Selected Trial Results for Newly Diagnosed Anaplastic Glioma

by Stephen Western
Astrocytoma Options.com

There is currently no well-established protocol for treating recurrent malignant gliomas, though many clinical trials have been carried out for this patient population, testing a wide variety of drugs and other therapies. Anaplastic gliomas are often treated together with glioblastomas in clinical trials. I have scoured the published literature for malignant glioma trials, with a focus on separating out the results for anaplastic gliomas (WHO grade III) which are far less studied than glioblastomas due to their relative rarity.

Since the 2008 discovery of the IDH1 mutation in the majority of grade II and III gliomas, it has become apparent that two different disease entities make up what has hitherto been considered a single disease. On a molecular and genetic level, anaplastic gliomas may be divided into two categories: those with mutations in IDH1 or IDH2, and those without. Those without IDH mutations are usually genetically similar to glioblastomas, and may belong to a new category: grade III glioblastoma, or "pre-glioblastoma".

This situation renders all previous trials for anaplastic gliomas difficult to interpret, since they include both IDH-mutant and IDH wild-type in unknown proportions. It is likely that IDH wild-type "pre-glioblastoma" tumours would respond to treatments in a similar manner to primary glioblastoma, and glioblastoma trial outcomes may reasonably be applied to this subgroup.

This page will include any future trial that stratifies patients and outcomes on the basis of IDH mutations. Young age and frontal lobe location are both factors which indicate a higher likelihood of carrying the IDH1 mutation. Unfortunately, very few published trial results include individual patient details. Future trials will surely see more inclusion of molecular data, including IDH mutations and 1p/19q codeletion. Until then, the most appropriate treatment for anaplastic glioma remains hazy and undefined.

Therapies requiring repeat surgery

Photodynamic Therapy

This retrospective study (13), which included 29 recurrent anaplastic astrocytoma patients treated in Australia with photodynamic therapy, showed the best survival outcome of any study I've seen for this patient subset. The median survival from second surgery and photodyamic therapy was 66.6 months for the AA patients, which far exceeds the median survival results obtained with any other therapy. This therapy was limited to those with resectable tumours at the brain surface, which likely contributed to the positive outcome. More details of photodynamic therapy can be found on the Photodynamic Therapy page and in Currently Recruiting Trials pages.

It remains unclear to what extent this positive outcome is related to successful surgery versus the subsequent photodynamic treatment. Other trial outcomes which include only patients undergoing repeat surgery may shed some light on this. In a Belgian retrospective study, 39 grade III glioma patients were treated with a tumour lysate-pulsed dendritic cell vaccine (14). 18 anaplastic astrocytoma patients had a median age of 30 years, 50% joined the trial at first recurrence, all had surgical tumour resection to obtain tissue to create the vaccine, and 61% had a complete tumour resection. While median progression-free survival for this cohort was an unimpressive 4.6 months, median survival from the time of vaccine therapy was 20.5 months. This outcome indicates that the exceptional results of the Australian photodynamic study (above) was due to more than simply successful surgery, and indicates an additional benefit to photodynamic treatment.

Reading between the lines: young age and frontal lobe location as a surrogate for IDH1 mutation

From 1999 to 2008, neuro-oncologist Marc Chamberlain (currently at the University of Washington) and co-authors published a series of small trials of various drugs for recurrent anaplastic astrocytomas. The drugs under study were paclitaxel (1999), tamoxifen (1999), cyclophosphamide (2005), irinotecan (2008) and bevacizumab (2008). Three of these studies (paclitaxel, tamoxifen, bevacizumab) are unique in that they tabulate results for each individual patient. The paclitaxel and tamoxifen trials (many of the patients in the paclitaxel trial switched to the tamoxifen trial at recurrence) were limited to patients under the age of 50, so their positive results cannot be fairly compared to trials for patients of all ages. Nevertheless, the tamoxifen trial proved that the drug can be effective for younger patients. Though the discovery of the IDH1 mutation in glioma was still 10 years away at the time of the tamoxifen and paclitaxel studies (1999), the fact that individual patient details were reported allows us to make inferences about the efficacy of these treatments for IDH-mutant tumours if we look at results for patients under age 40 with frontal lobe tumours. This patient subgroup has the highest likelihood of carrying the IDH1 mutation. Unfortunately, the small numbers of patients involved limits the certainty of this approach.

In the tamoxifen trial (1), tamoxifen was administered following failure of various second-line chemotherapies, including paclitaxel. The 24 patients in this trial were aged 19 to 45. 58% were progression-free at six months and median progression-free survival in this study was 12 months. As the results for each individual patient in this trial were reported, we can analyze the various sub-groups separately.

There were 9 patients in this trial under age 40 with a frontal lobe tumour. As mentioned above, this subgroup has the highest likelihood of having an IDH1 mutation. In this group of nine, age ranged from 25 to 36 (median 28). All had initially undergone a subtotal resection. Seven had received first-line PCV and the remaining two received first-line BCNU (carmustine). Five had also failed one prior salvage chemotherapy regimen (either etoposide, paclitaxel, or procarbazine) and four had failed two prior salvage chemo regimens (paclitaxel and either procarbazine or etoposide). Therefore these patients were heavily pretreated at the time of initiation of tamoxifen. A median of four (range one to eight) cycles of tamoxifen were given.

Six of these nine patients (67%) had disease stabilization with the tamoxifen therapy, and two (22%) had partial response (tumour shrinkage) for a total response plus stabilization rate of 8/9 or 89%. Median progression-free survival was 12 months (range 0 to 24 months). While the survival after progression post-tamoxifen in this trial was short, this may reflect the fact that most other available options had already been tried, and neither temozolomide nor bevacizumab were available at that time.

In the companion trial (2) of paclitaxel (Taxol), nine patients under age 40 with frontal lobe tumours had a similar outcome, with 8 of 9 (89%) having a stabilization or partial response to the paclitaxel treatment. However, median progression-free survival was shorter with paclitaxel than with tamoxifen (8 versus 12 months), despite the fact that patients in the paclitaxel trial were less heavily pre-treated.

In the trial of bevacizumab (Avastin) for recurrent anaplastic glioma (3):

• Patient one was 26 years old with a left frontal lobe astrocytoma and underwent subtotal resection initially. Prior chemo consisted of six cycles of TMZ with a partial response, and 3 cycles of PCV with stable disease. Six cycles of bevacizumab (BEV) were administered with stable disease lasting for 3 months.



• Patient 3 was 29 years old with a right frontal astrocytoma and underwent gross total resection initially. Prior chemo consisted of 6 cycles of TMZ with stable disease, and 6 cycles of PCV with stable disease, along with a repeat sub-total resection. 22 cycles of BEV were given leading to a partial response lasting 11 months.



• Patient 5 was 35 years old with a bi-frontal astrocytoma and underwent biopsy only. Prior chemo consisted of 12 cycles of TMZ with a partial response, and 3 cycles of PCV with a partial response. 14 cycles of BEV were given leading to a partial response lasting 7 months.



• Patient 6 was 38 years old with a right frontal tumour and underwent a gross total resection. Prior chemo consisted of Gliadel wafers (BCNU) with stable disease, and 12 cycles of TMZ with stable disease. 2 cycles of BEV were given without any benefit (progressive disease).

Median progression-free survival with bevacizumab was 5 months for these four patients (1, 3, 7, and 11 months). Four patients is far too small a cohort to draw firm conclusions however, and the true value of bevacizumab for lower grade and IDH-mutant glioma remains to be determined. This agent alone or in combination with irinotecan for anaplastic glioma is further discussed below.

Re-challenge with temozolomide

Temozolomide is the current standard of care chemotherapeutic agent for newly diagnosed glioma patients, and many oncologists will recommend its use again (re-challenging) in the case of tumour recurrence. Prospective trials have tested this re-use of TMZ at the time of recurrence. The RESCUE study (7) tested metronomic (daily) TMZ at the moderate dose of 50 mg per square meter of body surface. 29 anaplastic glioma patients were included (median age 43). The report did not break down the anaplastic glioma group into subcategories (astrocytoma vs oligodendroglioma), nor was median survival reported. More importantly, this trial was initiated before the discovery of IDH1 mutations in glioma, and so no IDH1 analysis was possible.

A more recent trial (16) of the 7-day on, 7-day off TMZ schedule at 150 mg per meter square body surface was published online in Neuro-Oncology (March 2014). 20 anaplastic glioma patients were included, all of whom had received prior first-line TMZ. As with the RESCUE trial (see above), outcomes were reported for anaplastic glioma as a group, without separate results for astrocytoma versus oligodendroglioma. This trial also was unable to include IDH information as the trial was initiated before IDH testing became routine at UCSF.

As no trial of TMZ for recurrent anaplastic glioma has yet been able to include IDH testing in their analysis, the decision-making value of these studies for IDH-mutant glioma patients are limited. Survival results in any trial for anaplastic astrocytoma and oligodendroglioma or oligoastrocytoma, are likely largely dependent on the proportion of IDH-mutant to IDH-wild type patients included in the trial.

In highly pretreated patients (third-line or higher chemotherapy)

Bevacizumab (Avastin)

Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), functioning as an inhibitor of angiogenesis. It received FDA approval for gliomas in May 2009. Due to its stabilizing effect on the blood-brain barrier, bevacizumab may result in an apparent response on MRI imaging which does not necessarily correspond to the actual degree of tumour inhibition. Therefore conventionally assessed progression-free survival may not be a trustworthy endpoint for anti-angiogenic agents such as bevacizumab. In recent phase III trials (8), bevacizumab increased the progression-free period of patients, but did not have significant effect on overall survival when used as a first-line therapy.

There is evidence that this drug increases the invasive behaviour of treated tumours and that it is more effective in older patients (9, 3). Finally, as lower grade astrocytomas typically have far less microvascular proliferation with lower levels of VEGF, the use of bevacizumab in grade II and III glioma, and for IDH-mutant glioma, must be clarified by further trials.

References

1. Salvage chemotherapy with tamoxifen for recurrent anaplastic astrocytomas. Chamberlain et al. 1999.
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2. Salvage chemotherapy with taxol for recurrent anaplastic astrocytomas. Chamberlain et al. 1999.
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3. Salvage chemotherapy with bevacizumab for recurrent alkylator-refractory anaplastic astrocytoma. Chamberlain et al. 2009.
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4. Procarbazine and high-dose tamoxifen as a second-line regimen in recurrent high-grade gliomas: a phase II study. Brandes et al. 1999.
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5. High-dose tamoxifen treatment increases the incidence of multifocal tumor recurrences in glioblastoma patients. Puchner et al. 2004.
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6. Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group. Yung et al. 1999.
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7. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. Perry et al. 2010.
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8. Roche announces final phase III study results of Avastin plus radiotherapy and chemotherapy in people with an aggressive form of brain cancer. Media Release. June 2013.
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9. Age-specific signatures of glioblastoma at the genomic, genetic, and epigenetic levels. Bozdag et al. 2013.
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10. A phase II trial of single-agent bevacizumab in patients with recurrent anaplastic glioma. Kreisl et al. 2011.
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11. Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas. Desjardins et al. 2008.
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12. Long-term outcome in patients with recurrent malignant glioma treated with perillyl alcohol inhalation. Da Fonseca et al. 2013.
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13. Photodynamic therapy of high grade glioma - long term survival. Stylli et al. 2005.
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14. Resection and Immunotherapy for Recurrent Grade III Glioma. Elens et al. 2012.
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15. Treatment of recurrent malignant gliomas with chronic oral high-dose tamoxifen. Couldwell et al. 1996.
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16. Phase II Trial of 7days on/7 days off temozolmide for recurrent high-grade glioma. Han et al. 2014.
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This page was created on 04/14/2014 and last updated on 04/21/2019