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Curonctry2PRACTICE GUIDELINE SERIES
Canadian recommendationsfor the treatment ofglioblastoma multiforme W.P. Mason MD, R. Del Maestro MD,D. Eisenstat MD, P. Forsyth MD, D. Fulton MD,N. Laperrière MD, D. Macdonald MD,J. Perry MD, and B. Thiessen MD for theCanadian GBM RecommendationsCommittee* ABSTRACT
The recommended clinical target volume should beidentified with gadolinium-enhanced T1-weighted Recommendation 1
MRI, with a margin in the order of 2–3 cm. Targetvolumes should be determined based on a postsurgi- Management of patients with glioblastoma multi- cal planning MRI. A shorter course of radiation may forme (GBM) should be highly individualized and be considered for older patients with poor perfor- should take a multidisciplinary approach involving neuro-oncology, neurosurgery, radiation oncology,and pathology, to optimize treatment outcomes. Pa- Recommendation 6
tients and caregivers should be kept informed of theprogress of treatment at every stage.
During RT, temozolomide 75 mg/m2 should be admin-istered concurrently for the full duration of radio- Recommendation 2
therapy, typically 42 days. Temozolomide should begiven approximately 1 hour before radiation therapy, Sufficient tissue should be obtained during surgery and at the same time on the days that no radiotherapy for cytogenetic analysis and, whenever feasible, for Recommendation 7
Adjuvant temozolomide 150 mg/m2, in a 5/28-day Surgery is an integral part of the treatment plan, to schedule, is recommended for cycle 1, followed by establish a histopathologic diagnosis and to achieve 5 cycles if well tolerated. Additional cycles may be safe, maximal, and feasible tumour resection, which considered in partial responders. The dose should be may improve clinical signs and symptoms.
increased to 200 mg/m2 at cycle 2 if well tolerated.
Weekly monitoring of blood count is advised during Recommendation 4
chemoradiation therapy in patients with a low white The preoperative imaging modality of choice is mag- blood cell count. Pneumocystis carinii pneumonia has netic resonance imaging (MRI) with gadolinium as the been reported, and prophylaxis should be considered.
contrast agent. Other imaging modalities, such aspositron emission tomography with [18F]-fluoro- Recommendation 8
deoxy-D-glucose, may also be considered in selected For patients with stable clinical symptoms during cases. Postoperative imaging (MRI or computed to- combined radiotherapy and temozolomide, comple- mography) is recommended within 72 hours of sur- tion of 3 cycles of adjuvant therapy is generally ad- gery to evaluate the extent of resection.
vised before a decision is made about whether tocontinue treatment, because pseudo-progression is a Recommendation 5
common phenomenon during this time. The recom- Postoperative external-beam radiotherapy is recom- mended duration of therapy is 6 months. A longer mended as standard therapy for patients with GBM.
duration may be considered in patients who show The recommended dose is 60 Gy in 2-Gy fractions.
CURRENT ONCOLOGY—VOLUME 14, NUMBER 3 Recommendation 9
berta Cancer Registry database of GBM patients diag-nosed between 1975 and 1991 reported that only 1.8% Selected patients with recurrent GBM may be candi- survived at least 3 years 9. A decade later, an analy- dates for repeat resection when the situation appears sis by the Glioma Outcomes Project of cases diag- favourable based on an assessment of individual pa- nosed between 1997 and 2001 reported a median tient factors such as medical history, functional sta- survival of 40.9 weeks for newly-diagnosed patients tus, and location of the tumour. Entry into a clinical . An analysis of the Surveillance, Epide- trial is recommended for patients with recurrent miology, and End Results database found no signifi- cant improvement in the GBM survival rate after the1980s 1.
The principal reasons for poor outcome in GBM The optimal chemotherapeutic strategy for patients are the high rates of recurrence and of resistance to who progress following concurrent chemoradiation chemotherapy. Choucair et al. estimated that more has not been determined. Therapeutic and clinical– than 90% of gliomas recur, typically at the site of the molecular studies with quality of life outcomes are original tumour 11. Numerous chemotherapy regi- mens, administered either before RT or adjuvantly,have been investigated, but they have had little im- KEY WORDS
pact on patient outcomes 12–16. Prognosis is affectedby the histologic features of the tumour, patient age, Brain tumour, glioblastoma, radiotherapy, chemo- Standard treatment for GBM was significantly al- tered following the results of a large phase III trial 1. INTRODUCTION
conducted by the European Organization for the Re-search and Treatment of Cancer (EORTC) and the Na- Glioblastoma multiforme (GBM) is a World Health tional Cancer Institute of Canada 19. The EORTC–NCIC Organization grade IV astrocytoma and the most com- CE3 trial randomized 573 newly-diagnosed glioblas- mon and aggressive primary brain tumour 1. In North toma patients to RT alone (2 Gy, 5/7-day schedule for America, the estimated age-adjusted incidence of GBM 6 weeks, 60 Gy total), or to RT in combination with is 3.0 per 100,000 population 1. It occurs more com- the oral alkylating agent temozolomide. The temo- monly in males (male:female ratio of approximately zolomide dose was 75 mg/m2 daily during RT, fol- 3:2) and is typically diagnosed in patients in their lowed by adjuvant temozolomide 150–200 mg/m2 daily in a 5/28-day schedule for 6 cycles. With the The preoperative imaging modality of choice is RT–temozolomide combination, 2-year survival was gadolinium-enhanced magnetic resonance imaging 26.5% as compared with 10.4% with RT alone. Me- (MRI). Although contrast-enhanced MRI may indicate dian survival was 12.1 months and 14.6 months re- a discrete border, GBM tumours are characterized by spectively. As a result, concurrent RT and extensive microvascular infiltration and rapid prolif- temozolomide, followed by 6 monthly cycles of ad- eration. Based on distinct pathogenetic features, at juvant temozolomide, became the new standard of least two subtypes of GBM can be defined. Primary care for patients newly diagnosed with GBM.
(de novo) glioblastoma is more common in older pa- However, numerous questions remain about how tients (mean age: 55 years) 2 and typically harbours to identify patients who will be more likely to respond overexpression or mutation of epidermal growth fac- to treatment and how to optimize a multimodal ap- tor receptor, genetic losses on chromosome 10, p16 proach to patient management. The recommendations or p19 alterations, or loss of the tumour suppressor that follow were developed by a multidisciplinary protein phosphatase and tensin homologue 3–6. Sec- panel of Canadian neuro-oncologists, neurosurgeons, ondary glioblastoma develops more slowly from a and radiation oncologists—based on level 1 evidence lower-grade tumour and typically occurs in younger where possible—as a guide to optimizing the man- patients (≤45 years). Genetic alterations may include TP53 mutation or overexpression of platelet-derivedgrowth factor receptor α 7.
2. THE RECOMMENDATIONS
Although imaging techniques and multimodal treatment strategies have improved since the mid- 2.1 General Principles
1980s, little impact has been made on the ultimateprognosis of GBM. A population-based cohort study Recommendation 1 Management of patients with
of all Ontario Cancer Registry cases of GBM identi- GBM should be highly individualized and should take fied between 1982 and 1994 found that the median a multidisciplinary approach involving neuro-oncol- survival of patients receiving radiotherapy (RT) and ogy, neurosurgery, radiation oncology, and pathol- surgery was 11 months; median survival with sur- ogy, to optimize treatment outcomes. The care path gery alone was 3 months 8. An analysis of the Al- of GBM is complex and requires the cooperation and CURRENT ONCOLOGY—VOLUME 14, NUMBER 3 integration of services from multiple health care spe- treated patients with promoter methylation. In the cialties and institutions so as to avoid unacceptable subgroup of patients with promoter methylation, 2-year survival was 46% in the RT–temozolomide All surgeries should be presented at a weekly group as compared with 22.7% in patients treated brain tumour conference, with the neurosurgeon, ra- with RT alone (Table I). In the subgroup of patients diation oncologist, and neuro-oncologist present. Ide- without promoter methylation, median survival was ally, for each case, the multidisciplinary team should only marginally superior with combined RT–temozol- review the patient’s clinical status, neuroimaging, and omide than with RT alone (12.7 months vs.
histopathologic findings to determine the optimal 11.8 months); 2-year survival was 13.8% as compared It is recommended that the neurosurgeon inform Temozolomide is a recommended treatment for the patient of the diagnosis. Patients and caregivers newly-diagnosed GBM and for recurrent high-grade should be kept informed of the progress of treatment gliomas. Although MGMT methylation status appears at every stage. Patients should receive a brain tumour to be a prognostic factor for increased survival and information package to help them understand GBM and possibly for better response to temozolomide, a pro- the treatment options, and to better inform their deci- spective study is required before promoter hyper- sion-making. Patient consent should be obtained for methylation can be used as a guide to treatment Recommendation 2 The molecular genetic determi-
nation of brain tumours is becoming increasinglyimportant, enabling more accurate diagnosis and Specific, unique genetic changes are common in as- prognosis. Sufficient tissue should be obtained dur- trocytic tumours. An estimated one half of grades II– ing surgery for cytogenetic analysis and, whenever III infiltrating astrocytomas have detectable mutations feasible, for tumour banking. The preliminary pathol- in the TP53 tumour suppressor gene 20. Loss of het- ogy report should be available within 48 hours post erozygosity on chromosomes 1p and 19q is usually surgery; the final report should be completed within associated with oligodendroglioma, but sometimes occurs in oligoastrocytomas. Loss of heterozygosityis associated with increased sensitivity to pro- 2.3 Surgery
carbazine–lomustine–vincristine chemotherapy 21. Inthat regard, two EORTC phase II trials reported that first- Recommendation 3 Surgery is an integral part of the
or second-line temozolomide produced a high re- treatment plan, to establish a histopathologic diag- sponse rate in patients with recurrent or progressive nosis and to achieve safe maximal tumour resection, oligoastrocytoma or oligodendroglioma 22,23; re- which may improve clinical signs and symptoms.
sponse was associated with 1p and 19q loss 24. Glio- A gross total resection, if achievable, is advised blastoma multiforme is more chemoresistant, and in any patients with a primary or recurrent malignant genetic markers do not appear to have comparable glial tumour if the surgery can be performed without prognostic significance 25. Of particular importance, significant risk to the patient. Simpson et al. analysed however, is O6-methylguanine DNA methyltransferase data from 645 GBM patients in three prospective Ra- (MGMT), a repair protein that removes methyl adducts diation Therapy Oncology Group trials 33. Surgery and transfers them to an internal cysteine residue 26.
consisted of total resection (19%), partial resection Because the O6 position is one of the targets of alky- (64%), or biopsy only (17%). Median survival was lating chemotherapeutic agents, MGMT activity en-hances tumour resistance by repairing cytoxicdamage. Conversely, tumour sensitivity is enhanced Effect of methylation status of methylguanine DNA if MGMT is silenced through hypermethylation of the methyltransferase (MGMT) promoter on progression-free survival CpG islands in the promoter region 27–29.
(PFS) and overall survival (OS) in patients receiving radiotherapy A number of studies have indicated that MGMT plus temozolomide (TMZ) versus radiotherapy (RT) alone a promoter methylation is predictive of a good responseto alkylating agents such as 1,3-bis(2-chloroethyl)- Following the phase III study of combined RT and tem- ozolomide 19, Hegi et al. analyzed the methylation status of 206 evaluable patients 32. In 92 tumours (44.7%), MGMT promoter methylation was detectable. Median survival was 18.2 months in pa- tients with promoter methylation as compared with 12.2 months in those without methylation, and me-dian survival was 21.7 months in RT–temozolomide- CURRENT ONCOLOGY—VOLUME 14, NUMBER 3 11.3 months for total resection, 10.4 months for par- ficacy, but are associated with significant toxicity 39.
tial resection, and 6.6 months for biopsy.
Most studies were reported decades ago, but a recentphase II trial evaluated BCNU 80 mg/m2 on days 1–3 Recommendation 4 The preoperative imaging mo-
every 8 weeks (maximum 6 cycles) in 40 patients dality of choice is MRI with gadolinium as the con- with recurrent GBM who had undergone surgery and trast agent. Other imaging modalities, such as positron . The median time to progression was 13 weeks; emission tomography with [18F]-fluoro-deoxy-D-glu- the 6-month progression-free survival (PFS) was cose, may also be considered in selected cases 34.
17.5%. Significant side effects included reversible Postoperative imaging (MRI or computed tomography) hematologic toxicities and chronic hepatic and pul- is recommended within 72 hours of surgery to evalu- Recommendation 6 During RT, temozolomide
75 mg/m2 should be administered concurrently for42 days 35. Temozolomide should be given approxi- The use of adjuvant external-beam RT is well estab- mately 1 hour before RT, and at the same time on the lished in the postoperative treatment of GBM. A pooled days when no RT is scheduled (weekends).
analysis of six randomized trials by Cancer Care Whether the clinical benefit of this combination Ontario reported a significant survival benefit is attributable in part to the radiosensitizing effects favouring postoperative RT as compared with no RT of temozolomide is unclear. To date, four in vitro stud- (risk ratio: 0.81) 35,36. Overall, median survival is ies have suggested a radiosensitizing effect with tem- approximately 36–48 weeks with adjuvant RT as com- ozolomide for some cancer cell lines 52–55, but pared with 14–22 weeks with surgery alone 37–39.
External-beam RT is generally administered over Recommendation 7 Adjuvant temozolomide
5–6 weeks, delivering a total dose of 50–60 Gy in 150 mg/m2, in 5/28-day schedule, is recommended 1.8- to 2.0-Gy fractions 40. Doses above 60 Gy and for cycle 1, followed by 5 cycles if well tolerated.
boost RT do not appear to influence survival 40,41.
Additional cycles may be considered in partial re- Alternative forms of fractionation have been in- sponders or in those with continuing radiologic im- vestigated. Accelerated fractionation delivers stan- provement. The dose should be increased to dard fraction sizes more frequently (for example, 2 200 mg/m2 at cycle 2 if well tolerated. Weekly moni- or 3 times daily) to reduce the overall treatment toring of blood count is advised during chemoradi- time. Several studies have reported no increased sur- ation therapy in patients with a low white blood cell v i v a l , a l t h o u g h n o i n c r e a s e d t o x i c i t y w a s count. Pneumocystis carinii pneumonia has been re- found 42–44. This approach may be an option for se- ported, and prophylaxis should be considered 56.
lected patients (such as the elderly), but additionalstudy is needed.
Recommendation 8 For patients with stable clinical
Hyperfractionation, which delivers a higher total symptoms during RT–temozolomide, completion of radiation dose in a larger number of smaller fractions, 3 cycles of adjuvant therapy is generally advised be- showed no improvement in time to tumour progres- fore a decision is made about whether to continue treatment. In the first few weeks or months follow- Radiotherapy should be initiated within 4 weeks ing completion of RT, MRI is not reliable to assess true progression. Evidence of progression outside the RTfield is indicative of true progression. A longer dura- Recommendation 5 Postoperative external-beam RT
tion may be considered in patients who show con- is recommended as standard therapy for patients with GBM. The recommended dose is 60 Gy in 2-Gy frac-tions 35,36. The recommended clinical target volume 2.6 Recurrent GBM
should be identified with gadolinium-enhancedT1-weighted MRI, with a margin in the order of 2– Recommendation 9 Selected patients with recurrent
3 cm, given that most recurrences will occur within GBM may be candidates for repeat resection when the a few centimetres of the tumour mass 47,48. Target situation appears favourable based on an assessment volumes should be determined based on a postsurgi- of individual patient factors such as medical history, cal planning MRI. A shorter course of radiation may functional status, and location of the tumour 57,58.
be considered for older patients with poor perfor- Entry into a clinical trial is recommended for patients 2.5 Chemotherapy
Recommendation 10 The optimal chemotherapeu-
tic strategy for patients who progress following
Glioblastoma multiforme has been viewed as a concurrent chemoradiation has not been determined.
chemoresistant tumour, and the nitrosoureas, the tra- Therapeutic and clinical-molecular studies with qual- ditional mainstays of treatment, have had modest ef- CURRENT ONCOLOGY—VOLUME 14, NUMBER 3 For patients not receiving chemotherapy at the Overall survival was 11.2 months. The most common time of progression, re-challenge with temozolomide grade 3–4 toxicity was granulocytopenia, which oc- to deplete MGMT might be attempted, but clinical data Some preliminary data suggest that novel dose- 3. CONCLUSIONS
intense schedules may provide some benefit. Khanet al. reported a 6-month PFS of 19% with temozolo- Surgery followed by RT still represents the primary mide 75 mg/m2 in a 42/70-day schedule 59. In a small approach to the treatment of GBM. The addition of phase II study by Wick et al., the 6-month PFS was temozolomide chemotherapy to the standard of care 48% with temozolomide 150 mg/m2 administered in has significantly increased the proportion of patients a 7-day on / 7-day off schedule 60. Although the find- who survive more than 2 years. However, additional ings are promising, additional phase II studies are re- progress still needs to be made, because almost one quired before the foregoing dosing regimens can be half of GBM patients will not survive the first year after surgery. Additional research is needed to build A number of chemotherapeutic agents, includ- on recent clinical gains and to focus on new drug ing nitrosoureas, carboplatin, etoposide, irinotecan, combinations or therapies that could potentially fur- and imatinib 61–64, have been used as salvage therapy ther improve outcomes in patients with GBM.
either alone or in combination. Additional trials witha variety of agents are underway, but preliminary re- 4. ACKNOWLEDGMENT
sults from single-agent studies have been disappoint-ing. Table II summarizes phase II studies in GBM.
Funding for the Canadian GBM Recommendations For patients who progress on temozolomide, com- Committee meeting was provided by Schering bination therapy may be possible; several recent trials have evaluated various temozolomide combinations(Table II). For example, the efficacy of bolus temo- 5. REFERENCES
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CURRENT ONCOLOGY—VOLUME 14, NUMBER 3
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