CNS Malignancies

Michael Guiou, M.D.

Outline

I. Benign primary brain tumors (5/4/2011)

II. Malignant primary brain tumors (5/6/2011)

III. Metastatic brain tumors (5/6/2011)

Annual Incidence of Brain Tumors (USA)

Adults•Primary: 17,000•Metastatic: 180,000

Children•Primary: 2,500

Primary Brain TumorsGlioma •Astrocytoma, oligo, mixed glioma, ependymoma

Meningioma•Benign•Atypical•Malignant

Pituitary adenoma

Acoustic schwannoma

Craniopharyngioma

Pediatric tumors

40 - 50%

15 - 20%

10%

6 - 10%

5%

5%

Brain Tumors: Prevelance

Benign tumors

• Menigniomas

• Pituitary tumors

• Vestibular schwannoma

• Craniopharyngioma

Meningioma

• Incidence 6/100,000 persons• Peak occurrence 60-70yrs• Women > men• Multiple in patients with NF2

• Vascular, non-glial tumors that arise from arachnoidal cells of leptomeninges; attached to dura

• WHO classification based on grade, histology, proliferative index, brain invasion

• Incidental meningiomas at autopsy 1.4%

HistopathologyWHO I

• Low proliferative index• Limited invasion

WHO II (atypical, choroidal, clear cell)– Increased mitotic activity ( > 4 or more mitoses per 10 hpf)– 3 or more of following (inc cellularity, hi N/C ratio, prominent nucleoli,

sheet-like growth, foci of spontaneous or geographic necrosis)

WHO III (anaplastic, papillary, rhabdoid)– Histologic features of frank malignancy

Hi mitotic index (20 or more mitoses/10 hpf)Usually fatal (<2yrs)

Meningioma

Neuroimaging•Isodense dural masses•Intense contrast enhancement•Characteristic feature is ‘dural tail’

Treatment

Incidental •Can observe with periodic imaging

Anything else•Gross total resection (GTR) is desirable.

•Extent of resection associated with risk of recurrence

•Radiotherapy•Adjuvant after STR•Salvage therapy•Primary therapy in elderly•Improves progression free survival (PFS) •No impact on overall survival (OS)

Meningioma: RT

Dose•Benign (54 Gy)•Atypical or Malignant (59.4 - 63 Gy)

Volumes (fractionated tx)•GTV: residual tumor volume or gross tumor•CTV: GTV + 1 cm•PTV: 3-5 mm

SRS• Limited to lesions < 3 cm with acceptable separation from

critical structures. Ctrl rate ~ 90%

Meningioma

Local RecurrenceS S+RT

GTR 12%STR 40% 18%STR at recurrence 76% 43%

Overall Survival5yr 10yr85% 77%

Goldsmith et al, J Neurosurg 1993

Vestibular schwannoma

Epidemiology• WHO grade I (a.k.a. acoustic neuroma)• Association with NF2

• Bilateral lesions

• Incidence 1/100,000 persons per year• Peak in 4th and 6th decades

Presentation• Tinnitus, hearing difficulties, facial

paresthesia

Vestibular schwannoma: Imaging• MR-well-circumscribed, cystic, enhancing

mass in the CP angle extending into IAC

Treatment

Surgery for lesions >3cm

Radiotherapy for lesions <3cm•SRS (12 Gy x 1)•Hypofractionated FSRT (5Gy x 5)•Conventional FSRT (45 -50 Gy)

** Hearing preservation ~50-65% if serviceable hearing at baseline

Craniopharyngioma

Epidemiology• 1-5% of all intracranial tumors • 0.5-3/million/yr

Histology• WHO grade I; benign • Partly cystic, partly solid epithelial tumor of sellar

region• Derived from Rathke pouch epithelium

• Bimodal incidence; peaks 5-14 yrs and >50 yrs

Craniopharyngioma

Presentation• Visual disturbances• Endocrine deficiencies

• GH, LH/FSH, ACTH, TSH, DI

• Cognitive impairment & personality changes in 50%

• Freq signs elevated ICP from compression of 3rd vent

Craniopharyngioma

Imaging• CT: contrast enhancement of solid portions

and cyst capsule, calcifications• MR: cystic portion isointense, and solids

parts hyperintense

Treatment• Surgery

• GTR • diff due to location; 10 yr PFS 30-40% w/

surg alone)• STR

• observe • postop RT (EBRT 50-54Gy or SRS); 10 yr PFS 55-

90%

CT

MRI

Glioma

WHO gradeI pilocytic astrocytoma

II astrocytoma, oligodendroglioma, mixed

III anaplastic astrocytoma

IV glioblastoma multiforme

Low Grade Glioma (LGG)

Epidemiology• 1/100,000 adults• Assoc w/ NF1, tuberous sclerosis

Presentation• Sz, HA, focal neurological deficit

Imaging • CT: hypodensity• MRI: T1 (hypodense), T2/FLAIR

(hyperintense)• Don't often contrast enhance

LGG: TreatmentEarly management unclear

Surgery• No class I data to support improved survival with maximal

safe resection• Class II data suggests improved survival & lower recurrence

Chemotherapy• Not all respond though role in some tumors• Oligo > astro

• LOH 1p, 19q: predicts response to chemo as well as OS

• Current clinical trials investigating RT + TMZ

LGG: Radiotherapy Is early RT better?

• RTOG 98-02 had observation only arm (pts < 40 yrs, completely resected with PFS-3 & OS-3 of 97%, 73%

Factors predicting recurrence• Age > 40, astrocytoma histo, max tumor dimension > 6 cm,

tumor crossing midline, presence of neurological deficit prior to surgery

• 0-2 = low risk (survival 7.8 yrs)• > 2 = high risk (survival 3.7 yrs)

Dose / Target volumes• GTV = T2 enhancement; CTV = GTV + 2 cm• Dose = 45 - 50.4 Gy (no benefit to dose escalation; higher

toxicity)

Glioblastoma

• 50-60% of all astrocytic neoplasms• 2-3 new cases per 100,000 population• Peak 45-70 years

Role of RT in GBM

• Address residual infiltrating disease• Improve progression-free survival• Improve overall survival

RTOG Target Delineation

GTV

edema

2cm

Initial TV to 46 Gy = contrast enhanced lesion + edema + 2cm

Field edge

• T1 post contrast

RTOG Boost Volume Delineation

GTV

2.5 cm

Field edge

Conedown to 60 Gy = contrast enhanced lesion (w/o edema) + 2.5 cm

• T1 post contrast delineation

Anaplastic astrocytoma

• RT guidelines are identical 60Gy/30 Fx

Poor KPS, Elderly GBM

• Short course RT• 50 Gy/ 20 fx/4 weeks• 30 Gy/10 fx ->2 wk break-> 21 Gy/7• 40 Gy/15 fx/3 weeks• 30 Gy/10 fx

Ependymomas

Ependymoma

Kun, Tarbell ASTRO 2003 Refresher Course

RT for ependymoma

• Grade 2 (Low grade)- 50-54 Gy• Grade 3 (High grade)- 60 Gy• Volume:• Involved field RT if no disease in CSF• Craniospinal RT to 36 Gy followed by boost to

involved field to 50-54 Gy (low grade) and 60 Gy (high grade)

Posterior Fossa Delineation

Adult medulloblastoma

• CSI alone

• chemo reserved for relapse

• 54Gy PF, 36Gy CSI, 1.5Gy/day

Technical pitfalls-Cribiform plate recurrences

• Important to clearly define cribiform plate on simulation film or on sagittal DRR

Technical pitfalls-Cribiform plate recurrences

• site of increased recurrences related to inadvertent shielding of the cribiform plate in attempt to shield the orbits

Cranial field design

• Blocks are drawn to include the entire cribiform plate which extends below the frontal lobes and the superior orbit

• block is drawn just anterior to vertebral bodies of cervical spine

• inferior border defined so that exit dose from spine field is below oropharnyx but above shoulders

Spinal field design

• Width typically 5-8cm • target volume is spinal

canal • Spade design or flaring

out at sacrum is not necessary

Conventional PF field design

• Approximated by drawing a line from foramen magnum to vertex

• draw perpendicular bisector of this line and divide into thirds

• PF is defined by connecting inion to posterior 1/3 and connecting to posterior clinoid

Junctioning fields

• junction is shifted 0.5cm every 5 fractions (usually 3 times)

• to match between upper and lower spine field if two spine fields --use standard gap calculation or computerized treatment planning

• match occurs at center of the spinal cord

Exact match

• Inferior border of cranial fields and upper border of spine fields form an exact match on skin by rotating the couch towards the gantry

Divergent match

• Alternatively, the couch can remain stationary

• this results in directly opposed cranial fields that diverge slightly into spine field

Divergence into lens

• Gantry rotated to avoid divergence into contralateral lens

• bony canthi are wired out for conventional simulation

Geometric match

• Collimator of cranial field is rotated to match divergence of spinal field

• This completes the geometric match

Various junction techniquesVarious junction techniques

• Figure A demonstrate MDACC technique

• Figure B shows exact match created by kicking couch

• Figure C shows a gap introduced as an extra margin of safety

• Illustration taken from Leibel et al Textbook of Radiation Oncology p946

Brain Metastases-Epidemiology-WBRT + SRS

Histology and Frequency

• Lung accounts for 30-60% of all brain mets– Ranks 2nd among tendency to metasize to brain– 18-65% of lung ca pts develop brain mets– >40% SCLC pts and adenoca have brain mets,2x

that of other types such as squamous

Histology & Frequency

• Ranks 2nd to lung as most frequenly occurring primary tumor in brain mets pts

• Among women, breast cancer is the most common cause of brain metastasis (5-30% of all brain mets)

• Ranks 3rd in tendency to metastasize to brain

Histology and Frequency

• Melanoma ranks 3rd among giving rise to brain mets

• Of patients with brain mets, 5-21% will have melanoma as primary

• Melanoma (4% of all cancers) has highest propensity of all malginant tumors to metastasize to brain (6-43% clinical,12-90% autopsy series)

Other histologies

• Renal cell frequency of brain metastases 11%• Colorectal cancers metastasize to brain 0.74-

10%, representing 1.8-4.8% of all metastatic brain tumors

• Prostate cancer metastasizes 0.6-4.4%, most detected at autopsy. Small cell+TCC much more likely than adenocarcinomas

Role of RT

• Plays major role in brain metastases• treatment with WBRT 20-40Gy/1-4wks results

in survival of 4-6 months (RTOG)• improved symptoms: H/A, seizures, symptoms

increased intra-cranial pressure, cranial nerve deficits

• CR to WBRT 50% cases, durability 65% 1y

Prognostic factors -RPA Class

• Gaspar et al defined RPA Class from database of 3 RTOG trials

• Class I -KPS >70, controlled primary, brain sole site of metastasis, <65 years

• Class II-KPS >70 not in class I• Class III KPS <70• Survival 7.1, 4.2 ,2.3 mos respectively

RTOG Dose-fractionation schemes

• 30Gy/10fx vs 30Gy/15fx vs 40Gy/2.67Gy/ 15 vs 40Gy/20fx

• 20Gy/5fx vs 30Gy/10fx vs 40Gy/2.67/15fx• 10Gy/1fx• 50Gy/20 fx vs 30Gy/10fx favorable pts• 48Gy-70.4Gy/1.6bid• 30Gy/10 vs 54.4Gy/1.6bid

RTOG dose fractionation schemes

• All treatment schedules comparable:frequency, duration improvement TTP, survival , palliation

• WBRT improved neuro function 50%• Neurologic response in “ultra-rapid” treatment

comparable to more protracted but duration of improvement less

RTOG altered fractionation

• Accelerated fractionation tested in RTOG Phase III study in 445 pts KPS >60 to 54.4Gy/1.6bid or 30Gy/30fx

• study failed to demonstrate any improvement in survival in group receiving 54.4Gy

Postoperative WBRT• Majority (4/6) retrospective studies do not

show a survival benefit but are conflicting• Patchell study is only randomized trial

– 95 patients with resected single brain met – Surgery +/- WBRT 50.4Gy/1.8Gy fx– recurrences 18% vs 70% p<0.001

original site 10% vs 46% p<0.01other sites in brain 14% vs 37% p<0.01neurologic deaths 14% vs 44% p=0.003

– overall survival 10-11mos p=NS

Stereotactic Radiosurgery

• Growing body of experience from different institutions supports use and effectiveness of SRS which must be compared to surgery

• Surgical gold standard Patchell study 1990 S+RT(n=25) v. RT(n=23) single brainmet

local recurrence 20% vs 52% p<0.02overall survival 40wks vs 15wk

p<0.01 function indep 38wks vs 8wk p<0.005

Radiosurgery data

• Multi-institutional outcome and prognostic factor analysis of RS for resectable brain met using same criteria as Patchell

• RS + WBRT for single brain met can produce substantial functional survival of 56 weeks [Auchter IJROBP 1996]

Patient selection for surgery verus radiosurgery

• Surgery allows complete resolution of mass effect, tissue diagnosis, no risk of radiation necrosis

• Radiosurgery advantages are decreased risk of hemorrhage and infection, no risk of tumor seeding, reduced costs

• cost-utility analysis [Mehta]– $31,454 vs $15,502/QALY, where QALY defined as

functional indep living

Complications of WBRT

• Acute effects-mild fatigue, hair loss, scalp erythema, hyperpigmentation

• Subacute-(3-10wks)somnolence syndrome or persistance fatigue especially in children

• Long term-DeAngelis reported 12 pts developed dementia, ataxia, urinary incontinence leading to severe disability

• total dose ranged from 25-39Gy/3-6Gy

WBRT +/-SRS for KPS >70 and controlled primary orSurgery (if highly symptomatic, or mass effect) + WBRT orWBRT for KPS <70 or uncontrolled primary

Primary Therapy for Metastatic Brain Disease

Lesion number Diagnostic uncertainty and asymptomatic

Observation If grows, surgery or SRS+/-WBRT

Surgery

1

<1cm

>1cm

Convincing Metastasis

Single

Solitary

2-3

>3

KPS > 70 and controlled primary

KPS < 70 or uncontrolled primary

Surgery +/- WBRT orSRS (<3cm) +/- WBRT for non-surgical candidate(if >3cm, WBRT only)

WBRT (surgery to lesions causing mass effect)

WBRT (Surgery if tumorcauses mass effect)

*Surgery or SRS (<3cm) +/- WBRT

or

RTOG 90-05

• Maximum tolerated dose for radiosurgery– 24 Gy < 2cm– 18 Gy 2-3 cm– 15 Gy 3-4 cm

Shaw E, et al Int J Radiat Oncol Biol Phys. 2000 May 1;47(2):291-8.