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Patient Assessment, Supportive Care and Managing Adverse Events

Patient Assessment, Supportive Care and Managing Adverse Events. Patrick Y. Wen, MD Director, Center for Neuro-Oncology Dana-Farber Cancer Institute Director, Division of Neuro-Oncology Brigham and Women’s Hospital Professor of Neurology Harvard Medical School Boston, Massachusetts.

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Patient Assessment, Supportive Care and Managing Adverse Events

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  1. Patient Assessment, Supportive Care and Managing Adverse Events Patrick Y. Wen, MD Director, Center for Neuro-Oncology Dana-Farber Cancer InstituteDirector, Division of Neuro-OncologyBrigham and Women’s Hospital Professor of Neurology Harvard Medical SchoolBoston, Massachusetts This program is supported by an educational grant from

  2. About These Slides • Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent • These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

  3. Faculty Disclosure Patrick Y. Wen, MD, has disclosed that he has received consulting fees from Merck, Novartis, and Stemline; fees for non-CME services from Merck; and contracted research from Amgen, AstraZeneca, Eisai, Exelixis, Genentech, Merck, Novartis, MedImmune, sanofi-aventis, and Vascular Biogenics.

  4. Overview • Patient Assessment, including determination of response • Supportive Care • Antinausea medications • Seizure prophylaxis • Treatment of peritumoral edema • Management of Adverse Events • Steroid-induced complications • Chemotherapy-induced cytopenias • DVT/PE and anticoagulation • Radiation necrosis • Bevacizumab-related adverse events

  5. Patient Assessment

  6. Patient Assessment and Determination of Benefit • Clinical/neurologic function • Performance score • Corticosteroid use • Neuropsychologic function • Quality of life • FACT-Br, EORTC QLQ-C30, MDASI-BT • Radiographic response

  7. Why Determine Response? • Accurate response assessment important for • Clinicians and patients • Continue beneficial treatments • Stop unhelpful treatments • Avoid unnecessary toxicity and cost • Evaluation of new brain tumor treatments • Identify promising new treatments • Abandon evaluation of inactive treatments

  8. Macdonald’s Criteria • Tumor size • Maximum cross-sectional area of contrast-enhancing tumor on CT or MRI scan • Neurological function • Steroid dose Macdonald DR, et al. J Clin Oncol. 1990;8:1277-1280.

  9. Macdonald’s Criteria • Limitations • Measures enhancing component only • Does not address nonenhancing tumors • Pseudoprogression • Antiangiogenic treatments • Pseudoresponse • Nonenhancing progression van den Bent MJ, et al. J Clin Oncol. 2009;27:2905-2908.

  10. Pseudoprogression 4 wks after RT Before RT 8 wks after RT 6 mos later Wen PY, et al. J Clin Oncol. 2010;28:1963-1972.

  11. Pseudoresponse Cediranib XL814 Wen PY, et al. J Clin Oncol. 2010;28:1963-1972.

  12. Wen PY, et al. J Clin Oncol. 2010;28:1963-1972.

  13. General Principles • Product of the maximal cross-sectional enhancing diameters will be used to determine the size of the contrast-enhancing lesions • Enhancing and nonenhancing tumor areas evaluated • Response (CR, PR) requires confirmatory scan (≥ 4 wks) • Steroid dose and clinical status must be recorded Wen PY, et al. J Clin Oncol. 2010;28:1963-1972.

  14. Measureable and Nonmeasurable Disease for Contrast-Enhancing Lesions • Measurable disease • Bidimensionally contrast-enhancing lesions with clearly defined margins, a minimal diameter of 1 cm, and visible on 2 axial slices which are preferably at least 5 mm apart with 0 mm skip • Nonmeasurable disease • Unidimensionally measurable lesions, masses with margins not clearly defined, or lesions with maximal perpendicular diameters < 1 cm Wen PY, et al. J Clin Oncol. 2010;28:1963-1972.

  15. Criteria for Entry Into Clinical Trials for Recurrent High-Grade Glioma • Currently, no minimum criteria for entry into trials, except that it has to be “worse” • 25% increase in the sum of the products of perpendicular diameters of the contrast-enhancing lesions on stable or increasing doses of corticosteroids • Worsening of nonenhancing disease if patients have received previous antiangiogenic therapy Wen PY, et al. J Clin Oncol. 2010;28:1963-1972.

  16. Determining Progression by Time From Initial Radiochemotherapy • Definition of PD less than 12 wks from completion of radiochemotherapy • New enhancing lesion outside of the radiation field (beyond the 80% isodose line) or • Unequivocal evidence of viable tumor on histopathology sampling (ie, 70% tumor cell nuclei in areas, high or progressive increase in MIB-1 proliferation index compared with previous biopsy, or evidence for histologic progression or increased anaplasia in tumor) Wen PY, et al. J Clin Oncol. 2010;28:1963-1972.

  17. Courtesy of Jan Drappatz, DFCI

  18. RANO Criteria Summary *Sustained for at least 4 wks. †Progression occurs when criterion is present. Wen PY, et al. J Clin Oncol. 2010;28:1963-1972.

  19. RANO Response Criteria for High-Grade Gliomas • Progressive disease • ≥ 25% increase in sum of the products of perpendicular diameters of enhancing lesions (over baseline or best response scan) and/or • Significant increase in T2/FLAIR nonenhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response following initiation of therapy, not due to comorbid events • Ideally this would be quantified like contrast-enhancing lesions • Difficult • Left to investigator’s discretion Wen PY, et al. J Clin Oncol. 2010;28:1963-1972.

  20. RANO Criteria • Proposed new criteria are a work in progress • Implementation and validation in clinical trials is important • Future revisions to include • Volumetric imaging • Advanced MRI • DCE, DSC, diffusion/ADC, MRS • PET (FLT, amino acid) • Neurocognitive status and HRQOL • Corticosteroids • RANO criteria for brain metastases, meningioma, and pediatric brain tumors (RAPNO)

  21. Patient With Increasing Subnormal ADC Low ADC Gerstner ER, et al. Neuro Oncol. 2010;12:466-472.

  22. Supportive Care

  23. Supportive Care • Antiemetic therapy • Seizure prophylaxis • Treatment of peritumoral edema • Other issues

  24. Antiemetic Therapy • Concomitant temozolomide • None, metoclopramide, or serotonin 5-HT3 antagonist (eg, ondansetron, granisetron) • Adjuvant temozolomide • 5-HT3 antagonist for up to 7 days • ± lorazepam • ± H2-blocker or proton pump inhibitor • ± corticosteroids • Neurokinin 1 antagonist (eg, aprepitant, fosaprepitant) • Adapted from 2011 NCCN guidelines

  25. Seizure Prophylaxis • Patients with seizures • Should be treated with standard AED • Preference for cytochrome P450-enzyme non-EIAED • EEG usually not necessary

  26. Phase I/II Study of Imatinib Mesylate for Recurrent Malignant Gliomas North American Brain Tumor Consortium Study 99-08 Imatinib Non-EIAED 160,000 Group AGroup B 140,000 120,000 100,000 AUC (ng*hr/mL) 80,000 EIAED 60,000 40,000 20,000 0 400 600 800 1000 1200 Dose (mg/day) Wen PY, et al. Clin Cancer Res. 2006;12:4899-4907.

  27. EIAEDs and Non-EIAEDs EIAEDs Carbamazepine Oxcarbazepine Phenytoin Fosphenytoin Phenobarbital Primidone Non-EIAEDs Valproic acid Gabapentin Lamotrigine Topiramate Tiagabine Zonisamide Levetiracetam Clonazepam Clonozam Pregabalin Lacosamide

  28. EORTC/NCIC Temozolomide Trial • 175 patients (30.5%) were AED free, 277 (48.3%) were receiving EIAEDs, and 135 (23.4%) were receiving non-EIAEDs • 97 patients receiving valproic acid alone had increased survival from treatment with RT and TMZ • Valproic acid median survival: 17.3 mos • EIAED only median survival: 14.4 mos • No AED median survival: 14.0 mos • Patients receiving valproic acid only had more grade 3/4 thrombocytopenia and leukopenia Weller M, et al. Neurology. 2011;77:1156-1164.

  29. EORTC/NCIC Temozolomide Trial Events/Patients Statistics HR & CI* AED Status No AED VPA only EIAED only Total TMZ/RT RT (O-E) Var. (TMZ/RT: RT) HR (95% CI) 90/103 41/49 105/113 236/265(89.1%) 71/72 47/48 134/139 252/259(97.3%) -15.7 -16.6 -21.1 -53.4 35.5 18.7 56.8 111.2 0.64 (0.46-0.89) 0.41 (0.26-0.65) 0.69 (0.53-0.89) 0.62 (0.51-0.74) 0.25 0.5 1.0 2.0 4.0 TMZ/RTBetter RTBetter Test for heterogeneityChi square = 3.73, df = 2: P > .1 Treatment effect; P < .00000 *95% CI everywhere Weller M, et al. Neurology. 2011;77:1156-1164.

  30. Prophylactic Anticonvulsants • No definite evidence that patients who have not had seizures benefit from prophylactic AED • Recommend tapering AED 1 wk after surgery Glantz MJ, et al. Neurology. 2000;54:1886-1893.

  31. Placebo-Controlled Phase III Trial of Prophylactic AED in High-Grade Gliomas • Primary objective • Time to first seizure • Secondary objectives • 1-yr risk of first seizure • Patient-reported symptoms Patients with newly diagnosed high-grade glioma(planned N = 302) Lacosamide Stratified by perioperative anticonvulsant use Placebo Taper any prestudy anticonvulsant ClinicalTrials.gov. NCT01432171.

  32. Peritumoral Edema • Glucocorticoids preferred • Twice daily dosing adequate • Use as little as possible

  33. Novel Treatments for Peritumoral Edema • COX-2 inhibitors[1] • Corticorelin acetate (corticotrophin-releasing factor)[2,3] • VEGF inhibitors (eg, bevacizumab, aflibercept) • VEGFR inhibitors 1. Portnow J, et al. Neuro Oncol. 2002;4:22-25. 2. Shapiro WR, et al. ASCO 2009. Abstract 2080. 3. Recht LD, et al. ASCO 2010. Abstract 2078.

  34. Cediranib: VEGFR Inhibitor

  35. Percent Change of Lowest Corticosteroid Dose From Baseline 50 50 Bevacizumab + Irinotecan (n = 43) Bevacizumab(n = 43) 0 0 % Change From Baseline % Change From Baseline -50 -50 -100 -100 0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45 Patient Index Patient Index Responders are colored in orange Friedman HS, et al. J Clin Oncol. 2009;27:4733-4740.

  36. Cabozantinib: Effects on Pts Receiving Corticosteroids at Baseline (N = 76) 8 61% experienced ≥ 50% reduction in dose of corticosteroids 46% experienced a 100% reduction in dose of corticosteroids 7 6 5 n = 76 n = 76 Median25th and 75th percentiles 4 Dexamethasone Equivalent Dose (mg)/Day n = 73 3 n = 57 n = 51 2 n = 41 n = 26 n = 17 n = 14 n = 33 n = 28 n = 7 1 0 2 4 6 8 10 12 14 16 18 20 22 0 Wks Wen PY, et al. ASCO 2010. Abstract 2006.

  37. Other Issues • Abulia, inattention (methylphenidate)[1] • Fatigue (modafinil, armodafinil, methylphenidate)[2,3] • Memory • Donepezil[4] • Memantine • Depression (often underdiagnosed) 1. Myers CA, et al. J Clin Oncol. 1998;16:2522-2527. 2. Kaleita TA, et al. ASCO 2006. Abstract. 1503. 3. Gerard ME, et al. SNO 2011. Abstract QL-18. 4. Shaw EG, et al. J Clin Oncol. 2006;24:1415-1420.

  38. Management of Adverse Events

  39. Management of Adverse Events • Steroid-induced complications • Chemotherapy-induced cytopenias • DVT/PE and anticoagulation • Radiation necrosis • Bevacizumab-related adverse events

  40. Neurologic Complications of Corticosteroids • Common • Myopathy • Behavioral changes • Visual blurring • Tremor • Insomnia • Reduced taste and olfaction • Cerebral atrophy • Uncommon • Psychosis • Hallucinations • Hiccups • Dementia • Seizures • Dependence • Epidural lipomatosis

  41. Pneumocystis Jerovecii (Carinii) Pneumonia Mahindra AK, et al. J Neurooncol. 2003;63:263-270.

  42. Osteoporosis and Compression Fractures

  43. Osteoporosis • Patients receiving chronic corticosteroid therapy should probably be given • Calcium supplements with vitamin D 800 IU/day or • An activated form of vitamin D (eg, alfacalcidiol 1 µg/day) or • Calcitriol 0.5 µg/day • Bisphosphonates such as etidronate, alendronate, risedronate, and zoledronate • Kyphoplasty: unclear benefit for compression fractures[1] • 2 negative trials have been reported 1. Muijs SP, et al. J Bone Joint Surg Br. 2011;93:1149-1153.

  44. Association Between Hyperglycemia and Survival in Newly Diagnosed GBM • N = 191 newly diagnosed patients with GBM and with good baseline KPS • Hyperglycemia was associated with shorter survival, after controlling for glucocorticoid dose and other confounders • Effect of intensive management of glucocorticoid-related hyperglycemia on survival deserves additional study Derr RL, et al. J Clin Oncol. 2009;27:1082-1086.

  45. OS in GBM by Quartiles of Time-Weighted Glucose 1.00 P for trend = .041 Quartile 1Quartile 2Quartile 3Quartile 4 0.75 0.50 Probability of OS 0.25 0 0 5 10 15 20 25 30 35 40 45 Mos Derr RL, et al. J Clin Oncol. 2009;27:1082-1086.

  46. Chemotherapy-Induced Cytopenias Concomitant TMZ + RT Adjuvant TMZ R 0 6 10 14 18 22 26 30 Wks RT Alone TMZ 75 mg/m2 PO QD for 6 wks, then 150-200 mg/m2 PO QD on Days 1-5 every 28 days for 6 cycles Focal RT daily—30 x 200 cGy; total dose: 60 Gy Stupp R, et al. N Engl J Med. 2006;352:987-996.

  47. Chemotherapy-Induced Cytopenias in RTOG Study of Adjuvant Temozolomide RTOG 0525: Adjuvant TMZ (arm 1, standard dose = 351; arm 2, dose-dense = 369) *1 grade 5 toxicity.Grade 3-5 adverse events were more common in arm 2 vs arm 1 (194 vs 120; P < .0001); mostly lymphopenia (107 vs 51) and fatigue (33 vs 12). Gilbert M, et al. ASCO 2011. Abstract 2006.

  48. Immunosuppression in High-Grade Gliomas Treated With RT and TMZ • N = 96 • Median CD4+ cell count before RT and TMZ: 664 cells/mm3 • CD4+ cell count nadir occurred 2 mos after initiating therapy; 73% had CD4+ cell counts < 300 cells/mm3, 40% had < 200 cells/mm3 • CD4+ cell counts remained low throughout the yr of follow-up • Infection risk low (2.5% rate of death from infection) Outlier90th percentile 75th percentile 25th percentile 10 percentile Outlier 2400 2200 2000 1800 1600 1400 1200 Absolute CD4+ Cell Count 1000 800 60 40 200 0 Baseline 1 2 3 4 5 6 7 8 9 10 11 12 Mo of Follow-up Grossman SA, et al. Clin Cancer Res. 2011;17:5473-5480.

  49. OS With RT + TMZ by CD4+ Cell Count at Month 2 1.0 0.9 0.8 CD4+ cell count ≥200 cells/mm3 0.7 0.6 0.5 Probability of Survival 0.4 0.3 0.2 CD4+ cell count <200 cells/mm3 0.1 0 0 6 12 18 24 30 36 42 48 54 Mos Grossman SA, et al. Clin Cancer Res. 2011;17:5473-5480.

  50. Pulmonary Angiogram Showing Intraluminal Filling Defects

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