The Standard of Care

This site is not meant to be exhaustive. My focus has been on researching non-prescription supplements, prescription drugs, chemotherapies and the biology and behaviour of astrocytomas. The details of surgery and radiation therapy have not been a primary focus. However, I have a few things to say about these.

Surgery

By the time you find this site, you’ll probably have already received a diagnosis, and may have already undergone surgery, as this is usually scheduled soon after tumour discovery.

Nobody relishes the thought of having their skull opened up, but however unpleasant, surgery is likely for the best. Surgical resection of the tumour mass is a quick way to reduce the tumour down to the most manageable size without systemic toxicity (as happens with chemotherapy). The smaller the residual tumour, the more effective further therapies will be. Even the most successful surgery, termed a Gross Total Resection (no visible tumour on an MRI scan), leaves behind residual tumour cells so that some form of further therapy will be necessary.

When attempting to judge the success of a surgery, the volume of residual tumour is likely more important than the percentage of tumour removed. The absolute amount left behind is what matters [1].

Dexamethasone

Dexamethasone (Decadron) is a potent synthetic glucocorticoid (a form of steroid) commonly used to reduce peritumoral edema (swelling). It is fast-acting, bringing down brain swelling and cranial pressure within hours. However it has many adverse side-effects. One side effect which occurs in up to 72% of primary brain tumour patients given dexamethasone is hyperglycemia, a known negative risk factor for malignant gliomas [3].

The six paragraphs below were written for the 2016 edition of Treatment Options for Glioblastoma and Other Gliomas, published annually on the VirtualTrials.com website.

Most glioma patients will be exposed to dexamethasone (Decadron) at some point, as this corticosteroid is the first-line treatment to control cerebral edema caused by the leaky tumor blood vessels. Many also require dexamethasone during radiotherapy, and perhaps beyond this time if substantial tumor remains post-resection. Dexamethasone is an analog to the body’s own cortisol, but is about 25 times more potent. Though often necessary, dexamethasone comes with a long list of adverse potential side effects with prolonged use, including muscle weakness, bone loss, steroid-induced diabetes, immunosuppression, weight gain, and psychological effects [2].

New evidence also shows an association between dexamethasone use and reduced survival time in glioblastoma. This evidence has to be weighed against the fact that uncontrolled cerebral edema can be fatal in itself, and that dexamethasone is often required for its control. However, the attempt should always be made to use dexamethasone at the lowest effective dose, and to taper its use after control of edema is achieved, under a physician’s guidance.

In a retrospective study of 622 glioblastoma patients treated at Memorial Sloan Kettering Cancer Center, multivariate regression analysis showed an independent negative association of steroid use at the start of radiotherapy with survival [20]. A similar negative association with survival outcomes was found in patients in the pivotal phase 3 trial that led to temozolomide being approved for glioblastoma in 2005, and for a cohort of 832 glioblastoma patients enrolled in the German Glioma Network.

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

In vivo mechanistic examination revealed that dexamethasone may interfere with radiation by slowing proliferation, leading to a higher number of cells in the more radioresistant G1 phase of the cell cycle, and fewer cells in the more radiosensitive G2/M phase. This finding has far-reaching implications about the potential interference by drugs with cytostatic mechanisms of action on the efficacy of radiation therapy.

The authors conclude by suggesting that antibodies against VEGF, most notably bevacizumab (Avastin), could be used as an alternative anti-edema drug during radiation in place of steroids. However, this use has to be weighed in importance against the exclusion from certain promising clinical trials due to prior use of Avastin being an exclusion criteria in some of these trials.

Radiation Therapy

Following surgery, you’ll be given about one to two months to heal, at which time your oncologist will likely want you to proceed with six weeks of focal radiation therapy if your tumour is classed as a grade III or IV. In cases of grade II gliomas with positive prognostic features, radiation therapy is usually reserved for later recurrences, as trials have not shown a definite survival benefit to early versus delayed radiotherapy in these cases.

In principle, radiation to the brain can lead to neurological defects and even to new malignancy within a timeframe of up to ten years [6]. A fortunate percentage of grade III astrocytomas will still be alive at the ten year mark, along with a larger percentage of grade II patients. Therefore, the long-term effects of radiation therapy should be taken into consideration.

A randomized prospective clinical trial whose outcome was published in 1978 [7] showed that whole-brain radiation (the previous standard form of radiation for brain tumours but no longer used) extended survival compared to no-radiation in a patient population consisting mainly of glioblastoma patients.

Radiation alone versus chemotherapy alone: the NOA-04 trial

In a German phase III trial (NOA-04), anaplastic glioma patients (grade III) were treated either with radiotherapy or with chemotherapy (either PCV or temozolomide) [8]. A recent study [13] re-classified patients in this trial according to molecular attributes (IDH and ATRX mutations, and 1p/19q chromosome co-deletion) rather than by conventional histological grouping. “Molecular” anaplastic astrocytomas were IDH-mutated and without 1p/19q co-deletion. Anaplastic oligoastrocytomas with IDH- and ATRX mutations, without 1p/19q co-deletion were also classed as “molecular astrocytoma”. “Molecular” anaplastic astrocytoma patients who received initial radiotherapy alone had a trend toward improved progression-free survival compared with chemotherapy alone (50.6 versus 25.1 months). The molecular oligodendroglioma and glioblastoma classes had similar outcomes with radio- versus chemotherapy. In short, for the specific molecular subgroup of IDH-mutant anaplastic astrocytoma without 1p/19q co-deletion, radiotherapy may be the more effective treatment as compared with chemotherapy alone.

The CATNON phase 3 trial for anaplastic astrocytoma

This section was written for the 2016 edition of Treatment Options for Glioblastoma and Other Gliomas, published annually on the VirtualTrials.com website.

Though the “Stupp protocol” of combined temoradiation (concomitant radiation and temozolomide chemotherapy) followed by monthly cycles of temozolomide has been routinely applied to anaplastic astrocytoma patients, prospective confirmation of this use in this patient population has awaited results of the “CATNON” randomized phase 3 trial for 1p/19q non-codeleted grade 3 gliomas. Results of the interim analysis for this trial were first released for the ASCO 2016 annual meeting. Between 2007 and 2015, 748 patients were randomized to receive either i) radiation alone, ii) radiation with concomitant temozolomide, iii) radiation followed by 12 adjuvant monthly cycles of temozolomide, or iv) radiation with temozolomide both concurrently and with follow-up monthly cycles. At the time of the interim analysis (October 2015), significant progression-free and overall survival benefit was found with adjuvant temozolomide treatment (arms iii and iv). Median progression-free survival was 19 months in arms i and ii (not receiving adjuvant temozolomide) versus 42.8 months (receiving adjuvant temozolomide). 5-year survival rate was 44.1% and 55.9% in arms i and ii versus iii and iv. Median survival was not yet reached for arms iii and iv.

This analysis did not address the benefit of temozolomide concurrent with radiation, a question that will be answered with further follow-up, and studies assessing the impact of IDH1 mutation and MGMT methylation were still ongoing.

Temozolomide (Temodar)

Prior brain tumour chemotherapy regimens consisted mainly of intravenous BCNU (carmustine), or PCV, a combination of oral procarbazine, oral CCNU (lomustine) and intravenous vincristine. Temozolomide (Temodar) is an improvement over these regimens by having nearly 100% bioavailability after oral ingestion, as well as readily crossing the blood-brain barrier. Temozolomide (TMZ) is a DNA alkylating agent, which inserts a methyl group on guanine, leading to mismatch during DNA replication. This triggers a futile cycle of DNA mismatch repair and ultimately to cell cycle arrest, senescence and/or apoptosis (programmed cell death).

Frequent toxicity during daily schedules includes plummeting lymphocyte counts [11], while the five-day schedule has a greater impact on platelet counts (see the Supplements section for the use of melatonin to boost platelet counts). Loss of hair is not common on this drug, and nausea is effectively treated with ondansetron, though anti-nausea medications in this class (serotonin receptor antagonists) may have other side-effects, such as constipation.

Temozolomide for low grade gliomas – the EORTC 22033-26033 trial

Soon after the publication of the pivotal phase 3 trial that led to the approval of temozolomide for newly diagnosed glioblastoma in 2005, a phase 3 trial was initiated to test radiation alone versus dose-dense temozolomide alone for low grade glioma patients requiring therapy beyond surgery alone. This trial is called EORTC 22033-26033 (NCT00182819).

Preliminary results were publicized in conjunction with the 2015 ASCO meeting. In contrast with earlier trials for low grade glioma, such as RTOG 9802, which classified patients according to histological diagnosis (astrocytoma, oligodendroglioma, oligoastrocytoma), this trial classifies patients according to molecular diagnostics, namely IDH mutation status and 1p/19q status. This is a significant advance forward, as molecular diagnostics has been found superior to histological diagnosis in predicting therapeutic response and survival.

Temozolomide was given in a dose-dense schedule of 75 mg/m2 daily for 21 days in a 28 day cycle, for up to 12 cycles. For the IDH1-mutated, 1p/19q codeleted group (molecular oligodendroglioma), progression-free survival was not significantly different between the radiation and temozolomide arms (p=0.913). For the IDH1-mutated, 1p/19q intact group (molecular astrocytoma), radiation was significantly more effective than temozolomide in prolonging progression-free survival (p=0.004). For the IDH non-mutated group (molecular glioblastoma), median progression-free survival was slightly longer in the temozolomide arm, though this did not reach statistical significance (p=0.244). These results confirm the results of the NOA-04 trial for grade 3 anaplastic gliomas, in which radiation was superior for the molecular astrocytoma subgroup, while the efficacy of radiation and temozolomide were approximately equal in the molecular oligodendroglioma and molecular glioblastoma groups. The question of which treatment is superior for the molecular glioblastoma (IDH non-mutant) group likely depends on MGMT status, as is the case for grade 4 glioblastoma.

Temozolomide for low grade gliomas – UCSF phase 2 trial

In August 2016, a phase 2 trial of standard schedule temozolomide, 5 days out of a 28 day cycle for up to 12 cycles, was published by UCSF investigators in Neuro-Oncology [21]. “All patients were required to have undergone either subtotal surgical resection or biopsy within 4 months prior to enrollment, with evaluable residual disease on postoperative MRI.” The patients were subdivided into groups based on histology and molecular diagnostics. The summary of the data here will focus on the molecular subgroups: 1p/19q codeleted (molecular oligodendroglioma, n=44), IDH-mutant but 1p/19q intact (molecular astrocytoma, n=37), and IDH1 non-mutant (n=16).

Median progression-free survival was 4.9 years for the 1p/19q codeleted group, 3.6 years for the IDH-mutant (1p/19q intact) group, and 0.6 years for the IDH non-mutant group (which other studies have termed “molecular glioblastoma”). There were no complete responses, and partial responses were seen in 11% of the 1p/19q codeleted group, 3% of the IDH-mutant (and 1p/19q intact) group, and no responses were observed in the IDH non-mutant group. None of the 1p/19q codeleted patients had disease progression while on treatment, and only 8% of the IDH-mutant (and 1p/19q intact) had disease progression while on treatment. In contrast, 56% of the IDH non-mutant patients progressed while on treatment. By inference, disease stabilization as best response was seen in 89% of the codeleted group, 89% of the IDH-mut (but 1p/19q intact) group, and 44% of the IDH non-mutant group.

This was a single arm trial testing temozolomide. As mentioned above, head-to-head comparisons in trials for both grade 2 and 3 gliomas shows radiation alone to be superior to temozolomide alone in prolonging progression-free survival in molecular astrocytomas (IDH-mutant, 1p/19q intact), with more equal activity between radiation and temozolomide for molecular oligoastrocytomas. Unfortunately, this study did not address how many patients in this trial developed hypermutated recurrence. That question will likely be addressed in future publications (see below for discussion of hypermutation).

Risk Factors

Myelodysplastic syndromes (which can progress to leukemia) are a risk factor with prolonged use of alkylating agents such as temozolomide [12], though the incidence rates are low.

A recent study at UCSF [15] examined tumour samples of ten grade 2 astrocytoma patients (all IDH1-mutant) who had been treated with the standard high dose temozolomide schedule (5 days on, 23 days off), mostly without prior radiotherapy. Disturbingly, 6 of these 10 patients were found to have developed TMZ-induced hypermutation, with thousands of new mutations in evidence which were not seen prior to TMZ therapy. These new mutations included mutations in genes involved in the PI3K/Akt/mTOR pathway and the RB (tumour suppressor) pathway, mutations which drive evolution to secondary glioblastoma. The hypermutation phenomenon has also been observed in glioblastomas treated with TMZ based radiochemotherapy, and is due to mutations in one or more mismatch repair genes, which provides tumour resistance to TMZ, but leads to TMZ-induced mutations accumulating in the absence of mismatch repair.

As the hypermutation phenomenon has been seen in some grade 2 astrocytomas and in glioblastomas following TMZ therapy, by extrapolation it is likely that it also occurs in grade 3 astrocytoma patients. The frequency of this occurrence will not be known until larger studies are completed. This new knowledge should have immediate impacts on chemotherapeutic strategies, especially for lower grade glioma.

Theoretically, the mismatch repair gene mutations which are at the root of TMZ-induced hypermutation are most likely to occur when TMZ is the main toxic pressure being applied, as mismatch repair mutations lead to TMZ resistance in the tumour cells. When other effective therapies (for example, radiation or chemotherapies which work by a different mechanism) are applied at the same time, there should be much less evolutionary fitness associated with mismatch repair mutations. If a decision is made to proceed with TMZ chemotherapy for lower grade (2 and 3) glioma patients in the post-radiation setting or in the absence of radiation, I believe the key to reducing the risk of TMZ-induced hypermutation is to apply a combination strategy, involving a simultaneous or alternating application of other cytotoxic therapies, which would reduce the evolutionary selective pressure exerted by TMZ alone. It is likely that fully resected tumors are less likely to acquire hypermutation, as there would be far fewer cells left behind, and therefore a statistically decreased risk that one of the cells left behind would have a pre-existing or newly acquired mutation in one of the mismatch repair genes, such as MSH6. It is also likely, though not yet confirmed, that hypermutation is an increased risk in gliomas with MGMT promoter methylation.

Temozolomide versus PCV

For anaplastic (grade 3) gliomas – astrocytoma, oligodendroglioma, oligoastrocytoma – only one phase 3 trial studying TMZ versus another regimen has been published, to my knowledge. This is the German NOA-04 trial, which published results in 2009. Newly diagnosed patients in this trial were randomized to receive either radiation therapy alone, or chemotherapy alone (with either TMZ or the PCV trio of drugs). There was no difference in progression-free survival (PFS) between TMZ and PCV chemotherapy for the group as a whole. A large retrospective study [19] also found no significant difference in PFS between TMZ and PCV for anaplastic astrocytomas following radiation therapy. The group receiving PCV had superior 3-year survival. There is no indication that TMZ is superior to the former PCV regimen for anaplastic glioma patients in terms of progression-free or overall survival. TMZ however, is relatively well-tolerated and convenient compared to PCV. PCV includes three different drugs, two of which (procarbazine and lomustine) are taken orally, with vincristine being administered intravenously.

Strategies for increasing the efficacy of radiation and chemotherapy

Diet

Animal studies have shown that dietary interventions may be one of the most effective ways to increase the therapeutic benefits of radiation and chemotherapy. In one of the most impressive animal studies I’ve seen [16], mice implanted with GL261 mouse glioma cells were treated with either a standard diet (control group), a ketogenic diet, a standard diet plus two 4 Gy fractions of radiation to the head, or a ketogenic diet plus two 4 Gy fractions of radiation. The ketogenic diet consisted of the KetoCal commercial formula, which is 72% fat, 15% protein and 3% carbohydrates (4:1 ratio of fats to protein plus carbohydrates). All mice were fed ad libitum (not calorically restricted).

While the ketogenic diet improved survival slightly versus the standard diet, the results in the group receiving both radiation therapy and a ketogenic diet are nothing short of spectacular. The mice receiving radiotherapy plus a standard diet were mostly (10/11) dead by day 70, with one surviving to day 150. Amazingly, 9 of 11 (82%) mice receiving a ketogenic diet plus two 4 Gy fractions of radiation to the head had a disappearance of their tumours by about day 60. At day 104 these 9 mice were switched back to a standard diet. At day 299 the mice were sacrificed for examination, still without tumor regrowth. The mice in this group had similar glucose levels and higher circulating ketone levels than mice in the standard diet group at day 13. The ketogenic diet plus radiation group also had a dip in weight at 3-6 days following treatment, but had regained this lost weight by day 15. The exact cause of this dramatic response to radiation therapy while on the ketogenic diet is a matter of speculation.

A separate study [17] used the GL26 mouse model to test “short-term starvation” (48 hour fasting) prior to exposure to radiation or prior to and after chemotherapy with temozolomide. These experiments showed increased survival in mice undergoing 48 hour fasts at the time of either irradiation or chemotherapy. In the radiation experiment, only 1/9 mice in the fasted group had died by day 31, while about 6/9 mice in the irradiated but not fasted group had died by that time. Unfortunately, data beyond this time point is not given, so we do not know if survival benefits were as dramatic as in the previous study.

These two experiments show that some sort of dietary intervention at the time of radiation and/or chemotherapy may provide great benefits. This could mean restricted diets such as the ketogenic diet, or short-term fasting, or even calorie-restriction mimetic drugs such as metformin. See the Diet page for a fuller description of these options.

References
  1. Volumetric extent of resection and residual contrast enhancement on initial surgery as predictors of outcome in adult patients with hemispheric anaplastic astrocytoma. Keles et al. 2006.
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  2. The use of dexamethasone in patients with high grade gliomas. Alberta Health Services, March 2013.
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  3. Association between hyperglycemia and survival in patients with newly diagnosed glioblastoma. Derr et al. 2009.
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  4. Boswellia serrata acts on cerebral edema in patients irradiated for brain tumors: a prospective, randomized, placebo-controlled, double-blind pilot trial. Kirste et al. 2011.
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  5. Avoiding glucocorticoid administration in a neurooncological case. Rutz et al. 2005.
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  6. Induction of glioblastoma multiforme in nonhuman primates after therapeutic doses of fractionated whole-brain radiation therapy. Lonser et al. 2002.
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  7. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. Walker et al. 1978.
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  8. NOA-04 Randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. Wick et al. 2009.
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  9. CATNON clinical trial details
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  10. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. Stupp et al. 2005.
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  11. Low peripheral lymphocyte count before focal radiotherapy plus concomitant temozolomide predicts severe lymphopenia during malignant glioma treatment. Ishikawa et al. 2010.
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  12. Temozolomide-induced myelodysplasia. Natelson et al. 2010.
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  13. ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis. Wiestler et al. 2013.
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  14. Recurrent brain cancers follow distinctive genetic paths. Farley, 2013.
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  15. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Johnson et al. 2013.
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  16. The Ketogenic Diet Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma. Abdelwahab et al. 2012.
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  17. Fasting Enhances the Response of Glioma to Chemo- and Radiotherapy. Safdie et al. 2012.
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  18. Protective properties of radio-chemoresistant glioblastoma stem cell clones are associated with metabolic adaptation to reduced glucose dependence. Ye et al. 2013.
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  19. Survival following adjuvant PCV or temozolomide for anaplastic astrocytoma. Brandes et al. 2006.
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  20. Corticosteroids compromise survival in glioblastoma. Pitter et al. 2016.
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  21. Chemotherapy for adult low-grade gliomas: clinical outcomes by molecular subtype in a phase II study of adjuvant temozolomide. Wahl et al. 2016.
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