Glioblastoma (GBM) is a highly malignant brain tumour that almost inevitably progresses or recurs after first line standard of care. There is no consensus regarding the best treatment/s to offer people upon disease progression or recurrence. For the purposes of this review, progression and recurrence are considered as one entity.
To evaluate the effectiveness of further treatment/s for first and subsequent progression or recurrence of glioblastoma (GBM) among people who have received the standard of care (Stupp protocol) for primary treatment of the disease; and to prepare a brief economic commentary on the available evidence.
We searched MEDLINE and Embase electronic databases from 2005 to December 2019 and the Cochrane Central Register of Controlled Trials (CENTRAL, in the Cochrane Library; Issue 12, 2019). Economic searches included the National Health Service Economic Evaluation Database (NHS EED) up to 2015 (database closure) and MEDLINE and Embase from 2015 to December 2019.
Randomised controlled trials (RCTs) and comparative non‐randomised studies (NRSs) evaluating effectiveness of treatments for progressive/recurrent GBM. Eligible studies included people with progressive or recurrent GBM who had received first line radiotherapy with concomitant and adjuvant temozolomide (TMZ).
Data collection and analysis
Two review authors independently selected studies and extracted data to a pre‐designed data extraction form. We conducted network meta‐analyses (NMA) and ranked treatments according to effectiveness for each outcome using the random‐effects model and Stata software (version 15). We rated the certainty of evidence using the GRADE approach.
We included 42 studies: these comprised 34 randomised controlled trials (RCTs) and 8 non‐randomised studies (NRSs) involving 5236 participants. We judged most RCTs to be at a low risk of bias and NRSs at high risk of bias. Interventions included chemotherapy, re‐operation, re‐irradiation and novel therapies either used alone or in combination. For first recurrence, we included 11 interventions in the network meta‐analysis (NMA) for overall survival (OS), and eight in the NMA for progression‐free survival (PFS). Lomustine (LOM; also known as CCNU) was the most common comparator and was used as the reference treatment. No studies in the NMA evaluated surgery, re‐irradiation, PCV (procarbazine, lomustine, vincristine), TMZ re‐challenge or best supportive care. We could not perform NMA for second or later recurrence due to insufficient data. Quality‐of‐life data were sparse.
First recurrence (NMA findings)
Median OS across included studies in the NMA ranged from 5.5 to 12.6 months and median progression‐free survival (PFS) ranged from 1.5 months to 4.2 months. We found no high‐certainty evidence that any treatments tested were better than lomustine. These treatments included the following.
Bevacizumab plus lomustine: Evidence suggested probably little or no difference in OS between bevacizumab (BEV) combined with lomustine (LOM) and LOM monotherapy (hazard ratio (HR) 0.91, 0.75 to 1.10; moderate‐certainty evidence), although BEV + LOM may improve PFS (HR 0.57, 95% confidence interval (CI) 0.44 to 0.74; low‐certainty evidence).
Bevacizumab monotherapy: Low‐certainty evidence suggested there may be little or no difference in OS (HR 1.22, 95% CI 0.84 to 1.76) and PFS (HR 0.90, 95% CI 0.58 to 1.38; low‐certainty evidence) between BEV and LOM monotherapies; more evidence on BEV is needed.
Regorafenib (REG): REG may improve OS compared with LOM (HR 0.50, 95% CI 0.33 to 0.76; low‐certainty evidence). Evidence on PFS was very low certainty and more evidence on REG is needed.
Temozolomide (TMZ) plus Depatux‐M (ABT414): For OS, low‐certainty evidence suggested that TMZ plus ABT414 may be more effective than LOM (HR 0.66, 95% CI 0.47 to 0.92) and may be more effective than BEV (HR 0.54, 95% CI 0.33 to 0.89; low‐certainty evidence). This may be due to the TMZ component only and more evidence is needed.
Fotemustine (FOM): FOM and LOM may have similar effects on OS (HR 0.89, 95% CI 0.51 to 1.57, low‐certainty evidence).
Bevacizumab and irinotecan (IRI): Evidence on BEV + irinotecan (IRI) versus LOM for both OS and PFS is very uncertain and there is probably little or no difference between BEV + IRI versus BEV monotherapy (OS: HR 0.95, 95% CI 0.70 to 1.30; moderate‐certainty evidence).
When treatments were ranked for OS, FOM ranked first, BEV + LOM second, LOM third, BEV + IRI fourth, and BEV fifth. Ranking does not take into account the certainty of the evidence, which also suggests there may be little or no difference between FOM and LOM.
Three studies evaluated re‐operation versus no re‐operation, with or without re‐irradiation and chemotherapy, and these suggested possible survival advantages with re‐operation within the context of being able to select suitable candidates for re‐operation. A cannabinoid treatment in the early stages of evaluation, in combination with TMZ, merits further evaluation.
Second or later recurrence
Limited evidence from three heterogeneous studies suggested that radiotherapy with or without BEV may have a beneficial effect on survival but more evidence is needed. Evidence was insufficient to draw conclusions about the best radiotherapy dosage. Other evidence suggested that there may be little difference in survival with tumour‐treating fields compared with physician’s best choice of treatment. We found no reliable evidence on best supportive care.
Severe adverse events (SAEs)
The BEV+LOM combination was associated with significantly greater risk of SAEs than LOM monotherapy (RR 2.51, 95% CI to 3.66, high‐certainty evidence), and ranked joint worst with cediranib + LOM (RR 2.51, 95% CI 1.29 to 4.90; high‐certainty evidence). LOM ranked best and REG ranked second best. Adding novel treatments to BEV was generally associated with a higher risk of severe adverse events compared with BEV alone.
For treatment of first recurrence of GBM, among people previously treated with surgery and standard chemoradiotherapy, the combination treatments evaluated did not improve overall survival compared with LOM monotherapy and were often associated with a higher risk of severe adverse events. Limited evidence suggested that re‐operation with or without re‐irradiation and chemotherapy may be suitable for selected candidates. Evidence on second recurrence is sparse. Re‐irradiation with or without bevacizumab may be of value in selected individuals, but more evidence is needed.
Plain language summary
Treatment options for people with recurrent and progressive glioblastoma
Why this is important
Glioblastoma multiforme (GBM) is a very aggressive type of brain tumour. Even after treatment involving surgery, radiotherapy and chemotherapy the tumour may continue growing (progress) and almost always comes back (recurs). In this review, we consider progression and recurrence as one entity. A number of different treatments have been tested, but there has been no agreement about the best treatment/s to offer when someone’s tumour progresses or recurs.
To evaluate which are the most effective treatments for people with progressive or recurrent GBM who have already received surgery, radiotherapy and chemotherapy. We looked at effectiveness in terms of length of overall survival (OS), survival without disease progression (progression free survival, PFS), serious side effects, and whether treatments affected quality of life. We looked at treatments given when the disease first progressed or recurred (first recurrence) and when it came back again after that (second or subsequent recurrences).
We searched for relevant research studies comparing the effectiveness of different treatments for recurrent GBM. We used network meta‐analysis (NMA) to compare different treatments. NMA is a statistical method that allows different treatments to be looked at together to decide which is best. This method allows different treatments to be ranked according to their effectiveness, even if treatments have not been directly compared with each other in research studies.
We included 42 studies (34 randomised controlled trials (RCTs) and 8 non‐randomised studies) involving 5236 people. Interventions included chemotherapy, re‐operation, re‐irradiation and newly developed treatments either used alone or in combination. NMA could not be performed for second or later recurrence due to insufficient data.
Survival outcomes for people with a first recurrence
We found no good evidence that any of the treatments tested were better than lomustine (also known as CCNU). Adding bevacizumab to lomustine (BEV + LOM) did not improve overall survival compared with lomustine alone. Other chemotherapy and novel agents either did not work, or the evidence on them was uncertain. Unfortunately, we did not find any studies on several commonly used treatments, such as PCV (procarbazine, CCNU, vincristine) and TMZ re‐challenge, to include.
Limited evidence suggested that a second operation with or without other treatments may have survival advantages for some individuals with a first recurrence. A small study of a cannabinoid treatment suggests this merits further investigation.
Survival outcomes for people with a second or later recurrence
For second or later recurrence, insufficient evidence meant that we were not able to carry out statistical analysis. Findings suggested that radiotherapy with or without BEV may have some survival advantages but this evidence is uncertain. We found no reliable evidence on best supportive care.
Serious adverse events (SAEs) from treatment
Most treatments caused some serious side effects (SAEs). The BEV + LOM combination was associated with a significantly greater risk of SAEs than lomustine alone. In general, adding treatments to bevacizumab was associated with more SAEs compared with BEV alone.
For treatment of first recurrence of GBM, lomustine appears the most effective chemotherapy treatment and other combination therapies tested had a higher risk of serious side effects. A second operation or radiotherapy, or both, may be of value in selected individuals. For second recurrence, radiotherapy with or without bevacizumab may have a role but more evidence is needed. Several commonly used treatments were not evaluated, such as PCV (lomustine plus procarbazine and vincristine) and temozolomide re‐challenge. More research is needed.