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Low Grade Gliomas

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different modalities of treatment in low grade gliomas

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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 diverse group of uncommon central nervous system (CNS) tumors that occur primarily in children and young adults. 2
  3. 3.  The concept of dividing astrocytomas into discrete grades associated with a distinct clinical prognosis dates back to the mid-1920s and early 1930s to the work of Bailey and Cushing, who recognized a subset of astrocytomas that had a more favorable 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 nuclear abnormalities, mitoses, endothelial proliferation, and necrosis, but the most widely used and accepted grading system today is the WHO system. 3
  4. 4.  WHO Grade I lesions have low proliferative potential, with the possibility of cure following surgery alone.  WHO Grade II neoplasms are infiltrative, often recur, and tend to progress to higher grades of malignancy (e.g., grade II astrocytoma transforms to grade III anaplastic astrocytoma) despite low level proliferative activity.  All grading schemes are limited by their need to separate gliomas artificially into three or four groups, when in actuality they exist along a biologic continuum. 4
  5. 5. Type WHO Grade  Astrocytic Tumors Subependymal giant cell astrocytomas I Pilocytic astrocytomas I Pleomorphic xanthoastrocytomas II Diffuse astrocytoma II  Oligodendroglial Tumors Oligodendrogliomas II  Oligoastrocytic Tumors Oligoastrocytomas II 5
  6. 6.  Low-grade astrocytomas make up 5% to 15% of adult primary brain tumors 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 the brain and spinal cord. The cytoplasmic processes that extend from the astrocytes contain a characteristic filamentous protein, glial fibrillary acidic protein (GFAP), which provides an immunohistochemical 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, and gemistocytic types.  They represent 70% of low-grade cerebral astrocytomas.  Diffuse astrocytomas are usually poorly circumscribed and are capable of undergoing anaplastic transformation. 7
  8. 8.  Fibrillary astrocytomas, the most common subtype, and Protoplasmic astrocytomas have been referred to as “ordinary” astrocytomas and share a similar prognosis. Over time, at least 50% of these tumors transform into more anaplastic lesions.  Gemistocytic astrocytomas are composed of large, plump astrocytes with abundant eosinophilic cytoplasm. Gemistocytes commonly transform into highly anaplastic cells, and behave in an aggressive fashion. 8
  9. 9.  The Pilocytic astrocytomas (WHO grade I), which comprise nearly all of the remainder of the cerebral astrocytomas, tend to be better circumscribed. They are composed of fusiform cells with unusually long, wavy processes called Rosenthal fibers. Mitosis is rarely seen. Pilocytic astrocytomas have a long natural history and rarely transform. Although they occur more commonly in the cerebellum of children (juvenile pilocytic astrocytoma), they also occur in the cerebral hemispheres and near the optic tracts.  Remaining are the uncommon low-grade glioma variants, including the Pleomorphic Xanthoastrocytomas, Subependymal Giant Cell Astrocytomas, and Dysembryoblastic Neuroepithelial tumor. 9
  10. 10.  A two-tiered system, low-grade and anaplastic, is used to grade Oligodendrogliomas. In the WHO classification low-grade lesions are labeled grade II and anaplastic lesions are labeled as grade III.  Patients with grade II tumors have a median survival of 9.8 years whereas those with grade III tumors have a median survival of 4.6 years.  An important additional diagnostic assessment that should be performed on all oligodendroglial tumors is for the presence of deletions of chromosomes 1p and 19q. If these deletions are present, tumors tend to behave more indolently and are more responsive to therapy (especially chemotherapy). 10
  11. 11.  Many oligodendrogliomas are admixed with astrocytoma or ependymoma components. The presence of up to 50% astroglial component is accepted to make the diagnosis of mixed Oligoastrocytoma in the WHO classification.  The median survival for patients with low-grade mixed oligoastrocytomas is 7 years.  Most oligoastrocytomas and 50% to 75% of oligodendrogliomas recur 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 values of 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) and glioblastoma multiforme (GM) tumors. 12
  13. 13.  Biologic Characteristics : Combined 1p and 19q deletions are associated with a superior outcome and are most common in oligodendrogliomas. TP53 mutations are more common in diffuse astrocytomas and are mutually exclusive from 1p/19q co-deletions. IDH1 mutations occur in the vast majority of low-grade gliomas and are found both in tumors with TP53 mutations and in tumors with 1p/19q co-deletions. 13
  14. 14.  Low-grade gliomas are generally a disease of patients in their 20s, 30s, or 40s.  The most common symptom is seizure, occurring in two thirds of patients. Focal seizures are more common than generalized ones.  Headache and weakness occur in approximately one third of patients.  The remaining symptoms (vomiting, motor deficit, visual or sensory loss, language disturbance, or personality change) occur in 15% or fewer patients.  Symptoms may be present for months or years before a diagnosis is made. 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 of the 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 large phase III adult low grade glioma trials (EORTC trials 22844 and 22845). The following negative risk factors were identified and validated: 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-risk group (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 has been justified in the literature for several reasons. These reasons include the relatively favorable natural history of the disease, the lack of proven benefit for invasive interventions such as surgical resection or radiation therapy, and the potential morbidities of treatment.  Patients who are observed should be monitored at regular intervals (e.g., every 6 months) to detect radiologic progression before new signs and symptoms occur. 18
  19. 19.  Despite the favorable survival rates observed in certain subsets of patients with low-grade gliomas, the natural history of all pathologic types of supratentorial low-grade gliomas, including the pilocytic astrocytomas (WHO I), diffuse astrocytomas, oligoastrocytomas, and oligodendrogliomas (WHO II), is significantly worse than that of an age- and sex matched control population, for which the expected survival rate is greater than 95%.  Based on this observation, some have argued that all such patients should undergo Maximal Safe Surgical Resection followed by postoperative 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 supratentorial low- grade gliomas are : whether to perform a biopsy on a patient whose clinical presentation and imaging studies suggest a low-grade glioma, and what should be the extent of resection.  Although one series in the literature suggests that the survival rate of patients irradiated for presumed low-grade glioma is comparable to that of patients irradiated for histologically verified low-grade astrocytoma, the possibility of inappropriate management in up to 50% of cases diagnosed by imaging underscores the need for histologic verification if a therapeutic intervention is planned. 22
  23. 23.  A number of retrospective studies have suggested a benefit for greater extent of resection.  A long-term follow-up (median, 13.6 years) study from the Mayo Clinic reviewed 314 adult low-grade glioma patients and found on multivariate analyses significantly improved OS and PFS rates with gross total resection or nearly gross total resection. Almost 50% of patients after gross total resection or nearly gross total resection were 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 216 low-grade glioma patients. Patients with at least 90% extent of resection had 5- and 8-year OS of 97% and 91%, respectively, whereas patients with less than 90% extent of 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 both predicted 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 of resection.  The phase II portion of RTOG 9802 prospectively observed 111 low-risk cases after neurosurgically defined gross total resection. Review of the post-operative MRI emphasized the importance of post-operative imaging to confirm the extent of resection because a substantial minority of patients had residual disease (32% with 1 to 2 cm of residual disease and 9% with more than 2 cm of residual tumor). The crude incidence of tumor recurrence was 26% with a residual tumor of less than 1 cm, 68% with a residual tumor of 1 to 2 cm, and 89% with a residual tumor of more than 2 cm. 25
  26. 26.  Although there are no randomized trials that directly assess the impact of maximal tumor resection in low-grade gliomas, a review of the literature suggests a benefit for Maximal Safe tumor Resection, recognizing the importance of achieving this with as little morbidity as possible. 26
  27. 27. External Beam Radiation  The key external beam irradiation (EBRT) issues in the management 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 the observation 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 prospectively observed 111 low-risk (age younger than 40 years and neuro-surgically defined 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, and pre-operative tumor diameter of 4 cm or more were 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 the most favorable subset (<1 cm residual tumor, preoperative tumor diameter <4 cm, and oligodendroglioma histology) of younger patients after a gross total resection (GTR). 30
  31. 31.  Radiation, however, has several other beneficial effects besides the potential delay in tumor recurrence.  In a small series of 25 patients with medically intractable epilepsy resulting from an underlying cerebral low-grade glioma, achieved a significant reduction (>50% decrease) in seizure frequency after radiotherapy.  In the EORTC phase III randomized trial 22845, there were no differences in seizure control at baseline, but at 1 year there were significantly fewer seizures in the irradiated group (25%) than in the observation group (41%). 31
  32. 32.  It has been suggested that radiation therapy may either increase or decrease the likelihood of malignant transformation or may delay its 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) between the study arms at the time of progression.  These data imply that irradiation neither increases nor decreases the likelihood of malignant transformation, suggesting that dedifferentiation is a biologic phenomenon observed in low-grade gliomas independent of the treatment. 32
  33. 33. Dose of Radiation  Regarding the potential benefit of higher doses of radiation therapy compared with lower doses, two prospective randomized clinical trials (EORTC 22844 and NCCTG 86-72-51) failed to show improved outcome with higher radiation therapy doses.  Taken together these trials support moderate doses in the range 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 Gy radiation therapy using multiple localized treatment fields. Initial analysis failed to demonstrate a difference in survival rates between 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 neurologic status 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 survival rates between the two doses. The 5-year OS was 73% with 50.4 Gy and 68% with 64.8 Gy. Best survival in patients <40 year, tumor <5 cm, oligo histology and GTR. Pattern of failure: 92% in field, 3% within 2 cm of RT field. 35
  36. 36.  Several series analyzing failure patterns in irradiated patients with low-grade hemispheric gliomas suggest that when tumor progression occurs, it almost always is at the site of the primary tumor within the treatment volume, which implies that Partial Brain Irradiation is appropriate.  This was confirmed in NCCTG 86-72-51 (prospective dose response trial) with 92% of failures occurring in the treatment field, 3% within 2 cm of the treatment field, and 5% more than 2 cm beyond the treatment field.  These data support the appropriateness of partial brain irradiation. 36
  37. 37.  Several phase II Chemotherapy studies have shown efficacy of both Temozolomide and PCV (procarbazine,CCNU, vincristine) chemotherapy in either newly diagnosed or progressing low-grade gliomas.  The studies on newly diagnosed tumors show that the response assessment may be difficult, and that most cases have radiologically stable disease as their best response to chemotherapy (at times, even despite clinical improvement and improved seizure control).  As a result, the PFS appears to be a more informative endpoint than the radiologic improvement rate. 37
  38. 38.  Data from phase III studies on chemotherapy in low-grade gliomas are scarce.  The most significant study is the INT/RTOG 9802 trial (ASCO abstract 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 to RT 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 radiotherapy followed by PCV chemotherapy. 38
  39. 39.  Recently, Temozolomide has shown its effectiveness in the initial treatment 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 median PFS 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 deletions on 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) were retrospectively evaluated for response by central review of MRI-s. Chromosome 1p and 19q deletions were detected by the loss of the heterozygosity 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 cycles delivered was 14 (range 2 to 30). 77 patients (53%) experienced an objective response (including 22 [15%] cases of partial response and 55 [38%] cases of minor response), 55 (37%) patients had stable disease, and 14 (10%) had a progressive disease. The median time to maximum tumor response 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 was significantly associated with a higher rate (p = 0.02) and longer objective response 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 chromosome 1p/19q predicts both a durable chemosensitivity and a favorable outcome. 41
  42. 42.  An EORTC trial attempts to address the role of temozolomide in newly diagnosed low-grade glioma patients. This EORTC trial randomizes patients with progressive disease, uncontrolled seizures despite anticonvulsants, or neurologic symptoms to standard radiation therapy or daily low-dose temozolomide. Patients are stratified based on 1p status (intact vs. deleted), as well as age, tumor size, and Karnofsky performance status (KPS) score with a primary endpoint of PFS.  An Intergroup phase III trial with similar eligibility criteria and stratification factors is investigating the efficacy of combined chemoradiation with temozolomide compared with radiotherapy alone. 42
  43. 43. Recommended Treatment  Juvenile Pilocytic Astrocytoma, Subependymal Giant Cell Astrocytoma, Pleomorphic Xanthoastrocytoma, Dysembryoblastic Neuroepithelial tumor : i) Gross Total Resection  Observation ii) 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 Astrocytomas GTV: contrast-enhancing lesion and any associated cyst PTV: GTV plus 1–1.5 cm Infiltrating Low-Grade Gliomas GTV: (FLAIR)/T2 abnormality and any contrast enhancement PTV: 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

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