1 Natural History and Management Options of Recurrent Glioblastoma

Benjamin H.M. Hunn and Katharine J. Drummond

Abstract

Glioblastoma (GBM) is the most common primary brain cancer in adults and carries a dismal prognosis. At first diagnosis, the standard of care for GBM is maximal safe resection, with subsequent radiotherapy and chemotherapy, a regimen that extends survival by months to years. Unfortunately, recurrence is inevitable and occurs, on average, 7.8 months after initial diagnosis. There is no standard of care for the treatment of recurrent disease and median survival is just 6.4 months. Younger patients, those with a higher performance status, and those with less diffuse disease may have extended survival. Delineating true tumor recurrence from “pseudoprogression” is critical. At GBM recurrence, no available salvage treatment has been clearly shown to improve survival. Retrospective analysis of repeat resection suggests improved survival; however, prospective data are lacking. Resection of recurrent GBM may be performed to relieve mass effect, or to gain tissue for further investigations, particularly for clinical trials of targeted agents. Surgery to prolong survival should be performed rarely, in younger patients with good performance status and tumor in a favorable location. Consensus expert opinion suggests that the benefit of reirradiation is higher when there is a greater disease-free interval since initial radiotherapy, and if GBM recurs in a noneloquent location. Stereotactic radiosurgery is also an unproven option for discrete recurrent GBM. No chemotherapy has been demonstrated to improve survival in recurrent GBM, but bevacizumab is frequently used and may control symptoms. Given treatment of recurrent GBM has a poor evidence base with little to commend any specific treatment, clinical trials are encouraged.

Glioblastoma (GBM) is a World Health Organization (WHO) grade IV malignant tumor of presumed neuroglial origin and conveys an overall poor prognosis (Fig. 1.1).¹ It is the most common primary brain cancer in adults, with an estimated incidence of between 3 and 5 cases per 100,000 person-year.^{1,​ 2,​ 7} GBM may occur de novo (primary), or arise from a lower-grade astrocytoma (secondary). Primary GBM accounts for over 90% of cases and has a slight male preponderance (1.3 times higher) with affected individuals generally older at presentation (mean age: 60 years).^{2,​ 3} Secondary GBM are less common and affect younger patients (mean age: 30–50 years) with no clear sex predilection.^{2,​ 4,​ 5,​ 6}

Mutations in the genes encoding isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are now used to separate primary from secondary GBM; IDH wild-type tumors are synonymous with primary GBM, whereas IDH mutations signify secondary GBM.⁹ In general, IDH mutant GBM is associated with longer survival.⁵ Primary GBM is further characterized by deletions of chromosome 10, amplification of the epidermal growth factor receptor (EGFR) gene, and mutations of the phosphate and tensin homolog (PTEN) tumor suppressor gene.¹⁰ Secondary GBM commonly acquires TP53 mutations as part of progression from lower-grade astrocytoma.¹¹ Methylation of the promoter of the deoxyribonucleic acid (DNA) repair gene O⁶-methylguanine-DNA methyltransferase (MGMT) is a positive prognostic factor in both primary and secondary GBM.¹²

Since 2005, the mainstay treatment at diagnosis involves maximal safe resection (or biopsy) with concurrent radiotherapy and temozolomide chemotherapy followed by adjuvant temozolomide chemotherapy. Surgery is performed to obtain tissue diagnosis, relieve mass effect, improve vasogenic edema, facilitate tolerance to adjuvant therapy, and provide additional tissue for research and clinical trial inclusion. Complete resection of GBM is difficult because of the inherent infiltrative nature of the disease, and the extent of resection (EOR) largely depends on the proximity of eloquent functional brain tissue. In general, resection of all contrast-enhancing tissue seen on the preoperative magnetic resonance imaging (MRI) is the accepted standard. A meta-analysis of 41,117 GBM patients demonstrated that increased EOR at first operation positively correlated with longer progression-free and overall survival,¹⁵ notwithstanding the inherent limitations of selection bias and retrospective data. Some authors have attempted to derive a prognostic threshold for EOR; typically, the best outcomes are seen after 70 to 80% resection.^{16,​ 17} One randomized prospective trial demonstrates that survival is correlated with the initial EOR, where 5-aminolevulinic acid was used to guide tumor resection.¹⁴

Efficacy of radiotherapy in prolonging survival in GBM is well established. A meta-analysis of six randomized controlled trials demonstrated that radiotherapy reduces risk of death within 1 year by 19%.¹⁸ Efficacy of temozolomide chemotherapy primarily comes from the Stupp study, which showed the addition of temozolomide to standard surgery and radiotherapy increased the number of patients surviving 2 years from 10.4 to 26.5%.¹⁹ Extended analysis of these patients demonstrated temozolomide increased survival after 5 years from 1.9 to 9.8%.¹²

GBM recurrence is inevitable, with recurrence within 2 cm of the original tumor margin in 90% of patients.^{8,​ 13} The therapeutic approach to recurrent GBM is less well defined. This chapter examined published literature on the natural history of recurrent GBM and available treatment options and recommendations.

1.2 Selected Papers on the Natural History of Recurrent Glioblastoma

●Michaelsen SR, Christensen IJ, Grunnet K, et al. Clinical variables serve as prognostic factors in a model for survival from glioblastoma multiforme: an observational study of a cohort of consecutive non-selected patients from a single institution. BMC Cancer 2013;13(1):402.

●van Linde ME, Brahm CG, de Witt Hamer PC, et al. Treatment outcome of patients with recurrent glioblastoma multiforme: a retrospective multicenter analysis. J Neurooncol 2017;135(1):183–192.

Recurrent GBM is invariably associated with substantial morbidity and mortality. A summary of studies that examine the natural history of recurrent GBM is provided in Table 1.1 (Fig. 1.2). These data demonstrate that GBM typically recurs within 4 to 14 months of diagnosis, either during or after first-line treatment. If recurrent GBM is untreated, death occurs within 2 to 7 months, although there is likely to be strong selection bias in those studies that suggest that treatment may prolong survival (overall survival: 5.8–14.0 months).

Table 1.1 Summary of studies examining the natural history of recurrent glioblastoma

The key prognostic factors to consider at tumor recurrence include the following (Fig. 1.2):

●Age: Younger patients have improved survival.^{33,​ 36}

●Performance status: In general, higher performance status at recurrence predicts improved survival.^{33,​ 37,​ 38,​ 39,​ 40}

●Extent of disease: Local recurrence is associated with a better prognosis than diffuse disease. Evidences of ventricular contact and ependymal spread are poor prognostic factors.^{36,​ 39,​ 40}

●Presence of neurological symptoms: Symptomatic recurrence correlates with a poor prognosis (median survival: 3 months), compared to 10 months for radiologic recurrence.²⁶

●Secondary GBM: In one of the few reports to distinguish between primary and secondary GBM, Da Fonseca et al demonstrated increased survival time in six patients with secondary GBM in their series of 89 GBM patients, although it must be noted that patients with secondary GBM were almost 20 years younger.⁴¹ A separate analysis by Mandel et al was underpowered to detect any difference between patients based on IDH status.⁴² Further research should examine the impact of IDH mutations on the natural history of recurrent GBM.

It is critical to delineate true tumor progression from “pseudoprogression,” which represents treatment response. This determination is important as it will ultimately affect treatment options. Typically, pseudoprogression occurs in the first 12 weeks following completion of chemoradiotherapy, in 15 to 30% of patients.^{20,​ 21,​ 22,​ 23} Most pseudoprogression (67%) is asymptomatic, whereas most true progression (67%) is symptomatic.²⁰

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