354

Neuro-Oncology Practice
9(5), 354–363, 2022 | https://doi.org/10.1093/nop/npac036 | Advance Access date 7 May 2022

Efficacy and safety of extended adjuvant temozolomide

compared to standard adjuvant temozolomide
in glioblastoma: Updated systematic review and
meta-analysis  

Tejpal Gupta , Riddhijyoti Talukdar, Sadhana Kannan, Archya Dasgupta , Abhishek Chatterjee, and
Vijay Patil

Department of Radiation Oncology, ACTREC/TMH, Tata Memorial Centre, Homi Bhabha National Institute (HBNI),
Mumbai, India (T.G., R.T., A.D., A.C.); Department of Clinical Research Secretariat, ACTREC/TMH, Tata Memorial
Centre, Homi Bhabha National Institute (HBNI), Mumbai, India (S.K.); Department of Medical Oncology, ACTREC/
TMH, Tata Memorial Centre, Homi Bhabha National Institute (HBNI), Mumbai, India (V.P.)

Corresponding Author: Tejpal Gupta, MD, Department of Radiation Oncology, ACTREC/TMH, Tata Memorial Centre, Homi Bhabha
National Institute (HBNI), Kharghar, Navi Mumbai-410210, India ([email protected]).

Abstract
Background. This study was designed to compare outcomes of extended adjuvant temozolomide (TMZ) vs
standard adjuvant TMZ following radiotherapy (RT) plus concurrent TMZ in newly diagnosed glioblastoma.
Methods. This systematic review and meta-analysis was carried out in accordance with Cochrane methodology.
Only prospective clinical trials randomly assigning adults with newly diagnosed glioblastoma after concurrent
RT/TMZ to 6 cycles of adjuvant TMZ (control arm) or extended (>6 cycles) adjuvant TMZ (experimental arm) were
eligible. Primary outcome of interest was overall survival, while progression-free survival and toxicity were sec-
ondary endpoints. Hazard ratio (HR) for progression and death with corresponding 95% confidence interval (CI)
were computed for individual primary study and pooled using random-effects model. Toxicity was defined as pro-
portion of patients with ≥grade 3 hematologic toxicity and expressed as risk ratio (RR) with 95% CI. Any P-value
<.05 was considered statistically significant.
Results. Systematic literature review identified five randomized controlled trials comparing standard (6
cycles) vs extended (>6 cycles) adjuvant TMZ in newly diagnosed glioblastoma. Outcome data could be ex-
tracted from 358 patients from four primary studies. Extended adjuvant TMZ was not associated with statisti-
cally significant reduction in the risk of progression (HR = 0.82, 95% CI: 0.61-1.10; P = .18) or death (HR = 0.87,
95% CI:0.60-1.27; P = .48) compared to standard adjuvant TMZ. Grade ≥3 hematologic toxicity though some-
what higher with extended adjuvant TMZ, was not significantly different between the two arms (RR = 2.01, 95%
CI: 0.83-4.87; P = .12).
Conclusions. There is low-certainty evidence that extended adjuvant TMZ is not associated with significant survival
benefit or increased hematologic toxicity in unselected patients with newly diagnosed glioblastoma compared to
standard adjuvant TMZ.

Keywords
extended | glioblastoma | safety | survival | temozolomide

Glioblastoma is the commonest malignant primary tumor of the standard of care2 for patients with newly diagnosed glioblas-
central nervous system (CNS) comprising nearly 40% of all pri- toma is focal conformal radiotherapy (RT) to the tumor bed with
mary brain tumors in adulthood.1The contemporary post-surgical margins using conventional fractionation (1.8-2 Gy per fraction

© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European
Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].
 Gupta et al. Extended adjuvant TMZ in glioblastoma 355

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Neuro-Oncology
for a total dose of 59.4-60 Gy in 30-33 fractions over 6-6.5 guidelines.16 Analysis, interpretation, and reporting in-
weeks) with concurrent oral temozolomide (TMZ) chemo- cluded a risk of bias assessment using the Cochrane Risk
therapy (75 mg/m2) followed by 6 cycles of adjuvant TMZ of Bias tool that assigns studies as having low, unclear, or
chemotherapy (150-200 mg/m2 D1-D5 every 4-weekly). The high risk of bias. Quality of evidence and strength of recom-
improvements in postoperative survival for newly diagnosed mendation was based on the Grades of Recommendation,
glioblastoma over time are clearly reflected in population- Assessment, Development, and Evaluation (GRADE) ap-
based analyses in the TMZ era.3 However, despite such ag- proach17 that involves consideration of methodological
gressive multi-modality therapy, the prognosis of patients quality, directness of evidence, heterogeneity, precision of
with glioblastoma remains dismal with an expected median effect estimates, and publication bias.
survival of 15 months, 2-year survival of 27%, and 5-year sur-
vival barely reaching 10%.2,3 The benefit of adding TMZ (both
concurrent and adjuvant) to RT was most pronounced in Literature Search Strategy
patients with epigenetic silencing of the O6-methylguanine
DNA methyltransferase (MGMT) gene promoter via methyl- An electronic search of Medline via PubMed was con-
ation,4 which has since been established as an independent ducted on March 15, 2021 and updated again on
prognostic factor as well as a predictive factor for response October 1, 2021 with no language, year, or publication
toTMZ chemotherapy.5 The benefit of addingTMZ to RT in pa- status restrictions. The Cochrane Central Register of
tients with unmethylated MGMT has been marginal2,4 raising Controlled Trials (CENTRAL) and Database of Abstracts
question marks over its usage in patients with unmethylated of Reviews of Effectiveness (DARE) were also searched
tumors.5,6 However, there exists considerable debate and electronically. Details of the search strategy are pre-
controversy regarding the most appropriate technique for sented in Supplementary file S1. Electronic search was
MGMT testing7 and defining the most optimal cutoff8 for further supplemented by hand-searching of review arti-
classifying glioblastoma as lacking MGMT gene promoter cles, cross-references, and conference proceedings.
methylation.
The optimal duration of adjuvant TMZ has remained con-
troversial with wide variations in practice globally. Many Study Eligibility
patients with glioblastoma who remain progression-free
after 6 cycles of TMZ receive further adjuvant TMZ till pro- Only RCTs testing the duration of adjuvant TMZ in
gression or 12 cycles (sometimes even more) based on newly diagnosed glioblastoma following postoper-
personal, physician, and institutional preferences. Several ative concurrent RT/TMZ were considered eligible.
physicians continue adjuvant TMZ (beyond 6 cycles) in pa- Prospective clinical trials randomly assigning patients
tients demonstrating good response to TMZ (particularly to extended (>6 cycles) adjuvant TMZ (experimental
with methylated MGMT) till clinico-radiological progression arm) or standard (6 cycles) adjuvant TMZ were included.
or toxicity. On the other hand, in most healthcare settings, Randomization in an individual study could have been
TMZ is generally stopped after 6 cycles based on prevalent done upfront before concurrent phase (RT/TMZ), after
local standards. A meta-analysis9 involving 1018 patients completion of concurrent RT/TMZ and before starting
with glioblastoma from seven studies reported statistically adjuvant phase, or after completion of standard adju-
significant improvements in progression-free survival (PFS) vant TMZ (6 cycles). Emulated RCTs, quasi-randomized
(P < .001) and overall survival (OS) (P = .018) with extended trials, propensity-matched analyses, non-randomized
adjuvant TMZ (>6 cycles) compared to standard 6 cycles. comparative studies, or observational studies were not
However, most such retrospective analyses and pooling of considered in this review.
data are prone to inherent biases and cannot guide thera-
peutic decision making which relies on high-quality evidence
generated through prospective randomized controlled trials Outcome Measures
(RCTs). The conduct and reporting of RCTs10–14 directly com-
Measures of efficacy included survival; the primary out-
paring extended adjuvant TMZ vs standard adjuvant TMZ in
come of interest was OS with PFS being considered as a
patients with newly diagnosed glioblastoma provides an op-
secondary outcome measure. OS was defined as the time
portunity to extract and pool the data to determine the effi-
interval between date of diagnosis (surgery) or date of
cacy and safety of such an experimental approach. The aim
inclusion in the study and last contact or death from any
of this updated systematic review and meta-analysis was to
cause. PFS was calculated from diagnosis or inclusion in
compare the efficacy and safety of extended adjuvant TMZ
the study till documented clinico-radiological progression,
(>6 cycles) vs standard adjuvant TMZ (6 cycles) in patients
last contact, or death whichever occurred earlier. Safety
with newly diagnosed glioblastoma.
outcomes included the comparison of TMZ-induced grade
3 or worse hematologic toxicity (anemia, neutropenia, and
thrombocytopenia) during adjuvant phase of therapy.
Materials and Methods
This systematic review was carried out in accordance with Data Extraction and Statistical Analyses
Cochrane methodology for systematic reviews of interven-
tional studies15 and reported as per the Preferred Reporting Two reviewers (R.T. and A.C.) independently read each ab-
of Systematic Reviews and Meta-Analyses (PRISMA) stract, pre-print, publication, protocol, or any other available
356 Gupta et al. Extended adjuvant TMZ in glioblastoma

study report and extracted relevant data from individual pri- Description of Included Studies
mary studies. Discrepancy, if any, was resolved through con-
sensus interpretation by a third reviewer (T.G.). Extracted Baseline characteristics and outcomes of interest in the four
data included study characteristics, patient characteristics, RCTs are summarized in Table 1. The first RCT11 was reported
number of participants randomized per arm, intervention from Egypt, wherein patients with glioblastoma without
details, and outcomes. Survival outcomes for individual pa- clinico-radiological evidence of progression following con-
tients were extracted manually from the published Kaplan- current RT/TMZ and 6 cycles of adjuvant TMZ were ran-
Meier survival curves using WebPlot digitizer.18 Using this domized to observation (n = 29) or extended adjuvant TMZ
individual participant level extracted data and published (n = 30). The number of cycles in the extended adjuvant TMZ
numbers at risk, survival curves for OS and PFS for each arm was not pre-defined, but continued till progression, with
study were reconstructed.19 The number of events and the median number of TMZ cycles being 11. Survival outcomes in
time points (t-risk and n-risk) were extracted from published the study were reported on intention-to-treat basis from date
data. If not reported explicitly, the same was derived from of surgery. At a median follow-up of 15.2 months, median PFS
available graphs as precisely as possible to generate com- (10.4 vs 13.2 months; P = .038) and OS (14.1 vs 18.8 months;
posite Kaplan-Meier survival curves that included individual- P = .070) were better with extended adjuvantTMZ.The second
level data from all four RCTs.18,19 The hazard ratio (HR) with RCT12 was conducted in India wherein patients with glioblas-
corresponding 95% confidence interval (CI) was computed toma were randomized after concurrent RT/TMZ to either 6
for each individual primary study and also compared with the cycles of adjuvant TMZ (n = 20) or 12 cycles of extended ad-
published HR (95% CI) if reported and reconciled as required juvant TMZ (n = 20). Survival outcomes in the study were
prior to statistical pooling. Grade 3 or worse hematologic tox- defined from date of surgery and reported on intention-
icity (anemia, neutropenia, and thrombocytopenia) was com- to-treat basis. At a median follow-up of 17.25 months, both
pared between the two arms and expressed as risk ratio (RR) median PFS (12.6 vs 16.8 months; P = .069) and OS (15.4 vs
with 95% CI. All data were pooled using the random-effects 23.8 months; P = .044) favored extended adjuvant TMZ arm.
model and expressed as HR or RR as appropriate with cor- The use of extended adjuvant TMZ was associated with in-
responding 95% CI. Any P-value <.05 was considered as sta- creased grade 3 or worse hematologic toxicity (15 vs 5%)
tistically significant. Sensitivity analysis (dropping one study during the adjuvant phase of treatment. The largest dataset13
at a time), subgroup analysis (based on MGMT methyla- comparing standard adjuvant TMZ with extended adjuvant
tion status), and publication bias (through funnel plot) were TMZ comes from a multicentric Spanish study (GEINO 14-01)
also assessed as appropriate. All analyses were done using wherein patients of newly diagnosed glioblastoma without
Review Manager (RevMan) version 5.3 and GRADE profiler evidence of progression after concurrent RT/TMZ plus 6
(GRADEpro) version 3.6.1 (The Nordic Cochrane Centre, cycles of TMZ were randomized to no further TMZ (n = 79)
Cochrane Collaboration, 2008), Stata 14.0 (StataCorp LP, vs continuing further TMZ up to a total of 12 cycles (n = 80),
College Station, TX, USA) and R Studio. The protocol is regis- stratified by MGMT and measurable disease. Survival out-
tered with the International Platform of Registered Systematic comes were defined and reported on intention-to-treat basis
Reviews and Meta-analysis Protocols (INPLASY2021120114). from date of inclusion in the study. At a median follow-up
No source of funding was involved in data extraction, anal- of 33.4 months, there were no significant differences in me-
ysis, interpretation, or reporting of results. dian PFS (7.7 vs 9.5 months; P = .95) or median OS (23.3 vs
18.2 months; P = .16) between the two arms. Toxicity of treat-
ment, such as lymphopenia (P < .001), thrombocytopenia
(P < .001), and nausea/vomiting (P = .001), although mild and
self-limiting was more frequent with extended adjuvant TMZ.
Results The most recent RCT14 reported from Iran in abstract form
The flow diagram of study selection and inclusion in the compared standard 6 cycles (n = 50) vs extended 12 cycles
meta-analysis as per PRISMA guidelines is depicted in (n = 50) of TMZ in patients with newly diagnosed high-grade
Figure 1. Detailed PRISMA checklist is also provided in glioma. At a median follow-up of 16.5 months, there was
Supplementary file S2. Comprehensive and systematic no statistically significant difference in 2-year OS (55.5% vs
search of the literature using the described search strategy 63.5%; P = .976) between the two arms.
identified a total of 257 potentially eligible records that
were retrieved for further review. After removing dupli- Evidence Synthesis
cates, inappropriate, or irrelevant reports (n = 66), 191 ab-
stracts were screened. Non-comparative studies and trials There was modest heterogeneity in included RCTs al-
involving lower-grade glioma (n = 161) were excluded lowing statistical pooling of results. Overall quality of in-
leaving 30 studies comparing extended adjuvant TMZ vs cluded studies was acceptable with low risk of bias for
standard adjuvant TMZ in patients with newly diagnosed efficacy outcomes and unclear to high risk of bias for tox-
glioblastoma that were reviewed in greater detail. Finally, icity outcomes. Aggregate data from all four RCTs based
five RCTs (three full-text publications and two abstract on reconstructed Kaplan-Meier curves showed no signif-
presentations) were identified for inclusion; however, icant difference between standard adjuvant TMZ vs ex-
outcomes could not be extracted from one abstract pub- tended adjuvant TMZ for PFS or OS (Figure 2). Extended
lication,10 leaving 358 patients enrolled in four RCTs11–14 adjuvant TMZ was not associated with statistically signif-
that were included in this updated systematic review and icant reduction in the risk of progression (HR = 0.82, 95%
meta-analysis. CI: 0.61-1.10; P = .18) or death (HR = 0.87, 95% CI:0.60-1.27;
 Gupta et al. Extended adjuvant TMZ in glioblastoma 357

Practice
Neuro-Oncology
  
Identification Records identified through Additional records identified through
database searching (n = 254) supplementary search (n = 3)

Duplicate, inappropriate, and/or irrelevant

records seen and removed (n = 66)
Screening

Records excluded (n = 161)

Records screened
non-comparative or studies
(n = 191)
in lower grade glioma

Full-text articles excluded (n = 26)

19 Retrospective studies
Studies/full-text articles 4 Editorials/letters
Eligibility

assessed for eligibility (n = 30) 2 Review articles

1 Randomized trial (abstract) with
lack of extractable data

Studies included in quantitative

Included

data synthesis (meta-analysis)

(n = 4)

Figure 1. Flow diagram of study selection and inclusion in the meta-analysis as per PRISMA guidelines. Abbreviation: PRISMA, Preferred
Reporting of Systematic Reviews and Meta-Analyses.
  

P = .48) compared to standard adjuvant TMZ (Figure 3). review and meta-analysis are summarized in Table 2.
The overall rate of grade 3 or worse hematologic tox- Despite pooling data only from prospective RCTs, quality
icity (Figure 4) during adjuvant phase though somewhat of evidence was graded as being of low quality both for
higher with extended adjuvant TMZ was not statistically efficacy and safety, implying that further research was very
significantly different between the two arms (RR = 2.01, likely to have an impact on the confidence in the estimate
95% CI: 0.83-4.87; P = .12). Individual hematological tox- of effect and was very likely to change that estimate.
icity during adjuvant TMZ, such as anemia (RR = 0.97,
95% CI: 0.10-9.08; P = .98), neutropenia (RR = 2.22, 95%
CI: 0.61-8.10; P = .23), or thrombocytopenia (RR = 2.41,
95% CI: 0.57-10.22; P = .23) were also not significantly Discussion
different (Figure 4). Sensitivity analysis (Supplementary
The currently established practice of postoperative concur-
Figure S3) demonstrated lack of influence of any single
rent RT/TMZ followed by 6 cycles of adjuvant TMZ (Stupp
study on the overall treatment effect, inferences, and
regimen) in patients with newly diagnosed glioblastoma is
conclusions. Subgroup analysis based on MGMT methyl-
based on a pivotal phase III trial demonstrating significant
ation status could not be done due to lack of extractable
improvements in survival with combined modality treat-
data in published reports. A relatively symmetric funnel
ment compared to RT alone.2 The benefit of adding TMZ to
plot (Supplementary Figure S4) ruled out significant pub-
RT was most pronounced in patients with methylation of
lication bias in the meta-analysis.
the MGMT gene promoter,4 with only a small minority of
patients with unmethylated tumors deriving benefit as evi-
Strength of Recommendation denced by tailing of the survival curves. However, MGMT
testing itself is disputed with no “gold-standard” technique
The quality of evidence and strength of recommendation making it difficult and challenging to withhold TMZ in pa-
for efficacy outcomes (PFS and OS) as well as safety out- tients with unmethylated glioblastoma.6–8 The ability of
comes (hematologic toxicity) in this updated systematic MGMT methylation for prediction of response to alkylating
358 Gupta et al. Extended adjuvant TMZ in glioblastoma

  
Table 1. Baseline Patient, Disease, and Treatment Characteristics With Summary Outcomes of Randomized Controlled Trials Comparing Standard
Adjuvant TMZ (6 Cycles) vs Extended Adjuvant TMZ (>6 Cycles) in Patients With Newly Diagnosed Glioblastoma

Author (Ref- Age Males RT Median FU Treat- Number Median PFS Median OS ≥Grade 3 Hematologic Toxicity
erence) Range Dose (months) ment Arm of Patients (months) (months) (Adjuvant TMZ)
(years)
Anemia Neutro- Thrombo-
penia cytopenia
Refae11 19-72 79.7% 59 15.2 6-cycle 29 10.4 14.1 0 9.5% 4.7%
Gy TMZ
>6-cycle 30 13.2 18.8 4.5% 18% 9%
TMZ
Bhandari12 19-65 60% 60 17.3 6-cycle 20 12.8 15.4 0 0 5%
Gy TMZ
>6-cycle 20 16.8 23.8 0 5% 10%
TMZ
a,b Balana13 29-83 52.2% NA/ 33.4 6-cycle 79 7.7 23.3 1.2% 0 0
NR TMZ
>6-cycle 80 9.5 18.2 0 1.3% 2.5%
TMZ
Javadinia14 ≥18 NA/NR NA/ 16.5 6-cycle 50 11.3 20.2 NA/NR NA/NR NA/NR
NR TMZ
>6-cycle 50 13.0 23.2 NA/NR NA/NR NA/NR
TMZ

Abbreviations: FU, follow-up; NA/NR, not available/not reported; OS, overall survival; PFS, progression-free survival; RT, radiotherapy; TMZ,
temozolomide.
aSurvival outcomes were reported from date of inclusion in the study (after 6-cycle TMZ) and not from date of diagnosis (surgery).
bUpdated results (at ASCO 2021) reported median OS of 22.0 months in control arm (6-cycle TMZ) and 18.2 months in experimental arm (>6-cycle

TMZ).
  

  
A 1.00 B 1.00
Progression free survival

0.80 0.80
Overall survival

0.60 0.60

0.40 0.40
6-cycles TMZ
6-cycles TMZ
0.20 0.20
>6-cycles TMZ
>6-cycles TMZ 0.00
0.00
0 5 10 15 20 25 30 35 40 45 50 0 5 10 15 20 25 30 35 40 45 50
Numbers at risk Months Months
Numbers at risk
>6-cycles TMZ 180 143 100 72 44 26 16 10 6 1 >6-cycles TMZ 180 169 144 114 84 57 31 20 10 4
6-cycles TMZ 178 141 100 60 42 31 23 13 4 3 6-cycles TMZ 178 170 146 107 74 48 38 22 10 8

Figure 2. Reconstructed Kaplan-Meier curves of progression-free survival (A) and overall survival (B) for individual-level participant data ex-
tracted from four randomized controlled trials comparing standard adjuvant temozolomide (6 cycles) vs extended adjuvant temozolomide (>6
cycles) in newly diagnosed glioblastoma. Note the completely overlapping curves suggesting no significant difference between the two arms.
  

TMZ chemotherapy coupled with longer survival of patients The benefit of extended adjuvant TMZ in patients with
with methylated tumors and low risk of cumulative toxicity newly diagnosed glioblastoma has been a subject of con-
has prompted continuation of adjuvant TMZ beyond the troversy and debate for several years now. In a pooled
standard 6-cycle regimen in different healthcare settings analysis20 of 2214 patients with glioblastoma enrolled in
across the world without high-quality evidence based on four prospective controlled trials of the Radiation Therapy
local standards and personal/institutional preferences. Oncology Group (RTOG) and European Organization for
 Gupta et al. Extended adjuvant TMZ in glioblastoma 359

Practice
Neuro-Oncology
  
A Progression-free survival Hazard ratio Hazard ratio Risk of bias
Study or subgroup Log[Hazard ratio] SE Weight IV, Random, 95% Cl Year IV, Random, 95% Cl A B C D E F G
Refae -0.5996 0.282002 18.0% 0.55 [0.32, 0.95] 2015 ? ? + + + + +
Bhandari -0.6399367 0.3493 13.4% 0.53 [0.27, 1.05] 2017 + + + + + + +
Balana 0.00957204 0.17016289 30.5% 1.01 [0.72, 1.41] 2020 + + + + + + +
Javadinia -0.0237 0.1195 38.1% 0.98 [0.77, 1.23] 2021 + + + + + + +

Total (95% Cl) 100.0% 0.82 [0.61, 1.10]

Heterogeneity: Tau2 = 0.04, Chi2 = 6.33, df = 3 (P = 0.10); I2 = 53%
Test for overall effect: Z = 1.34 (P = 0.18) 0.01 0.1 1 10 100
Favours [>6-cycles TMZ] Favours [6-cycles TMZ]
Risk of bias legend
(A) Random sequence generation (selection bias)
(B) Allocation concealment (selection bias)
(C) Blinding of participants and personnel (performance bias)
(D) Blinding of outcome assessment (detection bias)
(E) Incomplete outcome data (attrition bias)
(F) Selective reporting (reporting bias)
(G) Other bias

B Overall survival
Hazard ratio Hazard ratio Risk of bias
Study or subgroup Log[Hazard ratio] SE Weight IV, Random, 95% Cl Year IV, Random, 95% Cl A B C D E F G
Refae -0.4636 0.2746 22.3% 0.63 [0.37, 1.08] 2015 ? ? + + + + +
Bhandari -0.7897 0.4098 14.2% 0.45 [0.20, 1.01] 2017 + + + + + + +
Balana 0.2688 0.194565 29.0% 1.31 [0.89, 1.92] 2020 + + + + + + +
Javadinia 0.0088 0.1327 34.6% 1.01 [0.78, 1.31] 2021 + + + + + + +

Total (95% Cl) 100.0% 0.87 [0.60, 1.27]

Heterogeneity: Tau2 = 0.09, Chi2 = 8.37, df = 3 (P = 0.04); I2 = 64%
Test for overall effect: Z = 0.71 (P = 0.48) 0.01 0.1 1 10 100
Favours [>6-cycles TMZ] Favours [6-cycles TMZ]
Risk of bias legend
(A) Random sequence generation (selection bias)
(B) Allocation concealment (selection bias)
(C) Blinding of participants and personnel (performance bias)
(D) Blinding of outcome assessment (detection bias)
(E) Incomplete outcome data (attrition bias)
(F) Selective reporting (reporting bias)
(G) Other bias

Figure 3. Forest plot for progression-free survival (A) and overall survival (B) including risk of bias in individual studies comparing standard adju-
vant temozolomide (6 cycles) vs extended adjuvant temozolomide (>6 cycles) in newly diagnosed glioblastoma.
  

Research and Treatment of Cancer (EORTC), patients who Spain reported that TMZ was continued for more than 6
were progression-free after 6 cycles of adjuvant TMZ were cycles by 80.5% of neuro-oncologists; 44.4% only in the
identified (n = 624). Of these, 291 patients received ex- presence of residual disease, 27.8% for 12 cycles even in
tended adjuvant TMZ till progression or 12 cycles while 333 the absence of residual tumor, and 8.3% until progression
patients were observed. After adjusting for various con- with significant cost implications and economic burden to
founding factors, treatment beyond 6 cycles of TMZ was the society, prompting the design and conduct of a prospec-
associated with somewhat improved PFS (HR = 0.80, 95% tive multicenter study (GEINO 14-01) in Spain13 to assess
CI: 0.65-0.98; P = .03), which was more pronounced in pa- the benefit of extended adjuvant TMZ in patients with newly
tients with methylated MGMT (HR = 0.65, 95% CI: 0.50-0.80; diagnosed glioblastoma. Researchers from Germany com-
P < .01). However, OS was not impacted by a number of TMZ pared the medical costs and clinical outcomes of short-term
cycles (HR = 0.91, 95% CI: 0.71-1.19; P = .52) regardless of the TMZ (6 cycles) vs long-term TMZ (12 cycles or until progres-
MGMT status, leading to the conclusion that continuation sion) using a time-dependent Markov model23 and reported
of TMZ beyond the standard 6 cycles does not improve sur- incremental effectiveness of 0.022 quality-adjusted life years
vival in newly diagnosed glioblastoma. Similar analysis of (QALY) with long-term use of TMZ at an incremental cost-ef-
the German Glioma Network cohort21 identified 61 patients fectiveness ratio (ICER) of 351 909/QALY, making it highly ex-
with glioblastoma who were progression-free after 6 cycles pensive treatment.
of TMZ and received extended adjuvant TMZ compared to Secondary analysis of RTOG/EORTC trial database,20
81 patients who were observed after 6 cycles. There was post hoc analysis of registry data,21 and several retro-
no significant association of prolonged TMZ chemotherapy spective non-randomized comparative studies24–27 have
with PFS (HR = 0.8, 95% CI: 0.4-1.6; P = .56) or OS (HR = 1.6, provided conflicting results on the efficacy and safety of
95% CI: 0.8-3.3; P = .22) after adjusting for age, performance continuing TMZ beyond 6 cycles. A systematic review and
status, extent of resection, and molecular markers ques- meta-analysis9 pooled data from 1018 patients with gli-
tioning the practice of continuing TMZ beyond the standard oblastoma enrolled in seven comparative studies to as-
6 cycles. A questionnaire-based electronic survey22 from sess the impact of extended adjuvant TMZ. The authors
360 Gupta et al. Extended adjuvant TMZ in glioblastoma

  
>6-cycles TMZ 6-cycles TMZ Risk Ratio Risk Ratio Risk of bias
Study or subgroup Events Total Events Total Weight M-H, Random, 95% Cl Year M-H, Random, 95% Cl A B C D E F G
2.4.1 Anaemia
Refae 1 22 0 20 7.9% 2.74 [0.12, 63.63] 2015 ? ? – – + + +
Bhandari 0 20 0 20 Not estimable 2017 + + – – + + +
Balana 0 79 1 79 7.7% 0.33 [0.01, 8.06] 2020 + + – – + + +
Subtotal (95% Cl) 121 119 15.6% 0.97 [0.10, 9.08]
Total events 1 1
Heterogeneity: Tau2 = 0.00; Chi2 = 0.85, df = 1 (P = 0.36); I2 = 0%
Test for overall effect: Z = 0.03 (P = 0.98)

2.4.2 Neutropenia
Refae 4 22 2 21 31.0% 1.91 [0.39, 9.35] 2015 ? ? – – + + +
Bhandari 1 20 0 20 7.9% 3.00 [0.13, 69.52] 2017 + + – – + + +
Balana 1 80 0 79 7.7% 2.96 [0.12, 71.65] 2020 + + – – + + +
Subtotal (95% Cl) 122 120 46.7% 2.22 [ 0.61, 8.10]
Total events 6 2
Heterogeneity: Tau2 = 0.00; Chi2 = 0.10, df = 2 (P = 0.95); I2 = 0%
Test for overall effect: Z = 1.20 (P = 0.23)

2.4.3 Thrombocytopenia
Refae 2 22 1 21 14.5% 1.91 [0.19, 19.52] 2015 ? ? – – + + +
Bhandari 2 20 1 20 14.6% 2.00 [0.20, 20.33] 2017 + + – – + + +
Balana 2 80 0 79 8.6% 4.94 [0.24, 101.25] 2020 + + – – + + +
Subtotal (95% Cl) 122 120 37.7% 2.41 [0.57, 10.22]
Total events 6 2
Heterogeneity: Tau2 = 0.00; Chi2 = 0.29, df = 2 (P = 0.87); I2 = 0%
Test for overall effect: Z = 1.20 (P = 0.23)

Total (95% Cl) 365 359 100.0% 2.01 [0.83, 4.87]

Total events 13 5
Heterogeneity: Tau = 0.00; Chi = 1.72, df = 7 (P = 0.97); I2 = 0%
2 2

Test for overall effect: Z = 1.55 (P = 0.12) 0.01 0.1 1 10 100

Test for subgroup differences: Chi2 = 0.49, df = 2 (P = 0.78); I2 = 0% Favours [>6-cycles TMZ] Favours [6-cycles TMZ]
Risk of bias legend
(A) Random sequence generation (selection bias)
(B) Allocation concealment (selection bias)
(C) Blinding of participants and personnel (performance bias)
(D) Blinding of outcome assessment (detection bias)
(E) Incomplete outcome data (attrition bias)
(F) Selective reporting (reporting bias)
(G) Other bias

Figure 4. Forest plot for grade 3 or worse hematologic toxicity (anemia, neutropenia, and thrombocytopenia) during adjuvant temozolomide in
studies comparing standard adjuvant temozolomide (6 cycles) vs extended adjuvant temozolomide (>6 cycles) in newly diagnosed glioblastoma.
  

reported significant improvement in PFS (difference in methylated tumors might stand to benefit with continua-
means Z = 3.84 months, 95% CI: 2.559-7894; P < .001) tion of TMZ beyond 6 cycles; however, none of the included
and OS (difference in means Z = 2.375 months, 95% CI: RCTs comparing standard adjuvant TMZ with extended
1.002-10.467; P = .18) with extended adjuvant TMZ (>6 adjuvant TMZ used MGMT gene promoter methylation to
cycles) compared to standard (6 cycles) adjuvant TMZ. enrich their patient population. The GEINO 14-01 study13
However, the authors did acknowledge the methodolog- was stratified on MGMT status but did not find any sur-
ical limitations of their meta-analysis warranting cautious vival benefit even in patients with methylated tumors pos-
interpretation of the findings. Very recently, another sys- sibly due to low power inherent to much smaller sample
tematic review and meta-analysis28 of RCTs reported non- size (n = 97) for such comparison. Based on previously
significant improvement in median PFS (12 vs 10 months, published data,4,29 it is quite reasonable to believe that
P = .27) without corresponding improvement in median patients with glioblastoma with unmethylated MGMT de-
OS (23 vs 24 months, P = .73) with extended adjuvant rive very little benefit if at all with standard adjuvant TMZ,
TMZ. However, over 70% (n = 624) patients included in and it would be naïve to assume that this cohort would
that meta-analysis were from retrospective analysis of demonstrate any benefit with protracted duration of TMZ.
RTOG/EORTC trial database,7 which was erroneously de- Hence, the lack of significant benefit in unselected co-
scribed as a prospective trial randomly assigning patients horts of newly diagnosed glioblastoma is quite expected.
to 6 cycles vs >6 cycles of TMZ introducing strong selec- However, there still might be some merit in investigating
tion and performance bias with serious downgrading of the role of extended adjuvant TMZ in patients with methyl-
the evidence-base. ation of the MGMT gene promoter. Two ongoing Australian
The present updated systematic review and meta- trials EX-TEM (ACTRN12618001944224) and MAGMA
analysis provides low-certainty evidence that extended (ACTRN12620000048987) are currently testing the safety
adjuvant TMZ is not associated with significant benefits or and efficacy of extended adjuvant TMZ in patients with
harms in unselected patients with newly diagnosed glio- newly diagnosed glioblastoma using MGMT status for
blastoma and should not be offered outside the context of stratification. Biomarker-based Optimization of Adjuvant
prospective clinical trials. It is possible that patients with Therapy (BOAT) study is the lone ongoing prospective trial
   
Table 2. Summary of Findings With Quality of Evidence for the Benefits and Harms of Extended Adjuvant Temozolomide (>6 Cycles) Compared to Standard Adjuvant Temozolomide (6 Cycles) in Patients With
Newly Diagnosed Glioblastoma

Outcomes Number of Parti- Quality of the Evidence (GRADE) Relative Effect (95% Anticipated Absolute Effects
cipants (Studies) CI)
Risk With Risk Difference With Extended
Control Adjuvant Temozolomide (95% CI)
Overall survival 358 (4 studies) ⊕⊕⊝⊝ HR = 0.87 (0.6-1.27) 624 events 51 fewer events per 1000 (from
LOWa per 1000 180 fewer to 87 more)
due to inconsistency, imprecision
Progression-free survival 358 (4 studies) ⊕⊕⊝⊝ HR = 0.82 (0.61-1.1) 837 events 63 fewer events per 1000 (from
LOWa 1000 168 fewer to 27 more)
due to inconsistency, imprecision
Overall grade 3 or worse he- 724 (3 studies) ⊕⊕⊝⊝ RR = 2.01 (0.83-4.87) 14 events 14 more events per 1000 (from 2
matological toxicity LOWa due to risk of bias, imprecision per 1000 fewer to 54 more)
≥Grade 3 anemia 240 (3 studies) RR = 0.97 (0.1-9.08) 8 events 0 fewer events per 1000 (from 8
per 1000 fewer to 68 more)
≥Grade 3 neutropenia 242 (3 studies) RR = 2.22 (0.61-8.1) 17 events 20 more events per 1000 (from 7
per 1000 fewer to 118 more)
≥Grade 3 thrombocytopenia 242 (3 studies) RR = 2.41 (0.57-10.22) 17 events 24 more events per 1000 (from 7
per 1000 fewer to 154 more)

Abbreviations: CI, confidence interval; HR, hazard ratio; RR, risk ratio.
*The basis for the assumed risk (median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison
group and the relative effect of the intervention (and its 95% CI).
GRADE: Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
aOpposing effects seen in two studies—Balana and Javadinia. Index of heterogeneity (I2) is high.

  
Gupta et al. Extended adjuvant TMZ in glioblastoma

Practice
361

Neuro-Oncology
362 Gupta et al. Extended adjuvant TMZ in glioblastoma

(CTRI/2018/11/016349) that randomly assigns glioblastoma

patients only with methylated MGMT to standard 6 cycles Institutional Ethics Committee approval. Not applicable.
of TMZ vs extended adjuvant TMZ.30

Strengths and Limitations

Conflict of interest statement. None of the authors have any
Despite including only prospective RCTs for statistical
conflicts of interest to declare.
pooling using modern meta-analytic methods, several cav-
eats and limitations remain. All included primary studies
enrolled a small number of patients that were not ade-
quately powered to demonstrate differences in survival
between the two arms. Even after pooling of data from Authorship statement. Study concept, design, and protocol
four RCTs, the overall sample size still remained quite writing: T.G. Literature search: R.T., A.D., and T.G. Screening
small (N = 358) with low power to detect any meaningful records and data extraction: R.T. and A.C. Statistical analysis:
difference in outcomes precluding robust conclusions. S.K. and T.G. Manuscript writing: first draft—R.T., final draft—
Although patients in the largest study (GEINO 14-01) were T.G. Critical review and editing of manuscript: V.P. Final approval
stratified on MGMT gene promoter methylation status, of manuscript: all authors.
none of the trials were limited to biomarker-enriched pa-
tient population (methylated MGMT), which is expected to
derive the most benefit with extended adjuvant TMZ. All
included trials were open-label without any placebo con-
trol or blinding of patients/physicians with potential for Data Availability
significant performance and detection bias. Evidence syn-
thesis was primarily based on data reported in publications All extracted data from individual primary studies are vested
without access to individual patient data that could provide with the principal investigator and corresponding author that
more methodologic robustness. Finally, this review did not can be made available on reasonable request.
assess the impact of extended adjuvant TMZ on health-
related quality of life or its cost-effectiveness due to lack of
reporting of such data in individual primary studies.

References
Conclusion
1. Ostrom QT, Patil N, Cioffi G, et al. Statistical report: CBTRUS: primary
This meta-analysis suggests that extended adjuvant TMZ brain and other central nervous system tumors diagnosed in the United
is not associated with significant survival benefit or in- States in 2013–2017. Neuro Oncol. 2020;12(Suppl 2):iv1–iv96.
creased hematologic toxicity in unselected patients with 2. Stupp R, Mason W, van den Bent M, et al. Radiotherapy plus con-
newly diagnosed glioblastoma compared to standard ad- comitant and adjuvant temozolomide for glioblastoma. N Eng J Med.
juvant TMZ. However, based on the quality of data, level of 2005;352(10):987–996.
evidence is classified as low certainty for this statement. 3. Johnston A, Creighton N, Parkinson J, et al. Ongoing improvements
in postoperative survival of glioblastoma in the temozolomide era: a
population-based data linkage study. Neurooncol Pract. 2020;7(1):22–30.
4. Hegi M, Diserens A, Gorlia T, et al. MGMT gene silencing and benefit from
Supplementary Material temozolomide in glioblastoma. N Eng J Med. 2005;352(10):997–1003.
5. Alnahhas I, Alsawas M, Rayi A, et al. Characterizing benefit from temozolomide
Supplementary material is available at Neuro-Oncology in MGMT promoter unmethylated and methylated glioblastoma: a systematic
Practice online. review and meta-analysis. Neurooncol Adv. 2020;2(1):vdaa082.
6. Hegi ME, Stupp R. Withholding temozolomide in glioblastoma patients
with unmethylated MGMT promoter—still a dilemma? Neuro Oncol.
2015;17(11):1425–1427.
Funding 7. Malmstrom A, Lysiak M, Kristensen BW, et al. Do we really know who has an
MGMT methylated glioblastoma: results of an international survey regarding
No funding support was involved in this systematic review and use of MGMT analyses for glioma. Neurooncol Pract. 2020;7(1):68–76.
meta-analysis. 8. Hegi M, Genbrugge E, Gorlia T, et al. MGMT promoter methylation cutoff
with safety margin for selecting glioblastoma patients into trials omit-
ting temozolomide: a pooled analysis of four clinical trials. Clin Cancer
Res. 2019;25(6):1809–1816.
9. Alimohammadi E, Bagheri SR, Taheri S, et al. The impact of extended
Registration. The protocol is registered with the International adjuvant temozolomide in newly diagnosed glioblastoma multiforme: a
Platform of Registered Systematic Reviews and Meta-analysis meta-analysis and systematic review. Oncol Rev. 2020;14(1):461.
Protocols (INPLASY2021120114). 10. Renard L, Clement P, Hammouch F, et al. Safety analysis of randomized
Belgian phase II trial of extended use of adjuvant temozolomide in newly
 Gupta et al. Extended adjuvant TMZ in glioblastoma 363

Practice
Neuro-Oncology
diagnosed glioblastoma patients. Neuro Oncol. 2010;12:46–47. http:// 21. Gramatzki D, Kickingereder P, Hentschel B, et al. Limited role for ex-
hdl.handle.net/2078.1/58558. tended maintenance temozolomide for newly diagnosed glioblastoma.
11. Refae A, Ezzat A, Salem D, et al. Protracted adjuvant temozolomide in Neurology. 2017;88(15):1422–1430.
glioblastoma multiforme. J Can Ther. 2015;6:748–758. 22. Balana C, Vaz MA, Lopez D, et al. Should we continue temozolomide be-
12. Bhandari M, Gandhi AK, Devnani B, et al. Comparative study yond 6 cycles in the adjuvant treatment of glioblastoma without an evi-
of adjuvant temozolomide six cycles versus extended 12 cycles dence of clinical benefit? A cost analysis based on prescribing patterns
in newly diagnosed glioblastoma multiforme. J Clin Diagn Res. in Spain. Clin Transl Oncol. 2014;16:273–279.
2015;11(5):XC04–XC08. 23. Waschke A, Arefian H, Walter J, et al. Cost-effectiveness of the long-
13. Balana C, Vaz MA, Manuel Sepúlveda J, et al. A phase II randomized, term use of temozolomide for treating newly diagnosed glioblastoma in
multicenter, open-label trial of continuing adjuvant temozolomide be- Germany. J Neurooncol. 2018;138(2):359–367.
yond 6 cycles in patients with glioblastoma (GEINO 14-01). Neuro Oncol. 24. Roldán Urgoiti GB, Singh AD, Easaw JC. Extended adjuvant
2020;22(12):1851–1861. temozolomide for treatment of newly diagnosed glioblastoma
14. Javadinia S, Anvari K, Seilaniantousi M, et al. 354P Extended dosing multiforme. J Neurooncol. 2012;108:173–177.
(12 cycles) vs. conventional dosing (6 cycles) of adjuvant temozolomide 25. Darlix A, Baumann C, Lorgis V, et al. Prolonged administration of adju-
in adults with newly diagnosed high grade gliomas: a randomized, vant temozolomide improves survival in adult patients with glioblas-
single-blind, two-arm, parallel-group controlled trial. Ann Oncol. toma. Anticancer Res. 2013;33(8):3467–3474.
2021;32:S520–S521. 26. Skardelly M, Dangel E, Gohde J, et al. Prolonged temozolomide
15. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interven- maintenance therapy in newly diagnosed glioblastoma. Oncologist.
tions. The Cochrane Collaboration, 2011. https://www.handbook.cochrane.org 2017;22(5):570–575.
16. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for sys- 27. Quan R, Zhang H, Li Z, et al. Survival analysis of patients with glioblas-
tematic reviews and meta-analyses: the PRISMA statement. Br Med J. toma treated by long-term administration of temozolomide. Medicine.
2009;339:b2535. 2020;99(2):e18591.
17. Guyatt GH, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction— 28. Attarian F, Taghizadeh-Hesary F, Fanipakdel A, et al. A systematic review
GRADE evidence profiles and summary of findings table. J Clin and meta-analysis on the number of adjuvant temozolomide cycles in
Epidemiol. 2011;64(4):383–394. newly diagnosed glioblastoma. Front Oncol. 2021;11:779491.
18. Rohtagi A. WebPlot digitizer. Pacifica, California, USA, 2021. https:// 29. Kamson DO, Grossman SA. The role of temozolomide in patients
automeris.io/WebPlotDigitizer with newly diagnosed wild-type IDH, unmethylated MGMTp
19. Guyot P, Ades AE, Ouwens NJNM, et al. Enhanced secondary analysis glioblastoma during the COVID-19 pandemic. JAMA Oncol.
of survival data: reconstructing the data from published Kaplan-Meier 2021;7(5):675–676.
survival curves. BMC Med Res Methodol. 2012;12:9. 30. Gupta T, Chatterjee A, Patil V. Extended adjuvant temozolomide in newly
20. Blumenthal DT, Gorlia T, Gilbert MR, et al. Is more better? The impact diagnosed glioblastoma: is more less? Comment on “A phase II random-
of extended adjuvant temozolomide in newly diagnosed glioblastoma: ized, multicenter, open-label trial of continuing adjuvant temozolomide be-
a secondary analysis of EORTC and NRG Oncology/RTOG. Neuro Oncol. yond 6 cycles in patients with glioblastoma (GEINO 14-01)”. Neuro Oncol.
2017;19(8):1119–1126. 2020;22(12):1887–1888.