Low grade gliomas kiran

Low grade gliomas kiran

1. MANAGEMENT OF LOW GRADE GLIOMAS Dr Kiran

2. Introduction Low-grade gliomas (LGGs) account for 5% to 10% primary central nervous system (CNS) tumors. The term low-grade glioma (LGG) refers to tumors classified by the World Health Organization (WHO) as grades I and II. WHO Grade I lesions have low proliferative potential. WHO Grade II neoplasms are infiltrative, recur, and tend to progress to higher grades of malignancy despite low level proliferative activity.

3. LGGs ha v e a b e t t e r p rogno s i s than t h e i r a na p l a st i c counterparts; the 10-year overall survival rate for patients with WHO grade II astrocytoma's is 35%. LGGs have the potential to dedifferentiate into high-grade tumors, and approximately 50% to 75% of WHO grade II gliomas transform within 6 to 7 years of diagnosis. LGGs are primarily reported in the frontal lobes (44%) , followed by the temporal (28%) and parietal (14%) domains. The most common histologic subtype of LGG is astrocytoma (69.3%), followed by oligodendroglioma (21.1%)

4. Factors associated with an increased risk of glioma Exposure to high dose radiation. Increasing age. H er e dit a ry d is ord e rs s uch a s l i - F r a u m eni synd r o m e. Tuberous sclerosis. Neu r of i bro m a t os i s type 1. The mean age at diagnosis is 39 years.

5. Clinical Presentation : The most common symptom of patients with LGGs is seizures , followed by headaches. The remaining symptoms (vomiting, motor deficit, visual or sensory loss, language disturbance, or personality change) occur in 15% or fewer patients. Signs: 50% of affected patients have a normal neurologic examination signs at presentation is as follows: sensory or motor deficit, 42%; altered mental status, 23%; papilledema, 22%; aphasia, dysphasia, or decreased memory, 20%.

6. CNS location Signs/symptoms Frontal lobe Hemiparesis, seizures, alteration in mental status, urinary incontinence Occipital lobe Visual changes, seizures Parietal lobe Seizures, language disturbances (if a tumor is in the dominant hemisphere), difficulty with reading and calculations, spatial disorientation Temporal lobe Aphasia, seizures, emotional disturbance, difficulty with depth perception, altered sense of time Basal ganglia Hemiparesis Thalamus Impaired judgment and memory, behavioral changes ,altered motor and sensory integration Hypothalamus Alteration in thirst, urination, sleep, eating patterns, temperature, and blood pressure; emotional changes Optic tract Abnormal pupil reactions, impaired vision, eye movement Disorders Posterior fossa Headaches, nausea, vomiting, blurry vision, ataxia, dizziness, coordination problems, double vision, neck pain, head tilt

7. Diagnostic Workup: Magnetic Resonance (MR) is the standard of care. LGG Are hyper‑intense on T2W images and hypo‑intense on T1W images and do not enhance with contrast administration . FLAIR tends to show a larger area of signal abnormality than standard T2W images. The extent of the lesion on FLAIR images tends to better correlate with the adequacy of resection margins and is also the most useful in the follow‑up to detect recurrence . MR spectroscopy , have been used to differentiate glioma grades. Increased choline (cell membrane marker), low creatine (energy metabolite), and low N -acetyl-aspartate (a neuronal marker) are suggestive of malignancy on MR spectroscopy. Diffusion tensor imaging (DTI) has been used both in surgical planning and in trying to determine tumor grade using diffusivity parameters.

8. Diagnostic Neuroimaging for LGG A 35 -year-old woman presenting with partial motor seizures. (A and B ) The MRI reveals a right frontal mass which is hypointense on T1-weighted images, ( C and D ) Does not enhance following administration of contrast, ( E and F ) The lesion expands the cortex locally and has a sharp border with minimal surrounding vasogenic edema as seen on T2, ( G and H) FLAIR images . 29 - Ma r - 17 LGG Gliomas Do Not Enhance On Mri If Enhancing Treated As Hgg A B C D E F G H

9. Diagnostic Neuroimaging for LGG Diffusion tensor imaging (DTI) and tractography can provide an elegant visualization of the white matter tracts and their relationship with infiltrating tumors. In this example, the right corticospinal tract (motor fibers from the foot area) is displaced medially rather than being invaded by the tumor. The DTI and tractography can often help to maximize surgical resection while preserving neurological function 29 - Ma r - 17

10. Prognostic factors for survival in adult patients with cerebral low-grade glioma. 29 - Ma r - 17 Prognostic Factors, Patient Outcome, and Survival Pignatti F , van den Bent M , Curran D etal 2002

11. Treatment Symptom Management Surgery Observation Radiation Therapy Chemotherapy

12. Symptomatic Management Seizures: There is no standard antiepileptic drug regimen for seizure control in patients with tumors; however, levetiracetam(1000-4000mg/day) is preferentially used because of its favorable pharmacologic properties and relatively benign side-effect profile.(1) FOR PATIENT WHO HAVE UNDERGONE ANY FORM OF SURGERY,BIOPSY : prophylactic anticonvulsant given for shortest period of time.(2) 1. ( Yuan Y, Yunhe M, Xiang W, et al. P450 enzyme-inducing and non enzymeinducing antiepileptic drugs for seizure prophylaxis after glioma resection surgery: A meta-analysis. Seizure. 2014;23:616–621.) 2. ( Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors . Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;54:1886– 1893.)

13. Cerebral oedema : Glucocorticoids used : Dexamethasone preferred because of minimal mineral-corticoid effects. Lower doses :shown to be as effective as higher doses- 2 to 4 mg bd preferred should be discontinued or tapered to the lowest dose necessary, as soon as possible. Taper is necessary to prevent rebound in cerebral edema and also to allow the pituitary– adrenal axis to recover.

14. Observation : Includes MRI monitoring at regular intervals (e.g., every 6 months) to detect radiologic progression before new signs and symptoms occur. PROS: Low grade Gliomas: considered relatively favourable natural history compared o high grade lack of proven benefit for surgery or radiation therapy in improving overall survival No treatment associated morbidities CONS: Natural history is significantly worse than that of an age- and sex matched control population

15. Based on this observation , Maximal Safe Surgical Resection followed by PORT improve survival , and may cure pts. Survival curves for pts with various subtypes of low-grade glioma compared age and sex matched control population . , Adapted from Shaw EG: The low-grade glioma debate. Evidence defending the position of early radiation therapy. Clin Neurosurg 42:488-494, 1995.

16. Surgery Surgery is necessary in all cases to confirm the diagnosis of glioma, to differentiate tumor subtypes (astrocytoma vs. oligodendroglioma), and to define the grade and molecular profile. Of note, because gliomas are very heterogeneous, biopsies (even if performed in stereotactic condition guided by metabolic imaging) have a high risk of underrating tumor grade, which could result in inappropriate management. Thus, biopsies should be proposed only in the case of very diffuse LGG that cannot be removed (such as gliomatosis-like) or when surgical resection is contraindicated for other medical issues.

17. With advancement in technology ,morbidity of surgery has decreased hence surgery is the mainstay of treatment . Extent of resection : No prospective randomized trials to assess the impact of maximal tumor resection so maximal safe resection preferred Observation with MRI monitoring : can be reserved for very few patients with ≤ 1cm tumor and minimal symptoms

18. POST OP HISTOPATHOLOGY REPORT Grading (AMEN) Grade1 – Nuclear Atypia, MIB<5%. Grade2- MIB 5-10% Grade3- MIB >10% Grade4- Endothelial Proliferation or Necrosis. Histology – Pilocytic Astrocytoma, Ganglioganglioma , Pilocytic Xanthoastrocytoma . Grade - Nuclear atypia, Mitosis(MIB index), Endothelial proliferation, Necrosis. IHC.

19. IHC

20. Treatment after Surgery Grade 1 – Obseravtion with MRI brain every 6 months. Grade 2- Low Risk- <40years, GTR- Obseravtion with MRI brain every 6 months. High Risk- >40 years, STR, Biopsy, Neurologic Defecit , tumor size>4cm, Astrocytoma/Oligodendroglioma. Category1 – Radiotherapy+ Adjuvant PCV. Radiotherapy+ Temozolamide .

21. Adjuvant radiotherapy PROS Improves outcome in unresectable & partially resectable tumors increased Progression Free Survival RT does not decrease seizure CONS No improvement in overall survival Increased morbidity especially in young pt :neurocognitive decline , dementia , behavioural changes, vasculopathy, development of 2nd malignancy .

22. RT vs observation (RTOG 9802) A Phase II Study Of Observation In Favourable Low-grade Glioma And A Phase III Study Of Radiation With Or Without PCV Chemotherapy In Unfavorable Low-grade Glioma total 362 eligible pts accrued between 1998 and 2002. Median follow-up time 4 years. For 111 favourable pts observed on Arm 1, OS at 2- and 5-yrs is 99% and 94%. PFS at 2- and 5-yrs is 82% and 50% Risk Factors predictive of a poorer PFS Pre-operative tumor diameter of >/=4 cm Astrocytoma histology Residual tumor of >/=1 cm 2 on Postop MR Patients with: All 3 unfavorable factors- PFS at 5years -13% None of the three factors- PFS at 5years -70%

23. Indications for observation So, on the basis of above data Observation after surgery can be a reasonable strategy for the most favorable subset i.e. age ≤ 40 years . Preoperative tumor diameter <4 cm . gross total resection (GTR). <1 cm residual tumor

24. Timing of RT : Early vs. delayed Immediate, if significant mass or symptoms For incompletely resected unresectable or only biopsy tumors presence of ≥3 “high-risk” features on the basis of Pignatti score Delayed, if minimal mass or symptoms after gross total resection ≤ 2 high-risk” features on the basis of Pignatti score

25. phase III trial :311 pts (WHO 1–2, 51% astro., 14% oligo., 13% mixed oligo-astro) treated with surgery (42% GTR, 19% STR,35% biopsy) randomized to observation f/b RT at progression vs. post-op RT to 54 Gy. RT improved median PFS (5.3 year vs. 3.4 year hazard ratio 0.59, p<0.0001) but not OS . median survival 7.4 years RT arm vs. 7.2 in observation arm p=0.872). 65% pts in observation arm received salvage RT. Better seizure control rates at 1 year with early RT No difference in rate of malignant transformation (66–72%). CONCLUSION : early radiotherapy improves symptoms control & PFS but no improvement in OS delayed radiotherapy does not affect survival EORTC 22845 (Karim et al. 2002 ; van den Bent et al. 2005 )

26. P rognostic factor analysis done on Phase III adult LGG trials (EORTC 22844 and 22845): Risk Factors identified from EORTC 22844 & Validated in EORTC 22845 Multivariate analysis showed that unfavorable prognostic factors for survival were age ≥ 40 years, astrocytoma histology subtype largest diameter of the tumor > or = 6 cm tumor crossing the midline presence of neurologic deficit before surgery Low Risk Patient: </= 2 factors (Median Survival- 7.7 y rs ) High Risk: 3 or more factors (Median Survival- 3.2 years) Low risk patients are typically observed postoperatively and given RT at disease progression or recurrence

27. DOSE OF RT:THREE PHASE III TRIALS RT improved median PFS (5.3 year vs. 3.4 year)(p<.001) but not overall survival. Consequently, low-dose radiotherapy, 45 -54 Gy in 1.8 Gy-2Gy per fractions, has become an accepted practice

28. Target Volume For Radiotherapy in LGG . CTV= T2 FLAIR IMAGES +1-2 cm MARGIN may be used. PTV = CTV +0.5cm

29. Chemotherapy

30. INT/RTOG 9802 trial Phase III Study Of Radiation With Or Without PCV Chemotherapy In Unfavorable Low-grade Glioma Initial results 2006 From 1998 to 2002, 251 patients median follow up 6 years RESULTS 5-year OS rates for RT versus RT/PCV were 7.5 years versus not reached respectively ( p = 0.33) trend toward improved 5 year PFS 63 vs. 46%(p = 0.06) acute grade 3/4 toxicity occurred in 67% in RT plus PCV, vs. 9% in RT alone . Conclusion: PCV do not provide a survival advantage over RT alone

31. median follow-up time is 11.9 years. RT followed by PCV yielded significantly longer median survival (MST) compared to RT alone (13.3 vs. 7.8 years, p = 0.03) I mprovement in PFS (10.4 vs. 4.0 years, p = 0.002). Treatment arm was identified as a prognostic variable in favour of RT + PCV for both OS (p = 0.003) and PFS (p < 0.001). Conclusion: PCV provided significant survival advantage over RT alone International Journal of Radiation Oncology • Biology • Physics , Volume 90 , Issue 1 , S37 - S38

32. Role of temozolomide more preferable option compared to PCV chemotherapy oral administration better toxicity profile Retrospective series and small phase II studies showed objective response in disease progression 1-3 First-line treatment with TMZ compared to RT did not improve PFS in high-risk LGG patients (EORTC 22033) Further phase III trials needed Hoang-Xuan K, Capelle L, Kujas M, et al. Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions. J Clin Oncol 2004;22:3133–3138 Brada M, Viviers L, Abson C, et al. Phase II study of primary temozolomide chemotherapy in patients with WHO grade II gliomas. Ann Oncol 2003;14:1715–1721. Quinn JA, Reardon DA, Friedman AH, et al. Phase II trial of temozolomide in patients with progressive low-grade glioma. J Clin Oncol 2003;21:646–651.

33. Conclusion for chemotherapy in high risk LGG* RTOG 9802 (1998-2002) shows significant survival advantage with PCV chemotherapy However, in the intervening decade novel molecular markers as well as newer chemotherapy agents such as temozolomide have been developed. So optimal parameter for selecting patients for adjuvant PCV has yet to be decided . And It is still unclear if temozolomide can replace PCV . Hence further trials needed . *Van den Bent MJ. Practice changing mature results of RTOG study 9802: another positive PCV trial makes adjuvant chemotherapy part of standard of care in low-grade glioma. Neuro-Oncology . 2014;16(12):1570-1574. *Radiation Therapy Oncology Group 9802: Controversy or Consensus in the Treatment of Newly Diagnosed Low-Grade Glioma? Seminars in Radiation Oncology Volume 25, Issue 3, July 2015, Pages 197–202

34. RECURRENT DISEASE Most of the time the lesion progresses at the original site At the time of progression, often (in up to 70% of patients) the lesion has dedifferentiated to a higher grade of malignancy. Patients must be managed on an individual basis, depending on the timing of the relapse, previous treatments, and accessibility for clinically significant surgery. Treatment options for recurrence include surgery, reirradiation (e.g., EBRT, brachytherapy, stereotactic radiation therapy, radiosurgery) and chemotherapy (or second-line chemotherapy).

35. SUMMARY Grade I Gliomas Complete resection: offers excellent survival, : majority (>90%) cured of the tumor; no adjuvant therapy is necessary. Incomplete resection: associated with long-term survival rates of 70% to 80% at 10 years hence usual recommendation is for close follow-up, PORT: indicated in very few cases depending on the location of the tumor, the extent of residual disease, the feasibility of repeated surgical excision, and availability for follow-up

36. Grade II Gliomas Maximal surgical resection Postoperative Radiochemotherapy improves progression-free survival and seizure control were superior. The typical radiotherapy dose is 45 to 54 Gy . Chemotherapy: Indicated in high risk LGG post Radiotherapy.(PCV -6cycles)

37. Thank You Reference: 1.Perez and Brady principles of Radiation Oncology 7 th edition. 2. Gunderson & Tepper’s CLINICAL RADIATION ONCOLOGY 5 th edition.