Management of high grade gliomas
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Management of high grade gliomas






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  • The CUSA permits the neurosurgeon to remove large tumors from teh inside out, "debulking" them quickly and effectively, without traction or manipulation and with minimal transmission of movement to adjacent normal tissues. The instrument's hollow titanium tip, vibrating 23,000 times per second, rapidly fragments even firm tumors. Simultaneously, it delivers an irrigating solution that converts the fragmented tissue into an emulsion and then aspirates the particles, 
  • the anti-integrin cilengitide (CENTRIC) and other agents suchas the VEGFR tyrosine kinase inhibitor cedirinib, are currentlyaddressing this issue.

Management of high grade gliomas Management of high grade gliomas Presentation Transcript

  • Management ofHigh Grade Gliomas Dr. S. Moses Arunsingh PG MDRT Free Powerpoint Templates Page 1
  • Surgery• Maximal surgical resection• One of the more controversial factors in the setting of high grade gliomas has been the extent of surgical resection.• One of the largest involved over 400 patients at the M.D. Anderson Cancer Center and demonstrated improved median survival (13 months vs. 8.8 months;p < .0001) following at least 98% resection Free Powerpoint Templates Page 2
  • • High-grade gliomas are not surgically curable, because of their extensive infiltration.• Goal is the safe removal of the largest possible volume of tumor to establish a diagnosis and relieve mass effect. Free Powerpoint Templates Page 3
  • • Frameless image-guided neuronavigation systems are employed to localize subcortical tumors along with intraoperative ultrasound and MRI.• Occasionally, tumors may be removed en bloc via circumferential dissection, but more frequently, resection is effected in piecemeal fashion. Free Powerpoint Templates Page 4
  • • A cavitational ultrasonic surgical aspirator (CUSA) facilitates removal of a firm, adherent, or calcified tumor.• The first MRI is obtained within 24 to 48 hours after surgery before postoperative changes set in. Free Powerpoint Templates Page 5
  • • If biopsy rather than resection is pursued, choices include stereotactic options with CT or MRI guidance or open craniotomy and biopsy.• Usually, stereotactic biopsy can be performed using either frame-based or frameless neuro navigation systems. Free Powerpoint Templates Page 6
  • ?? Reasons for Resection ??1. Accurate diagnosis. Gliomas are heterogeneous, and therapy is guided by the most aggressive grade in the specimen. – More complete resections are more likely to provide a high-grade diagnosis and to detect an oligodendroglial component Free Powerpoint Templates Page 7
  • 2. Relieves mass effect3. Response to postoperativeradiation therapy is more favorable4. Cytoreduction Free Powerpoint Templates Page 8
  • Radiotherapy• External beam irradiation (EBRT) has historically been the cornerstone of the therapeutic approach to GBM and anaplastic astrocytoma. Free Powerpoint Templates Page 9
  • Free Powerpoint Templates Page 10
  • RT PLANNING• Initially, large opposed lateral fields were employed to cover the entire brain volume.• Brain Tumor Cooperative Group trial 80- 01: Compare partial brain irradiation with whole-brain radiotherapy.• No difference in OS or change in the patterns of failure was seen. Free Powerpoint Templates Page 11
  • • Hochberg and Pruitt used CT scans to determine that nearly 90% of GBM recurrences occurred within 2 cm of the primary tumor site. Free Powerpoint Templates Page 12
  • • Although the dose computation component of treatment planning is still based on CT imaging, effective image registration with MRI has made this the modality of choice for contouring. Free Powerpoint Templates Page 13
  • • Simulated after the surgeon has removed the craniotomy staples (generally, 10 to 14 days after the operation).• An immobilization mask is fashioned to reduce motion during and between fractions. Free Powerpoint Templates Page 14
  • • The planning CT scan is extended to encompass the head and neck region to allow sufficient anatomic areas for proper image fusion and generation of high- quality digitally reconstructed radiographs (DRRs) and to permit the introduction of non coplanar beams• Ideally, the slice thickness should match that of the fusion Postoperative MRI. Free Powerpoint Templates Page 15
  • • The T1 contrast enhanced sequences are used to define the gross tumor volume (GTV)• The T2 or FLAIR sequences plus a margin define the microscopic disease extent, or clinical target volume (CTV) which reflects the bulk of microscopic infiltration• Planning target volume (PTV), both organ motion and setup error must be taken into account Free Powerpoint Templates Page 16
  • RTOG• In the lexicon of the RTOG, the PTV 1 includes the T2 or FLAIR CTV with a margin and is treated to 46 Gy in 2-Gy fractions.• The PTV 2 includes the T1-enhancing GTV with a margin and is treated to an additional 14 Gy. Free Powerpoint Templates Page 17
  • EORTC• The EORTC recommends a single-phase technique using one treatment volume throughout the course of therapy. Free Powerpoint Templates Page 18
  • Treatment Volumes Free Powerpoint Templates Page 19
  • Free Powerpoint Templates Page 20
  • • Accordingly, 45 to 50 Gy delivered, in 1.8- to 2-Gy fractions, to the T2/FLAIR abnormality seen on the image, followed by a boost to raise the total dose to 60 Gy based on the T1-enhancing abnormality, is generally prescribed. Free Powerpoint Templates Page 21
  • • With the advent of functional imaging tools (e.g., functional MRI [fMRI]) it may be possible to specifically modify irradiation doses to functional brain areas.• Region governing motor control (e.g., finger tapping) is delineated to enable an accounting for dose deposition. In this case, this region in the right hemisphere (i.e., governing tapping by the left upper extremity) is included in the high-dose region but the contralateral side is well spared. Free Powerpoint Templates Page 22
  • QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic)• Lawrence and colleagues postulated that the original estimates of Emami and colleagues, suggesting a 5% risk of chronic brain damage at 5 years when one-third of the brain is irradiated to 60 Gy, were overly conservative. Free Powerpoint Templates Page 23
  • IMRT• Despite the absence of level I evidence, IMRT is increasingly used, sometimes to escalate the dose and at other times to spare surrounding tissues or to explore the concomitant boost concept.• However, clinical data supporting the value of IMRT in high-grade gliomas are essentially nonexistent. Free Powerpoint Templates Page 24
  • RT DOSE• A stepwise improvement in survival was observed with doses ranging from less than 45 Gy to 60 Gy, consistent with dose response.• A comparison of 70 Gy versus 60 Gy demonstrated no survival or local control advantage for the 70-Gy dose.• These results established 60 Gy as the standard of care. Free Powerpoint Templates Page 25
  • • There are now multiple techniques for dose escalation, including three- dimensional conformal irradiation, radiosurgery, and brachytherapy, but these have not yielded higher rates of disease control or survival. Free Powerpoint Templates Page 26
  • Fractionation• Various trials examining Hyperfractionation in High Grade Gliomas have been conducted.• None of them showed improved survival. Free Powerpoint Templates Page 27
  • Stereotactic Irradiation• RTOG 93-05 compared conformal irradiation plus carmustine with or without a radiosurgical boost for newly diagnosed GBM.• No differences were observed in terms of OS (median, approximately 13 months in each arm) or quality of life. Free Powerpoint Templates Page 28
  • Brachytherapy• It offers a mechanism for focal dose escalation.• GliaSite radiation therapy system: This intracavitary device isimplanted at the time of tumordebulking, and a solution ofiodine-125 (125I) is injected intoan expandable closed-catheterballoon. Free Powerpoint Templates Page 29
  • • A retrospective study suggested reasonable safety and promising efficacy.• A phase I study was conducted. However, the implant induces changes in imaging that complicate determination of disease progression Free Powerpoint Templates Page 30
  • • Acute radiation morbidity: Fatigue, erythema, alopecia, headache, and, rarely, nausea with or without vomiting; these are generally not severe and are usually self- limiting.• Late effects of radiation: Somnolence and cognitive impairments. Free Powerpoint Templates Page 31
  • • The impact of partial brain irradiation on neurocognitive decline continues to be a hotly debated topic. The confounding factor is always the extent to which there is baseline cognitive impairment or decreased mentation secondary to uncontrolled tumor. Free Powerpoint Templates Page 32
  • • Brain necrosis is a serious and uncommon late toxicity, and recently bevacizumab has been explored as a treatment.• In a small trial, all patients showed improvement of MRI abnormalities as well as a reduction in corticosteroid requirements. Free Powerpoint Templates Page 33
  • CHEMOTHERAPY• Meta-analysis of these trials showed that 15% to 20% of patients treated with radiation therapy (RT) and nitrosoureas survived at least 18 months versus 5% treated with radiotherapy alone Free Powerpoint Templates Page 34
  • • Nitrosoureas, especially carmustine, were the most commonly used drugs• The combination of procarbazine, lomustine (CCNU), and vincristine, also called PCV,had no clear benefit (yet much greater toxicity) versus carmustine for anaplastic astrocytoma, and this regimen has been largely abandoned. Free Powerpoint Templates Page 35
  • Anaplastic Gliomas• Anaplastic astrocytomas, anaplastic oligodendrogliomas, and anaplastic oligoastrocytomas. Free Powerpoint Templates Page 36
  • • In a German study (NOA-04), survival rates were equivalent whether chemotherapy or radiotherapy was used first among patients with anaplastic gliomas.• However, time to progression following RT was longer than after chemotherapy, and initial radiation therapy achieved more complete and partial responses than initial chemotherapy. Free Powerpoint Templates Page 37
  • • University of Heidelberg with either RT alone or RT in combination with temozolomide during a 20-year period (from 1988 to 2007).• In this retrospective study, no significant advantage in rates of OS or PFS could be attributed to the combination. Free Powerpoint Templates Page 38
  • RTOG trial 9813• Randomized patients with anaplastic astrocytomas (or oligoastrocytomas) to radiotherapy• With concurrent nitrosourea (carmustine or lomustine) or with temozolomide.• Results are pending. Free Powerpoint Templates Page 39
  • 1p/19q chromosomal status• The CATNON and CODEL study designs are premised on the belief that the 1p/19q chromosomal status may be more important than the histologic subtype for WHO grade III lesions.• Tumors with 1p,19q co-deletion are now known to be very sensitive to chemotherapy, with virtually all tumors responding to PCV chemotherapy Free Powerpoint Templates Page 40
  • CATNON• Concurrent vs. Adjuvant Temozolomide for NON 1p19q co-deleted anaplastic gliomas Free Powerpoint Templates Page 41
  • CODEL• 1p/19q CO-DELeted tumors Free Powerpoint Templates Page 42
  • Anaplastic Oligodendroglioma• The role of radiotherapy most controversial because of the tumor’s reported sensitivity to chemotherapy especially tumors with 1p/19q co-deletion.• Two separate randomized studies that compared radiation therapy with radiation therapy plus chemotherapy (RTOG 94-0210 and EORTC 2695111) failed to demonstrate a survival advantage from the addition of chemotherapy.• PCV chemotherapy prolonged PFS.• Both trials provided validation of the prognostic value of the allelic loss of heterozygosity of the 1p and 19q chromosomes. Free Powerpoint Templates Page 43
  • • Temozolomide has produced high response rates in patients with anaplastic oligodendroglioma.• The results of RTOG 0131, a phase 2 trial in which temozolomide was given before radiotherapy to newly diagnosed patients with anaplastic oligodendroglioma/ oligoastrocytoma.• The objective response rate was 33%. The 6- month progression rate was 10%.• Response to temozolomide has also been shown to be significantly associated with loss of 1p in a small retrospective study. Free Powerpoint Templates Page 44
  • Temozolamide• Currently, the most widely used chemotherapeutic agent is temozolomide.• Whether it is more effective than nitrosoureas has not been investigated, but it is unquestionably better tolerated with significant myelosuppression in less than 20% of patients.• Temozolomide was first approved for recurrent anaplastic astrocytomas following a phase II study.• A randomized study also demonstrated superior efficacy to procarbazine in recurrent GBM. Free Powerpoint Templates Page 45
  • Free Powerpoint Templates Page 46
  • MGMT• Hegi and colleagues reported that methylation of the promoter for the O6-methylguanine DNA methyltransferase (MGMT) gene, which encodes the DNA repair enzyme O6-alkylguanine DNA alkyltransferase (AGT or AGAT, but now commonly also referred to as MGMT), was correlated with prolonged survival. Free Powerpoint Templates Page 47
  • Pseudoprogression• For suspected progression that occurs within 3 months of completing radiotherapy, the possibility of pseudoprogression should be strongly considered.• Histologically proven treatment injury rather than disease progression in approximately 50% of patients with symptomatic resectable lesions felt to represent worsening disease following concurrent radiotherapy and temozolomide. Free Powerpoint Templates Page 48
  • • The incidence of pseudoprogression has been reported to be as high as 75%• At this time, histologic analysis is the only validated method of distinguishing it from true progression. Free Powerpoint Templates Page 49
  • Gliadel• Intratumoral delivery of chemotherapy for residual postoperative disease is most commonly in the form of carmustine- eluting (Gliadel) wafers.• During resection of recurrent GBM and newly diagnosed malignant gliomas. Free Powerpoint Templates Page 50
  • • Patients undergoing wafer implantation during surgery for recurrent GBM survived approximately 2 months longer than patients without wafers in one study (p = .02).• Treatment of newly diagnosed disease also yielded a 2-month prolongation of average survival.• However, this was not statistically significant when the analysis was restricted to patients with GBM histology. Free Powerpoint Templates Page 51
  • Convection-enhanced delivery (CED)• Designed to circumvent the BBB and BTB• CED requires the implantation of catheters directly into the brain tissue followed by continuous infusion of the drug under a constant pressure gradient.• This results in much larger volumes of distribution with CED than are achieved with diffusion. Free Powerpoint Templates Page 52
  • Elderly Patients with GBM• A randomized study in patients over age 60 years demonstrated that 40 Gy in 15 fractions was not inferior to 60 Gy in 30 fractions.• The EORTC is currently conducting a trial to assess the benefit of combined temozolomide and RT in elderly patients with GBM. Free Powerpoint Templates Page 53
  • Recurrent Disease• The “BRAIN” trial was a noncomparative phase II study for recurrent GBM that randomized 167 patients to either bevacizumab alone or bevacizumab combined with irinotecan.• The 6-month progression-free survival rate was 43% with bevacizumab and 50% with bevacizumab plus irinotecan.• To date, however, there are no data clearly demonstrating a survival advantage for the use of bevacizumab, and major potential toxicities include thromboembolic disease and hypertension. Free Powerpoint Templates Page 54
  • • In addition, treatment following progression on bevacizumab may have little to no efficacy and the timing of bevacizumab for either first or later recurrence remains controversial.• The potential toxicity, as well as the fear of inducing a more invasive tumor phenotype, also tempers enthusiasm for use of this agent in newly diagnosed disease until randomized data become available. Free Powerpoint Templates Page 55
  • EGFR Inhibitors• Inhibitors of EGFR, erlotinib and gefitinib, for treatment of recurrent high-grade gliomas. Both drugs have shown modest single-agent activity.• Variant 3 mutant (EGFRvIII), with resulting constitutive activation of EGFR tyrosine kinase activity, along with intact phosphatase and tensin analog (PTEN), appear to be somewhat more responsive to treatment with Powerpoint Templates Free EGFR inhibitors Page 56
  • • Chemotherapy for anaplastic astrocytomas that recur following radiation is of benefit, and both nitrosourea-based regimens and temozolomide have efficacy.• The Food and Drug Administration granted accelerated approval for temozolomide on the basis of its activity in recurrent anaplastic astrocytoma• The response rate was 35% for patients who had not received chemotherapy and 20% for patients who had received nitrosourea-based therapy. Free Powerpoint Templates Page 57
  • Reirradiation• Focal radiotherapy approaches are often employed with limited volume recurrences.• It is most likely that the damage from reirradiation is underestimated because the majority of patients do not live long enough to express such damage. Free Powerpoint Templates Page 58
  • • Single-arm trial from the Memorial Sloan- Kettering Cancer Center demonstrated reasonable safety and efficacy of combined bevacizumab and reirradiation using IMRT to small recurrent malignant gliomas.• No radionecrosis was observed and survival appeared to be prolonged relative to historic controls, suggesting that bevacizumab may not only treat radionecrosis but may protect against it. Free Powerpoint Templates Page 59
  • Jefferson Medical College• Treated 147 patients with recurrent high- grade glioma to 35 Gy in 3.5-Gy fractions with stereotactic radiation therapy.• This hypofractionated stereotactic radiation therapy (HSRT) approach was associated with a median survival time in excess of 10 months. Free Powerpoint Templates Page 60
  • Gliomatosis Cerebri• Gliomatosis cerebri is a rare condition with diffuse involvement of multiple parts of the brain (greater than two lobes), sparing neurons and normal structures.• Type I: Classical type with diffuse growth• Type II: Focal mass usually a high grade glioma in addtion to diffuse involvement Free Powerpoint Templates Page 61
  • • Treatment remains undefined• 63 patients with gliomatosis cerebri were treated initially with PCV or temozolomide.• Objective responses were observed in 33% of patients and radiologic responses in 26% with no significant difference between the two regimens.• Median PFS and overall survival were 16 and 29 months, respectively. Free Powerpoint Templates Page 62
  • • Regardless of regimen, patients with an oligodendroglial component had significantly better outcomes in terms of progression-free and overall survival.• The impact on survival of radiotherapy remained unclear. Free Powerpoint Templates Page 63
  • Radioimmunotherapy• Monoclonal antibodies against EGFR tagged with 125I.• Surgical resection or biopsy followed by definitive external-beam radiotherapy and one or multiple doses (35 to 90 mCi per intravenous or intra-arterial infusion) of 125I-labeled monoclonal antibody.• The total cumulative dose ranged from 40 to 224 mCi.• With a minimum follow-up of 5 years, median survival was 13.4 months for those with GBM Page 64 Free Powerpoint Templates
  • • Another potential target is tenascin, an extracellular protein overexpressed in malignant gliomas but not found in normal tissue.• Radiolabeled monoclonal antibodies to tenascin injected directly into the surgical resection cavity in 33 patients with untreated malignant glioma.• Patients were subsequently treated with external-beam radiotherapy and 1 year of alkylator-based chemotherapy. Even after accounting for prognostic factors, median survival (86.7 weeks) was longer than that of historical controls. Free Powerpoint Templates Page 65
  • Particle Therapy• Alternate radiation modalities used in the treatment of gliomas include neutrons, protons, helium ions, other heavy nuclei, negative pi-mesons, and thermal neutrons.• Despite theoretical advantages with respect to dose distribution and/or radiobiologic effect, most trials have failed to demonstrate improved survival. Free Powerpoint Templates Page 66
  • Gliosarcoma• Biphasic tissue pattern with both glial and sarcomatous components.• Sarcomatous components rich in reticulin fibres and GFAP negative spindle cells resembling a fibrosarcoma. Free Powerpoint Templates Page 67
  • • Treatment similar to that of GBM• Median OS for the entire group of GS patients was 28– 32 weeks.• Overall survival for GS at 1year & 2 year were 32 %, 4.6% respectively. Free Powerpoint Templates Page 68
  • Thank You Free Powerpoint Templates Page 69