Low Grade Gliomas


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different modalities of treatment in low grade gliomas

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  • Delay in recurrence
  • Low Grade Gliomas

    1. 1. LOW GRADE GLIOMAS DR ARNAB BOSE Dept. of Radiotherapy NRS Medical Colleg,Kolkata 1
    2. 2.  Low-grade gliomas are a pathologically and clinically diversegroup of uncommon central nervous system (CNS) tumorsthat occur primarily in children and young adults. 2
    3. 3.  The concept of dividing astrocytomas into discrete gradesassociated with a distinct clinical prognosis dates back to themid-1920s and early 1930s to the work of Bailey and Cushing,who recognized a subset of astrocytomas that had a morefavorable outcome than glioblastoma. There have been many grading systems(e.g., Kernohan, St. Anne-Mayo, and Ringertz systems) in the past,and most of these grading systems share an assessment of nuclearabnormalities, mitoses, endothelial proliferation, and necrosis,but the most widely used and accepted grading system today is theWHO system. 3
    4. 4.  WHO Grade I lesions have low proliferative potential, withthe possibility of cure following surgery alone. WHO Grade II neoplasms are infiltrative, often recur, and tend toprogress to higher grades of malignancy (e.g., grade II astrocytomatransforms to grade III anaplastic astrocytoma) despite low levelproliferative activity. All grading schemes are limited by their need to separate gliomasartificially into three or four groups, when in actuality they exist along abiologic continuum. 4
    5. 5. Type WHO Grade Astrocytic TumorsSubependymal giant cell astrocytomas IPilocytic astrocytomas IPleomorphic xanthoastrocytomas IIDiffuse astrocytoma II Oligodendroglial TumorsOligodendrogliomas II Oligoastrocytic TumorsOligoastrocytomas II 5
    6. 6.  Low-grade astrocytomas make up 5% to 15% of adult primary braintumors and 67% of low-grade gliomas,the remainder of low-grade gliomas being mixed Oligoastrocytomas(19%) and Oligodendrogliomas (13%). Astrocytic gliomas, arise from astrocytes, the supporting cells of thebrain and spinal cord. The cytoplasmic processes that extend from theastrocytes contain a characteristic filamentous protein,glial fibrillary acidic protein (GFAP), which provides animmunohistochemical marker for these tumors. 6
    7. 7.  The Diffusely infiltrative low-grade astrocytomas (WHO grade II)are the most common and include the fibrillary, protoplasmic, andgemistocytic types. They represent 70% of low-grade cerebral astrocytomas. Diffuse astrocytomas are usually poorly circumscribed and arecapable of undergoing anaplastic transformation. 7
    8. 8.  Fibrillary astrocytomas, the most common subtype, andProtoplasmic astrocytomas have been referred to as “ordinary”astrocytomas and share a similar prognosis. Over time, at least 50% ofthese tumors transform into more anaplastic lesions. Gemistocytic astrocytomas are composed of large, plump astrocyteswith abundant eosinophilic cytoplasm. Gemistocytes commonlytransform into highly anaplastic cells, and behave in an aggressivefashion. 8
    9. 9.  The Pilocytic astrocytomas (WHO grade I), which comprisenearly all of the remainder of the cerebral astrocytomas, tendto be better circumscribed. They are composed of fusiform cells withunusually long, wavy processes called Rosenthal fibers. Mitosis is rarelyseen. Pilocytic astrocytomas have a long natural history and rarelytransform. Although they occur more commonly in the cerebellumof children (juvenile pilocytic astrocytoma), they alsooccur in the cerebral hemispheres and near the optic tracts. Remaining are the uncommon low-grade glioma variants,including the Pleomorphic Xanthoastrocytomas, SubependymalGiant Cell Astrocytomas, and Dysembryoblastic Neuroepithelial tumor. 9
    10. 10.  A two-tiered system, low-grade and anaplastic, is used to gradeOligodendrogliomas. In the WHO classification low-grade lesions arelabeled grade II and anaplastic lesions are labeled as grade III. Patients with grade II tumors have a median survival of 9.8 yearswhereas those with grade III tumors have a median survival of 4.6years. An important additional diagnostic assessment that should beperformed on all oligodendroglial tumors is for the presence ofdeletions of chromosomes 1p and 19q. If these deletions are present,tumors tend to behave more indolently and are more responsive totherapy (especially chemotherapy). 10
    11. 11.  Many oligodendrogliomas are admixed with astrocytoma orependymoma components. The presence of up to 50% astroglialcomponent is accepted to make the diagnosis of mixedOligoastrocytoma in the WHO classification. The median survival for patients with low-grade mixedoligoastrocytomas is 7 years. Most oligoastrocytomas and 50% to 75% of oligodendrogliomasrecur as AAs or GBM. 11
    12. 12.  Tumor Proliferation can be assessed with Ki-67 labeling. A large review on Ki-67 labeling revealed increasing valuesof Ki-67/MIB-1 labeling index with increasing grade of malignancy. The MIB-1 labeling index differentiates diffuse astrocytomas(WHO grade II) from anaplastic astrocytomas (WHO grade III) andglioblastoma multiforme (GM) tumors. 12
    13. 13.  Biologic Characteristics :Combined 1p and 19q deletions are associated with a superioroutcome and are most common in oligodendrogliomas.TP53 mutations are more common in diffuse astrocytomas and aremutually exclusive from 1p/19q co-deletions.IDH1 mutations occur in the vast majority of low-grade gliomas andare found both in tumors with TP53 mutations and in tumors with1p/19q co-deletions. 13
    14. 14.  Low-grade gliomas are generally a disease of patients in their20s, 30s, or 40s. The most common symptom is seizure, occurring intwo thirds of patients. Focal seizures are more common thangeneralized ones. Headache and weakness occur in approximately one third ofpatients. The remaining symptoms (vomiting, motor deficit, visual orsensory loss, language disturbance, or personality change)occur in 15% or fewer patients. Symptoms may be present for months or years before a diagnosis ismade. 14
    15. 15.  MRI : T1 - pre and post-gadolinium(contrast), T2, and FLAIR (fluid attenuation inversion recovery, removes increased CSF signal on T2). Tumor enhancement with gadolinium correlates with breakdown ofthe blood–brain barrier. Tumor: High grade – increased signal on T1 post-gadolinium and T2 (T2 also shows edema). Low grade – increased signal on T2 / FLAIR. 15
    16. 16.  Pilocytic astrocytoma (Grade I) : enhancing nodule, highly vascular, 50% associated with cysts. Diffuse astrocytoma (Grade II) : non-enhancing, hypo-intense on T1, hyper-intense on T2/FLAIR , well-circumscribed, solid. Oligodendroglioma : calcifications associated frequently 16
    17. 17.  A Prognostic Scoring system was developed using imaging, patient,and tumor characteristics derived from the databases of two largephase III adult low grade glioma trials (EORTC trials 22844 and22845). The following negative risk factors were identified andvalidated: age 40 years or older, astrocytoma histology subtype(compared to oligo/mixed), largest diameter of the tumor of 6 cm or more, tumor crossing the midline, and presence of neurologic deficit before surgery. The presence of 2 of these factors or fewer identified a low-riskgroup (median survival, 7.7 years),whereas 3 risk factors or more identified a high-risk group(median survival, 3.2 years). 17
    18. 18. Observation The decision to Observe a patient with low-grade glioma hasbeen justified in the literature for several reasons. Thesereasons include the relatively favorable natural history of thedisease, the lack of proven benefit for invasive interventionssuch as surgical resection or radiation therapy, and the potentialmorbidities of treatment. Patients who are observed should be monitored at regular intervals(e.g., every 6 months) to detect radiologic progression before newsigns and symptoms occur. 18
    19. 19.  Despite the favorable survival rates observed in certain subsets ofpatients with low-grade gliomas, the natural history of all pathologictypes of supratentorial low-grade gliomas, including the pilocyticastrocytomas (WHO I), diffuse astrocytomas, oligoastrocytomas, andoligodendrogliomas (WHO II), is significantly worse than that of anage- and sex matched control population, for which the expectedsurvival rate is greater than 95%. Based on this observation, some have argued that all such patientsshould undergo Maximal Safe Surgical Resection followed bypostoperative radiation therapy. 19
    20. 20. 20
    21. 21. Surgery vs. Observation Pros: i)If symptoms are uncontrolled medically, then benefits of surgery on seizures / raised ICT are fairly dramatic ii)Imaging can be misleading in upto 40% cases iii)Early Surgery delays reappearance of symptoms and tumor growth iv)Survival advantage to gross resection in retrospective literature Cons: i)Possibility of complications in a minimally symptomatic person 21
    22. 22. Surgery The key surgical issues in the management of supratentoriallow- grade gliomas are : whether to perform a biopsy on a patientwhose clinical presentation and imaging studies suggest a low-gradeglioma, and what should be the extent of resection. Although one series in the literature suggests that the survival rateof patients irradiated for presumed low-grade glioma is comparable tothat of patients irradiated for histologically verified low-gradeastrocytoma, the possibility of inappropriate management in up to50% of cases diagnosed by imaging underscores the need forhistologic verification if a therapeutic intervention is planned. 22
    23. 23.  A number of retrospective studies have suggested a benefit forgreater extent of resection. A long-term follow-up (median, 13.6 years) study fromthe Mayo Clinic reviewed 314 adult low-grade glioma patients andfound on multivariate analyses significantly improved OS and PFSrates with gross total resection or nearly gross total resection. Almost50% of patients after gross total resection or nearly gross total resectionwere free of recurrence 10 years after diagnosis. 23
    24. 24.  Investigators from the University of California San Francisco(UCSF) measured tumor volumes based on FLAIR imaging in 216low-grade glioma patients.Patients with at least 90% extent of resection had 5- and 8-year OS of97% and 91%, respectively, whereas patients with less than 90% extentof resection had 5- and 8-year OS of 76% and 60%, respectively.After adjusting for age, Karnofsky performance status (KPS) score,tumor location, and tumor subtype, OS and PFS outcomes were bothpredicted by post-operative tumor volume.Limitation of this study was the relatively short follow-up (4.4yrs). 24
    25. 25.  Prospective trials have also found a benefit for greater extent ofresection. The phase II portion of RTOG 9802 prospectivelyobserved 111 low-risk cases after neurosurgically defined gross totalresection. Review of the post-operative MRI emphasized theimportance of post-operative imaging to confirm the extent ofresection because a substantial minority of patients had residualdisease (32% with 1 to 2 cm of residual disease and 9% with more than2 cm of residual tumor).The crude incidence of tumor recurrence was 26% with a residualtumor of less than 1 cm, 68% with a residual tumor of 1 to 2 cm, and89% with a residual tumor of more than 2 cm. 25
    26. 26.  Although there are no randomized trials that directly assess theimpact of maximal tumor resection in low-grade gliomas, a review ofthe literature suggests a benefit for Maximal Safe tumor Resection,recognizing the importance of achieving this with as little morbidity aspossible. 26
    27. 27. External Beam Radiation The key external beam irradiation (EBRT) issues in themanagement of supratentorial low-grade gliomas are twofold.The issues include the timing of radiation with regard to when radiation is given (post-operative vs. at the time of recurrence), and the appropriate dose and treatment volume. 27
    28. 28.  EORTC 22845 (Karim et al. 2002; van den Bent et al. 2005) –phase III: 311 patients (WHO 1–2, 51% astro., 14% oligo., 13%mixed oligo-astro) treated with surgery (42% GTR, 19% STR,35% biopsy) randomized to observation vs. post-op RT to 54 Gy.RT improved median PFS (5.3 year vs. 3.4 year), 5-year PFS (55 vs.35%), but not OS (68 vs. 66%). Sixty-five percent of patients in theobservation arm received salvage RT.No difference in rate of malignant transformation (66–72%).No survival benefit, but RT delays time to relapse by ~2 years. 28
    29. 29.  The RTOG phase II portion of protocol 9802 prospectivelyobserved 111 low-risk (age younger than 40 years and neuro-surgicallydefined gross total resection) low-grade glioma patients.In this “low-risk” population, the 5-year OS was 93%.Astrocytoma histology,residual tumor of 1 cm or more according to MR imaging, andpre-operative tumor diameter of 4 cm or morewere found to be predictive of a poorer PFS. 29
    30. 30. In patients with all three unfavorable prognostic factors,the 2- and 5-year rates of PFS were 60% and 13%, respectively.In patients with none of the three unfavorable prognostic factors,the 2- and 5-year rates of PFS were 100% and 70%, respectively.These data suggest that observation is a reasonable strategy for themost favorable subset (<1 cm residual tumor, preoperative tumordiameter <4 cm, and oligodendroglioma histology) of younger patientsafter a gross total resection (GTR). 30
    31. 31.  Radiation, however, has several other beneficial effects besidesthe potential delay in tumor recurrence. In a small series of 25 patients with medically intractable epilepsyresulting from an underlying cerebral low-grade glioma, achieved asignificant reduction (>50% decrease) in seizure frequency afterradiotherapy. In the EORTC phase III randomized trial 22845, there were nodifferences in seizure control at baseline, but at 1 year there weresignificantly fewer seizures in the irradiated group (25%) than in theobservation group (41%). 31
    32. 32.  It has been suggested that radiation therapy may either increase ordecrease the likelihood of malignant transformation or may delayits onset. However, in the EORTC phase III randomized trial 22845,there were no differences in the malignant transformation rate(observation group-66% vs.72% in the irradiated group) betweenthe study arms at the time of progression. These data imply that irradiation neither increases nor decreases thelikelihood of malignant transformation, suggesting that dedifferentiationis a biologic phenomenon observed in low-grade gliomas independentof the treatment. 32
    33. 33. Dose of Radiation Regarding the potential benefit of higher doses of radiationtherapy compared with lower doses, two prospective randomizedclinical trials (EORTC 22844 and NCCTG 86-72-51) failedto show improved outcome with higher radiation therapy doses. Taken together these trials support moderate doses in therange of 45 to 54 Gy using localized fields. 33
    34. 34.  EORTC 22844 (Karim et al. 1996) – phase III: 343 patients(WHO 1–2, astro., oligo. and mixed) treated with surgery (25% GTR,30% STR, 40% biopsy) randomized to post-op RT 45 Gy vs. 59.4 Gyradiation therapy using multiple localized treatment fields.Initial analysis failed to demonstrate a difference in survival ratesbetween the two doses. The 5-year OS was 58% with 45 Gy and 59%with 59.4 Gy.Five-year OS oligo vs. astro = 75 vs. 55%, <40 year vs. >40 year = 80 vs. 60%. Age <40 year, oligo histology, low T-stage, GTR, and good neurologicstatus are important prognostic factors. 34
    35. 35.  INT/NCCTG (Shaw et al. 2002) – phase III: 203 patients(WHO 1–2, astro, oligo, mixed) treated with surgery (14% GTR,35% STR, 51% Bx) randomized to post-op RT 50.4 Gy vs. 64.8 Gy.also using multiple localized treatment fields.Initial analysis also failed to demonstrate a difference in survivalrates between the two doses. The 5-year OS was 73% with50.4 Gy and 68% with 64.8 Gy.Best survival in patients <40 year, tumor <5 cm, oligo histology andGTR.Pattern of failure: 92% in field, 3% within 2 cm of RT field. 35
    36. 36.  Several series analyzing failure patterns in irradiated patients withlow-grade hemispheric gliomas suggest that when tumor progressionoccurs, it almost always is at the site of the primary tumor within thetreatment volume, which implies that Partial Brain Irradiation isappropriate. This was confirmed in NCCTG 86-72-51 (prospective doseresponse trial) with 92% of failures occurring in the treatment field,3% within 2 cm of the treatment field, and 5% more than 2 cmbeyond the treatment field. These data support the appropriateness of partial brain irradiation. 36
    37. 37.  Several phase II Chemotherapy studies have shown efficacy ofboth Temozolomide and PCV (procarbazine,CCNU, vincristine)chemotherapy in either newly diagnosed or progressing low-gradegliomas. The studies on newly diagnosed tumors show that the responseassessment may be difficult, and that most cases have radiologicallystable disease as their best response to chemotherapy(at times, even despite clinical improvement and improvedseizure control). As a result, the PFS appears to be a more informative endpoint thanthe radiologic improvement rate. 37
    38. 38.  Data from phase III studies on chemotherapy in low-gradegliomas are scarce. The most significant study is the INT/RTOG 9802 trial (ASCOabstract 2008): phase III of low-grade gliomas.Low-risk (<40 year + GTR) observed until symptoms.251 high-risk (>40 year or STR or biopsy) patients randomized toRT alone vs. RT --> PCV ×6 cycles q8 weeks.RT 54 Gy to FLAIR + 2 cm margin. No boost.Five-year OS was 72 vs. 63% (p = 0.33), 5-year PFS was 63 vs. 46%(p = 0.06) in favour of addition of chemotherapy. This study noted an increase of PFS but not OS with radiotherapyfollowed by PCV chemotherapy. 38
    39. 39.  Recently, Temozolomide has shown its effectiveness in the initialtreatment of low-grade glioma. In the largest reported retrospective analysis of 149 patients,Kaloshi and colleagues reported a 15% partial response (PR) and 37%stable disease with temozolomide as the initial therapy. The medianPFS was 2.8 years and the 3-year overall survival was 70%.**(Kaloshi G, Benuaich-Amiel A, Diakite F, et al: Temozolomide for low grade gliomas: predictive impact of 1p/19q loss on response and outcome. Neurology 2007; 68:1831- 1836.) 39
    40. 40. Abstract of the study by Kaloshi et al OBJECTIVE:To evaluate the predictive impact of chromosome 1p/19q deletionson the response and outcome of progressive low-grade gliomas (LGG)treated with up-front temozolomide (TMZ) chemotherapy. METHODS:Adult patients with measurable, progressive LGG (WHO grade II)treated with TMZ delivered at the conventional schedule(200 mg/m(2)/day for 5 consecutive days, repeated every 28 days) wereretrospectively evaluated for response by central review of MRI-s.Chromosome 1p and 19q deletions were detected by the loss of theheterozygosity technique (LOH). 40
    41. 41.  RESULTS:A total of 149 consecutive patients were included in this retrospective,single center observational study. The median number of TMZ cyclesdelivered was 14 (range 2 to 30). 77 patients (53%) experienced anobjective response (including 22 [15%] cases of partial response and 55[38%] cases of minor response), 55 (37%) patients had stable disease, and14 (10%) had a progressive disease. The median time to maximum tumorresponse was 12 months (range 3 to 30 months). The median progression-free survival (PFS) was 28 months (95% CI: 23.4 to 32.6).Combined 1p/19q LOH was present in 42% of the cases and wassignificantly associated with a higher rate (p = 0.02) and longer objectiveresponse to chemotherapy (p = 0.017), and both longer PFS (p = 4.10(-5))and overall survival (p = 0.04). CONCLUSION:Low-grade gliomas respond to temozolomide and loss of chromosome1p/19q predicts both a durable chemosensitivity and a favorable outcome. 41
    42. 42.  An EORTC trial attempts to address the role of temozolomide innewly diagnosed low-grade glioma patients. This EORTC trialrandomizes patients with progressive disease, uncontrolled seizuresdespite anticonvulsants, or neurologic symptoms to standard radiationtherapy or daily low-dose temozolomide. Patients are stratified basedon 1p status (intact vs. deleted), as well as age, tumor size,and Karnofsky performance status (KPS) score with a primaryendpoint of PFS. An Intergroup phase III trial with similar eligibility criteria andstratification factors is investigating the efficacy of combinedchemoradiation with temozolomide compared with radiotherapyalone. 42
    43. 43. Recommended Treatment Juvenile Pilocytic Astrocytoma, Subependymal Giant CellAstrocytoma, Pleomorphic Xanthoastrocytoma,Dysembryoblastic Neuroepithelial tumor :i) Gross Total Resection  Observationii) Sub Total Resection  consider Observation vs. Re-resection vs. Radiotherapy vs. Stereotactic Radiosurgery,depending on the location of tumor, symptoms, age of patient 43
    44. 44.  Oligodendroglioma, Oligoastrocytoma, Astrocytoma (adults) :i) Maximal safe resection (GTR or STR)  Observation if - age <40 years, oligodendroglioma, GTR, good function Serial MRIs - if progresses  Radiotherapy 50–54 Gy (standard dose for low-grade gliomas is 54 Gy) 44
    45. 45. Or,ii) Immediate Post-operative Radiothrapy to 54 Gy. No survival benefit, but RT delays time to relapse by ~2 years (EORTC study) Quality of life gained by delaying recurrence must be weighted against QOL lost due to late toxicities of RT 45
    46. 46.  Oligodendroglioma, Oligoastrocytoma, Astrocytoma (children) :i) Maximal safe resection (GTR or STR)  Observation and serial MRIs. Adjuvant Radiotherapy may improve DFS, but not recommended for children <3 years.ii) Consider Second Surgery for operable progression, and Radiotherapy for inoperable progression (doses 45–54 Gy) 46
    47. 47.  Dose : EBRT: 1.8 Gy/fx to 50.4–54 Gy. Volume of Treatment : Pilocytic AstrocytomasGTV: contrast-enhancing lesion and any associated cystPTV: GTV plus 1–1.5 cm Infiltrating Low-Grade GliomasGTV: (FLAIR)/T2 abnormality and any contrast enhancementPTV: GTV plus 1–1.5 cm Follow Up :MRI 2–6 weeks after Radiotherapy, then every 6 month for 5 years,then annually. 47
    48. 48. thank you 48