How I treat glioblastoma in older patients

JGO-00309; No. of pages: 6; 4C: J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 5 ) XX X–XX X

Available online at www.sciencedirect.com

ScienceDirect

Meet the Experts

How I treat glioblastoma in older patients Nimish A. Mohile⁎ Department of Neurology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, NY 14642, USA

AR TIC LE I N FO

ABS TR ACT

Article history:

Glioblastoma, a WHO grade IV astrocytoma, is the most common primary malignant brain

Received 4 September 2015

tumor in adults. It is characterized by molecular heterogeneity and aggressive behavior.

Received in revised form 2

Glioblastoma is almost always incurable and most older patients survive less than

November 2015

6 months. Supportive care with steroids and anti-epileptic drugs is critical to improving

Accepted 4 December 2015

and maintain quality of life. Young age, good performance status and methylation of the methyl guanyl methyl transferase promoter are important positive prognostic factors.

Keywords:

Several recent clinical trials suggest that there is a subset of the elderly with prolonged

Glioblastoma

survival that is comparable to younger patients. Treatment of glioblastoma in older patients

Malignant gliomas

includes maximal safe resection followed by either radiation, chemotherapy or combined

MGMT

modality therapy. Recent advances suggest that some patients can avoid radiation entirely

Temozolomide

and be treated with chemotherapy alone. Decisions about therapy are individual and based

Elderly

on a patient's performance status, family support and molecular features. Future work

Radiotherapy

needs to better determine the role for comprehensive geriatric assessments in this patient

Cognitive dysfunction

population to better identify patients who may most benefit from aggressive therapies. © 2015 Elsevier Ltd. All rights reserved.

Contents 1. Introduction . . . . . . . . . . . 2. Prognostic Factors . . . . . . . . 3. Surgical Treatment . . . . . . . 4. Adjuvant Therapy . . . . . . . . 5. Treatment of Recurrent Disease 6. Supportive Care . . . . . . . . . 7. Conclusion . . . . . . . . . . . . References . . . . . . . . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

1. Introduction Glioblastoma (GBM), the most common malignant primary brain tumor to afflict adults, is an inexorably progressive and

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

. . . . . . . .

0 0 0 0 0 0 0 0

incurable tumor1. The current standard of care is defined by the EORTC–NCIC trial that randomized glioblastoma patients to radiotherapy (RT) alone versus combined modality therapy that included radiation and the alkylating chemotherapy,

⁎ Tel.: + 1 585 276 3972; fax: +1 585 276 2463. E-mail address: [email protected].

http://dx.doi.org/10.1016/j.jgo.2015.12.001 1879-4068/© 2015 Elsevier Ltd. All rights reserved.

Please cite this article as: Mohile NA., How I treat glioblastoma in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/ j.jgo.2015.12.001

2

J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 5 ) XX X–XXX

temozolomide (TMZ)2. Median survival with combined modality therapy was 14.6 months compared to 12.1 months for patients who received RT only. However, no patients over the age of 70 were enrolled. A recent randomized trial examined the addition of alternating electric field therapy with the Optune device and demonstrated an improvement in median overall survival to 19.6 months3. This was recently approved by the Food and Drug Administration in the United States and may emerge as the new standard of care. The median age in this study was 57 but did include patients up to the age of 83. While the device has no systemic toxicity, older patients will likely need support to manage skin care, wearing the device and carrying a battery pack that can weigh up to 10 lbs. Despite these advances, population based studies consistently demonstrate that older patients with GBM die earlier and median survival is less than 6 months4,5.There is no clear standard of care in older patients and treatment regimens are often extrapolated from trials in younger patient populations. Some GBM patients are likely undertreated out of fear of toxicity while others are over-treated in an effort to provide the standard of care. Patients most often present with seizures, stroke-like symptoms or progressive cognitive decline. In older patients, sudden onset neurologic symptoms are most often confused with stroke. MRI with gadolinium of the brain is superior to computed tomography (CT) in ruling out stroke and demonstrating tumor. MRI is optimal for better delineation of tumor, to evaluate non-contrast enhancing areas of disease, to identify smaller distant enhancing tumors and to make decisions about surgery. Neuroimaging classically demonstrates a heterogeneously enhancing tumor with mass effect and predilection for the corpus callosum. In this urgent setting, clinicians are faced with diagnostic and treatment dilemmas concerning the role of surgery, radiation and chemotherapy in a disease that is fatal, rapidly progressive and can have profound impact on patient function and quality of life.

single modalities. A comprehensive geriatric assessment (CGA) may help guide patients and physicians to the best treatment options, but little data exists on this in the brain tumor population. Interpretation of a CGA prior to treatment is complicated by the direct impact of brain tumor on language, cognition, balance and motor and sensory functions. Clinical trials for older patients with brain tumors have not incorporated the CGA as standard practice and creating a brain-tumor specific CGA may be beneficial to incorporate in future studies.

3. Surgical Treatment Although gross total resection is associated with improvement in survival, surgery is never curable and surrounding brain continues to harbor malignant cells12. In non-randomized studies, patients who undergo biopsy alone live only a median of 3 to 4 months compared to 7 to 8 months if they undergo a subtotal or gross total resection13–15. However, in these retrospective analyses, GTR is likely performed on patients with higher performance status, less frailty and less comorbidities. In patients with significant aphasia, cognitive dysfunction or hemiparesis that is attributable to the tumor, a decision needs to be made about whether tumor removal will improve their neurologic function. This depends on whether symptoms are directly related to the tumor or related to peri-tumoral edema. A multi-disciplinary discussion involving neuroradiology and neurosurgery is often useful and can better define the risks and benefits of resection. Specialized MRI with functional imaging or white matter tractography can also be helpful in surgical planning. In patients with deep, inaccessible tumors, tumors in eloquent areas or significant medical comorbidities, a stereotactic biopsy should be done at minimum to definitively determine diagnosis. Glioblastomas should not be treated empirically and averting a biopsy is only appropriate in patients who definitively choose a palliative approach to care from the outset. I advocate for maximal safe resection in patients with good pre-morbid performance status with the intent to palliate edema, prevent neurologic symptoms and improve survival.

2. Prognostic Factors GBM is a disease that preferentially affects older patients and incidence rates increase with age, peaking in the eighth and ninth decades of life1. The most important favorable clinical prognostic factors are young age, good performance status and extent of resection6. Methylation of the methyl-guaninemethyl-transferase (MGMT) promoter predicts response to alkylating chemotherapy and is critical in identifying those patients most likely to benefit from TMZ7. The IDH1 mutation is a diagnostic biomarker for secondary GBM, a tumor that arises from a lower grade glioma, and is associated with improved survival8. In older patients, GBM harbors more angiogenic features, has distinct molecular genetics and rarely harbors IDH1 mutations9–11. Poor survival in older GBM patients is related to underlying tumor biology, older age and may also be impacted by patient and physician choices about optimal treatments. A key challenge in managing older patients with GBM is to discriminate those patients that can tolerate aggressive therapies from those that may derive sufficient benefit from

4. Adjuvant Therapy There are essentially four post-surgical options for GBM in older patients: supportive care alone, RT alone, TMZ alone or combined modality therapy with chemoradiation. Table 1 details survival in randomized studies of newly diagnosed GBM in older patients. A French multicenter study randomized patients over the age of 70 to RT (50 Gy in 1.8 Gy fractions over 6 weeks) or best supportive care and demonstrated a survival benefit from radiation: 29 weeks versus 17 weeks16. Measures of quality of life and cognitive function were not worse in the RT group, but in both groups, these measures worsened over time, suggesting that many older patients may be at their best prior to therapy. The median increase in survival of 12 weeks needs to be placed in the context of the burden of 6 weeks of daily radiotherapy. Several studies have aimed to lessen the burden and duration of RT. Conventionally, RT is given over 6 to 7 weeks at a dose of 60 Gy and can result in fatigue that can last for weeks to months after

Please cite this article as: Mohile NA., How I treat glioblastoma in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/ j.jgo.2015.12.001

3

J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 5 ) XX X–XX X

Table 1 – Survival in randomized prospective studies of malignant glioma in older patients. Clinical study

Age

No. of patients

Radiation: total dose/ fraction/length (weeks)

Chemotherapy

ANOCEF trial16 Supportive care alone Standard radiotherapy

70–85 70–84

42 GBM 39 GBM

50 Gy/1.8 Gy/6

16.9 weeks [13.4–21.4] 29.1 weeks [25.4–34.9]

Roa et al.17 ⁎ Standard Radiotherapy Hypofractionated RT

60+ 60+

47 GBM 48 GBM

60 Gy/2 Gy/6 40 Gy/2.67/3

5.1 months 5.6 months

IAEA trial18 ⁎⁎ Hypofractionated RT 50+ 1 week hypofractionated RT 50+

50 GBM 48 GBM

40 Gy/2.67/3 25 Gy/5/1

6.4 months [5.1–7.6] 7.9 months [6.3–9.6]

Nordic trial22 Standard radiotherapy Hypofractionated RT Temozolomide

60–80 60–83 60–88

100 GBM 98 GBM 93 GBM

30 Gy/2 Gy/6 34 Gy/3.4 Gy/2

6.0 months [5.1–6.8] 7.5 months [6.5–7.8] 8.3 months [7.1–9.5]

NOA-8 trial21 Radiotherapy Temozolomide

66–82 66–84

153 GBM, 23 AA 178 GBM, 17 AA

60 Gy/2 Gy/6

Adjuvant TMZ b

Median overall survival [95% CI]

9.6 months [8.2–10.8] 100 mg/m2, 7 days on, 8.6 months [7.3–10.2] 7 days off

GBM = Glioblastoma, AA = Anaplastic astrocytoma, TMZ = Temozolomide, and NR = Not reported. Concurrent TMZ dosing, 75 mg/m2 daily for 42 days. b Adjuvant TMZ dosing, 150 mg–200 mg/m2 for 5 days in a 28 day cycle. ⁎ This was a non-inferiority study. Hazard ratio = 0.89 (95% CI, 0.59–1.36). ⁎⁎ Study included patients who were non-elderly and frail (age > 50, KPS 50–70), elderly (age > 65, KPS ≥ 80) or elderly and frail (age > 65, KPS 50–70).

a

treatment. Hypofractionated radiation (HfRT), given over a shorter time period with higher dose fractions, is associated with more long-term side effects of radiation, but given the poor survival of elderly GBM patients, this is rarely a problem. HfRT given over a 2 to 4 week course may significantly reduce caregiver burden and acute toxicities of therapy. Roa et al. randomized 100 patients over the age of 60 to a 3 week (40 Gy in 15 fractions) versus a 6 week (60 Gy in 30 fractions) course and demonstrated median survival of approximately 6 months in both arms17. More recently, a randomized trial evaluated the efficacy of a single week of radiotherapy in frail, older patients and demonstrated equivalent survival when compared to the 3 week course18. Concerns over acute neurocognitive decline during radiation have led investigators to evaluate TMZ as a single modality therapy in older patients19,20. Two trials, the NOA-8 study and the Nordic Clinical Brain Tumor Study Group Trial both demonstrated that temozolomide was non-inferior to radiation alone21,22. Most notably, patients who were MGMT methylated had a significant benefit from TMZ while unmethylated patients receiving TMZ did not. This provides further evidence of MGMT as a predictive biomarker in GBM. The option to avoid or defer RT in older patients is an important one and obtaining MGMT methylation status quickly is critical to aid in decision making. In methylated patients who may not be able to tolerate combined modality therapy or have other barriers to daily radiation, I recommend using TMZ dosed at 150 mg/m2– 200 mg/m2 daily for 5 days in a 28 day cycle. Unmethylated patients should undergo HfRT and in patients with insufficient tissue to test for MGMT methylation. Individual decisions are made based on tumor location. Radiation treatment fields that encompass the hippocampus or large parts of the frontal and

temporal lobes are most likely to result in meaningful cognitive dysfunction and TMZ alone should be considered, with the option to radiate at disease progression. Combined modality therapy remains an option in older patients with excellent performance status. Although no patients over the age of 70 were included, many clinicians extrapolate the data from the EORTC–NCIC trial to older patients. Patients older than 60 in this study derived no benefit in median overall survival, but combined modality therapy did result in more patients living greater than 2 years6. Data from high functioning patients at academic institutions also suggest benefit from combined modality therapy and demonstrate median survivals comparable to younger patients23. Several single arm prospective studies adopting the EORTC–NCIC regimen in older patients with good performance status have resulted in median survival ranging from 10 to 15 months24,25. In one study, replacing a 6 week course of RT with HfRT demonstrated superior tolerability and equivalent survival but this remains to be duplicated26. In patients who are cognitively intact, independent in ADLs and have no major comorbidities, I recommend treatment with combined modality therapy as no single modality has demonstrated equivalent survival. My approach to decisions regarding adjuvant therapy is described in Fig. 1. In patients with poor or borderline performance status, combined modality therapy should be avoided and the physician has to make a decision between supportive care, radiation and chemotherapy. Patients must clearly understand that RT can lengthen survival and potentially prevent further neurologic decline but that it may not palliate current symptoms. HfRT is a good option in patients with limited support to come to daily radiation sessions and in patients who may need to get RT while in the inpatient setting due to insufficient home support. When considering radiation

Please cite this article as: Mohile NA., How I treat glioblastoma in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/ j.jgo.2015.12.001

4

J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 5 ) XX X–XXX

Fig. 1 – Algorithm for adjuvant therapy in older patients with newly diagnosed glioblastoma. Legend: GBM = Glioblastoma, KPS = Karnofsky Performance Status, MGMT = Methyl-guanine-methyl-transferase, TMZ = Temozolomide, HfRT = Hypofractionated radiotherapy, and RT = Radiotherapy.

alone, there is likely no benefit to a 6 week course over a 2 to 3 week course in this population. Recent findings of equivalent survival and quality of life in a 1 week course are intriguing and should be considered in the frailest of older patients who are still interested and eligible for treatment.

5. Treatment of Recurrent Disease Unfortunately, at time of recurrence, many patients have had a meaningful decline in performance status and can no longer tolerate therapy. Common options used in non-elderly patients such as re-resection, re-irradiation and clinical trials are rarely used. Although there has been no clear survival benefit to the addition of bevacizumab in the recurrent setting, it remains FDA approved in the United States and it can dramatically reduce cerebral edema and improve neurologic symptoms27. Bevacizumab is associated with some fatigue in older patients but is generally well tolerated and usually does not contribute to decline in function or quality of life28. Older patients are at higher risk of the less common but serious toxicities associated with bevacizumab including stroke and bowel perforation due to underlying vascular disease and diverticulosis, respectively29,30. A Dutch study, the BELOB trial, suggests that the addition of CCNU to bevacizumab may be superior to either bevacizumab or CCNU alone, but was not powered sufficiently to definitively make this conclusion31. Another option is the Optune device which was found to be non-inferior to cytotoxic agents and can be used safely in combination with bevacizumab32. In patients with large and symptomatic areas of cerebral edema, who may also be steroid dependent, I consider a trial of single agent bevacizumab (10 mg/kg every 2 weeks for 4 doses) to see if there is symptomatic improvement. Often,

there is marked improvement in neuroimaging, but I only continue bevacizumab if there has been some reversal of neurologic symptoms. I consider the addition of CCNU in patients with excellent performance status and who have had no significant bone marrow suppression from prior chemotherapy. The effects of bevacizumab rarely last for more than a few months in older patients and should not be given if a hospice plan is necessary to provide adequate care for the patient.

6. Supportive Care Excellent supportive and neurologic care is important to maintain quality of life no matter what anti-neoplastic therapy is being considered. Management of brain edema is one of the biggest challenges. Blood brain barrier breakdown in GBM is due to alteration in surrounding vasculature, secretion of pro-angiogenic proteins and damage to tight junctions33. This leads to excess deposition of fluid in the peri-tumoral region and vasogenic edema. The edema typically affects surrounding white matter and can result in disabling neurologic symptoms. Corticosteroids help decrease brain edema but should only be used to improve neurological symptoms and function. They come with the added benefit of increased appetite and energy but numerous toxicities including emotional lability, diabetes, myopathy, bone loss, poor wound healing, and gain in adipose tissue. Dexamethasone is used most commonly in brain tumors because it has less mineralocorticoid activity than other corticosteroids. Twice daily dosing is almost always sufficient in the outpatient setting. I recommend that patients take their second dose in the afternoon so as to interfere less with sleep at night. With chronic use, myopathy can become especially

Please cite this article as: Mohile NA., How I treat glioblastoma in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/ j.jgo.2015.12.001

J O U RN A L OF GE RI A T RI C O NC O L O G Y XX ( 20 1 5 ) XX X–XX X

problematic in patients with pre-existing weakness from corticospinal tract dysfunction and patients should always be on the lowest possible dose. Seizures occur in 50% of GBM but there is no data for prophylactic therapy with anti-epileptic drugs (AED)34,35. Seizures can have a serious and negative impact on quality of life leading to fear, social withdrawal, further depression and more frequent hospitalizations36,37. Treatment with an AED is initiated with the first seizure and enzyme inducing AEDs should be avoided due to interactions with chemotherapy and corticosteroids. I use levetiracetam as a first line agent because it is generally best tolerated in this population. Although irritability and hostility are rare side effects, they do appear to be more common in older patients and are certainly compounded by use of corticosteroids and behavioral changes related to a brain tumor38. Second line therapy with valproate can stabilize mood but can lead to sedation, exacerbation of tremors, alopecia, weight gain and rarely, pancytopenia. In patients that require multiple AEDs or who failed multiple AEDs due to intolerability or ineffectiveness, a consultation from an epileptologist may help in promptly finding an efficacious and tolerable regimen.

7. Conclusion Clinical trials of combined modality therapy suggest that patients with good performance status, irrespective of age, reap the survival benefits of aggressive treatment. However, these survival statistics stand in contrast to population based analyses. Patients enrolled on clinical trials are not representative of all patients and the applicability of these studies to the broader population is questionable. Clinicians need to evaluate older patients with GBM individually to best make decisions about the role and extent of surgery, need for adjuvant therapy and determining optimal time to limit care to supportive care. Future studies in elderly GBM patients should incorporate a CGA that aids in decision making for brain tumor patients and outcomes need to focus not only on survival, but tolerability and measures of quality of life.

REFERENCES

1. Ostrom QT, Gittleman H, Liao P, Rouse C, Chen Y, Dowling J, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro Oncol Oct 2014;16(Suppl 4):iv1-iv63. 2. Stupp R. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352(10):987. 3. Stupp R, Wong E, Scott C, et al. Interim analysis of the EF-14 trial: a prospective, multi-center trial of NovoTTF-100A together with temozolomide compared to temozolomide alone in patients with newly diagnosed GBM. Neuro Oncol 2014;16:167. 4. Paszat L, Laperriere N, Groome P, Schulze K, Mackillop W, Holowaty E. A population-based study of glioblastoma multiforme. Int J Radiat Oncol Biol Phys Sep 1 2001;51(1):100–107. 5. Iwamoto FM, Reiner AS, Panageas KS, Elkin EB, Abrey LE. Patterns of care in elderly glioblastoma patients. Ann Neurol Dec 2008;64(6):628–634.

5

6. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-–NCIC trial. Lancet Oncol 2009;10(5):459–466. 7. Hegi ME. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352(10):997. 8. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med Feb 19 2009;360(8):765–773. 9. Amelot A, De Cremoux P, Quillien V, Polivka M, Adle-Biassette H, Lehmann-Che J, et al. IDH-mutation is a weak predictor of long-term survival in glioblastoma patients. PLoS One Jul 9 2015;10(7):e0130596. 10. Batchelor TT, Betensky RA, Esposito JM, Pham LD, Dorfman MV, Piscatelli N, et al. Age-dependent prognostic effects of genetic alterations in glioblastoma. Clin Cancer Res Jan 1 2004;10(1 Pt 1):228–233. 11. Bozdag S, Li A, Riddick G, Kotliarov Y, Baysan M, Iwamoto FM, et al. Age-specific signatures of glioblastoma at the genomic, genetic, and epigenetic levels. PLoS One Apr 29 2013;8(4): e62982. 12. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol May 2006;7(5):392–401. 13. Scott JG, Suh JH, Elson P, Barnett GH, Vogelbaum MA, Peereboom DM, et al. Aggressive treatment is appropriate for glioblastoma multiforme patients 70 years old or older: a retrospective review of 206 cases. Neuro Oncol Apr 2011;13(4): 428–436. 14. Noorbakhsh A, Tang JA, Marcus LP, McCutcheon B, Gonda DD, Schallhorn CS, et al. Gross-total resection outcomes in an elderly population with glioblastoma: a SEER-based analysis. J Neurosurg Jan 2014;120(1):31–39. 15. Chaichana KL, Chaichana KK, Olivi A, Weingart JD, Bennett R, Brem H, et al. Surgical outcomes for older patients with glioblastoma multiforme: preoperative factors associated with decreased survival. Clin Artic J Neurosurg Mar 2011;114(3): 587–594. 16. Keime-Guibert F. Radiotherapy for glioblastoma in the elderly. N Engl J. Med 2007;356(15):1527. 17. Roa W, Brasher PM, Bauman G, Anthes M, Bruera E, Chan A, et al. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol May 1 2004;22(9):1583–1588. 18. Roa W, Kepka L, Kumar N, Sinaika V, Matiello J, Lomidze D, et al. International Atomic Energy Agency randomized phase III study of radiation therapy in elderly and/or frail patients with newly diagnosed glioblastoma multiforme. J Clin Oncol Sep 2015;21. 19. Monje M. Cranial radiation therapy and damage to hippocampal neurogenesis. Dev Disabil Res Rev 2008;14(3):238–242. 20. Surma-aho O, Niemela M, Vilkki J, Kouri M, Brander A, Salonen O, et al. Adverse long-term effects of brain radiotherapy in adult low-grade glioma patients. Neurology May 22 2001;56(10): 1285–1290. 21. Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol Jul 2012;13(7):707–715. 22. Malmstrom A, Gronberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol Sep 2012;13(9): 916–926.

Please cite this article as: Mohile NA., How I treat glioblastoma in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/ j.jgo.2015.12.001

6

J O U RN A L OF GE RI A TR I C O NC OLO G Y XX ( 20 1 5 ) XX X–XXX

23. Barker CA, Chang M, Chou JF, Zhang Z, Beal K, Gutin PH, et al. Radiotherapy and concomitant temozolomide may improve survival of elderly patients with glioblastoma. J Neurooncol Sep 2012;109(2):391–397. 24. Brandes AA, Vastola F, Basso U, Berti F, Pinna G, Rotilio A, et al. A prospective study on glioblastoma in the elderly. Cancer Feb 1 2003;97(3):657–662. 25. Minniti G, Lanzetta G, Scaringi C, Caporello P, Salvati M, Arcella A, et al. Phase II study of short-course radiotherapy plus concomitant and adjuvant temozolomide in elderly patients with glioblastoma. Int J Radiat Oncol Biol Phys May 1 2012;83(1):93–99. 26. Minniti G, De Sanctis V, Muni R, Rasio D, Lanzetta G, Bozzao A, et al. Hypofractionated radiotherapy followed by adjuvant chemotherapy with temozolomide in elderly patients with glioblastoma. J Neurooncol Jan 2009;91(1):95–100. 27. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol Feb 10 2009;27(5):740–745. 28. Taphoorn MJ, Henriksson R, Bottomley A, Cloughesy T, Wick W, Mason WP, et al. Health-related quality of life in a randomized phase III study of bevacizumab, temozolomide, and radiotherapy in newly diagnosed glioblastoma. J Clin Oncol Jul 1 2015;33(19):2166–2175. 29. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy—temozolomide for newly diagnosed glioblastoma. N Engl J Med Feb 20 2014;370(8): 709–722. 30. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med Feb 20 2014;370(8):699–708. 31. Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, et al. Single-agent bevacizumab or

32.

33.

34.

35.

36.

37.

38.

lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol Aug 2014;15(9):943–953. Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, et al. NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer Sep 2012;48(14):2192–2202. Wolburg H, Noell S, Fallier-Becker P, Mack AF, Wolburg-Buchholz K. The disturbed blood–brain barrier in human glioblastoma. Mol Aspects Med Oct-Dec 2012;33(5-6): 579–589. Wychowski T, Wang H, Buniak L, Henry JC, Mohile N. Considerations in prophylaxis for tumor-associated epilepsy: prevention of status epilepticus and tolerability of newer generation AEDs. Clin Neurol Neurosurg Nov 2013;115(11): 2365–2369. Glantz MJ, Cole BF, Forsyth PA, Recht LD, Wen PY, Chamberlain MC, et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology May 23 2000;54(10):1886–1893. Laxer KD, Trinka E, Hirsch LJ, Cendes F, Langfitt J, Delanty N, et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav Aug 2014;37:59–70. Moots PL, Maciunas RJ, Eisert DR, Parker RA, Laporte K, Abou-Khalil B. The course of seizure disorders in patients with malignant gliomas. Arch Neurol Jul 1995;52(7):717–724. Mbizvo GK, Dixon P, Hutton JL, Marson AG. The adverse effects profile of levetiracetam in epilepsy: a more detailed look. Int J Neurosci Sep 2014;124(9):627–634.

Please cite this article as: Mohile NA., How I treat glioblastoma in older patients, J Geriatr Oncol (2015), http://dx.doi.org/10.1016/ j.jgo.2015.12.001