Abstract

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adult. Its incidence increases with age and nearly half of the all newly diagnosed GBM cases are older than 65 years. Management of GBM in elderly is challenging and recurrence poses further challenge. This article aims to review the literature, evaluate the various options, and to decide the treatment plan in elderly cases with GBM recurrence.

Methods: A systemic search was performed with the phrase “recurrent GBM (rGBM) in elderly and management” as a search term in PubMed central, Medline, and Embase databases to identify all the articles published on the subject till February 2022. The review included peer-reviewed original articles, review articles, clinical trials, and keywords in title and abstract.

Results: Out of 473 articles searched, 15 studies followed our inclusion criteria and were included in this review. In 15 studies, ten were original and five were review articles. The minimum age group included in these studies was ≥65 years. Out of 15 studies, eight studies had described the role of resurgery, four chemotherapy, three resurgery and/or chemotherapy, and only one study on role of reradiotherapy in patients with rGBM. Out of eight studies described the role of resurgery, six have mentioned improved survival and two have no survival advantage of resurgery in cases of rGBM.

Conclusion: Resurgery is the main treatment option in selected elderly rGBM cases in good performance status. In patients with poor performance status, chemotherapy has better post progression survival than best supportive care.

Keywords: Elderly, Glioblastoma, Recurrent, Treatment

INTRODUCTION

Glioblastoma (GBM) is the most common primary malignant brain tumor in adult. The current median age is 64 years.[ 27 ] Its incidence increases with age and approximately half of all newly diagnosed GBM patients are older than 65 years.[ 11 ] Despite advanced diagnostic modalities and optimal multidisplinary treatment, most patients experience tumor progression with nearly universal mortality. Median survival in large retrospective studies is 6 months for newly diagnosed GBM patients older than 65 years.[ 3 , 17 ]

While the current standard of care for younger patients includes surgical resection followed by concurrent chemoradiation and adjuvant chemotherapy with temozolomide (TMZ),[ 21 , 36 ] managing elderly cases with GBM can be challenging due to medical comorbidities, lower organ function reserve, less aggressive treatment, increase toxicity of therapy, and more aggressive tumor behavior.[ 2 , 8 ] Many clinical trials in the oncology exclude elderly patients, as such there is less evidence to guide treatment in elderly patients.

Several studies show the benefit from active treatment for newly diagnosed GBM in elderly[ 20 , 22 ] but still there is no optimal treatment for recurrent GBM (rGBM) in elderly and/or frail patients. The aim of this review is to provide a practical overview of the evidence for treating rGBM in this special subgroup of patients.

MATERIALS AND METHODS

The review was designed in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-analysis.

Search strategy

Articles published in PubMed central, Medline, and Embase data bases till March 2022 were all searched. In relevant literature, references were manually searched for additional articles. We screened the title and abstract by combining the term (“recurrent” [All Fields] AND (“GBM” [MeSH Terms] OR “GBM” [All Fields]) AND (“aged” [MeSH Terms] OR “aged” [All Fields] OR “elderly” [All Fields]) AND (“therapy” [Subheading] OR “therapy” [All Fields] OR “treatment” [All Fields] OR “therapeutics” [MeSH Terms] OR “therapeutics” [All Fields]).

Eligibility criteria

Only nonexperimental and nonanimal clinical studies were included in the study. Articles written only in English language were considered. We have included only those published articles on elderly rGBM, in which patients were managed previously by surgery and postoperative chemoradiotherapy before recurrence, while excluding those articles in which GBM cases were managed either with surgery or radiotherapy.

Outcomes

Median overall survival (OS) (in weeks), progression free survival (PFS) (in weeks), and post progression survival (PPS) (in weeks) were the values collected. These variables were defined as the median time of intervention to death as median OS and to clinical or radiological evidence of tumor recurrence/progression as median PFS. PPS is defined as the time from tumor progression to death after the treatment.

Data management

Results of literature search were imported to EndNote X9 (Clarivate Analytics, Philadelphia, Pennsylvania). Software utilization sought to reduce data entry errors and bias (i.e., duplicating references). All investigation reports were reviewed to assess for in consistencies (e.g., design description, outcome presentation, and total patients analyzed).

Statistical analysis

Data work entered in Microsoft Office Excel 2007 and analyzed using SPSS version 24.0 (IBM Corp.; Chicago, United states. Data were analyzed at two levels, descriptive and analytical. Frequency, percentage, range, means, and median were used to describe the characteristics of study participants. P < 0.05 was considered statistically significant.

RESULTS

Out of 473 articles searched, 15 studies followed our inclusion criteria and were included in this study [ Figure 1 ].

Figure 1:

Flow chart (Preferred reporting items for systematic review and meta-analysis) for articles selection.

In 15 studies, ten were original and five were review articles. The minimum age group included in these studies was ≥65 years. Out of 15 studies, eight studies had described the role of re-surgery, four chemotherapy, three resurgery and/or chemotherapy, and only one study on role of reradiotherapy in patients with rGBM. Out of eight studies described the role of resurgery, six had mentioned improved survival and two had no benefit of resurgery in cases of rGBM. Three studies had mentioned the role of TMZ rechallenge, three fotemustine (FTM), one lomustine, and one on the role of bevacizumab (BEV) [ Table 1 ].

Table 1:

The previous studies on elderly recurrent glioblastoma.

DISCUSSION

Management of elderly patients with GBM is difficult due to the poor prognosis, multiple comorbidities, and an increased risk of adverse effects from radiotherapy.[ 30 ] Most clinical trials have excluded patients older than 65 years, which has resulted in no uniform optimal chemotherapy regimen and treatment protocol for elderly patients with GBM.[ 29 , 36 ] Recurrence of GBM in elderly poses further challenge for the treatment as the patients have limited life expectancy. The management of rGBM generally depends on the extent of disease and patient condition and is particularly difficult in the elderly subgroup, as they are very heterogeneous population.[ 24 ] In elderly patients, it remains unclear to what extent additional treatment including resurgery, reirradiation, and chemotherapy would be appropriate. There is only a little evidence regarding the best course of treatment when facing a GBM recurrence in elderly.[ 10 , 31 , 32 ]

Decision-making

Age, although associated with comorbidities and overall frailty, does not necessarily reflect the patients physiologic reserve or functional capacity[ 11 ] and thus should not preclude active management of recurrence. Performance status, being the next most important prognostic factor for survival,[ 30 ] must be factored heavily into the decision-making process, as it generally reflects the patient ability to receive any form of active treatment. Other factors such as site and size of tumor help to decide the appropriate form of treatment. O⁶ methylguanine DNA methyl transferase (MGMT) methylation helps to decide the form of chemotherapy and is associated with better prognosis. Status of isocitrate dehydrogenase (IDH) mutation helps in prognostication of patients. Salvage treatment should be decided on the basis of performance status of the patients.

(A) Elderly rGBM patients in good performance status (KPS ≥70%).

In these cases, local treatment (surgery and/or radiotherapy) results in better survival.

Resurgery versus conservative

The decision for resurgery after recurrence should be individualized as it is associated with greater morbidity and mortality.[ 35 ] The goal of resurgery should be to relieve the mass effect and to achieve safe maximal extent of resection which improves survival and also the overall effect of adjuvant therapy. Resurgery should be considered when (1) patient is in good functional status, (2) the procedure can reduce the raised intracranial pressure, (3) it can reasonably improve the quality of life of the patients, (4) it did not causes significant new neurological deficit or morbidity, (5) when it is possible to resect the contrast enhancing tumor tissue, and (6) the disease is focal and not involving eloquent brain regions, deep structures, or both hemispheres.[ 32 ] Several previous studies had reported improved post recurrence survival of at least 7 months for patients who underwent resurgery at GBM recurrence in elderly.[ 5 , 7 ]

Nuñez et al.[ 26 ] done a prospective study on 39 elderly rGBM patients which were reoperated on recurrence and showed significant survival benefit (HR: 0.6, 95% CI 0.36–0.9, P = 0.0427) for the reoperated group (18 months, 95% CI 13.97–23.2 months) compared to the group without resurgery (10.1 months, 95% CI 8.09–20.9 months). Young et al.[ 39 ] reported that reoperation seemed to be the most effective salvage strategies in selected elderly patients with a KPS ≥60%. Most of the other studies like Chen et al.[ 6 ] (12.0 months versus 5.0 months, HR = 0.666, P < 0.0001) and Zanello et al.[ 40 ] (aHR, 0.67 [95% CI: 0.56–0.81], P < 0.001) had also reported increased survival with resurgery. Only two studies had no survival benefit with resurgery.[ 13 , 15 ] It may be due to poor selection of elderly rGBM cases for resurgery.

Chen et al.[ 6 ] studied 496 cases of elderly rGBM cases of age ≥66 years and reported that only 12% of cases underwent at least 1 reoperation at an average of 7.2 months after the initial diagnosis. There were no significant differences in the complication of initial and resurgery. The overall complication rate was 21.7% in the initial resection versus 20.4% in the first reoperation group and 25.3% in the second reoperation group. Nuñez et al.[ 26 ] also have similar complication rates.

Resurgery versus chemotherapy

Resurgery had more survival benefits as compare to systemic therapy (chemotherapy) in rGBM in elderly patients with good KPS. A Korean study had evaluated the outcome of various salvage strategies in rGBM patients after upfront maximum debulking surgery followed by chemoradiotherapy and adjuvant TMZ, median PPS was 13.2 months after resurgery versus 5.6 months after TMZ chemotherapy^.[ 16 ] Socha et al.[ 34 ] in his study of 98 elderly rGBM patients reported that patients receiving resurgery (51 weeks, 95% CI 6.3–95.7 weeks) had better median PPS as compare to CHT (21 weeks, 95% CI 11.4–34.6), P = 0.36.

Resurgery versus reradiotherapy

Elderly rGBM cases managed with resurgery had better survival benefit as compare to reradiotherapy. On analyzing the previous literature, it is found that patients managed with resurgery (51 weeks, 95% CI 28.9–73.1 weeks) have better median PPS as compare to patients given only re-RT (17 weeks, 95% CI 12.2–21.8 weeks), P = 0.62.[ 34 ] Further studies are required to validate these results.

(B) Elderly rGBM patients in poor performance status (KPS<70%)

Chemotherapy versus local treatment

Local treatment (resurgery) results in improved survival benefit in rGBM in elderly patients with good KPS score, but it is associated with poor outcome in patients with poor KPS score (KPS <70%) probably due to postoperative complications. In this special subgroup, chemotherapy seems to be optimal therapeutic approach.

Zanello et al.[ 40 ] reported that age of ≥70 year was not a significant independent predictor of OS (median 19.6 versus 17.0 months, aHR, 1.17 [95%CI: 0.93–1.46], P = 0.190). The performance status of the patients at recurrence is the most important factor deciding the OS of the patients. Elderly patients with a KPS at recurrence of 60 or less did not benefit from surgery or radiotherapy at that time compared with chemotherapy instead.

After multiple adjustment using cox models, poor KPS from recurrence was independently associated with shorter OS from recurrence (aHR, 1.52 [95% CI: 1.27–1.82], P < 0.001). On reviewing the literature, patients treated with chemotherapy had better median PPS (21 weeks, 95% CI 8.8–33.2) as compare to patients treated with local treatment (14 weeks, 95% CI 0.9–46.7) P = 0.88.[ 34 ]

Several studies[ 1 , 19 , 33 ] have reported that FTM is a valuable therapeutic option for elderly patients with rGBM. Paccapelo et al.[ 28 ] and Perry et al.[ 31 ] had compared the FTM with TMZ rechallenge in elderly rGBM cases and reported that TMZ seemed to be active in early and late progression while FTM was always active in recurrent cases. The major difference was registered in GBM patients who failed after more than 6 months of TMZ.[ 28 ] Young et al.[ 39 ] had reported that oral nitrosourea (lomustine) has emerged as an option for rGBM in elderly patients. This chemotherapeutic drug is easily dosed, typically 110 mg/m² once every 6 weeks for a total of six cycles if efficacious and tolerated.[ 37 , 38 ] Prolonged cytopenia caused by this drug should be kept in mind during treatment in elderly and frail patients.

Best supportive care (BSC) versus any treatment

Elderly rGBM patients with poor KPS need not be automatically precluded from salvage treatment. Instead, the treatment should be individually tailored based on the presenting symptoms and the patient specific needs and goals. Some previous study[ 34 ] had reported that rGBM patients with poor KPS may also benefit from active treatment, as the active treatment approach more than doubled median PPS in these patients (21 weeks vs. 9 weeks with BSC, P = 0.014). Socha et al.[ 34 ] had compared outcomes in elderly rGBM with poor KPS treated with BSC and with any treatment and reported that median PPS with BSC was 9 weeks (95% CI 2.9–15 weeks) and 21 weeks (95% CI 8.9–33.1 weeks) with any treatment, P = 0.014. Nibali et al.[ 25 ] have similar results.

BEV may be most beneficial for patients with more robustly enhancing tumors that are associated with substantial cerebral edema. This therapeutic agent is associated with improved PPS and radiographic response rate, which are secondary in part to its mechanism of action of decreasing cerebral edema and normalizing the tumor vasculature.[ 12 , 18 ]

The newer treatment modalities such as molecular targeted therapy, immunotherapy, tumor treating fields, photodynamic therapy, intraoperative radiotherapy, laser interstitial thermal therapy, nuclear medicine thermal therapy, chimeric antigen receptor T-cell therapy, and various combination therapy have been investigated in elderly patients with newly diagnosed GBM cases but not in recurrent cases. At present, there is no evidence to support the role of these newer treatments outside the clinical trials, particularly for elderly cases. Further randomized control trials are required to validate efficacy and safety of these newer treatments and to analyze the role of molecular markers such as IDH mutant status, EGFR amplification, and MGMT methylation status to prognosticate these patients.

CONCLUSION

Management of elderly rGBM depends on the extent of the disease and performance status of the patients. Resurgery has better OS than other modalities of treatment and should be considered in selected elderly rGBM patients with good performance status. It has comparable complication rates as in nonelderly rGBM cases. Chemotherapy has better survival than BSC in elderly rGBM cases with poor performance status. Role of reradiotherapy and other newer treatments require further evaluation in well-designed, randomized, and control trials.

Declaration of patient consent

Patient’s consent not required as there are no patients in this study.

Financial support and sponsorship

Publication of this article was made possible by the James I. and Carolyn R. Ausman Educational Foundation.

Conflicts of interest

There are no conflicts of interest.

References

1. Addeo R, Lamberti G, Simonetti G, Iodice P, Marinelli A, Montella L. Biweekly fotemustine schedule for recurrent glioblastoma in the elderly: Activity and toxicity assessment of a multicenter study. CNS Oncol. 2019. 8: CNS32

2. Barnholtz-Sloan JS, Williams VL, Maldonado JL, Shahani D, Stockwell HG, Chamberlain M. Patterns of care and outcomes among elderly individuals with primary malignant astrocytoma. J Neurosurg. 2008. 108: 642-8

3. Buckner JC. Factors influencing survival in high grade glioma. Semin Oncol. 2003. 30: 10-4

4. Carola LC, Christian F, Eva KM, Marosi C. Guiding treatment choices for elderly patients with glioblastoma by a comprehensive geriatric assessment. Curr Oncol Rep. 2020. 22: 93

5. Chaichana KL, Chaichana KK, Olivi A, Weingart JD, Bennett R, Brem H. Surgical outcomes for older patients with glioblastoma multiforme: Preoperative factors associated with decreased survival. Clinical article. J Neurosurg. 2011. 114: 587-94

6. Chen YR, Sole J, Ugiliweneza B, Johnson E, Burton E, Woo SY. National trends for reoperation in older patients with glioblastoma. World Neurosurg. 2018. 113: e179-89

7. Colson KE, Rudolph KE, Zimmerman SC, Goin DE, Stuart EA, van der Laan M. Optimizing matching and analysis combinations for estimating causal effects. Sci Rep. 2016. 6: 23222

8. Curran WJ, Scott CB, Horton J, Nelson JS, Weinstein AS, Fischbach AJ. Recursive partitioning analysis of prognostic factors in three radiation therapy oncology group malignant glioma trials. J Natl Cancer Inst. 1993. 85: 704-10

9. D’Amico RS, Cloney MB, Sonabend AM, Zacharia B, Nazarian MN, Iwamoto FM. The safety of surgery in elderly patients with primary and recurrent glioblastoma. World Neurosurg. 2015. 84: 913-9

10. Ewelt C, Goeppert M, Rapp M, Steiger HJ, Stummer W, Sabel M. Glioblastoma multiforme of the elderly: The prognostic effect of resection on survival. J Neurooncol. 2011. 103: 611-8

11. Ferguson M, Rodrigues G, Cao J, Bauman G. Management of high-grade gliomas in the elderly. Semin Radiat Oncol. 2014. 24: 279-88

12. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009. 27: 4733-40

13. Goldman DA, Reiner AS, Diamond EL, DeAngelis LM, Tabar V, Panageas KS. Lack of survival advantages among re-resected elderly glioblastoma patients: A SEER-medicare study. Neurooncol Adv. 2020. 3: vdaa159

14. Ironside SA, Sahgal A, Detsky J, Das S, Perry JR. Updates on the management of elderly patients with glioblastoma: A narrative review. Ann Palliat Med. 2021. 10: 899-908

15. Jasmin H, Eva H, Sarah K, Dinc N, Won SY, Senft C. Impact of resection on overall survival of recurrent glioblastoma in elderly patients. Clin Neurol Neurosurg. 2018. 174: 21-5

16. Kim HR, Kim KH, Kong DS, Seol HJ, Nam DH, Lim DH. Outcome of salvage treatment for recurrent glioblastoma. J Clin Neurosci. 2015. 22: 468-73

17. Kita D, Ciernik IF, Vaccarella S, Franceschi S, Kleihues P, Lütolf UM. Age as a predictive factor in glioblastomas: Population based study. Neuroepidemiology. 2009. 33: 17-22

18. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I. Phase II trial of single agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009. 27: 740-5

19. Lombardi G, Luisa B, Ardi P, Puppa AD, Fiduccia P, Farina M. Clinical outcome of an alternative fotemustine schedule in elderly patients with recurrent glioblastoma: A mono-institutional retrospective study. J Neurooncol. 2016. 128: 481-6

20. Louis DN, Perry A, Reifenberger G, von Deimling A, FigarellaBranger D, Cavenee WK. The 2016 world health organization classification of tumors of the central nervous system: A summary. Acta Neuropathol. 2016. 131: 803-20

21. Lukas RV, Mrugala MM. Pivotal therapeutic trials for infiltrating gliomas and how they affect clinical practice. Neurooncol Pract. 2016. 4: 209-19

22. Lutterbach J, Bartelt S, Momm F, Becker G, Frommhold H, Ostertag C. Is older age associated with a worse prognosis due to different patterns of care? A long-term study of 1346, patients with glioblastomas or brain metastases. Cancer. 2005. 103: 1234-44

23. Mallick S, Benson R, Hakim A, Rath GK. Management of glioblastoma after recurrence: A changing paradigm. J Egypt Natl Canc Inst. 2016. 28: 199-210

24. Nabors LB, Portnow J, Ammirati M, Baehring J, Brem H, Brown P. Central nervous system cancers, Version 1.2015. J Natl Compr Canc Netw. 2015. 13: 1191-202

25. Nibali MC, Gay LG, Sciortino T, Rossi M, Caroli M, Bello L. Surgery for glioblastoma in elderly patients. Neurosurg Clin N Am. 2021. 32: 137-48

26. Nuñez MT, Pamela F, Debora C, Neidert N, Behringer SP, Mader I. Resection of recurrent glioblastoma multiforme in elderly patients: A pseudo-randomized analysis revealed clinical benefit. J Neurooncol. 2020. 146: 381-7

27. Ostrom QT, Gittleman H, Xu J, Kromer C, Wolinsky Y, Kruchko C. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2009-2013. Neuro Oncol. 2016. 18: v1-75

28. Paccapelo A, Lolli I, Fabrini MG, Silvano G, Detti B, Perrone F. A retrospective pooled analysis of response patterns and risk factors in recurrent malignant glioma patients receiving a nitrosourea-based chemotherapy. J Transl Med. 2012. 10: 90

29. Palmer JD, Siglin J, Yamoah K, Dan T, Champ CE, Bar-Ad V. Re-resection for recurrent high-grade glioma in the setting of re-irradiation: More is not always better. J Neurooncol. 2015. 124: 215-21

30. Perry JR, Laperriere N, O’Callaghan CJ, Brandes AA, Menten J, Phillips C. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med. 2017. 376: 1027-37

31. Perry JR, Rizek P, Cashman R, Morrison M, Morrison T. Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule: The “rescue” approach. Cancer. 2008. 113: 2152-7

32. Ringel F, Pape H, Sabel M, Krex D, Bock HC, Misch M. Clinical benefit from resection of recurrent glioblastomas: Results of a multicenter study including 503 patients with recurrent glioblastomas undergoing surgical resection. Neuro Oncol. 2016. 18: 96-104

33. Santoni M, Scoccianti S, Lolli I, Fabrini MG, Silvano G, Detti B. Efficacy and safety of second-line fotemustine in elderly patients with recurrent glioblastoma. J Neurooncol. 2013. 113: 397-401

34. Socha J, Lucyna K, Sunita G, Roa W, Kumar N, Sinaika V. Outcome of treatment of recurrent glioblastoma multiforme in elderly and/or frail patients. J Neurooncol. 2016. 126: 493-8

35. Soffietti R, Trevisan E, Bertero L, Cassoni P, Morra I, Fabrini MG. Bevacizumab and fotemustine for recurrent glioblastoma: A phase II study of AINO (Italian Association of Neuro-Oncology). J Neurooncol. 2014. 116: 533-41

36. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005. 352: 987-96

37. Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): A randomised controlled phase 2 trial. Lancet Oncol. 2014. 15: 943-53

38. Wick W, Brandes A, Gorlia T, Bendszus M, Sahm F, Taal W. LB-05 phase III trial exploring the combination of bevacizumab and lomustine in patients with first recurrence of glioblastoma: The EORTC 26101 trial. Neuro Oncol. 2015. 17: v1

39. Young JS, Chmura SJ, Wainwright DA, Yamini B, Peters KB, Lukas RV. Management of glioblastoma in elderly patients. J Neurol Sci. 2017. 380: 250-5

40. Zanello M, Roux A, Ursu R, Peeters S, Bauchet L, Noel G. Recurrent glioblastomas in the elderly after maximal first-line treatment: Does preserved overall condition warrant a maximal second-line treatment?. J Neurooncol. 2017. 135: 285-97