Recent Advances in High Grade Gliomas (HGG)

Dr Rajesh BAssociate Professor

Department of Radiotherapy Christian Medical College, Vellore

Learning Objectives

• Current management strategy for High Grade Gliomas

• Radiotherapy treatment planning guidelines for High Grade Gliomas

• Chemo irradiation for HGG - How to titrate dose of TMZ during RT

• How to assess response for Gliomas – RANO Guidelines

• Recent advances in RT /chemo for HGG

• Clinical trials which would answer our queries in Future

Objectives of Radiation in Malignant Glioma

• Potential for cure

• Prolong survival times with improved quality of life

• Control local infiltration of cancer cells

• Palliation

Overall, the objectives of radiation in the treatment of CNS malignancies include:

Current management strategies in HGG

Treatment Algorithm for management of GBM

Radiotherapy treatment planning guidelines for HGG

Simulation Process

• Simulate after removal of Craniotomy Staples / Sutures

• Start RT within 4-6 weeks of surgery

• 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 (Atleast upto C4 levels) to allow sufficient anatomic areas for

proper image fusion and genera tion of high quality digitally

reconstructed radiographs (DRRs) and to permit the introduction of

noncoplanar beams;

• Slice Thickness for CT images – 2.5 - 3mm

• Do MR Fusion for good TV delineation

Radiotherapy Volumes for HGG’s

Planning Target Volume (PTV)

- To account for both organ

motion and setup error

- Organ motion in the brain

is minimal (e.g., <1 mm)

- Modify PTV to exclude

normal tissue in areas

where gliomas are unlikely

to infiltrate.

Tips for Planning

• Check the critical organ delineation carefully

• Check BEVs

• Avoiding entrance and exit dose to the eye may be a relatively simple means of preventing not only cataracts but also conjunctivitis and a dry eye

• Contour the ear canals, as there is now a greater awareness of the risks of developing otitis externa as well as otitis media

• For tumors located in the temporal lobes, the exit dose to the parotid gland may bring about xerostomia.

• Always contour Brain tissue outside the PTV as a organ and try to limit dose to the same as low as achievable.

• Use functional MRI or MRS data if available for planning purposes

• RT dose prescription as per RTOG guidelines.• A clinical judgment was made to modify the

planning target volume to exclude sensitive structures by presuming that ‘‘natural barriers’’ would impede the contiguous spread of tumor cells.

• As such, the traditional 2–2.5-cm margin was not added in the direction of the temporal bone.

Dose constraints to critical organs

Hippocampus contouring

http://www.rtog.org/CoreLab/ContouringAtlases/HippocampalSparing.asp

Hippocampus delienation by software

Courtesy : Dr Minesh Mehta

Chemoirraditation for HGG

ChemoRT schedule

• RT - Five fractions per week

• Prophylactic antiemetics

• PCP prophylactics

• Low dose steroids with H1 blocker

• Weekly blood counts

• Give Temozolomide for a maximum of 49 days and then STOP

Dose modification for Concomittant Temozolomide

Dose Level Dose (mg/m2/day) Remarks

-1 100 Reduction for prior toxicity

0 150 Dose during Cycle 1

1 200Dose during Cycles 2-6 in absence of

toxicity

Toxicity Reduce TMZ by 1 Dose Level* Discontinue TMZ

Absolute Neutrophil Count < 1.0 x 109/L (< 1000) See footnote†

Platelet Count < 50 x 109/L (<50,000) See footnote†

CTC Nonhematological Toxicity (except for alopecia, nausea, vomiting)

CTC Grade 3 CTC Grade 4†

†TMZ is to be discontinued if dose reduction to < 100 mg/m2 is required or if the same Grade 3 nonhematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction. TMZ=temozolomide; CTC=Common Toxicity Criteria.

Dose modification for Adjuvant Temozolomide

Response Assessment for HGG

RANO Basics

The Revised Assessment in Neuro-Oncology (RANO) criteria was published in 2010, as an update to the existing MacDonald criteria (see references at end)

• Used for assessing disease progression and treatment response in glioblastoma multiforme (GBM)

References

Print Version:“Updated Response Assessment Criteria for High-Grade Gliomas: ResponseAssessment in Neuro-Oncology Working Group.” Journal of Clinical Oncology.2010 Apr 10; 28(11):1963-72.

Online Version:http://jco.ascopubs.org/content/28/11/1963.abstract

Image Acquisition

•MRI is the only modality used to assess response and progression

•Minimum sequences required:

– Pre-contrast T1, T2/FLAIR

– Post-contrast T1, with two orthogonal planes (or a volume acquisition)

recommended

•Recommended slice thickness ≤5 mm with no gap

•Additional imaging that may be helpful:

– Diffusion (DWI, ADC)

Definitions

Measurable lesions

Contrast enhancing lesions

Minimum size: two perpendicular diameters ≥10 mm

If slice + gap thickness >5 mm, minimum size is 2 times the total

Do not include cavity, cyst, or necrosis in the measurement

Non-measurable lesions

Lesions that are too small (e.g. 12 x 8 mm)

Lesions that do not enhance (seen only on T2/FLAIR)

Lesions with a poorly defined margin

Pseudoprogression

• Enhancement that simulates tumor growth, most often caused by radiation (whole brain or focal)

• Growth of existing lesions or appearance of new lesions within 12 weeks of completion of radiation therapy may be the result of treatment effects rather than growth of tumor.

• Clinically the neurological status of the patient would be stable / improved

• Continued follow-up imaging can determine whether initial lesion growth was true progression or pseudoprogression.

– If lesion continues to enlarge, the initial growth is called true progression– If lesion stabilizes or shrinks, the initial growth is confirmed as pseudoprogression

• In such cases, the baseline SPD is no longer included when choosing the nadir value for the purposes of determining when progression occurs

• Diffusion weighted imaging can help distinguish pseudoprogression from true tumor growth, but its use is still experimental.

• The use of MR perfusion and spectroscopy is also being explored.

Recent advances in Chemotherapy & Radiotherapy management of HGG

Positive Phase III Trials Evaluating the Role of Irradiation, Chemotherapy, or Chemoradiation in the Treatment of Malignant Gliomas

Methylation status as a Prognostic marker

Methylation status as a Prognostic marker

RTOG-0525- Dose intense Vs Conventional Schedule in Adjuvant therapy

Treatment Plan

ChemoRT: Focal RT ( 60 Gy /30 #, Conc TMZ 75 mg/m2) followed by 6 cycles of adjuvant TMZ

Adjuvant chemotherapy: (Both arms – six cycles of 28 days)Group A : Dose Dense - 150 mg/m2 daily days 1 to 7 and 15 to 21 of each cycleGroup B: Metronomic Arm- 50 mg/m2 daily days 1– to 28 of each cycleAntiemetics / Supportive care inculding Growth factor support at discretion of physician

Maintenance doses of 13-cis-retinoic acid - 100 mg/m2 daily days 1 to 21 of a 28-day cycle till PD.

Dose Dense Vs Metronomic Schedule in Adjuvant therapy for GBM

Control : Focal RT ( 60 Gy /30 #, Conc TMZ 75 mg/m2) followed by 6 cycles of adjuvant TMZ

Trial Group: 2 cycles neoadjvuant chemotherapyACNU (40 mg/m2/day) and CDDP (40 mg/m2/day) CI 72 hrs Q6 weeksFollowed by RT and Adj TMZ as in control group

Median survival

Overall survival

1yr 2yr

Control 18.9 m 81.7% 27.8%

Treatment 28.4m 72.4% 50.9%

Study stopped inbetween due to 30% Grade 4 toxicty of the neoadjvuant arm

RTOG 9305: Newly Diagnosed GBM Stereotactic Radiosurgery Phase III Trial

Arm 1RT – 60Gy / 30 #BCNU 80mg/m2 D1-3 of RT thenQ8weeks for 6 cycles

Arm 2SRS followed byRT – 60Gy / 30 #BCNU 80mg/m2 D1-3 of RT thenQ8weeks for 6 cycles

SRS Dose24Gy – Lesion < 2cm18 Gy- Lesion 2.1 -3 cm15 Gy – Lesion 3.1-4 cm

• For patients with malignant glioma, there is Level I-III evidence that the use of radiosurgery boost followed by external beam radiotherapy and BCNU does not confer benefit in terms of overall survival, local brain control, or quality of life as compared with external beam radiotherapy and BCNU.

• The use of radiosurgery boost is associated with increased toxicity.

• For patients with malignant glioma, there is insufficient evidence regarding benefits / harm of using

– radiosurgery at the time progression or recurrence. – stereotactic fractionated radiation therapy in patients with newly

diagnosed or progressive/recurrent malignant glioma

http://njms.umdnj.edu/gsbs/stemcell/scofthemonth/scofthemonth2/braincancer/2.jpghttp://www.medscape.com/viewarticle/578097_3

Results of Irradiation of CSC Niches

In the human brain, the 3-5 mm thick lateral periventricular region of the lateral ventricles - thesubventricular zone (SVZ ) - and a subsection of the hippocampal formation - the subgranular layer ( SGL ) – have been shown to harbor normal brain stem cells

These regions are believed to contain specific regions of so-called stem cell niches, which support neuronal stem cells and keep them in an undifferentiated state .

Hypofractionated IMRT with Field in Field Boost for Newly diagnosed GBM

CT – MRI fusion done ( Post op MRI)Combination of coplanar and noncoplanar beams

GTV = CE tumor on T1W + Entire resection cavityCTV = Edema visible on T2-weighted MRI images

TV i = GTV + CTV + 1 cmTV b = GTV + 0.5 cm

5mm minimum margin to spare critical normal OARs

Results of Hypofractionated IMRT

• Median OS – 13.6 months

(Range – 0.9-40.2 months )

• Median PFS – 6.5 months

(Range – 0.9-40.2 months )

• 1yr survival – 57 %

• 2yr survival – 19%

• No difference in OS among dose groups

Accelerated Hypo IMRT with TMZ

• Total of 35 patients ( 74% pats in old RPA Class 5 or 6)

• Patients whose tumors were within 1.5 cm of either the optic chiasm or the brainstem were not included

• The GTV was defined as the surgical cavity and/or postoperative contrast-enhancing lesion on MRI fusion.

• The PTV was taken as the GTV plus a 1.5-cm margin. Visible edema outside the PTV margin was not included in the volume.

• Treatments were delivered with an isocentric technique, often with three or more non coplanar beams.

• GTV - 60 Gy in 20 daily 3-Gy fractions – 95–100% isodose line covered the GTV– 65–70% line encompassed the PTV (40Gy in 20 daily fractions)

• Concomitant TMZ at a dose of 75 mg/m2 daily during hypo-IMRT, followed by adjuvant TMZ at a dose of 150–200 mg/m2 daily for 5 days every 28 days, according to the EORTC/NCIC regimen

Results of Accelerated HypoIMRT trial

• Median follow-up - 12.6 m.

• 82.8% - completed CRT and

71.4%- received a median of

four cycles of adjuvant TMZ.

• Median OS - 14.4 m

• Median DFS - 7.7 m

Elderly GBM – NOA-08 / Methvsalem Trial (Age >65yrs)

Inclusion criteria: Age >65 yrs

Median Survival:

RT 9.8 mo TMZ 8.6 moHazard ratio 1.28 (0.94-1.63)

TMZ alone inferior to RTUnexpected toxicity in elderly

Elderly GBM – Nordic Trial (Age >60yrs)

Temozolomide may be an alternative to RT

Recursive Partioning Analysis of GBM

MRS Study for Volume delineation in our institute

MRS based volume delineation

• Multivoxel MRS was done at various levels on the FLAIR sequences.

– At levels of enhancing component that contains enhancing lesion

– Surrounding enhancing edema

– Regions with non enhancing edema alone and

– Areas with normal brain.  

• Peak parameters for choline, creatine, NAA, lipid and lactate was estimated on a voxel by voxel basis and the choline-creatine index (CCI) and Choline-NAA index (CNI) was defined.

• At these image levels, following areas were defined on a voxel by voxel basis

– Choline Creatine Index of more than 1.5

– Choline NAA Index (CNI) of more than 3

– CNI of 1.5 to 3 and CNI of less than 1 was defined

• Areas with CNI more than 3 and those areas with CNI between 1.5 and 3 were defined on a voxel by voxel basis. The parameters defined at these image levels on which MRS was performed, was extrapolated to other images of FLAIR MRI on which MRS was not performed.

• The three dimentional MRS volume defining the high risk area encompassing CNI of more than 3and intermediate risk area encompassing CNI of 1.5 to 3 was compared with the volume defined by post Gadolinium T1W and T2W FLAIR sequences.

• Disjoint and conjoint volumes were then defined by comparing the volumes defined by the MRI alone and combined MRI & MRS. Similar comparison was made between volumes defined by areas encompassing CNI less than 1.5 and non enhancing edematous component on FLAIR MRI.

 

MRI VOLUMES MRS VOLUMES

T1W GTV ( Enhancing componenton T1W image)

CNI of more than 3

T2W GTV (Enhancing component onT2W FLAIR image)

CNI of 1.5 to 3 and CCI more than 1.5

PTV (GTV + 2.5 cm uniform margin) CNI less than 1.5 + 5 mm

MRS analysis for volume delineation was done later than the MRI and hence the MRS data was not utilized for treatment of these patients .

Treatment planning of all patients were done as per CT-MRI based volume delineation.

This study was only a dosimetric study and volumes generated using MRS was not used to treat these patients

Comparison of T2 FLAIR GTV volume (cc) to MRS defined GTV Volume [Intermediate Risk area (CNI 1.5)

 Comparison of PTV volume in MRI (GTV T2 FLAIR+2.5 cm) and PTV in MRS (CNI< 1.5+ 5 mm)

Wilcoxon signed-rank test:Adjusted variance = 96.25z = 2.803P = 0.0051

Picture below Depicts the Conjoint T1 GTV Volume (Blue) of MRI in a patient with Glioblastoma that is much less than the corresponding High Risk Area (Brown) in MRS seen as disjoint area

The pictures shows the conjoint and disjoint PTV volumes of MRI

and MRS MRI defined PTV (dark) extends

into the orbit whereas the extension is not seen in the PTV defined by

MRS.

Clinical trials that would answer our questions

Major ongoing Trials in High Grade Gliomas

CATNON: Phase III trial comparing no adjuvant chemotherapy versus adjuvant therapy until progression

for anaplastic glioma without 1p/19q loss

CODEL : Phase III Intergroup Study in Newly Diagnosed Anaplastic ODG or Anaplastic Mixed Glioma with Chromosomal cowith co--deletions of 1p and 19q.

Trials of anti-angiogenic agents fornewly-diagnosed glioblastomas

• VEGF– Bevacizumab (RTOG, Roche)– Aflibercept (VEGF VEGF-Trap) (ABTC)

• VEGFR– Cediranib (VEGFR, PDGFR)– Vandetanib (VEGFR, EGFR)– Sorafenib (VEGFR, PDGFR, Raf)– XL184 (VEGFR, Met) (Exelixis)– Pazopanib (VEGFR, PDGFR, cKIT)

• PKCβ– Enzastaurin (UCSF, multiple)

• Integrins– Cilengitide (Merck KG)

TMZ/RT ±Cilengitide in MGMTmethylated GBM CENTRIC/EORTC 26071 / 22072

BRAIN Study Design – Recurrent GBMAvastin ± Irenotecan

AVAglio study or RTOG-0825

• Longest documented GBM patient in Literature -20 yrs

• He had been treated with surgery and partial brain irradiation (59 Gy of 6-MV photons in conventional fractionation delivered via the shrinking-field technique).

• The authors speculated that the outcome may have stemmed from the fact that he had a favorable molecular profile (e.g., methylated MGMT promoter, PTEN positive, and TP53 positive, which the authors termed “triple positive” similar to the nomenclature of breast cancer).

• 5 yr survival in GBM from the EORTC-NCIC - 10%, and

• 5 yr survival for pts with favorable prognostic factors ~ 30%

Thank You