The Standard of Care for the initial treatment of Glioblastoma Multiforme

Here we are at the second episode of the translation project of Ben Williams’ guide on treatment options for glioblastoma multiforme. This is Chapter 1 of the guide which includes the description of the standard of care for Glioblastoma, for Anaplastic Astrocytoma with some thoughts on the evaluation of the efficacy of chemotherapy, on the methylation factor MGMT and on Dexamethasone. Enjoy the reading!

The standard of care for initial treatment
Glioblastoma

Although chemotherapy has a long history of ineffectiveness as a treatment for glioblastoma, a large European-Canadian randomized clinical trial (EORTC study 26981/22981) showed clear benefits of adding the new chemotherapy agent, temozolomide (trade name Temodar in the US , Temodal elsewhere in the world) to radiation treatment alone (2). This treatment, followed by 6 or more monthly courses of temozolomide, became known as the “Stupp protocol”, named after Roger Stupp, the Swiss oncologist who led the trial. In this study, one group of patients received radiation only; the other group received radiation plus Temodar, first at low daily doses during the six weeks of radiation, followed by the standard higher dose Temodar schedule for days 1-5 on each 28-day cycle. Median survival was 14.6 months, compared with a median survival of 12 months for patients who received radiation alone, a statistically significant difference. More striking was the difference in the two-year survival rate, which was 27% for patients receiving temodar but 10% for those receiving radiation only. Long-term follow-up indicated that the temozolomide (TMZ) benefit persists for at least five years: the difference in survival rates between the two treatment conditions was 16.4% versus 4.4% after three years, 12.1% versus 3.0% after four years and 9.8% versus 1.9% after five years (3). As a result of these findings, this protocol has become the “standard of care”. Note, however, that all of these numbers are somewhat inflated as patients over the age of 70 were excluded from the study.

In July 2016, the National Comprehensive Cancer Network (NCCN) recommended the Optune device as a category 2A treatment for newly diagnosed glioblastoma in combination with standard temozolomide-based chemotherapy. This assessment indicates a uniform consensus by the NCCN on the adequacy of this treatment. As the NCCN is recognized for setting standards for cancer treatment in the United States and other countries around the world following its guidelines, the Optune device in combination with chemotherapy and radiotherapy can now be considered a new standard of care for newly diagnosed glioblastoma. For more information on the Optune device, refer to Chapter 3.

Anaplastic astrocytoma

Although the “Stupp protocol” (concomitant radiotherapy and temozolomide chemotherapy) followed by monthly temozolomide courses has been routinely applied to patients with anaplastic astrocytoma, prospective confirmation of this use in this patient population is awaiting the results of the randomized study ” CATNON “phase 3 for grade 3 gliomas no co-deleted 1p / 19q ie without concomitant deletion of chromosomes 1p and 19q. Interim analysis results for this study were first published for the 2016 ASCO Annual Meeting. Between 2007 and 2015, 748 patients were randomly selected to receive i) radiation only, ii) radiation with concomitant temozolomide, iii) radiation followed by 12 monthly adjuvant cycles of temozolomide, or iv) radiation with temozolomide both concurrently and with monthly follow-up cycles. There is currently a significant progression-free and overall survival benefit with adjuvant temozolomide treatment (arms iii and iv). Median progression-free survival was 19 months in arms i and ii (not receiving adjuvant temozolomide) compared with 42.8 months in arms iii and iv (receiving adjuvant temozolomide). The 5-year survival rate was 44.1% and 55.9% in arms i and ii and iii and iv respectively. Median survival has not yet been calculated for arms iii and iv. This analysis did not address the benefit of temozolomide in conjunction with radiation, a question that will be answered with further follow-up and studies to evaluate the impact of the IDH1 mutation and MGMT methylation are still ongoing.

Determine who will benefit from it

A two-year survival rate of less than 30% obviously cannot be considered an effective treatment, as the vast majority of patients receiving the treatment achieve less benefit at best, accompanied by significant side effects (although Temodar is much better tolerated compared to previous chemotherapy, especially compared to cumulative toxicity to the bone marrow). This raises the question of how to determine who will benefit from the treatment and, more importantly, how to improve treatment results.

One approach to determining whether a single patient will benefit from chemotherapy is to simply try 1-2 cycles to see if there is any regression of the tumor. The debilitating effects of chemotherapy typically occur in subsequent courses, at which point a cumulative drop in blood counts occurs. The extreme nausea and vomiting associated with chemotherapy in the minds of the lay public is now almost completely preventable by anti-nausea agents, including Zofran (ondansetron), Kytril (granisetron) and Emend (aprepitant). Marijuana can also be very effective in controlling these effects, and recent research has suggested that it also has anti-cancer properties. Therefore, for those patients who are well and strong after surgery and radiation, a certain amount of chemotherapy experimentation should be possible without great difficulty.

An alternative way to ascertain the effectiveness of chemotherapy for a single patient is the use of chemosensitivity tests for the various drugs that are available as treatment. These tests typically require a live sample of the tumor and therefore must be planned before surgery. Growing live cells is often problematic, but a number of private companies across the country (US) offer this service. Costs range from $ 1000 to $ 2500, depending on the scope of the drugs tested. Such a test is controversial, in part because the cell population evolves during the culture process, which results in cells possibly differing substantially from the original tumor sample. However, recent evidence has shown that chemosensitivity tests can improve treatment efficacy for a variety of different types of cancer, including a recent Japanese study that used chemosensitivity tests with glioblastoma patients (4). However, this study did not involve cell culture but direct chemosensitivity tests for the cells collected at the time of surgery. In general, when chemosensitivity tests indicate that an agent has no effect on a patient’s tumor, the drug is unlikely to have any clinical benefit. On the other hand, if the tests that indicate that a tumor culture is sensitive to a particular agent, its clinical efficacy is not guaranteed, but the chances that the agent have benefits are increased.

The role of MGMT

Significant progress in determining which patients will benefit from Temodar was reported by the same research group that reported the results of the definitive study combining Temodar with radiation. Tumor samples from patients in that study were tested for the level of activation of a specific gene involved in resistance to alkylating chemotherapy (which includes temozolomide and nitrosoureas, BCNU, CCNU, and ACNU). Specifically, there is an enzyme produced by the MGMT gene that allows damaged cancer cells to repair themselves, with the result that chemotherapy is less effective.

Patients whose tumors have an inactivated MGMT gene through gene promoter methylation (35-45% of patients) are significantly more likely to respond to Temodar than those for whom the gene is still functional (5). For patients receiving both radiation and temozolomide, those with methylated MGMT had a two-year survival rate of 46%, compared with 14% of those with unmethylated MGMT. This implies that patients should have the tumor tissue removed at the time of surgery so that they can be tested for the methylation status of the MGMT gene.

The use of genetic markers to predict treatment outcome is an important advance, but so far it has not been routinely incorporated into clinical practice. There is considerable controversy over the predictive validity of the MGMT marker, since several studies have failed to demonstrate a relationship between this marker and clinical outcome. This appears to be mainly due to different measurement procedures. A recent paper (6) compared the degree of expression of the MGMT protein using commercial anti-MGMT antibodies and an assessment of the methylation status of the MGMT gene promoter region. The two measures correlated only weakly, and only the extent of gene promoter methylation strongly correlated with survival time. New methods have recently been introduced to assess methylation (7) which could resolve the controversy.

The predictive validity of the methylation status of the MGMT gene promoter is an important issue to address because temozolomide appears to produce a small improvement in survival for those whose MGMT gene is active (i.e. the MGMT gene promoter is not methylated). Therefore, patients with unmethylated MGMT may be better served using a different chemotherapeutic agent. For example, a bifunctional alkynant agent known as VAL-083 or dianhydrogalactitol is currently being tested in phase 2 and 3 studies for recurrent glioblastoma. It damages DNA in a way that is not subject to repair by the MGMT enzyme and could therefore be more beneficial for patients with unmethylated MGMT status. Find more details on VAL-083 in Chapter 13.

In addition to changing the chemotherapy agent, there are other possible strategies for patients with unmethylated promoter of the MGMT gene. One is about the Temodar program. An alternative to the standard 5 in 28 day scheme is a low-dose daily program. Previous studies using metronomic schemes have not found any effect of MGMT status on clinical outcome. The question of the best program for Temodar will be discussed in a later section of Chapter 2. The second strategy is to use drugs that can inhibit MGMT expression (in preclinical studies). Two of these drugs are Antabuse (disulfiram) and Keppra (levetiracetam) (10, 206), discussed in Chapter 6.

Dexamethasone

Most patients with glioma will be given dexamethasone (Decadron) sooner or later, as this corticosteroid is the first-line treatment to control brain edema caused by bleeding tumor blood vessels. Many patients will use dexamethasone during radiotherapy, and possibly beyond this period if a substantial portion of the tumor remains after resection. Dexamethasone is an analogue of cortisol in our body, but it is about 25 times more potent. Although often needed, dexamethasone comes with a long list of potential negative side effects for prolonged use, including muscle weakness, bone loss, steroid-induced diabetes, immunosuppression, weight gain and psychological effects.

New evidence also shows an association between the use of dexamethasone and the reduced survival time in glioblastoma. This evidence must be weighed against the fact that uncontrolled brain edema can be fatal in itself and that dexamethasone is often necessary for its control. However, you should always try to use dexamethasone at the lowest effective dose and reduce its use after obtaining control of edema, under the guidance of a doctor.

In a retrospective study of 622 patients with glioblastoma treated at the Memorial Sloan Kettering Cancer Center, multivariate regression analysis showed an independent negative association of steroid use at the start of radiotherapy with survival (324). A similar negative association with the same survival outcomes was found in patients in the phase 3 study that led to the approval of temozolomide for glioblastoma in 2005 and for a cohort of 832 patients with glioblastoma enrolled in the German Glioma Network.

Follow-up studies in mice helped clarify these retrospective clinical observations. In a genetically modified PDGFB-driven glioblastoma model, dexamethasone alone had no effect on survival, but pretreatment with dexamethasone for 3 days prior to a single 10 Gy radiation dose negatively impacted radiation efficacy. This negative impact of dexamethasone on radiation efficacy was even more dramatic with multiple doses of dexamethasone administered before 5 2 Gy radiation treatments, which more closely mimic what GBM patients are exposed to. In contrast, an antibody against VEGF, which could be considered a surrogate for Avastin, did not interfere with the effectiveness of the radiation.

In vivo mechanistic examination revealed that dexamethasone can interfere with radiation bringing more cells into the more radioresistant G1 phase of the cell cycle and fewer cells in the more radiosensitive G2 / M phase. This discovery has far-reaching implications on the potential interference of drugs with cytostatic mechanisms of action on the efficacy of radiotherapy. The authors conclude by suggesting that antibodies to VEGF, particularly bevacizumab (Avastin), could be used as an alternative anti-edema drug during radiation instead of steroids. However, this use must be weighed against the potential for exclusion from some promising clinical trials as having used Avastin is often an exclusion criterion.

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(2) Stupp, R., et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England J. Med, 2005, 352 (22), 987-996.
(3) Stupp, R., Hegi, M.D., et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol., 2009, May; 10(5): 459-66.
(4) Iwadate, Y. et al. Promising survival for patients with glioblastoma multiforme treated with individualized chemotherapy based on in vitro drug sensitivity testing. British Journal of Cancer, 2003, Vol. 89, 1896-1900.
(5) Hegi, M.E, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. New England J. of Med, 2005, 352(10), 997-1003.
(6) Preusser, M. et al. Anti-06-methylguanine –methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: Observer variability and lack of association with patient survival impede its use as a clinical biomarker. Brain Pathol. 2008, 18 (4) 520-32.
(7) Vlassenbroeck, I. et al. Validation of real-time methylation-specific PCR todetermine 06-Methylguanine-DNA methylation-specific PCR to determine 06-methylguanine-DNA methyltransferase gene promoter methylation in glioma. Journal of Mol. Diagn. 2008, 10 (4) 332-37.
(10) Kast, R.E., Boockvar, J. A., Bruening, A., et al. A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care. Oncotarget, 2013, 4(4), 502-530.
(206) Bobustuc, G. C., Baker, C. H. Limaye,A., et al. Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide. Neuro-oncology, 2010, 12(9), 917-27.
(324) Pitter, Kenneth L et al. “Corticosteroids compromise survival in glioblastoma.” Brain (2016): aww046.

Good! I hope you enjoyed reading, I have been as faithful as possible. A new chapter very soon!