21/03/2017. Disclosure. Practice Changing Articles in Neuro Oncology for 2016/17. Gliomas. Objectives. Gliomas. No conflicts to declare

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1 Practice Changing Articles in Neuro Oncology for 2016/17 Disclosure No conflicts to declare Frances Cusano, BScPharm, ACPR April 21, 2017 Objectives Gliomas To describe the patient selection, methodology and outcomes of study RTOG 9802 involving use of radiation therapy plus procarbazine, lomustine and vincristine in low grade glioma. To describe outcomes of the CCTG CE6 abstract involving shortcourse radiotherapy with or without concomitant and adjuvant temozolomide in elderly. To understand the preliminary results of the CATNON study, involving RT with or without temozolomide in 1p/19q codeleted anaplastic glioma. To understand the benefit of deprescribing in palliative and develop an approach to incorporate deprescribing into your practice. Composed of glial cells - surround the CNS or form specialized anatomic structures -give rise to astrocytomas, oligodendrogliomas and ependymomas Anatomy Corner 2017 World Health Organization Tumour Histologic grade description Nomenclature of glial Histologic tumours features 1 Astrocytomas Grade II Diffuse astrocytoma Well-differentiated fibrillary or gemistocytic astrocytes; moderately increased cellularity; occasional nuclear atypia Grade III Anaplastic astrocytoma Increased cellularity, nuclear atypia, and mitotic activity relative to grade II Grade IV Glioblastoma In addition to grade III features, microvascular proliferation and/or pseudopalisading necrosis Oligodendrogliomas Grade II Oligodendroglioma Monomorphic cells with round nuclei and perinuclear halo appearance due to an artifact from tumour processing; chicken wire vasculature; may have microcalcifications; may have occasional mitosis present Grade III Anaplastic Cells retain some grade II features, oligodendroglioma but more poorly differentiated cell types, prominent mitotic activity; may have microvascular proliferation and/or necrosis Gliomas Incidence 1 : -Grade III and IV gliomas: -5/100,000 person years % glioblastoma % anaplastic astrocytoma -10% anaplastic oligodendroglioma -5-10% anaplastic ependymoma, anaplastic gangliogliomas -Grade II gliomas: -1/100,000 person years 1

2 Gliomas Prognosis 1 : -not curable (Gr 2 4) -survival determined by grade of tumour, molecular markers, extent of resection, performance status, patient age -generally low grade gliomas have greater survival Risk factors 1 : -ionizing radiation -rare hereditary syndromes Pivotal trials for newly diagnosed gliomas Tumour grade Nomenclature Clinical trial Astrocytomas Grade II Diffuse astrocytoma Buckner et al RT + PCV vs RT alone Grade III Anaplastic astrocytoma CATNON trial/cec.1 6 Preliminary results Nov 2016 RT vs RT + TMZ in 3 arms (concurrent/adjuvant 5/28 x 1 year, concurrent + adjuvant x 1 year) Grade IV Glioblastoma Stupp et al : -concurrent RT/temozolomide followed by adjuvant temozolomide vs RT alone -OS 12.1 vs 14.6 months CE.6 trial 5 ASCO Annual Mtg Abstract 2016 Short course RT + TMZ in elderly Oligodendrogliomas Grade II Oligodendroglioma Buckner et al RT + PCV vs RT alone Grade III Anaplastic oligodendroglioma Cairncross et al : -PCV + RT vs PCV alone -OS 14.7 vs 7.3 years RTOG 9802: RT + PCV for Low Grade Glioma RTOG 9802: RT + PCV for Low Grade Glioma Patients with newly diagnosed Grade 2 glioma -Age >40 -Biopsy or subtotal resection (n=251) RT Only (54 Gy/30 fractions) (n=126) RT + PCV chemotherapy RT = 54 Gy/30 fractions N Engl J Med 2016;374: PCV = (6 x 8 week cycles) Procarbazine 60 mg/m 2 po D8-21 CCNU (lomustine) 110 mg/m 2 D1 Vincristine IV 1.4 mg/m 2 (max 2) D1 & 29 (n=125) 2

3 RTOG 9802: RT + PCV for Low Grade Glioma Conclusions Questions Consider Change in Practice: RT + PCV for with newly diagnosed Gr 2 glioma age > 40 or with an incomplete resection Can we use temozolomide? -RTOG Phase 2 study of high risk low grade glioma -Received RT + concurrent temozolomide + adjuvant temozolomide -3 year OS rate 73.1% vs historical controls (54%) -NOA Phase 3 study of Grade 3 gliomas -Received RT vs PCV vs temozolomide at diagnosis -No difference in OS between groups Can we wait to treat? 3

4 Abstract/Plenary session 2016 ASCO Annual Meeting Perry J, Laperriere N, O Callaghan CJ et al. -Stupp et al. demonstrated increased OS with concomitant temozolomide (TMZ) + RT followed by adjuvant TMZ in years of age -RCT s in elderly showed noninferiority of 40 Gy/15 fractions vs 60 Gy/30 fractions 9,10 Patients > 65 years with newly diagnosed glioblastoma -diagnostic surgery within last 4 weeks -ECOG 0-2 Results: -RT + TMZ significantly improved OS vs RT alone - median 9.3 months vs 7.6 months (HR 0.67, 95%CI , p<0.0001) RT 40 Gy/15 fractions (n=281) RT + TMZ RT = 40 Gy/15 fractions TMZ = 75 mg/m 2 po daily during RT, then mg/m 2 po daily x 5/28 days up to 12 cycles (n=281) -MGMT methylated benefitted most - median 13.5 months vs 7.7 months (HR 0.53, 95%CI , p<0.0001) -Unmethylated patient benefit not statistically significant - median 10.0 months vs 7.9 months (HR 0.75, 95%CI , p<0.055) Side effects/quality of life: -increased adverse events in combination arm, especially nausea, vomiting and constipation. -small increase in grades 3/4 hematologic toxicity -no difference between arms in quality of life assessments Consider Change in Practice: -for methylated glioblastoma > 65, consider three week RT + TMZ -for unmethylated elderly glioblastoma, effectiveness not confirmed 4

5 CEC1/CATNON trial: RT + TMZ in non-1p/19q deleted anaplastic glioma -Benefit of adding chemotherapy to RT in anaplastic glioma without 1p/19q codeletion unknown -Concurrent and Adjuvant Temozolomide Chemotherapy in NON-1p/19q Deleted Anaplastic Glioma (CATNON) designed to assess value of adding TMZ to RT for these CEC1/CATNON trial: RT + TMZ in non-1p/19q deleted anaplastic glioma RT Only (59.4 Gy/33 fractions) Patients with newly diagnosed anaplastic glioma - Age > 18 - WHO performance status 0-2 RT + Concurrent TMZ (75 mg/m 2 daily) RT + Adjuvant TMZ ( mg/m 2 days 1-5/28 x 12 cycles) RT + Concurrent + Adjuvant TMZ CEC1/CATNON trial: RT + TMZ in non-1p/19q deleted anaplastic glioma Preliminary results SNO November randomized HR reduction for OS of (95% CI ; p=0.0014) for adjuvant TMZ arms Consider Change in Practice: Add temozolomide to RT for anaplastic astrocytoma Advantages of deprescribing in palliative care : Decrease medication adverse effects Decrease pill burden Decrease financial impact to Improve quality of life Develop OncoPal Deprescribing Guideline Prospective chart review of palliative cancer with a <6 month prognosis Pharmacist applies OncoPal to assess for PIMs Expert panel independently assesses for PIMS Compare Panel vs. Guidelines for concordance PIM = Potentially Inappropriate Medication 5

6 Results: medications Median 10 meds/patient, range 4 21 medications Concordance of 0.83 between OncoPal Deprescribing Guideline and expert panel (95% CI, ) 132 PIMS identified by expert panel 70% of found to have at least one PIM 21.4% of total medications found to be a PIM Change in Practice: Practice deprescribing for cancer with very limited life expectancy Consider practicing deprescribing along the continuum of care Conclusion Emerging evidence for use of chemotherapy, in addition to radiation therapy, for: -Patients with Grade II gliomas -Elderly -Patients with anaplastic astrocytomas As we add chemotherapy, we should constantly consider the risk vs benefit of the other medications. References 1. Packer RJ and Schiff D. Neuro-oncology. John Wiley and Sons Stupp R, Mason WP, van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352: Cairncross G, Wang M, Shaw E et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long term results of RTOG JCO 2013;31: Buckner JC, Shaw EG, Pugh S et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med 2016;374: Perry JR, Laperriere N, O Callaghan CJ et al. A phase III randomized controlled trial of short-course radiotherapy with or without concomitant and adjuvant temozolomide in elderly with glioblastoma (CE.6) ASCO Annual Meeting abstract LBA2. 6. Van den Bent M, Vogelbaum M, Erridge S et al. Phase III CATNON trial on concurrent and adjuvant temozolomide in anaplastic glioma without 1p/19q co-deletion, an intergroup trial. Neuro Oncol 2016;18(6):vi Fisher BJ, Hu C, Macdeonald DR et al. Phase 2 study of temozolomide-based chemoradiation therapy for high-risk low-grade gliomas: preliminary results of radiation therapy oncology group Int J Radiation Oncol 2015;91: Wick W, Hartmann C, Engel C et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. JCO 2009;27: Idbaih A, Taillibert S, Simon JM et al. Short course of radiation therapy in elderly with glioblastoma multiforme. Cancer Radiother 2008:12(8): Roa W, Brasher PM, Bauman G et al. Abbreviated course of radiation therapy in older with glioblastoma multiforme: a prospective randomized clinical trial. JCO 2004;22: