Dilemma in glioma
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1) Glioblastoma treatment outcomes can be difficult to assess due to pseudo-progression, radiation necrosis, or pseudo-response. Imaging findings and tumor markers may resemble progression even when the tumor is stable or shrinking. 2) Pseudo-progression involves early imaging changes within 3-6 months of radiation/chemotherapy that mimic growth but reflect treatment effects like blood brain barrier disruption. MGMT methylation predicts higher pseudo-progression risk. 3) Radiation necrosis typically occurs 18-24 months post-treatment and shows abnormal perfusion on PET/MRI not seen with true recurrence/progression.
![DR KANHU CHARAN PATRO
RADIATION ONCOLOGIST
MD, DNB[RT],FAROI[USA],MBA[HA],PDCR, CEPC
206/01/18](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
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Dilemma in glioma
- 1. DILEMMA IN GLIOBLASTOMA PROGRESSION vs. PSEUDO PROGRESSION VS. RADIO-NECROSIS VS. PSEUDO-RESPONSE 106/01/18
- 2. DR KANHU CHARAN PATRO RADIATION ONCOLOGIST MD, DNB[RT],FAROI[USA],MBA[HA],PDCR, CEPC 206/01/18
- 3. O N O L Y O M G C H R I C G R S P E U S P E C I L T Y I VISAKHAPATNAM,1/7-MVP[AP] 306/01/18
- 4. 406/01/18
- 5. Statistics • Near 10 million new cases are detected each year • Near 20 million people living with cancer in the world today • Near 7 million people will die from cancer • Every day, around 1700 Americans die of the disease • 1 in 3 people will be diagnosed with cancer in the UK and • 1 in 4 will die from their disease 506/01/18
- 6. Lung Breast Colon/Rectum Stomach Liver Prostate Cervix uteri Oesophagus Bladder Non-Hodgkin Lymphoma Leukaemia Oral cavity Pancreas Kidney Ovary 1000 800 600 400 200 0 200 400 600 800 1000 Men Women From: D.M. Parkin The Lancet Oncology 2: 533-543 (2001) (Thousands) Incidence Mortality 337 293 105 0370 241 318 446 234 165 166 471 233 133 111 76 33 121 68 113 86 47 97 101 101 34 71 192 114 810 902 558 405 255 499 398 384 204 543 279 260 227 99 93 167 144 109 81 170 116 112 57 119 5.3 million cases 3.5 million deaths 4.7 million cases 2.7 million deaths The Global Burden of Cancer 2000 606/01/18
- 8. 806/01/18
- 9. 906/01/18
- 10. 1006/01/18
- 12. Glioblastoma (WHO grade IV) • Previously known as glioblastoma multiforme • Peak age of onset is 50-60yrs. • Common in deep white matter, basal ganglia, thalamus, rarely in cerebellum • Grossly may appear circumscribed • Microscopic infiltrates widely, often to other hemisphere via corpus callosum. • May be Multifocal • Extracranial metastasis rare. • Survival 1-1.5 yrs after treatment. 1206/01/18
- 13. • Central yellow or white zone of necrosis and hemorrhage surrounded by of endothelial hyperplasia. • Surrounded by edematous brain (mixture of vasogenic edema, tumour infiltrates and gliosis) • TP53, IDH1 and IDH2 mutation less common in primary. • 30-40% have EFGR mutation • MGMT mutation- favorable prognosis. Glioblastoma (WHO grade IV) 1306/01/18
- 14. Fig 2.1B: Axial T1 Weighted (Wtd.) MRI Fig 2.1A: Axial Flair MRI Fig 2.1C: Post- Contrast Axial T1 Wtd. MRI 1406/01/18
- 15. 1506/01/18
- 16. 1606/01/18
- 17. 1806/01/18
- 18. 1906/01/18
- 19. Chemo-RT schedule • RT - Five fractions per week • Prophylactic antiemetics • PCP prophylaxis • Low dose steroids with H1 blocker • Weekly blood counts • Give Temozolomide for a maximum of 49 days and then STOP2006/01/18
- 20. Dose modification for Concomittant Temozolomide 2106/01/18
- 21. 2206/01/18
- 22. Methylation status as a Prognostic marker 2306/01/18
- 23. Response evaluation • The most widely used criteria for assessing treatment response are based on a 2D measurement of the enhancing area on MR imaging known as the • Macdonald Criteria • RANO criteria 2406/01/18
- 24. 2506/01/18
- 25. Challenges • Recurrence/progression • Pseudo-progression • Radio-necrosis • Pseudo-response 2606/01/18
- 26. MANAGEMENT DILEMMA • CONTINUING SAME THERAPY • 2ND LINE THERAPY • 2ND SURGERY 2706/01/18
- 27. Radiation effect • Acute – (during radiation), • Subacute or early-delayed – (up to 12 weeks after radiation ends) • Late – (months to years post radiation) 2806/01/18
- 28. Cause-acute and sub-acute • Both the acute and subacute types of radiation-induced injury are thought to be caused by vasodilation, disruption of the BBB, and edema. 2906/01/18
- 29. Cause-Late Blood vessel damage ISCHEMIA Increased capillary permeability Fluid transudation Brain edema NECROSIS 3006/01/18
- 30. INCREASED ENHANCEMENT • Increased enhancement can be induced by a variety of non-tumoral processes, such as treatment-related inflammation. –Postsurgical changes, – Ischemia, –Subacute radiation effects, –And radiation necrosis Micro-ischemic lesions immediately after surgery and radiotherapy can cause BBB disruption 3106/01/18
- 31. TO DIFFERENTIATE • Imaging –MRI –MRS –PERFUSION –PET-CT –PET-MR – DSC -dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging-rCBV 3206/01/18
- 32. 3306/01/18
- 34. MRI FINDINGS • Edema • New lesions • Increased size of contrast-enhancing lesions within the immediate vicinity of the irradiated tumor volume. 3506/01/18
- 35. • Reduced NAA peaks • Increased choline peak • Increased choline/creatinine ratio • Choline/creatinine peak>3:1 predicts high grade tumour. MR spectroscopy-recurrance 3606/01/18
- 36. 3706/01/18
- 37. 12 MONTHS AFTER RESECTION AND RADIATION P.C. Sundgren AJNR Am J Neuroradiol 2009;30:1469-1476 ©2009 by American Society of Neuroradiology MR spectrum shows moderately increased Cho and reduced NAA signal intensities consistent with recurrent tumor, and normal signal intensities of NAA, Cho, and Cr in the right hemisphere 3806/01/18
- 38. A 12 months after resection, radiation P.C. Sundgren AJNR Am J Neuroradiol 2009;30:1469-1476 ©2009 by American Society of Neuroradiology Significantly increased Cho and almost-absent NAA signal intensities in the contrast- enhancing areas, consistent with tumor recurrence 3906/01/18
- 39. 4006/01/18
- 40. 4106/01/18
- 42. Radio-necrosis • Radiation necrosis typically occurs 18–24 months post-treatment and has repeatedly been shown to be difficult to distinguish from recurrence. 4306/01/18
- 43. 4406/01/18
- 44. 18 MONTHS AFTER RESECTION AND RADIATION P.C. Sundgren AJNR Am J Neuroradiol 2009;30:1469-1476 ©2009 by American Society of Neuroradiology Swiss cheese-like contrast enhancement surrounding the hemorrhagic lesion, suggestive of radiation injury 4506/01/18
- 45. • An extensive metabolic peak of lipids/lactate has been demonstrated in radiation-injured brain tissue. 4606/01/18
- 46. OBTAINED 8 MONTHS AFTER RESECTION, RADIATION, AND CHEMOTHERAPY P.C. Sundgren AJNR Am J Neuroradiol 2009;30:1469-1476 ©2009 by American Society of Neuroradiology MR spectroscopy spectrum shows slightly decreased NAA and mildly increased Cho signal intensities Bilaterally, suggestive of radiation injury. 4706/01/18
- 47. obtained 10 months after resection and radiation P.C. Sundgren AJNR Am J Neuroradiol 2009;30:1469-1476 Slightly increased Cho and normal NAA and Cr signal intensities are indicative of radiation injury, 4806/01/18
- 48. PET-CT • FDG-PET can demonstrate differences in the analysis of areas of radiation injury and residual/recurrent brain tumors. • However the reported sensitivity and specificity are low. • LIMITATION-The high glucose use in the brain, which results in high background activity and by the fact that inflammatory processes can demonstrate high glucose metabolism on PET examinations. 4906/01/18
- 49. 5006/01/18
- 50. 5106/01/18
- 51. 5206/01/18
- 53. PSEUDO-PROGRESSION • Essentially psPD refers to post-treatment imaging changes in the tumor. • Where the tumor appears larger and/or brighter from greater contrast uptake as compared to the pre-treatment baseline CT or MRI image. 5406/01/18
- 54. Patho-physiology • Effective treatment can involve disruption of the BBB, which facilitates passage of the drug and, thus, results in an enhancement of its activity. • This damage to the BBB can persist for several months after treatment, showing an enhanced lesion that appears larger than before initiation of RT and thus simulates disease progression. 5506/01/18
- 55. 5606/01/18
- 56. 5706/01/18
- 58. 5906/01/18
- 59. Time to onset • Pseudo-progression has been reported to occur predominantly (in almost 60% of cases) within the first 3 months after completing treatment, but it may occur from the first few weeks to 6 months after treatment 6006/01/18
- 60. O6-Methylguanine DNA MGMT Promoter • The methylation status of the MGMT promoter has been shown to be a potent prognostic factor in patients with GBM. • Methylated MGMT may be a good indicator of therapeutic response and a better prognosis, given that an increased overall survival has been observed in these patients • MGMT promoter status may predict pseudo- progression in 90% of patients with methylated glioblastoma. 6106/01/18
- 61. Clinical course of pseudoprogression in a 65-year-old patient with glioblastoma multiforme. Alba A. Brandes et al. Neuro Oncol 2008;10:361-367 Copyright 2008 by the Society for Neuro-Oncology 62 Psot sx Post RT 06/01/18
- 62. 6306/01/18
- 63. 6406/01/18
- 64. rCBV • rCBV values are also useful for differentiating treatment-related effects from viable tumor because they can provide evidence of neoangiogenesis in lesions. • Recently, rCBV values have been used to predict pseudoprogression 6506/01/18
- 65. 6606/01/18
- 66. Mangla R-Radiology 2010;256:575–84 • rCBV values in patients with GBM before and 1 month after RT+TMZ. • In patients with pseudoprogression, There was a 41% mean decrease in rCBV, • While cases of true tumor progression showed a 12% increase in rCBV from pretreatment to post treatment. – Tsien et al • Demonstrated a reduction in rCBV in patients with pseud-oprogression 6706/01/18
- 67. DWI -diffusion-weighted imaging • DWI has been assessed to differentiate tumor progression and/or residual tumor from necrosis. • ADC values were noted to be higher in necrotic tissue than in recurrent tumor tissue 6806/01/18
- 68. 6906/01/18
- 70. ANGIOGENESIS • Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels. • Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g. VEGF). Growth factors such as bFGF and VEGF can induce capillary growth into the tumor, which some researchers suspect supply required nutrients, allowing for tumor expansion 7106/01/18
- 72. ANGIOGENESIS INHIBITORS • Cediranib • Bevacizumab 7306/01/18
- 73. 7406/01/18
- 74. 7506/01/18
- 75. MECHANISM • The early decrease in contrast enhancement suggests a change in vascular permeability, with a “normalization” of the BBB, rather than a true tumor reduction, as being the underlying cause of the improvement. • DRUG HOLIDAY • Normalization of the BBB and subsequent reduction in the vasogenic edema can result in an • Improvement of symptoms, – A reduction of steroid dependence, and – An improvement of brain function and quality of life, – Bringing clinical benefits to patients 7606/01/18
- 76. 7706/01/18
- 77. 2010 7806/01/18
- 78. 2010 7906/01/18
- 79. 2010 8006/01/18
- 89. AUGUST 2015-HIGH DOSE STEROID 9006/01/18
- 91. MIBI NUCLEAR SCAN OCTOBER 2015 9206/01/18
- 92. MIBI NUCLEAR SCAN OCTOBER 2015 9306/01/18
- 94. TAKE HOME MESSAGE Progression – New enhancing lesion – Increase choline peak – Decrease NAA level – Increase perfusion Necrosis – Enhancing lesion – Slight Increase choline peak – Near normal NAA level – Increase lipid lactate peak – Decrease perfusion 9506/01/18
- 95. TAKE HOME MESSAGE Pseudo-Progression – Larger enhancing lesion than before – Disruption of the BBB – Seen with in 3months after RT – Seen in more than 50% of cases – RT+TMZ>RT – Decrease perfusion Pseudo-Response – Seen in treatment with VEGF inhibitors – Due to early normalization of BBB/vessels – T2 usually shows no response 9606/01/18
- 97. 98 ? 9806/01/18
Editor's Notes
- A, Postcontrast T1-weighted MR image obtained 12 months after resection and radiation of an ependymoma shows new contrast-enhancing lesions within the irradiated volume suspicious for tumor recurrence (arrow). B, 2D CSI MR spectroscopy (point-resolved spectroscopy sequence; TE, 144 ms, TR, 1500 ms) with manually placed voxels in the contrast-enhancing lesion and in the corresponding region in the contralateral hemisphere. C, (lower row).
- A, Postcontrast T1-weighted image obtained 12 months after resection, radiation, and chemotherapy of an astrocytoma in the left frontal lobe shows diffuse feathery contrast-enhancing areas in the vicinity of the resection cavity within the irradiated volume, suspicious for tumor recurrence. B, Multivoxel 2D CSI MR spectroscopy (point-resolved spectroscopy sequence; TE, 144 ms; TR, 1500 ms) with manually placed voxels in contrast-enhancing areas, in the cystic cavity, and in normal-appearing brain parenchyma in both left and right hemispheres. C, verified at histopathology.
- A, Axial noncontrast T1-weighted MR image obtained 18 months after resection and radiation of an anaplastic astrocytoma presenting with a hemorrhagic lesion in left parietal region. B, Postcontrast T1-weighted MR image demonstrates feathery. C, Axial T2-weighted MR image shows the extensive edema surrounding the lesion in the left hemisphere.
- A and B, Fluid-attenuated inversion recovery (FLAIR) (A) and postcontrast T1-weighted MR (B) images obtained 8 months after resection, radiation, and chemotherapy of an anaplastic oligodendroglioma in the left frontal lobe show a new area of hyperintensity on FLAIR (arrow, A) and a contrast-enhancing nodule (arrow, B) in the right frontal lobe within the irradiated volume, suspicious for radiation injury. C, Multivoxel 2D CSI MR spectroscopy (point-resolved spectroscopy sequence; TE, 144 ms; TR, 1500 ms) with manually placed voxels in the contrast-enhancing lesion and in the corresponding area in the left hemisphere. D,.
- A, Postcontrast T1-weighted image obtained 10 months after resection and radiation of an astrocytoma in the left frontal lobe shows an irregular peripherally contrast-enhancing mass lesion with central necrosis surrounded by edema suspicious for tumor recurrence. The patient had the lesion resected, and histopathology revealed a high-grade astrocytoma. B, At follow-up MR imaging 6 months later and after additional radiation, a new diffuse contrast-enhancing lesion was present within the irradiated volume. 1H-MR spectroscopy by using SVS (point-resolved spectroscopy sequence; TE, 144 ms; TR, 2000 ms) was performed with the volume placed in over the contrast-enhancing lesion. C,, which was histopathologically confirmed after additional resection.
- Clinical course of pseudoprogression in a 65-year-old patient with glioblastoma multiforme. (A) Presurgical MRI scan. (B) Postsurgical MRI scan. (C) MRI scan performed 1 month after combined temozolomide (TMZ)/radiotherapy; adjuvant TMZ was continued. (D) Four months later, during administration of maintenance TMZ. (E) Eight months later, during administration of maintenance TMZ.