Management of high grade gliomas

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Management of High Grade Gliomas

Dr. S. Moses ArunsinghPG MDRT

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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



• 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.



• 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.



• 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.



• 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.



?? 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



2. Relieves mass effect

3. Response to postoperative radiation therapy is more favorable

4. Cytoreduction



Radiotherapy

• External beam irradiation (EBRT) has historically been the cornerstone of the therapeutic approach to GBM and anaplastic astrocytoma.





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.



• Hochberg and Pruitt used CT scans to determine that nearly 90% of GBM recurrences occurred within 2 cm of the primary tumor site.



• 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.



• 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.



• 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.



• 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



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.



EORTC

• The EORTC recommends a single-phase technique using one treatment volume throughout the course of therapy.



Treatment Volumes





• 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.



• 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.



QUANTEC (Quantitative Analysisof 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.



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.



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.



• 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.



Fractionation

• Various trials examining Hyperfractionation in High Grade Gliomas have been conducted.

• None of them showed improved survival.



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.



Brachytherapy

• It offers a mechanism for focal dose escalation.

• GliaSite radiation therapy system:

This intracavitary device is implanted at the time of tumor debulking, and a solution of iodine-125 (125I) is injected into an expandable closed-catheter balloon.



• 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



• 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.



• 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.



• 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.



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



• 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.



Anaplastic Gliomas

• Anaplastic astrocytomas, anaplastic oligodendrogliomas, and anaplastic oligoastrocytomas.



• 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.



• 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.



RTOG trial 9813

• Randomized patients with anaplastic astrocytomas (or oligoastrocytomas) to radiotherapy

• With concurrent nitrosourea (carmustine or lomustine) or with temozolomide.

• Results are pending.



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



CATNON

• Concurrent vs. Adjuvant Temozolomidefor NON 1p19q co-deleted anaplastic gliomas



CODEL

• 1p/19q CO-DELeted tumors



AnaplasticOligodendroglioma

• 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.



• 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.



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.





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.



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.



• 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.



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.



• 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.



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.



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.



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.



• 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.



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 EGFR inhibitors



• 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.



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.



• 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.



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.



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



• 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.



• 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.



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



• 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.



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.



Gliosarcoma

• Biphasic tissue pattern with both glial and sarcomatous components.

• Sarcomatous components rich in reticulin fibres and GFAP negative spindle cells resembling a fibrosarcoma.



• 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.



Thank You


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Management of high grade gliomas