Anticonvulsant Prophylaxis and Steroid Use in Adults with Metastatic Brain Tumors ASCO and SNO Endorsement of the Congress of Neurological Surgeons Guidelines

SUMMARY: Brain metastases are the most common intracranial tumors in adults in the United States. In patients with systemic malignancies, brain metastases occur in 10-30% of adults, with Lung, Breast, and Melanoma continuing to be the leading cause of brain metastases. The incidence of brain metastases may be on the rise due to both improved imaging techniques, as well as better control of extracerebral disease from advances in systemic therapy.

The Congress of Neurological Surgeons (CNS) developed a series of guidelines for the treatment of adult patients with metastatic brain tumors, including systemic therapy and supportive care topics. The ASCO/SNO (Society of NeuroOncology) Expert Panel determined that the recommendations from the CNS anticonvulsants and steroids guidelines, published January 9, 2019, are clear, thorough, and based on the most relevant scientific evidence. ASCO/SNO endorsed these two CNS guidelines with minor alterations. This guideline was developed by a multidisciplinary Expert Panel that included a patient representative and an ASCO guidelines staff member with health research methodology expertise.

Guideline Questions

CNS Anticonvulsant Guideline

1) Do prophylactic antiepileptic drugs decrease the risk of seizures in nonsurgical patients with brain metastases who are otherwise seizure free?

2) Do prophylactic antiepileptic drugs decrease the risk of seizures in patients with brain metastases and no prior history of seizures in the postoperative setting?

CNS Steroids Guideline

1) Do steroids improve neurologic symptoms and/or quality of life in patients with metastatic brain tumors compared with supportive care only or other treatment options?

2) If steroids are administered, what dose should be given?

Target Population

Adults with metastatic brain tumors.

Target Audience

Medical oncologists, Neurologists, and others who provide care for adults with metastatic brain tumors.

Recommendations

CNS Anticonvulsants Guideline: 

1) Prophylactic antiepileptic drugs are not recommended for routine use in patients with brain metastases who did not undergo surgical resection and who are otherwise seizure free.

2) Routine postcraniotomy antiepileptic drug use for seizure-free patients with brain metastases is not recommended.

CNS Steroids Guideline: Steroid Therapy Versus No Steroid Therapy

Patients with asymptomatic brain metastases without mass effect:

Insufficient evidence exists to make a treatment recommendation for this clinical scenario.

Patients with brain metastases with mild symptoms related to mass effect:

1) Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. It is recommended for patients who are symptomatic from metastatic disease to the brain that a starting dose of Dexamethasone 4 to 8 mg/day be considered. Patients with brain metastases with moderate to severe symptoms related to mass effect

2) Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. If patients exhibit severe symptoms that are consistent with increased intracranial pressure, it is recommended that higher doses, such as Dexamethasone 16 mg/day or more, be considered.

Choice of steroid:

If corticosteroids are administered, Dexamethasone is the best drug choice, given the available evidence.

Duration of corticosteroid administration:

Corticosteroids, if administered, should be tapered as rapidly as possible, but no faster than clinically tolerated, on the basis of an individualized treatment regimen and a full understanding of the long-term sequelae of corticosteroid therapy.

ASCO/SNO Expert Panel comment: The Panel’s expert opinion is that, given the important adverse effects of steroids, the minimum effective dose (often no more than 4 mg) should be used where possible and night-time doses of steroids should be avoided to minimize toxicity.

Note regarding CNS Level 3 recommendation classification: CNS defines a Level 3 recommendation as, one based on “Evidence from case series, comparative studies with historical controls, case reports, and expert opinion, as well as significantly flawed randomized controlled trials”

Anticonvulsant Prophylaxis and Steroid Use in Adults With Metastatic Brain Tumors: ASCO and SNO Endorsement of the Congress of Neurological Surgeons Guidelines. Chang SM, Messersmith H, Ahluwalia M, et al. J Clin Oncol 2019;37:1130-1135

AFINITOR® (Everolimus)

The FDA on April 10, 2018 approved AFINITOR® for the adjunctive treatment of adult and pediatric patients aged 2 years and older with Tuberous Sclerosis Complex (TSC)-associated partial-onset seizures. AFINITOR® is also approved for two other manifestations of TSC: TSC-associated SubEpendymal Giant cell Astrocytoma (SEGA) and TSC-associated renal angiomyolipoma. AFINITOR® is a product of Novartis Pharmaceuticals Corp.

OPTUNE® Together with Temozolomide Significantly Improves Overall Survival in Newly Diagnosed Glioblastoma

SUMMARY: Glioblastoma Multiforme (GBM)) is the most common malignant tumor of the central nervous system in adults and originates in astrocytes which are specialized glial cells. It is estimated that approximately 12,500-18,000 new cases of GBM are diagnosed annually in the United States. The most frequent location for GBM is cerebral hemispheres and 95% of these tumors arise in supratentorial region. The etiology remains unclear and genetic predisposition has been observed in only 5-10 % of cases. GBM can be primary when arising de novo without clinical and histological evidences of a precursor lesion or secondary when they progress slowly from preexisting lower-grade astrocytoma. Primary GBMs are associated with hallmark genetic alterations and they include Epidermal Growth Factor Receptor (EGFR) gene mutation and amplification, over expression of Mouse Double Minute 2 (MDM2), deletion of p16 and Loss of Heterozygosity (LOH) of chromosome 10q holding Phosphatase and Tensin homolog (PTEN) and TERT promoter mutation.

GBM is not curable and management includes maximal safe debulking of the tumor followed by concurrent chemoradiation and then adjuvant chemotherapy. Current chemotherapy agents with FDA approval for treatment of GBM include Temozolomide, Bevacizumab (AVASTIN®), Lomustine (GLEOSTINE®), Carmustine (BiCNU®) and Carmustine Implant (GLIADEL® Wafer for intraoperative implantation). The median survival for GBM patients from diagnosis, with the current therapies, is about 15 months.Mechanism-of-Action-of-Tumor-Treating-Fields

Tumor-Treating Fields (TTFields) delivery system (OPTUNE®) is a novel external therapeutic device that slows and reverses tumor growth by inhibiting mitosis. The battery operated-TTF delivery system generates low intensity, intermediate frequency, alternating electrical fields to the brain. These electrical fields exert selective toxicity in dividing cells by interfering with organelle assembly in the cell and thereby facilitates apoptosis (programmed cell death), by preventing cell division. The non-dividing cells are not affected by these electrical fields. Tumor Treating Fields (TTFields) delivery system, OPTUNE®, along with Temozolomide is presently approved by the FDA for the treatment of adult patients with newly diagnosed, supratentorial Glioblastoma (GBM) following maximal debulking surgery and radiation with concurrent chemotherapy. It is also approved for the treatment of recurrent GBM as a monotherapy, after surgical and radiation options have been exhausted. Insulated ceramic discs (transducer arrays) are placed directly on the scalp and held by adhesive bandages. They deliver the electrical fields after they are connected to the TTFields delivery system, OPTUNE®. Patients wear the device for at least 18 hours a day and for at least four weeks.OPTUNE-is-Local-Delivery-System-and-Temozolomide-is-Systemic-Therapy

Previously published studies had shown that TTFields, in addition to its antimitotic effect on the dividing cell, can augment response to alkylator-based chemotherapy. These durable responses were sometimes delayed after an initial progression, and there was a high correlation between treatment compliance and survival. The EF-14 trial is a randomized, multicenter, open-label, phase III study, in which 695 patients with newly diagnosed grade IV GBM, who had completed standard treatment with surgery (resection or biopsy) and concurrent chemoradiation with Temozolomide, were randomized within 7 weeks of their last radiation dose, in a 2:1 ratio to TTFields plus maintenance Temozolomide chemotherapy (N=466) or Temozolomide alone (N=229). The TTFields, consisted of low-intensity, 200 kHz frequency, alternating electric fields and was delivered 18 hours/day or more, via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both treatment groups at 150-200 mg/m2 PO for 5 days per 28 day cycle for 6-12 cycles. Patients had a Karnofsky Performance Score of 70 or more, with supratentorial tumor location and non-progressive disease. Patients were excluded if the tumor location was infratentorial and if there was evidence of increased intracranial pressure. The median age was 56 years, and majority of the patients were male. The Primary endpoint was Progression Free Survival (PFS) and the Secondary endpoint was Overall Survival (OS).

A preliminary report from this trial was published in 2015 and the authors now report the results of their final analysis. The median PFS from randomization was 6.7 months in the TTFields plus Temozolomide group and 4.0 months in the Temozolomide alone group (HR=0.63; P<0.001). The median OS was 20.9 months in the TTFields plus Temozolomide group versus 16.0 months in the Temozolomide alone group (HR=0.63; P< 0.001). This meant a 37% improvement in PFS and OS for patients who received TTFields plus Temozolomide compared to patients who received Temozolomide alone. The statistically significant benefit of TTFields with Temozolomide on Overall Survival, was seen in all pre-specified patient subgroups, regardless of prognostic factors such as age, performance status, MGMT promotor methylation and extent of resection. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients in the TTFields plus Temozolomide group.

The authors concluded that the results in the final analysis were consistent with the previous interim analysis results, and for GBM patients who had received standard chemoradiation therapy, the addition of TTFields to maintenance Temozolomide chemotherapy, resulted in statistically significant improvement in PFS and OS, compared with maintenance Temozolomide alone. This is the first positive phase III trial in newly diagnosed GBM, since the efficacy of Temozolomide was established in 2005. Stupp R, Tailibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: A randomized clinical trial. JAMA. 2017;318:2306-2316

GLEOLAN® (AminoLevulinic Acid Hydrochloride)

The FDA on June 6, 2017 approved GLEOLAN® as an optical imaging agent, indicated in patients with Gliomas (suspected World Health Organization Grades III or IV on preoperative imaging), as an adjunct for the visualization of malignant tissue during surgery. GLEOLAN® is a product of NX Development Corp.

Late Breaking Abstract – ASCO 2015 Adjuvant Whole Brain Radiation Therapy Not Recommended After Stereotactic RadioSurgery

SUMMARY: Brain metastases from an extracranial primary, occur in approximately 15% of cancer patients and this is estimated to be about 400,000 to 600,000 patients annually. The incidence of brain metastases has been on the rise with the availability of more effective systemic therapies and better control of systemic disease. The most frequent malignancies associated with brain metastases include Lung cancer, Breast cancer and Melanoma. Majority of the patients with brain metastases have synchronous extracerebral metastases. A significant number of patients present with solitary or fewer than 3 brain metastases and they may be amenable to focal therapeutic interventions. However, Whole Brain Radiation Therapy (WBRT) has been the standard treatment strategy since the 1950’s. It is also well recognized that WBRT can be associated with neurocognitive dysfunction. Stereotactic RadioSurgery (SRS) is a non-surgical procedure that allows delivery of significantly higher doses of precisely focused radiation to the tumor, compared to conventional radiation therapy, with less collateral damage to the surrounding normal tissue. The technologies used for SRS include GAMMA KNIFE® which uses highly focused gamma rays, Proton Beam therapy which uses ionized hydrogen or Protons, Linear Accelerator and CYBER KNIFE® which use Photons, to target the tumor tissue.

NCCTG N0574 is a federally funded, randomized phase III clinical trial, designed to determine whether cognitive deterioration occurred less frequently with SRS alone compared to SRS followed by WBRT, in patients with 1-3 brain metastases. In this study, 213 patients with 1-3 brain metastases, each measuring less than 3 cm by contrast MRI, were enrolled and randomized to SRS alone or SRS plus WBRT. All patients underwent cognitive testing before and after treatment. Sixty eight percent (68%) of the enrolled patients had a Lung primary and the median age was 60 years. Baseline characteristics were similar in both treatment groups. The median follow up was 7.2 months. The authors used several tools to assess cognitive dysfunction and the primary endpoint was the cognitive decline at 3 months following treatment. It was noted that at 3 months, with the addition of WBRT to SRS, 91.7% of patients experienced cognitive decline compared with 63.5% for those receiving SRS alone (P=0.0007) and there was statistically significant decline in immediate recall, delayed recall and verbal fluency, in the SRS plus WBRT group. Patients who received SRS plus WBRT also reported significantly worse Quality of Life. There was however better intracranial tumor control at 6 and 12 months with SRS plus WBRT compared to SRS alone (P< 0.001), but this local control had no significant impact on the median Overall Survival (OS), with similar OS outcomes noted in both treatment groups (P=0.93). The authors concluded that the addition of WBRT to SRS can result in significant decline in neurocognitive function, without any Overall Survival benefit, compared to SRS alone. It is therefore recommended that patients with newly diagnosed brain metastases amenable to SRS, be closely monitored after SRS, with consideration given to WBRT, at the time of symptomatic progression. NCCTG N0574 (Alliance): A phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases. Brown PD, Asher AL, Ballman KV, et al. J Clin Oncol 33, 2015 (suppl; abstr LBA4)

Oncoprescribe Blog VEGF In Brain Tumors

It appears that VEGF (Vascular Endothelial Growth Factor) is the main driver for low and high grade malignant gliomas. These tumors, as one would expect, also harbor high concentrations of VEGF receptors. In fact, tumor VEGF receptor concentration appears to be directly related to poor clinical outcomes. This would make perfect sense as VEGF development was based on Glioblastoma Multiforme xenograft models.

No wonder, Bevacizumab (AVASTIN), a humanized antibody targeting VEGF in combination with chemotherapy, improved response rates, progression free survival and overall survival.