensity modulated radiotherapy (IMRT), which permit maximal sparing of normal brain, retreatment appears attractive, and deserves scientific validation. Even fraction sizes of 3-5 Gy appear to be well tolerated in limited-volume recurrences as long as the total dose is limited to 30-35 Gy. Salvage chemotherapy or targeted agents should be prospectively tested against re-irradiation alone. key words: radiotherapy, reirradiation, corticosteroid, dexamethasone, glioblastoma, recurrent glioma.

Introduction 2

The integration of temozolomide into current protocols of postoperative first-line treatment for glioblastoma (GBM) has improved progression-free and overall survival, yet long-term disease-free survival is rare (1). A second course of radiotherapy is among the re-treatment options, and two reviews demonstrated that re-irradiation achieves survival comparable to that observed after other palliative approaches such as chemotherapy (2, 3). They also suggested that no clear survival differences between conventional external beam radiotherapy, stereotactic radiotherapy and various methods of brachytherapy exist. As re-irradiation is not a curative approach, the palliative effects should be examined in greater detail including evaluation of the clinical course, quality of life parameters, side effects and surrogate endpoints such as corticosteroid reduction. Therefore, a comprehensive review of published series of reirradiation was undertaken, with a focus on palliative endpoints.

Methods

The present review examines different quality of life parameters published in studies of re-irradiation for GBM in adult patients and is based on a systematic literature search by use of Medline (Pub Med by the National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA). The key words used were “recurrent brain tumor”, “recurrent glioma”, “recurrent astrocytoma” and “recurrent glioblastoma”. The final search was performed on May 31, 2007 and included the reference lists of all articles. Only studies with more than 10 patients were included. With special emphasis on 3

articles published in the last 10 years, pre-specified variables were extracted and compared in Table 1. They include all factors related to clinical course, quality of life and side effects.

Results

Re-irradiation has not been evaluated in a randomized setting so far. All data are therefore less than level 1 evidence. As published previously, median survival after various methods of re-irradiation for GBM was 26-60 weeks (3). Tumor progression usually occurred within 20-27 weeks, but is not a very reliable endpoint as it is difficult to distinguish it from treatment effects, especially after brachytherapy and radiosurgery (RS). We evaluated and present the results by method of re-irradiation.

External-beam irradiation External-beam irradiation was used by Veninga et al. in 29 patients with astrocytoma (4). Seventeen had GBM, but at least 4 had low-grade tumors. Therefore, results will be focused on the GBM subgroup when possible. Initial treatment included radiotherapy with 50-60 Gy, as in other trials. The minimum re-irradiation interval was 11 months, i.e. only highly selected patients were retreated. Median re-irradiation dose was 46 Gy at 2 Gy per fraction. Ten patients were on steroids and 8 of them were unable to reduce the dose. Some patients were able to complete re-irradiation without any steroids. Clinical improvement after re-irradiation compared to baseline was noted in 24%, and the median time to progression in GBM was 4.3 months. Progression during treatment or in the first 3 months was observed in 31%. Progression-free survival (PFS) at 6 months is unknown, while overall survival at 1 year was 24% for all 29 astrocytoma patients. Arcicasa et al. reported on a smaller series of 24 patients treated with re-irradiation and CCNU (5). Not all of them had GBM. As shown in Table 1, no detailed late toxicity or quality of life data are available. PFS at 6 months is unknown, while overall survival at 1 year was 52%. As estimated from the published survival curve, just below 10% of the patients died during the first 3 months. In the light of these incomplete publications, we decided to update our experience with hyperfractionated re-irradiation for GBM, initially published in 1999 (6). The group of 24 4

patients treated to 45 Gy included 3 patients with incomplete re-irradiation. These 3 patients had early clinical and imaging-confirmed progression. Their Karnofsky performance status (KPS) before re-irradiation was 50-60. None underwent re-resection before re-irradiation. Another 3 patients progressed within 3 months after re-irradiation. Regarding corticosteroids, 4% completed treatment without dexamethasone, 17% had initial daily doses below 10 mg, 54% had 10-16 mg, 8% 24-30 mg and 17% 32 mg. After treatment, 17% discontinued completely, 13% reduced by 50% or more, 29% reduced by up to 50% and 41% remained on stable doses. KPS improved in 8%, was stable in 67% and worsened in 25% compared to the baseline value immediately before reirradiation. PFS at 6 months was 39%, while overall survival at 1 year was 18%.

Fractionated stereotactic radiotherapy Several reports of fractionated stereotactic radiotherapy (FSRT) have been published, including one by our own group (7); some have utilized standard 1.8-2 Gy/fraction, whereas others have utilized a hypofractionated schedule. Unfortunately, systematic quality of life data are not available for all patients because many of our patients were followed elsewhere. A trial of FSRT in 53 patients with GBM was reported by Combs et al. (8). Median re-treatment dose was 36 Gy, using 5 fractions of 2 Gy per week. The authors found a PFS at 6 months of 28% and a 1-year overall survival rate of 23%. Approximately 17% of the patients progressed within the first 3 months, but less than 10% died during this interval. No detailed quality of life data were published. Vordermark et al. used FSRT (median 30 Gy in 6 fractions) in 19 patients (14 GBM) with a median KPS of 90% (9). Median time to progression was 20 weeks in GBM. PFS at 6 months was not reported, while overall survival at 1 year was 21% in GBM patients. Approximately 10% died within the first 3 months. Hudes et al. reported on another group of 19 GBM patients treated with FSRT (10). Several had persistent tumor after initial treatment rather than classic recurrence. While PFS is not available, 1-year survival rate was 20%. Less than 10% of patients died within 3 months. High rates of neurologic improvement (45%) and decreased steroid requirement (60%) were observed, but duration of these effects is not known. Shepherd et al. used relatively high total doses, which resulted in considerable toxicity (11). However, the number of patients whose Barthel Index, a performance score of activities of daily living with 20 achievable points (12) deteriorated by $3 points within the first 6 months was only 25%. An additional 12% of patients failed to complete the 6 months assessment, presumably because of early death. PFS at 6 months is not available, while 1-year survival was 33% (oligodendroglial tumors and previous low-grade tumors excluded). Ernst-Stecken et al. treated 15 patients including 11 with GBM with FSRT (13). The dose per fraction was relatively high, i.e. 7 Gy, but all tumors were #5 cm in diameter and the median planning target volume was 22.4 cc. Unfortunately, the results are not stratified by histological tumor type. PFS at 6 months was very high, i.e. 75%, 1-year overall survival was 43% and only 13% progressed within the first 3 months. Eight patients were on dexamethasone before FSRT. Steroid dose was decreased after treatment in 33%, unchanged in 47% and increased in 20%. Quality of life as assessed by the EORTC QLQ-C30 was maintained in 14 of 15 patients (one had incomplete data) over the median follow-up period of 9 months, range 3-20 months. The exact number of quality 5

of life assessments during follow-up is not known. A Japanese group combined FSRT with hyperbaric oxygen treatment (14). Out of 25 patients, 11 had GBM. Survival at 1 year was 28% in the GBM group, PFS at 6 months not reported. No detailed quality of life data were published. Wurm et al. combined FSRT with topotecan in 20 patients (15). Toxicity was acceptable and not different from FSRT only trials. PFS at 6 months was high (50%), as was 1-year overall survival (46%). Early deterioration within 3 months was observed in approximately 20% of the patients, as estimated from the published graph. Detailed quality of life data are not available.

Radiosurgery and brachytherapy In their non-randomized comparison of FSRT and RS, Cho et al. did not observe differences in early KPS declines (16). However, late complications and re-operations were more common after RS. In both groups, approximately 10% of the patients died within the first 3 months. The median RS dose was 17 Gy (range 9-40 Gy) prescribed to the 50% isodose line (range 30-90%). The median target volume size was 30 ml, maximum 125 ml. Not all groups have observed higher toxicity rates after RS. Combs et al. treated 32 patients with recurrent GBM to a somewhat lower median dose of 15 Gy, range 10-20 Gy prescribed to the 80% isodose line that encompassed the target volume (17). The median planning target volume size was 10 ml, maximum 59 ml. PFS at 6 months was 33%, 1-year overall survival 38% and early death rate within 3 months just below 10%. No detailed quality of life data were published. Simon et al. reported on brachytherapy in 42 patients (18). Three patients (7%) had early progression and died within 12 wks, all had a KPS of 60. Median survival with KPS $70 was 26 wks, PFS at 6 months is unknown and 1-year overall survival was 48%. The reoperation rate was 24%. Chan et al. treated 24 patients with GliaSite brachytherapy after resection (19). Death within 3 months occurred in 10%, PFS at 6 months is unknown and 1-year overall survival was 33%. Detailed quality of life data are not available. An updated multiinstitutional experience with this method included 95 patients (not all with GBM) and confirmed the initial figures, except for a lower rate of pathologically documented radiation necrosis (3%) (20).

Combined radiotherapy and thermotherapy A recent feasibility study of intracranial thermotherapy using magnetic nanoparticles combined with external beam radiotherapy included 11 patients with recurrent GBM (21). Tumor diameter was limited to less than 5 cm and median volume was 11 cc. Two heat treatments (1 hour per session) were applied in the alternating magnetic field applicator MFH® 300F within each week of re-irradiation (5 fractions of 2 Gy per week, 6

total dose 16-40 Gy, median 29 Gy). The maximum temperature measured in the treatment area was 42.4-49.5°C (median 45.5°C). A temperature above 42°C was achieved in 15-100% of the treated area (median 57%). The 90% Quantile of intratumoral temperature (T90) ranged from 39.3-45.5°C (median 41°C). The cumulative equivalent minutes at a T90 converted to 43°C ranged from 2.3-502.2 (median 5.3 minutes). Median age was 50 years, median KPS 70 and median interval between initial treatment and re-irradiation 4.3 months (minimum 1 month). PFS at 6 months was 50%, median PFS 6.2 months and 1-year overall survival 36%. Quality of life and late toxicity were not reported in sufficient detail.

Discussion

Treatment of recurrent GBM remains a formidable challenge (22). Re-resection is feasible in only a minority (3). The major advantages of re-resection are rapid symptom palliation and confirmation of diagnosis, as necrosis and pseudo-progression can sometimes mimic tumor progression. With re-resection alone, median survival is typically less than 6 months (2, 3). Chemotherapy has been shown to induce responses in some patients with recurrent GBM and responding patients might enjoy relatively favourable survival (2, 3). However, long-term disease-free survival remains highly unlikely. In pharmaceutical therapy trials, PFS at 6 months is associated with overall survival at 12 months (23). With investigator-declared non-efficacious regimens pooled from 16 studies, PFS at 6 months was 9% and overall survival at 1 year 14% (23). Table 2 provides data on recently published studies suggesting that more efficacious

7

regimens achieve PFS at 6 months in the order of 18-32% and 1-year survival of 2044%.

Based on the present review of re-irradiation studies including more than 300 GBM patients, this approach deserves further consideration and evaluation, because of 6months PFS of 28-39% (6, 8, 17) and 1-year survival of 18-48%, without additional chemotherapy (2 used topotecan or CCNU). The median value for the 1-year survival rate in these studies is 26%.

RS and conventional external beam treatment are clearly different. This is emphasized by the differences in early death rates, which were #10% for most brachytherapy and RS trials. With the inclusion of patients with poorer prognosis in the conventional therapy studies, these figures increase to 20-31%. Patients with KPS <70 appear at higher risk of early progression and are less likely to benefit from re-irradiation (6, 18).

Few studies included data on clinical course and quality of life. In these, clinical improvement was observed in 24 and 45% of the patients respectively (4, 10). Most studies suggest that stabilisation of the performance status is a realistic aim, which was obtained in 67% of our own patients (6). Cho et al. also found stable or improved KPS for 3 months or longer in more than 70% of their patients (16). Ernst-Stecken et al. measured the quality of life with the EORTC QLQ-C30 (13). Their patients maintained pre-treatment values for the median follow-up of 9 months. However, this does not reflect the situation of patients with progressive disease, which are unable to return to

8

the hospital for follow-up examinations and quality of life assessments. A further FSRT study reported a deterioration of the Barthel Index by $3 points during the first 6 months in only 25% of the patients (11). Also in this case, some drop-out effects have to be considered. With brachytherapy, the median survival with KPS $70 was 6 months (18). Four studies reported on corticosteroid use during and after re-irradiation (4, 6, 10, 13). The percentage of patients that reduced their dose was 20, 33, 59 and 60%, respectively. Overall, these data support those of PFS and overall survival, suggesting that re-irradiation maybe a valuable treatment option for selected patients, despite the fact of sub-optimal quality of life assessments in many studies.

In patients with heavily pretreated, malignant glioma, assessment of late toxicity is not trivial. The current review suggests that serious late toxicity is uncommon both after conventional treatment and FSRT, except of course in dose escalation studies such as (11). More recent RS studies (17) have not reported toxicity rates as high as the earlier ones (16), which were performed before the RTOG dose escalation trial was published. In the RTOG recurrent primary brain tumors and brain metastases RS dose escalation trial, which was stratified by maximum diameter of the lesion, 15% of the patients had improved KPS within 3 months, while 46% were stable (36). Of those not requiring steroids at RS, 73% remained steroid-free. Among the patients with initial steroid usage, 32% were able to discontinue. The $grade III toxicity rates were 14, 20 and 10% for tumor diameters of 31-40, 21-30 and <21 mm, respectively, which were treated with 15, 18 and 24 Gy, respectively. The brachytherapy data are also conflicting with regard to variations in reoperation and necrosis rates (18-20).

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Whether the favourable results of re-radiation alone, or when combined with chemotherapy are consequential to the treatment itself or patient selection can not be completely determined in the absence of randomized trials. However, the rapidly fatal outcome after progression in this disease (expected 1-year survival of 14%), compared to the 26% median rate (range 18-46%) with re-irradiation warrants more judicious evaluation and should be borne in mind when evaluating the benefits of salvage chemotherapy.

In light of recent technological advances and with the aim of sparing as much normal brain tissue as possible, techniques such as FSRT and IMRT are very appealing. Fraction sizes of 3-5 Gy appear to be well tolerated in limited-volume recurrences as long as the total dose is limited to 30-35 Gy. Improvements in target volume delineation from integration of functional and biological imaging would enhance patient selection and possibly outcomes (7). The role of additional chemotherapy or targeted agents needs to be prospectively tested against re-irradiation alone.

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28 29

30

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radiotherapy combined with topotecan in recurrent malignant glioma. Int J Radiat Oncol Biol Phys 2006;66: S26-32. Cho KH, Hall WA, Gerbi BJ, et al. Single dose versus fractionated stereotactic radiotherapy for recurrent high-grade gliomas. Int J Radiat Oncol Biol Phys 1999;45: 1133-41. Combs SE, Widmer V, Thilmann C, et al. Stereotactic radiosurgery (SRS): treatment option for recurrent glioblastoma multiforme. Cancer 2005;104: 216873. Simon JM, Cornu P, Boisserie G, et al. Brachytherapy of glioblastoma recurring in previously irradiated territory: predictive value of tumor volume. Int J Radiat Oncol Biol Phys 2002;53: 67-74. Chan TA, Weingart JD, Parisi M, et al. Treatment of recurrent glioblastoma multiforme with gliasite brachytherapy. Int J Radiat Oncol Biol Phys 2005;62: 1133-9. Gabayan AJ, Green SB, Sanan A, et al. GliaSite brachytherapy for treatment of recurrent malignant gliomas: a retrospective multi-institutional analysis. Neurosurgery 2006;58: 701-9. Maier-Hauff K, Rothe R, Scholz R, et al. Intracranial thermotherapy using magnetic nanoparticles combined with external beam radiotherapy: results of a feasibility study on patients with glioblastoma multiforme. J Neurooncol 2007;81: 53-60. Tsao MN, Mehta MP, Whelan TJ, et al. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma. Int J Radiat Oncol Biol Phys 2005;63: 47-55. Ballman KV, Buckner JC, Brown PD, et al. The relationship between six-month progression-free survival and 12-month overall survival end points for phase II trials in patients with glioblastoma multiforme. Neuro-oncol 2007;9: 29-38. Kappelle AC, Postma TJ, Taphoorn MJB, et al. PCV chemotherapy for recurrent glioblastoma multiforme. Neurology 2001;56: 118-20. Brandes AA, Tosoni A, Amista P, et al. How effective is BCNU in recurrent glioblastoma in the modern era? Neurology 2004;63: 1281-4. Brandes AA, Tosoni A, Basso U, et al. Second-line chemotherapy with irinotecan plus carmustine in glioblastoma recurrent or progressive after first-line temozolomide chemotherapy: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). J Clin Oncol 2004;22: 4727-34. Burch PA, Bernath AM, Cascino TL, et al. A North Central Cancer Treatment Group phase II trial of topotecan in relapsed gliomas. Invest New Drugs 2000;18: 275-80. Chang SM, Theodosopoulos P, Lamborn K, et al. Temozolomide in the treatment of recurrent malignant glioma. Cancer 2004;100: 605-11. Prados MD, Yung WK, Fine HA, et al. Phase 2 study of BCNU and temozolomide for recurrent glioblastoma multiforme: North American Brain Tumor Consortium study. Neuro-oncol 2004;6: 33-7. Chua SL, Rosenthal MA, Wong SS, et al. Phase 2 study of temozolomide and Caelyx in patients with recurrent glioblastoma multiforme. Neuro-oncol 2004;6: 38-43.

31 Kesari S, Schiff D, Doherty L, et al. Phase II study of metronomic chemotherapy for recurrent malignant gliomas in adults. Neuro-oncol 2007;9: 354-63. 32 Silvani A, Lamperti E, Gaviani P, et al. Salvage chemotherapy with procarbazine and fotemustine combination in the treatment of temozolomide treated recurrent glioblastoma patients. J Neurooncol 2007; epub. 33 Reardon DA, Egorin MJ, Quinn JA, et al. Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol 2005;23: 9359-68. 34 Franceschi E, Cavallo G, Lonardi S, et al. Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Br J Cancer 2007;96: 1047-51. 35 Cloughesy TF, Wen PY, Robins HI, et al. Phase II trial of tipifarnib in patients with recurrent glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study. J Clin Oncol 2006;24: 3651-6. 36 Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 2000;47: 291-8.

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Table 1. Overview of re-irradiation studies included in this review Reference

n

Veninga et al.

29*

Median age and KPS 34 years,

unknown

2001 (4)

Arcicasa et al.

24*

44 years,

70

1999 (5)

Nieder et al.

24

48 years,

70

1999 (updated)

Endpoints and results

EB median 46 Gy in 23

Median time to progression 4.3 mo, clinical

fractions, minimum interval 11

improvement in 24%, one radionecrosis,

mo (median interval 33 mo)

one other serious late toxicity

EB 34.5 Gy in 23 fractions plus

Median time to progression 8.4 mo,

CCNU, minimum interval 6 mo

improved KPS in 17%, stable KPS in 62%,

(median 14 mo)

unknown late toxicity

EB 45 Gy in 30 fractions bid,

Median time to progression 5.4 mo,

minimum interval 4 mo (median improved KPS in 8%, stable KPS in 67%, 2

(6) Combs et al.

Reirradiation regimen

53

55 years,

80 or 90

2005 (8)

15 mo)

patients with radionecrosis

SFRT median 36 Gy in 2-Gy

Median time to progression 5.0 mo, no

fractions, minimum interval 3

grade III late toxicity

mo (median 10 mo) Vordermark et al. 2005 (9)

14

50 years,

90

Hypofractionated SFRT,

Median time to progression 4.6 mo, no

median 30 Gy in 6 fractions,

severe late toxicity such as radionecrosis

minimum interval 3 mo (median 19 mo) 14

Hudes et al.

20*

52 years,

80

1999 (10)

Shepherd et al.

33*

37 years,

80

1997 (11)

Ernst-Stecken

15*

et al. 2007 (13)

49 years,

80

(58 years in GBM)

Hypofractionated SFRT 24-35

Neurologic improvement in 45%,

Gy in fractions of 3-3.5 Gy,

decreased steroid requirement in 60%, no

median interval 3 mo

grade III late toxicity

Hypofractionated SFRT 20-50

25% of patients deteriorated in BI between

Gy in fractions of 5 Gy, median

3 and 6 months after SFRT, 5/18 treated

interval 29 months

with 30 or 35 Gy developed late toxicity

Hypofractionated SFRT 35 Gy

Median time to progression 7.0 mo, no

in 5 fractions, minimum interval

reoperation due to toxicity

2 mo (median 10) Kohshi et al.

25*

46 years,

70

2007 (14)

SFRT, median margin dose 22

No severe acute toxicity, but high

Gy in 8 fractions plus HBO,

reoperation rate of 28% with a

minimum interval 2 mo (median

radionecrosis rate of at least 16%

13 mo) Wurm et al.

20

45 years,

80

2006 (15)

SFRT, 25-30 Gy in 5-6

Median progression-free survival 5.6 mo,

fractions plus Topotecan,

no grade III late toxicity, 12% grade II

minimum interval 3 mo (median 12 mo) Cho et al. 1999 15

46*

48 years,

70

SRS, median dose 17 Gy,

Stabl e or improved KPS for 3 months or

(16)

Combs et al.

25*

32

53 years,

56 years,

60

80

2005 (17)

Simon et al.

42

49 years,

80

2002 (18)

median interval 10 mo

longer in 75% after SRS and 72% after

SFRT, median 37.5 Gy in 15

SFRT, late complications in 30 vs. 8%

fractions, median interval 19

(mainly necrosis), reoperation rate 22 vs.

mo

12%

SRS, median dose 15 Gy,

Median progression-free survival 5.0 mo,

minimum interval 1 mo (median

no severe late toxicity such as

10)

radionecrosis

BT 192Ir implant 40-60 Gy,

BT discontinuation in 2 patients (neurol.

median interval 11 mo

deterioration), 3 patients with KPS 60 had early progression and died within 12 wks, median survival with KPS $70 was 26 wks, reoperation rate 24%

Chan et al. 2005

24

48 years,

(19)

80

BT GliaSite 125I, mean dose

Headache RTOG I/II in 42%,

53±9 Gy, interval not reported

nausea/vomiting in 4%, symptomatic necrosis in 8%, neurologic deficit in 4%

KPS: Karnofsky performance status, BI: Barthel index (12), EB: external beam reirradiation, SFRT: stereotactic fractionated radiotherapy, HBO: hyperbaric oxygen, SRS: stereotactic radiosurgery, BT: brachytherapy, bid: 2 daily fractions, mo: months, wks: weeks 16

* not all patients had GBM Table 2. Overview of recent studies on systemic treatment with different agents. Reference

n

Kappelle et al.

63

Median age and KPS 46 years,

80

Treatment regimen

Endpoints and results

PCV, median 2 cycles

Median time to progression 3 mo, PFS6

2001 (24) Brandes et al.

29%, median survival 7.6 mo 40

50 years,

70

2004 (25) Brandes et al.

42

53 years,

80

2004 (26) Burch et al.

33

47 years,

ECOG1

2000 (27) Chang et al.

213*

53 years,

80

2004 (28) Prados et al.

38

53 years,

80

2004 (29) Chua et al. 17

22

55 years,

ECOG1

BCNU, unknown number of

Median time to progression 3 mo, PFS6

cycles

18%, median survival 7.6 mo

BCNU plus Irinotecan, mean 3

Median time to progression 3.9 mo, PFS6

cycles

30%, median survival 11.7 mo

Topotecan, unknown number

Median time to progression 3.4 mo, PFS6

of cycles

unknown, median survival 4.6 mo

Temozolomide, median 2

Median time to progression 2.3 mo, PFS6

cycles

18%, median survival 7.3 mo

Temozolomide plus BCNU,

Median time to progression 2.5 mo, PFS6

unknown number of cycles

21%, median survival 7.8 mo

Temozolomide plus Caelyx,

Median time to progression 3.2 mo, PFS6

2004 (30) Kesari et al.

28

2007 (31)

Silvani et al.

54

unknown number of cycles

32%, median survival 8 mo

Etoposide plus

For GBM: median progression-free

(incl. 20 non-GBM

Cyclophosphamide,

survival 2.5 mo, PFS6 9%, median survival

patients)

Thalidomide and Celecoxib

4.8 mo

Procarbazine plus Fotemustine

Median progression-free survival 4.4 mo,

53 years,

53.5 years,

70

70

2007 (32) Reardon et al.

PFS6 27%, median survival 6.6 mo 33

52 years,

90

Imatinib plus Hydroxyurea

Median progression-free survival 3.3 mo,

2005 (33)

PFS6 27%, median survival 11.2 mo

Franceschi et

28 (16 55 years,

al. 2007 (34)

GBM)

Cloughesy et al.

67

ECOG1

Gefitinib

Median time to progression 1.9 mo, PFS6 14%, median survival 5.6 mo

49 years,

80

Tipifarnib

Median time to progression 1.8 mo, PFS6

2006 (35)

<17%, median survival unknown

KPS: Karnofsky performance status, PFS6: progression-free survival at 6 months, mo: months, wks: weeks * not all patients had GBM, however, the presented data refer to the GBM subgroup

18