Recurrent glioblastoma treatment

Recurrent glioblastoma treatment

Less than 10% of recurrent gliomas recur away from the original tumor site 1).

Reoperation extends survival by an additional 36 weeks in patients with glioblastoma, and 88 weeks in anaplastic astrocytoma 2) 3) (duration of high quality survival was 10 weeks and 83 weeks, respectively, and was lower with pre-op Karnofsky score < 70). In addition to Karnofsky performance score, significant prognosticators for response to repeat surgery include: age and time from the first operation to reoperation (shorter times → worse prognosis) 4). Morbidity is higher with reoperation (5–18%); the infection rate is ≈ 3x that for first operation, wound dehiscence is more likely


The standard of care management for newly diagnosed GBM includes surgery, radiation, temozolomide (TMZ) chemotherapy, and tumor treating fields 5).

There is no consensus as to the standard of care as no therapeutic options have produced substantial survival benefit for recurrent glioblastomas (GBMs) 6) 7).

A purely radiological diagnosis of recurrence or progression can be hampered by flaws induced by pseudoprogression, pseudoresponse, or radionecrosis.

Based on parameters like localization and tumor volume, patient’s Karnofsky Performance Score, time from initial diagnosis, and availability of alternative salvage therapies, reoperation can be considered as a treatment option to extend the overall survival and quality of life of the patient.

The achieved extent of resection of the relapsed tumor—especially with the intention of having a safe, complete resection of the enhancing tumor—most likely plays a crucial role in the ultimate outcome and prognosis of the patient, regardless of other modes of treatment. Validated scores to predict the prognosis after reoperation of a patient with a recurrent glioblastoma can help to select suitable candidates for surgery. Safety issues and complication avoidance are pivotal to maximally preserve the patient’s quality of life. Besides a possible direct oncological effect, resampling of the recurrent tumor with detailed pathological and molecular analysis might have an impact on the development, testing, and validation of new salvage therapies 8).

Options

Options include repeat surgical resection, repeat fractionated radiation, radiosurgery.

Bevacizumab (BEV) plus daily temozolomide (TMZ) as a salvage therapy have been recommended to recurrent glioma.

Given the lack of consensus on optimal management of recurrent GBM, knowledge of care patterns used for these patients and the criteria used to determine therapeutic strategy is germane to clinicians who care for these patients.


In a study, Hundsberger et al investigated which treatments are currently being used for recurrent GBM within a single nation (Switzerland) and how clinicians are deciding to use them 9)

The authors surveyed Swiss hospitals with comprehensive multidisciplinary neuro-oncology practices (neurosurgery, radiation therapy, medical neuro-oncology, and a dedicated neuro-oncology tumor board) about treatment recommendations for recurrent GBM. They identified relevant clinical decision-making criteria, called diagnostic nodes or “dodes,” and compared treatment recommendations using a decision-tree format.

Eight hospitals participated. The most common treatment options for recurrent GBM were combination repeat surgical resection with temozolomide or bevacizumab, monotherapy temozolomide or bevacizumab, and best supportive care. Alternative therapies, including radiotherapy, were less common. Despite widespread disagreement between centers in clinical decision making, the decision-tree analysis found agreement (>63%) between most centers for only 4 specific clinical scenarios. Patients without an appropriate performance status were usually managed with best supportive care. Patients with rapid recurrence, nonresectable tumors, unmethylated O(6)-methylguanine DNA methyltransferase (MGMT) promoter, and high performance status were usually managed with bevacizumab. Patients with late recurrence, nonresectable tumors, overt clinical symptoms, methylated MGMT promoter, multifocal disease, and high performance status were usually managed with repeat temozolomide therapy. Patients with late recurrence, nonresectable tumors, no clinical symptoms, methylated MGMT promoter, tumor multifocality, and high performance status were usually managed with temozolomide.The findings of this study underscore the lack of effective first- and second-line treatments for GBM, and the interhospital variability in practice patterns is not surprising. It seems likely that similar heterogeneity would also be noted in a study of American neuro-oncology centers. It is interesting to note that despite the availability of an increasing number of molecular markers for GBM stratification, MGMT promoter methylation appears to be the only biological marker widely used across multiple centers in this study. It remains to be seen when and how broadly other markers such as the epidermal growth factor receptor variant III or isocitrate dehydrogenase mutations will be adopted for clinical decision making.The authors are to be congratulated for identifying core clinical decision-making criteria that may be useful in future studies of recurrent GBM. This decision tree is an excellent reference for clinical trial development, and several active clinical trials already target the dodes identified in this study. Subsequent studies may help to determine whether similar decision trees exist in American neuro-oncologic centers now or will exist in the future 10).

Figure. A through F, clinical decision-making tree for recurrent glioblastoma multiforme (GBM) based on clinical scenarios that achieved a majority recommendation (ie, at least 5 of 8 Swiss hospitals). BEV, bevacizumab; BSC, best supportive care; rGBM, recurrent glioblastoma multiforme; TMZ, temozolomide. Modified with kind permission from Springer Science+Business Media: Journal of Neuro-Oncology, Patterns of care in recurrent glioblastoma in Switzerland: a multicenter national approach based on diagnostic nodes (published online ahead of print October 12. 2015), Hundsberger T, Hottinger AF, Roelcke U, et al [doi: 10.1007/s11060-015-1957-0. Available at: http://link.springer.com/article/10.1007%2Fs11060-015-1957-0 ].

Resection

Temozolomide

Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation 11).

Bevacizumab

Intraarterial chemotharapy

Intrarterial chemotherapy is a viable methodology in recurrent GBM patients to prolong survival at the risk of procedure-related complications and in newly diagnosed patients with the benefit of decreased complications 12).

Low-dose fractionated radiotherapy LD-FRT and chemotherapy for recurrent/progressive GBM have a good toxicity profile and clinical outcomes, even though further investigation of this novel palliative treatment approach is warranted 13).

Second surgery plus carmustine wafers followed by intravenous fotemustine

Second surgery plus carmustine wafers followed by intravenous fotemustine in twenty-four patients were analyzed. The median age was 53.6; all patients had KPS between 90 and 100; 19 patients (79%) performed a gross total resection > 98% and 5 (21%) a gross total resection > 90%. The median progression-free survival from second surgery was 6 months (95% CI 3.9-8.05) and the median OS was 14 months (95% CI 11.1-16.8 months). Toxicity was predominantly haematological: 5 patients (21%) experienced grade 3-4 thrombocytopenia and 3 patients (12%) grade 3-4 leukopenia.

This multimodal strategy may be feasible in patients with recurrent glioblastoma, in particular, for patients in good clinical conditions 14).

Immunotherapy

The HSPPC-96 vaccine is safe and warrants further study of efficacy for the treatment of recurrent GBM. Significant pretreatment lymphopenia may impact the outcomes of immunotherapy and deserves additional investigation 15).

Laser induced interstitial thermotherapy

see Laser interstitial thermotherapy.

Galldiks et al monitored the metabolic effects of stereotaxy-guided LITT in a patient with a recurrent GBM using amino acid positron emission tomography (PET). Serial 11C-methyl-L-methionine positron emission tomography (MET-PET) and contrast-enhanced computed tomography (CT) were performed using a hybrid PET/CT system in a patient with recurrent GBM before and after LITT. To monitor the biologic activity of the effects of stereotaxy-guided LITT, a threshold-based volume of interest analysis of the metabolically active tumor volume (MET uptake index of ≥ 1.3) was performed. A continuous decline in metabolically active tumor volume after LITT could be observed. MET-PET seems to be useful for monitoring the short-term therapeutic effects of LITT, especially when patients have been pretreated with a multistep therapeutic regimen. MET-PET seems to be an appropriate tool to monitor and guide experimental LITT regimens and should be studied in a larger patient group to confirm its clinical value 16).

Outcome

A more favorable prognosis following surgery for recurrence or progression is associated with younger age, smaller tumor volume (~50%), motor speech-middle cerebral artery scoring and preoperative Karnofsky performance score (KPS) >80% 17) 18).

Reviews

Optimal treatment for recurrent high grade glioma continues to evolve. Currently, however, there is no consensus in the literature on the role of reoperation in the management of these patients.

In a analysis, of reoperation in patients with World Health Organization grade III or IV recurrent gliomas, focusing on how reoperation affects outcome, perioperative complications, and quality of life. An extensive literature review was performed through the use of the PubMed and Ovid Medline databases for January 1980 through August 2013. A total 31 studies were included in the final analysis. Of the 31 studies with significant data from single or multiple institutions, 29 demonstrated a survival benefit or improved functional status after reoperation for recurrent high-grade glioma. Indications for reoperation included new focal neurological deficits, tumor mass effect, signs of elevated intracranial pressure, headaches, increased seizure frequency, and radiographic evidence of tumor progression. Age was not a contraindication to reoperation. Time interval of at least 6 months between operations and favorable performance status (Karnofsky Performance Status score ≥70) were important predictors of benefit from reoperation. Extent of resection at reoperation improved survival, even in patients with subtotal resection at initial operation. Careful patient selection such as avoiding those individuals with poor performance status and bevacizumab within 4 weeks of surgery is important. Although limited to retrospective analysis and patient selection bias, mounting evidence suggests a survival benefit in patients receiving a reoperation at the time of high-grade glioma recurrence 19).

Case series

2018

Twenty patients with recurrent glioma were treated with BEV (5-10 mg/kg, i.v. every 2 weeks) plus daily TMZ (daily, 50 mg/m2). The treatment response was evaluated via the RANO criteria. HRQL were measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (QLQ-C30) and Brain Module (QLQ-BN20).

Twenty patients received a total of 85 cycles of BEV with a median number of 4 cycles (range: 2-10). No patients showed complete response (CR) to treatment. Twelve patients had partial response (PR), stable disease (SD) in 5 patients with, and 3 patients showed progressive disease (PD). In the functioning domains of QLQ-C30, physical functioning, cognitive functioning and emotional functioning significantly improved after the second cycle of BEV compared to baseline, with the mean score of 45.0 vs. 64.0 (p = 0.020), 55.8 vs. 71.7 (p = 0.020) and 48.3 vs. 67.5 (p = 0.015), respectively. In the symptom scales, the scores of pain and nausea/vomiting significantly decreased compared to baseline from the mean score of 39.1 to 20.0 (p = 0.020) and 29.2 to 16.7 (p = 0.049), respectively. Score of global health status also increased from 47.5 to 63.3 (p = 0.001). As determined with the QLQ-BN20, motor dysfunction (43.3 vs. 25.0, p = 0.021), weakness of legs (36.7 vs. 18.3, p = 0.049), headache (38.3 vs. 20.0, p = 0.040), and drowsiness (50.0 vs. 30.0, p = 0.026) after the second cycle of BEV also significantly improved compared to baseline.

BEV plus daily TMZ as a salvage therapy improved HRQL in patients with recurrent glioma 20).

References

2016

Quick-Weller et al. performed tumour resections in seven patients with rGBM, combining 5-ALA (20 mg/kg bodyweight) with iMRI (0.15 T). Radiologically complete resections were intended in all seven patients.

They assessed intraoperative fluorescence findings and compared these with intraoperative imaging. All patients had early postoperative MRI (3 T) to verify final iMRI scans and received adjuvant treatment according to interdisciplinary tumour board decision.

Median patient age was 63 years. Median KPS score was 90, and median tumour volume was 8.2 cm(3). In six of seven patients (85%), 5-ALA induced fluorescence of tumour-tissue was detected intraoperatively. All tumours were good to visualise with iMRI and contrast media. One patient received additional resection of residual contrast enhancing tissue on intraoperative imaging, which did not show fluorescence. Radiologically complete resections according to early postoperative MRI were achieved in all patients. Median survival since second surgery was 7.6 months and overall survival since diagnosis was 27.8 months.

5-ALA and iMRI are important surgical tools to maximise tumour resection also in rGBM. However, not all rGBMs exhibit fluorescence after 5-ALA administration. They propose the combined use of 5-ALA and iMRI in the surgery of rGBM 21).

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Dejaegher J, De Vleeschouwer S. Recurring Glioblastoma: A Case for Reoperation? In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): Codon Publications; 2017 Sep 27. Chapter 14. Available from http://www.ncbi.nlm.nih.gov/books/NBK469991/ PubMed PMID: 29251867.
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The Glioma Book

The Glioma Book

Michael E. Sughrue

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This is the first step-by-step technical guide focused on aggressively resecting different types of gliomas. The book is logically organized, starting with a foundation of fundamental knowledge, then progressing to practical applications. Chapters focus on the skills necessary to perform glioma surgery, specific techniques, and systematic approaches to gliomas in different brain regions.

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About 30 high-quality videos posted online provide insightful procedural guidance The role of connectomic imaging in visualizing the cerebrum, and other innovative techniques including awake brain mapping and diffusion tensor tractography

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1p/19q codeletion

1p/19q codeletion

Complete deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) is pathognomonic for oligodendroglioma 1) 2) It is strongly associated with IDH mutation and is mutually exclusive of ATRX & TP53 mutations.

Loss of one arm of a hybrid chromosome is called loss of heterozygosity (LOH) for that chromosome region. LOH in 1p & 19q occurs as a result of unbalanced whole-arm translocations between chromosome 1 & chromosome 19, 3) which occurs early in the pathogenesis of oligodendrogliomas.

1p/19q codeletion should be tested whenever oligodendroglial features are present or if oligodendroglioma is suspected on other grounds. This is tested using FISH (fluorescence in situ hybridization) or PCR. It is often sent out, results typically take 3–7 days. Cost for FISH is on the order of $200 U.S., PCR is $300–500 U.S.

Less invasive method for prediction of pathological type-even gene status-is desired.

11C methionine positron emission tomography/MRI based texture analysis and conventional features may be a promising noninvasive predictor for differentiating the varied gliomas 4).


In the revised 4th edition of the World Health Organization Classification of Tumors of the Central Nervous System 2016, classification of especially diffuse gliomas has fundamentally changed: for the first time a large subset of these tumours is now defined based on presence/absence of IDH mutation and 1p19q codeletion. Following this approach, the diagnosis of anaplastic oligoastrocytoma can be expected to largely disappear 5).

While in cases of histologically classical oligodendroglioma 1p/19q analysis is essential for making the final (integrated) diagnosis, this is less clear for cases with less pronounced oligodendroglial differentiation or even for histologically astrocytic tumors. The WHO Classification states that the presence of an astrocytic component is compatible with the diagnosis of oligodendroglioma when molecular testing reveals the entity-defining combination of IDH mutation and 1p/19q codeletion. This means that histologically pure astrocytomas do not need to be analyzed for 1p19q codeletion. On the other hand, in the review article written by the editors of the WHO Classification, it is stated that “genotype trumps histological phenotype”, i.e., a diffuse glioma that histologically appears astrocytic, but proves to have IDH mutation and 1p/19q codeletion necessitates a diagnosis of oligodendroglioma, IDH-mutant, and 1p/19q-codeleted 6).

This means that 1p/19q analysis would be required in all cases of diffuse glioma. The most appropriate practical approach may depend on the amount/representativeness of the material in the individual case as well as on systematic studies revealing the actual frequency of this kind of constellation, i.e., completely disparate genotype versus histotype. Some clarification and ideally consensus appears useful.


Otani et al. analyzed 170 WHO grade II to IV gliomas resected in there institution. 1p/19q status was analyzed by microsatellite analysis, and genetic mutations were analyzed by next-generation sequencing and Sanger sequencing. For validation, the Brain Lower Grade Glioma dataset of the TCGA was analyzed. Of the 42 grade III IDH-mutated gliomas, 12 were 1p-intact/19q-intact (anaplastic astrocytomas: AA), 7 were 1p-intact/19q-loss (AA), and 23 showed 1p/19q-codeletion (anaplastic oligodendrogliomas: AO). Of the 88 IDH-wild type GBMs, 14 showed 1p-intact/19q-loss status. All of the seven 1p-intact/19q-loss AAs harbored TP53 mutation, but no TERT promotor mutation. All 19q-loss AAs had regions presenting oligodendroglioma-like morphology, and were associated with significantly longer overall survival (OS) compared to 19q-intact AAs (p=0.001). This tendency was observed in the TCGA Lower Grade Glioma dataset. In contrast, there was no difference in OS between the 19q-loss GBM and 19q-intact GBM (p=0.4). In a case of 19q-loss AA, both oligodendroglial morphology and 19q-loss disappeared after recurrence, possibly indicating correlation between 19q-loss and oligodendroglial morphology. We showed that there was a subgroup, although small, of IDH-mutated astrocytomas harboring 19q-loss that present oligodendroglial morphology, and also were associated with significantly better prognosis compared to other 19q-intact astrocytomas 7).


In oligodendrogliomas, mutations in IDH1 and codeletion of chromosomes 1p and 19q are associated with improved survival with upfront use of combined chemotherapy and radiation, and these tumors also have unique mutations of CIC and FUBP1 genes

The 1p-/19q- combination appears to be an objective diagnosis marker of classic oligodendrogliomas, one that can be used, in combination with histological examination, to improve the diagnosis of oligodendroglioma. Fluorescence in situ hybridization on touch preparations is a simple way to obtain information on 1p-/19q- in 24 hours 8).

Chromosome 1p/19q deletion is an established prognostic and predictive marker in the WHO grade III oligodendroglial tumors (OT).

Oligodendroglioma patients with 1p/19q LOH and Sox17 protein expression had a better prognosis. Thus, analysis of 1p/19q LOH and Sox17 protein expression could significantly enhance diagnostic accuracy, guide treatment, and improve the prognosis 9).


The diagnosis and classification of diffusely infiltrative gliomas are based on their histopathological appearance; however, histopathological delineation of diffuse gliomas can be difficult because of vague and subjective histopathological criteria. Combined loss of chromosome arms 1p and 19q (denoted as 1p-/19q-) has proven to be a powerful predictor of chemotherapeutic response and survival in oligodendrogliomas.

Fluorescence in situ hybridization using probes specific for chromosomes 1 and 19 was performed on 22 paraffin-embedded tissues retrospectively; 15 touch-preparation smear samples were studied prospectively; and loss of heterozygosity (LOH) screening was performed on 11 samples with microsatellite markers specific to chromosome 1 and chromosome 19. Of the 37 cases, 24 had 1p-/19q-, 1 case had 1p- only, 2 cases had 19q- only, and 10 cases had no deletion. The length of the largest deletion was mapped between markers D1S2795 (1p36.31 locus) and D1S2722 (1p34.2 locus) and between markers D19S416 (19q13.11 locus) and D19S397 (19q13.14 locus), using LOH. All of the pure oligodendrogliomas (n=7) harbored 1p-/19q-. In light of previous findings, the 1p-/19q- combination appears to be an objective diagnosis marker of classic oligodendrogliomas, one that can be used, in combination with histological examination, to improve the diagnosis of oligodendroglioma. Fluorescence in situ hybridization on touch preparations is a simple way to obtain information on 1p-/19q- in 24 hours 10).


Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed 11).

Indications

References

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Zhao K, Yu P, Xue Z, Liu J, Yao A, Zhao Y, Yang F, Tian J, Xu B. (11)C-Methionine Integrated PET/MRI-Based Texture Analysis Features May Have a Potential Ability to Distinguish Oligodendroglioma (IDH-Mutant and 1p/19q-Codeleted) From Varied Gliomas. Acad Radiol. 2019 Oct 10. pii: S1076-6332(19)30446-5. doi: 10.1016/j.acra.2019.09.013. [Epub ahead of print] PubMed PMID: 31607471.
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Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016 Jun;131(6):803-20. doi: 10.1007/s00401-016-1545-1. Review. PubMed PMID: 27157931.
7)

Otani R, Uzuka T, Higuchi F, Matsuda H, Nomura M, Tanaka S, Mukasa A, Ichimura K, Kim P, Ueki K. IDH-mutated astrocytomas with 19q-loss constitute a subgroup that confers better prognosis. Cancer Sci. 2018 May 12. doi: 10.1111/cas.13635. [Epub ahead of print] PubMed PMID: 29752851.
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Gadji M, Fortin D, Tsanaclis AM, Drouin R. Is the 1p/19q deletion a diagnostic marker of oligodendrogliomas? Cancer Genet Cytogenet. 2009 Oct;194(1):12-22. doi: 10.1016/j.cancergencyto.2009.05.004. PubMed PMID: 19737649.
9)

Li J, Miao N, Liu M, Cui W, Liu X, Li X, Shi X, Qing S, Ma Y, Zhang W, Biekemituofu H. Clinical significance of chromosome 1p/19q loss of heterozygosity and Sox17 expression in oligodendrogliomas. Int J Clin Exp Pathol. 2014 Dec 1;7(12):8609-15. eCollection 2014. PubMed PMID: 25674225; PubMed Central PMCID: PMC4313992.
10)

Gadji M, Fortin D, Tsanaclis AM, Drouin R. Is the 1p/19q deletion a diagnostic marker of oligodendrogliomas? Cancer Genet Cytogenet. 2009 Oct;194(1):12-22. doi: 10.1016/j.cancergencyto.2009.05.004. PubMed PMID: 19737649.
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van den Bent MJ, Baumert B, Erridge SC, Vogelbaum MA, Nowak AK, Sanson M, Brandes AA, Clement PM, Baurain JF, Mason WP, Wheeler H, Chinot OL, Gill S, Griffin M, Brachman DG, Taal W, Rudà R, Weller M, McBain C, Reijneveld J, Enting RH, Weber DC, Lesimple T, Clenton S, Gijtenbeek A, Pascoe S, Herrlinger U, Hau P, Dhermain F, van Heuvel I, Stupp R, Aldape K, Jenkins RB, Dubbink HJ, Dinjens WNM, Wesseling P, Nuyens S, Golfinopoulos V, Gorlia T, Wick W, Kros JM. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet. 2017 Aug 8. pii: S0140-6736(17)31442-3. doi: 10.1016/S0140-6736(17)31442-3. [Epub ahead of print] PubMed PMID: 28801186.
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