Best Published Clinical Trial Outcomes for Recurrent Glioblastoma

by Stephen Western

Optune (NovoTTF) Tumor Treating Fields

In June 2014, survival outcomes from the patient registry including all recurrent glioblastoma patients treated with Novocure's NovoTTF device in the US between October 2011 and November 2013 (total of 457 patients) were made available. NovoTTF at first recurrence led to a median survival of 20 months (from the time of recurrence). Though the full details have not yet been published, these statistics indicate that NovoTTF may be the single most effective therapy yet reported for recurrent GBM. This therapy was approved by the FDA in 2011 for use in recurrent, adult glioblastoma. Read the news item on the newly released statistics here.

Very Low-dose Temozolomide combined with Celecoxib (Celebrex)

A retrospective study (15) carried out in Germany and published in the Journal of Neuro-Oncology in 2010 showed a surprisingly positive outcome for very low dose daily temozolomide (10 mg per square meter of body surface, twice daily) plus 200 mg Celebrex every day. 28 recurrent GBM patients received this treatment, with 24 of these patients at first recurrence and 4 patients at second recurrence. Most of these patients (n=24) had undergone standard radiation plus TMZ as first-line treatment. 19 patients (68%) underwent a second resection prior to low-dose TMZ/Celebrex. 17 patients were tested for MGMT methylation status, with 8 of these patients (47%) having a methylated MGMT promoter, though MGMT status did not prove to make a significant difference in survival outcomes.

Median progression-free survival in this study was 4.2 months, and 6-month PFS rate was 43%. Even more impressive is a median overall survival of 16.8 months from the most recent tumour relapse prior to the start of the study. Upon disease progression (25 patients), the most common follow-up treatments included Avastin plus irinotecan (7 patients), repeat tumour resection (5 patients) and PCV chemotherapy (5 patients), while 9 patients received only palliative care.

We may speculate that the longer than expected median survival following low-dose TMZ plus Celebrex for these recurrent glioblastoma patients can be attributed to the majority of patients having had repeat resection prior to the study, the immune-stimulating and anti-angiogenic effects of both the very low dose TMZ and Celebrex treatments, and the fact that ~13-16 of 25 patients received further aggressive treatment upon disease progression.

Tumor lysate pulsed dendritic cell vaccine with imiquimod

Investigators from Cedars-Sinai Medical Center in Los Angeles presented results of a phase I/II trial of a dendritic cell vaccine at the 2013 annual meeting of the Society for Neuro-Oncology (see abstract 029). After maximal surgical resection, 31 recurrent glioblastoma patients received the vaccine along with the toll-like receptor 7 agonist, Imiquimod. Median survival from trial start was 15 months, one of the best median survival outcomes seen in any trial for recurrent glioblastoma.

Bevacizumab (Avastin) plus CCNU (lomustine)

The Dutch BELOB trial (16), published in 2014, was a randomized phase 2 trial comparing Avastin alone, lomustine alone, and the combination of Avastin plus lomustine. Patients were recruited at the time of first recurrence. Combination treatment led to superior outcomes in terms of both progression-free survival (PFS-6 of 41% in the combination group, versus 16% and 13% in the Avastin and lomustine monotherapy groups), as well as median survival from trial start. On the basis of these outcomes, lomustine, an oral nitrosourea, is now commonly being given along with Avastin to patients with recurrent GBM.

Rindopepimut plus bevacizumab for bevacizumab-naive EGFRvIII-positive recurrent glioblastoma

In November 2013, Celldex Therapeutics published preliminary data from the ReAct trial for recurrent glioblastoma, which is testing their anti-EGFRvIII vaccine, rindopepimut, along with the anti-VEGF agent bevacizumab (Avastin). Interim results were available for the first 40 patients in group 1, which consisted of patients without previous exposure to bevacizumab. 20 patients received both the rindopepimut vaccine and bevacizumab, while another 20 received bevacizumab without the vaccine. The 20 patients receiving the vaccine had a trend towards improved survival of 12 months, versus 7.9 months in the control group. Patients enrolled in this trial are required to have a mutation in the EGFR gene called EGFR variant III, which causes perpetual activation of the epidermal growth factor receptor (EGFR).


Fotemustine is a "third generation" nitrosourea, in the same family as carmustine (BCNU) and lomustine (CCNU). As with other alkylating agents, most frequent toxicity with fotemustine use is myelosuppression, such as leukopenia and thrombocytopenia (1). It is a common therapy in Europe for recurrent glioblastoma, where approval of Avastin for this indication was refused by the European Medicines Agency (2).

Several clinical trials, mostly carried out in Italy, have shown the impressive efficacy of this drug in glioblastoma patients at first recurrence upon failure of standard radiochemotherapy with temozolomide.

In one of these trials (3), 41 glioblastoma patients at first recurrence (median age, 57 years) were given intravenous fotemustine at a dose of 100 mg per square meter of body surface area once a week for 3 weeks. A maintenance dose was give once every three weeks. All patients had been previously treated with standard radiochemotherapy with TMZ. Median progression-free survival outcome was 5.9 months and the six month progression-free survival rate was 48.7%.

A later trial, using a slightly different dosing regiment, had even better progression-free survival outcomes (4). In this trial, 40 patients (median age, 53) received fotemustine at a dosage of 80 mg per square meter once every two weeks for five cycles. The maintenance dose was 100 mg per square meter once every three weeks, as in the previous trial. All patients had been previously treated with standard radiochemotherapy. The median progression-free survival time was 6.7 months and the six month progression-free survival rate was 61%. Median survival from initiation of fotemustine was 11.1 months. 24 of 40 patients (60%) were tested for MGMT promoter methylation, and of these, 29% were found to be methylated.

Somewhat confusingly, a similar trial of fotemustine showed less impressive results (5). The drug schedule used was 75-100 mg per square meter once a week for three weeks, with maintenance of 100 mg per square meter once every three weeks, similar to the first study described above (3). 43 recurrent glioblastoma patients (median age, 51) had all received prior temozolomide. 34 of 43 patients (79%) were tested for MGMT promoter methylation, and of those, 24% were methylated. Median progression-free survival in this trial was 1.7 months (compared with 5.9 and 6.7 in the trials described above). The six month progression-free survival rate was 20.9% (compared with 48.7% and 61%, above). Median survival from initiation of fotemustine was only 6 months (compared with 11.1 months). It is unknown why the patients in this trial did poorly compared to other trials of fotemustine with similar patient populations. A clearer picture will likely emerge in trials where all patients are tested for MGMT expression and stratified on that basis.

Second or higher recurrence

Perillyl alcohol

Brazilian investigators recently published the outcome of a phase II trial (10) of nasally inhaled perillyl alcohol in recurrent malignant gliomas, including 155 glioblastoma patients (mean age 51). 11 of these patients were secondary glioblastoma, and the remainder were primary glioblastoma. Eligible patients for this trial were required to have had at least two relapses. While median progression-free survival and median survival times were not reported, the six month progression-free survival rate was an impressive 48%. Patients also did not suffer from gastrointestinal or hematological toxicity with this natural plant-derived agent. The nasal inhalation method was said to have an increased central nervous system penetration compared with the oral route. Hopefully more trials will be carried out with this potentially promising agent (11).

Bevacizumab (Avastin)

For an in-depth look at this drug, please see the Bevacizumab (Avastin) page. Several recent retrospective studies (13, 14) indicate that there is likely an advantage to delaying Avastin therapy until second or later recurrences, as there tends to be a fixed survival time associated with Avastin therapy regardless of the number of prior recurrences. One retrospective study (14) showed that recurrent glioblastoma patients treated with Avastin at second or higher recurrence had statistically improved overall survival (25.9 months) compared with patients treated with Avastin at first recurrence (20.8 months). There is likely some bias included in these latter statistics as those treated with Avastin at second recurrence by definition underwent a second salvage therapy, while those treated with Avastin at first recurrence may not have underwent further salvage therapies at second recurrence. The hypothesis that delaying therapy with Avastin until other options have been exhausted leads to improved overall survival will require prospective clinical investigation.

Fotemustine plus procarbazine

Italian investigators also tried the addition of oral procarbazine to fotemustine therapy for recurrent glioblastoma patients as a second- or third-line chemotherapy (9). 23 patients (median age 50) received this treatment as a third-line chemotherapy (having failed two prior chemotherapy regimes). Six month progression-free survival rate was 45.8%, and median progression-free survival was 4.5 months. Puzzlingly, the 31 patients (median age 56) who received the treatment as a second-line chemotherapy were reported to have a lesser six month progression-free survival rate (17.1%) as compared with the third-line patients. Median age was somewhat younger in the third-line patients (50 years versus 56).


  1. Fotemustine: A third-generation nitrosourea for the treatment of recurrent malignant gliomas. Beauchesne, 2012.

  2. Bevacizumab for the treatment of glioblastoma. Gil-Gil et al. 2013.

  3. A multi-institutional phase II study on second-line Fotemustine chemotherapy in recurrent glioblastoma. Fabrini et al. 2009.

  4. A new schedule of fotemustine in temozolomide-pretreated patients with relapsing glioblastoma. Addeo et al. 2011.

  5. Fotemustine as second-line treatment for recurrent or progressive glioblastoma after concomitant and/or adjuvant temozolomide: a phase II trial of Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). Brandes et al. 2009.

  6. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. Friedman et al. 2009.

  7. Bevacizumab and fotemustine for recurrent glioblastoma: a phase II study of AINO (Italian Association of Neuro-Oncology). Soffietti et al. 2013.
    READ SOURCE DOCUMENT (abstract only)

  8. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. Vredenburgh et al. 2007.

  9. Salvage chemotherapy with procarbazine and fotemustine combination in the treatment of temozolomide treated recurrent glioblastoma patients. Silvani et al. 2008.

  10. Long-term outcome in patients with recurrent malignant glioma treated with perillyl alcohol inhalation. da Fonseca et al. 2013.
    READ SOURCE DOCUMENT (abstract only)

  11. Perillyl alcohol for the treatment of temozolomide-resistant gliomas. Cho et al. 2012.

  12. Photodynamic therapy of high grade glioma - long term survival. Stylli et al. 2005.

  13. Deferred use of bevacizumab for recurrent glioblastoma is not associated with diminished efficacy. Piccioni et al. 2014.
    READ ABSTRACT Email me for a PDF copy

  14. Survival outcome of early versus delayed bevacizumab treatment in patients with recurrent glioblastoma. Hamza et al. 2014.
    READ ABSTRACT Email me for a PDF copy

  15. Continuous low-dose temozolomide and celecoxib in recurrent glioblastoma. Stockhammer et al. 2010.
    READ ABSTRACT Email me for a PDF copy

  16. 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. Taal et al. 2014.
    READ ABSTRACT Email me for a PDF copy

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