Treatment of Pineoblastoma and Germ Cell Tumors

By

Dr Parneet Singh

Max Hospital,Saket

Introduction• Pineal & Germ cell Tumors <1%of all intracranial tumors in adults and 3-8%

in children

• Germinomas are the most common 33-50%of pineal tumors

• Peak incidence of GCT in 2nd decade

• Gliomas & pineal parenchymal tumors-25% each

• 10-15% CNS dissemination at diagnosis

• Male:Female 3:1

• Patients present with raised intracranial pressure symptoms and parinaud’ssyndrome

• GCTs arise from a pluripotent embryonic cell that escapes normal developmental signals and progresses to CNS GCTs

WHO Tumor Classification(2007)

• GCT

1. Germinoma

2. Embryonal carcinoma

3. Yolk sac tumor

4. Choriocarcinoma

5. Teratoma

6. Mixed germ cell tumor

• Pineal parenchymal Tumors

1. Pineocytoma

2. Pineal parenchymal tumor of intermediate differentiation

3. Pineoblastoma

• Glial

1. Astrocytoma

2. Paillary tumor of pineal region

3. Ganglioglioma

• Others

1. Mets

2. Dermoid/Epidermoid

Investigative Work-Up

• Detailed history

• Physical Examination

• CE MRI

• Biopsy open biopsy, stereotactic biopsy or endoscopic biopsy

• Serum & CSF levels of AFP and βHCG shunting

• CSF cytology

• Endocrine evaluation

• Visual field testing(suprasellar tumors)

T1-Non Contrast

T1Contrast

T1c Coronal and Saggital

T2

Flair

MRS

• Soft tissue mass lesion measureing2.9 X 2.7 X 2.7 cm

• Hypointense T1,hyperintense T2 / FLAIR signal & homogenous post-contrast enhancement

• Lesion is compressing the superior portion of the cerebral aqueduct with moderate supratentorial hydrocephalus

• MRS of the lesion shows

• Elevation of the choline and lipid lactate peaks.

IHC Markers

Tumor Type βHCG AFP PLAP

Choriocarcinoma + _ _

Embroynal Carcinoma _ _ _

Germinoma + _ +

Immature Teratoma +/- +/- +/-

Mature teratoma _ _ -

Mixed germ cell tumor +/- +/- +/-

Pure germinoma _ _ +

Yolk Sac tumor _ + _

Serum & CSF markers

Tumor Type βHCG AFP

Choriocarcinoma +++ -

Embryonal Ca + +

Germinoma +/- -

Teratoma - +

Yolk Sac tumor - +++

Chang’s Modified Staging

Pineocytoma• WHO grade I

• Slow growing tumor

• Occur typically in adults

• Surgical resection by occipital transtentorial/ infratentorial supracerebellarapproach

• If complete/subtotal resection done then progression free survival 90-100%

• Infratentorial supracerebellar approach-

Surgical corridor in midline b/w tentorium above and sup. Surface of cerebellum below

• Occipital transtentorial approach

Under the occipital lobe and through an incision in the tentorium to reach the pineal region

• Obstructive hydrocephalus if present then endoscopic IIIrdventriculostomy with transventricular biopsy Cipri et al 2005

• VP shunting also done

• CSF sampling for cytological analysis & tumor markers

• If radial resection done then post op MRI scan should be done within 48 hours of surgery for residual disease.

• Post-op RT is recommended in case of residual disease

• Target volume is local

• Macroscopic residual ds +1-2 cm margin for CTV

• Dose of 50-55 Gy over 6 weeks. (schild et al Cancer 1996)

• University of Pennsylvania; 1987 (1975-1985)-- "Pineocytomas of childhood. A reappraisal of natural history and response to therapy." (D'Andrea AD, Cancer. 1987 Apr 1;59(7):1353-7.)

•

– Retrospective. 6 children

– Surgery + CSI+boost (n=3) or local RT (n=2) or chemo-RT (n=1).

– Outcome: 4/6 recurrences, median 2 years after diagnosis. 3 leptomeningeal dissemination

– Conclusion: Aggressive tumors in pediatric population; RT alone inadequate

• Stereotactic Radiosurgery as

Primary

Adjuvant

Salvage therapy

• Retrospective study from Pittsburg in 2005 evaluated 15 patients with mean dose of 15Gy and tumor volume of 5cm3 with mean follow up of 52 months

• Local control was 100%

• 3 patients died due to leptomengial or extracranial spread

• Barrow Neurological Institute; 2004 (Arizona) (Deshmukh VR, Neurosurgery. 2004

• 3 GTR, 6 subtotal or bx. Adjuvant RT in 5/9 patients (n=2 IMRT 54/30, n=3 GKS)

– Outcome: 4/9 local recurrences (3 clinical, 1 radiographic). Mean time to recurrence 3.5 years

– Radiosurgery: all stable or decreased at 3 years

– Treatment recommendations: If symptomatic, attempt resection. For subtotally resected, adjuvant GKS. For small asymptomatic tumors, stereotactic biopsy and primary GKS. Need close follow-up

Pineal Parenchymal Tumor of intermediate differentiation

• WHO grade II/III

• Moderate nuclear atypia &low to moderate mitotic activity

• 10% of pineal parenchymal tumors

• Unpredictable growth rate & behaviour

• 2 extremes

• In some series only surgery is recommended

• In others tumors have seeding potential so post-op CSI is recommended(Schild Cancer 1993)

Pineoblastoma

• WHO grade IV

• Embryonal PNET with highly aggressive behavior

• Occurs in young children (estimated 40-50% in age <1 year)

• Children <3 years appear to have particularly aggressive disease, with frequent advanced presentation

• Sheets of densely packed cells with high mitotic rate and necrosis

• Large and multilobulated

• Frequently invade adjacent structures & disseminate through CSF

• Leptomeningeal spread 20-50%

• Present with enlarged head circumference & raised ICT

• Surgical resection often incomplete due to location

• Typical approach is surgery, f/b chemotherapy & RT

• Older children can have a reasonable survival

• Efforts to eliminate RT in young children have resulted in poor outcomes (POG, CCG, and German trials)

• Long-term CSI toxicity is severe, so efforts are under way for dose intensification with stem cell transplant

• Post op children older than 3 year treated with RT and chemotherapy

• Chemo is used for delaying RT- risk of neurocognitivefunctions

Sx resection---->post-op CSI 36Gy (@1.8-Gy/#) followed by boost tumor bed to 54 Gy with concurrent chemo-------> 8 cycles of adjuvant chemo.(cisplatin +Vincristine+CCNU)

(Freeman et al Med Pediatr oncol 2002)

RADIOTHERAPY

Objective:

• To treat microscopic cancer cells

• Residual tumor with the goal of reducing its size or stopping its progression

• Prevent or treat spread through CSF

• Covering entire subarachnoid space

Target volume for CSI• CSI includes irradiation of both CNS & entire subarachnoid

space (neuraxis)

• Whole brain with its meninges

• Spinal cord down to the caudal end of the thecal sac(usually S2 but should be verified by sagittal MRI)

Primary tumor site

• Initial GTV – primary tumor site

• Initial CTV – whole brain + entire spinal cord with 1-2 cm margin(including skull base & cribriform plate)

• Boost GTV – tumor bed+ residual

• Boost CTV – boost GTV + 1-1.5cm margin

• German HIT-SKK87, HIT 91, and HIT-SKK92 (1987-1992, 1992-1997)

– Subset of 11 patients with PB. If <3 years, surgery + chemo with RT deferred until >3 years or progression (n=5). If >3 years, surgery + chemo + CSI (35.2/22 + 20/10 boost) +/- maintenance chemo (n=6)

– Hinkes BG, J Neurooncol. 2007

• Older children (>3): 5/6 alive with median OS/PFS 7.9 years after chemo and RT. All had M0 disease

• Younger children (<3): 0/5 alive with median OS 0.9 years and PFS 0.6 years. All had M1 disease and/or postop residual disease. Response to chemo lower, only 1/5 received RT

• Role of RT: All older children received it, & benefited (PR->CR or stayed in CR).

• One younger child received who, after progressing on chemo, and showed PR to it

• Conclusion: Combined chemo and RT feasible and effective if >3 years.

• More intensified regimens necessary for <3 years

• Subsequent HIT trial for young children with supratentorial PNET investigates short dose-intense induction, followed by high-dose chemo and CSI

• Baby POG I (1986-90)

– Prospective. 198 children < 3 yrs (132 < 2 yrs, 66 age 2-3 yrs), treated with maximal surgery, postop chemo (CTX/VCR followed by cis/etopo) for 2 yrs (if age < 2 at dx) or 1 yr (age 2-3) or until disease progression, followed by RT.

– RT -CSI 35.2 Gy + boost to primary to 54 Gy.If no residual disease after chemo, reduced RT to CSI 24 Gy and primary site 50 Gy. Infants <2 years 90% of dose

– Duffner PK et al Med Pediatr Oncol. 1995

• Subset of PB infants (age <3 years, but 8/11 <1 year). 11 patients. Partial surgical resection

• Outcome: All children failed chemo, 9/11 in primary site, 8/11 had leptomeningeal progression at time of failure. All children died, survival 4-13 months

• Conclusion: Chemo alone not effective

• CCG 921 (1986-1992)

– Older children (>1.5 years) treated with surgery + CSI + chemo; infants (<1.5 years) treated with surgery + chemo (8-in-1) only

– Pineal only; 1995 (Jakacki et al J Clin Oncol. 1995

• Pineoblastoma subset of 25 patients, 17 age >1.5, 8 infants

– Infants: all infants developed progressive disease, median PFS 4 months

– Older children: 3-year PFS 61% .After RT, 70% had residual pineal region mass, which persisted as long as 5 years before resolving

• Conclusion: Chemo alone (8-in-1) ineffective for infants. CSI + chemo effective for older children

(methylprednisolone, VCR, CCNU or carmustine, procarbazine, hydroxyurea, cisplatin, cytarabine and cyclophosphamide

• UCSF; 1995 (1975-1992) Chang SM, Neurosurgery. 1995

– Retrospective. 11 patients. Median age 36 years (17-59). All with symptomatic hydrocephalus. Gross total resection 1/11. CSI 10/11 (CSI 24-45 Gy with tumor boost to 54-59.4 Gy). 7/11 chemo

– Outcome: M+ (5/10) alive median PFS 10 months, median OS 2.5 years; M0 (5/10) all alive at 2.2 years follow-up

– Conclusion: M0 patients can do well after surgery + CSI, benefit of chemo unclear

SRS• Marseille; 2006 - Reyns N Acta Neurochir (Wien). 2006

– Retrospective. 13 patients (8 pineocytomas, 5 pineoblastomas). SRS alone in 6 cases, after surgery 3 cases, with chemo 3 cases, s/p EBRT 1 case. Mean dose 15 Gy (11-20 Gy). Mean F/U 2.8 years

– Outcome: pineocytoma 8/8 alive, pineoblastoma 2/5 alive

– Toxicity: none major

– Conclusion: SRS effective and safe for pineocytoma, should have a role in multimodality treatment for pineoblastoma

• Hasegawa T, Neurosurgery. 2002(Pittsburg)

– Retrospective. 16 patients treated with SRS as primary or adjuvant. Pineocytoma (n=10), mixed tumor (n=2), pineoblastoma(n=4). Mean dose 15 Gy. Mean F/U 4.3 years

– Outcome: 2-year OS 75%, 5-year OS 67%; LC rate 100%; 5/16 died, 4 secondary to leptomeningeal or extracranial spread

– Conclusion: SRS valuable modality for pineocytomas; can be used as boost for malignant pineal tumors

• Kobayashi T, J Neurooncol. 2001(Japan)

– Retrospective. 5 patients with pineal & nearby tumors. Pineocytoma (n=3), pineoblastoma (n=2). Pineal RT mean dose 15.7 Gy

– Outcome: pineocytoma 2/3 CR, 1/3 PR, no progression at 22 months; pineoblastoma 1/2 PR, 1/2 PG

– Conclusion: GKS is expected to be effective approach

Brachytherapy-Iodine 125

• Budapest; 2006 "Review of radiosurgery of pineal parenchymaltumors. Long survival following 125-iodine brachytherapy of pineoblastomas in 2 cases." (Julow J, Minim Invasive Neurosurg. 2006

– Case report. 2 patients. Follow-up 5.1 and 4.8 years

– Outcome: shrinkage 73% and 77%, both negative on PET

– Conclusion: Two successful treatments reported

Simulation-cranial field

Opposing lateral fields are applied to the whole brain and upper spine

Isocentre positioned at midline.

AP width & superior border include the entire skull with 2 cm clearance

Inferior border placed around C2-3

Lower border is matched with the superior border collimator rotation of 7-11 o to match the divergence of the direct posterior spinal field

Spinal field

• Upper border- at low neck

• Lateral border – 1cm lateral to the lateral edge of each I/L pedicles or to include the transverse processes in their entirety to cover the spinal cord and meninges along the nerve roots upto the spinal ganglia

• Lower border at termination of thecal sac or S2 whichever is lower

• If whole spinal axis cannot be included in single field

Treatment at extended SSD

Advantage

• Single spinal field and overcoming the issue of junction between two spinal

fields

Disadvantage

• Higher percentage depth dose

• Greater penumbra

Treatment with split fields in which 2 spinal fields are used to treat spinal

axis

Radiotherapy Planning

Phase I- CSI

Two lateral cranial fields

1 or 2 spinal fields

Phase II: Boost

Two lateral cranial fields

TECHNIQUES OF MATCHING CS FIELDS

Collimator/Couch rotation

Half beam block

Asymmetric jaws

Planned gaps

Moving Junction technique

Collimator rotation

• Divergence of upper spinal field into cranial field overcome by collimator rotation so that its inferior border is parallel to divergence of superior aspect of spinal fields

• Collimator angle = tan-1 { ½L1/SSD}

• L1 is spinal field length

SSD = source to surface distance of posterior spine field

COUCH ROTATION

Rotation of the couchDivergence of cranial field

Divergence of cranial field into upper spinal field overcome by

couch rotation

Couch angle = tan-1 { ½ L2/SAD}

L2 is cranial field length

Half beam block

Aligning Spinal field

Field gap technique

Double junction technique

Feathering

Gap calculation-formula

Disadvantage-Dose above the junction will be lower – Cold spot.

Below the junction higher than the junction dose- Hot spot

Germinomas

• Rare primary CNS tumor, 3-5% of childhood brain tumors

• Typical age at presentation is early teens

• Located in midline structures, suprasellar

region or pineal gland

• Can be M+ in as much as 24% histologically verified cases; Disease outside of CSF is very rare

• Bifocal germinomas (synchronous suprasellar and pineal tumors) regarded as M+ in USA but M0 in Europe

• Natural spread along subependymal lining of 3rd and 4th ventricles, leading to intraventricular relapse before spinal dissemination

• Very sensitive to both radiation and chemotherapy

• T/t of M0 disease Historically CSI was the gold standard, but with local control >99% and 10-year survival rates >90%, limiting side-effects is essential

• Then WBRT & now to tumor + ventricles only.

• Isolated spinal relapse appears comparable between CSI and whole-brain RT or whole-ventricular RT with neoadjuvant chemo

• M+ disease to be treated with CSI

• Now

– Whole ventricular volume: 3rd, 4th, lateral, prepontine cistern

– Involved field volume: pre-chemotherapy volume + clinical margin 1-1.5 cm

– Dose to primary disease is typically 40-45 Gy, and to subclinical disease 20-24 Gy(SFOP Neuro Oncol 2010)

•

• Rogers SJ, Lancet Oncol. 2005

– Reviewed 20 studies since 1988. 788 patients. 66% cases histologicallyconfirmed, 12/20 series 100% confirmation. Median F/U 6.4 years

– CSI: local control 99.7%; relapses 3.8% but half of them outside CS axis; isolated spinal relapse 1%

– WBRT or Whole-ventricular RT+boost: both comparable. local control 97%; relapses 8%; isolated spinal relapse 3%

– Focal: local control 93%; relapses 23%; isolated spinal relapses 11%

– Conclusion: Whole-ventricular RT + boost should replace craniospinalRT in completely staged localized intracranial germinomas

• MAKEI 83/86/89, 1983-93 (German)

– Prospective, non-randomized. Goal: dose reduction. 60 pts. Germinomas. Three trials: 83(pilot) and two successive trials. Biopsy only (no resection)

– In MAKEI 83/86 (11 pts), RT to 36 Gy to craniospinal axis + 14 Gy boost to tumor (total 50 Gy, at 1.8-2 Gy/fx).

– In MAKEI 89 (49 pts), 30 Gy (CSI) + 15 Gy (total 34 Gy at 1.5 Gy/fx).

– Mean f/u 59 mos. CR in all pts. 5-yr RFS 91%, OS 93%

• Conclusion: Dose reduction is feasible.

• Huh S. 1996

– Retrospective. 32 patients, confirmed intracranial germinomas (14 suprasellar, 12 basal/thalamus, 4 pineal, 2 multiple). CSI in 29 patients. RT tumor bed 54 Gy, whole-brain 36 Gy, spinal axis 24 Gy

– Outcome: 5-year OS 97%, 10-year OS 97%; 1 death with persistent tumor 2 months after RT; no intracranial or spinal recurrence

– Toxicity: 1 severe intellectual deterioration, 3 vertebral growth impairment

– Conclusion: Excellent result with RT alone

• Proton Therapy

• Harvard Macdonald SM, Int J Radiat Oncol Biol Phys. 2010

– Retrospective. 22 patients, CNS germ cell tumors, treated with 3D PT

– Patients also replanned with IMRT and IMPT. Median F/U 2.3 years

– Outcome: Local control 100%, no CNS recurrences, PFS 95%, OS 100%

– Treatment planning: Comparable CTV coverage with IMRT, 3D-CPT, and IMPT. Substantial normal tissue sparing with either PT over IMRT. IMPT may yield additional brain and temporal lobe sparing

– Conclusion: Preliminary disease control favorable; superior dose-distribution compared to IMRT

RT doses for geminomas

• In less favourable or leptomeningel spread

• 21 Gy to CSI f/b boost to primary tumor to 40-45 Gy

• If chemo 2 -6 cycles of PIE

• If CR 24Gy/15# @1.6 Gy to WVRT in 3 weeks

• If PR 16Gy in 10# in 2 weeks boost total 40Gy/25 #

• (Alapetite et al neuro onco 2010)

Chemotherapy

• 4 cycles of Chemotherapy at 21 day interval for NGMGCT

• Chemotherapy is based on a combination of Cisplatin, Etoposide and Ifosfamide (PEI)

• Chemotherapy as in SIOP CNS GCT 96

• Each course of PEI consists of:

• Cisplatin 20 mg/m²/day days 1, 2, 3, 4, 5

• Etoposide 100 mg/m²/day days 1, 2, 3

• Ifosfamide 1500 mg/m²/day days 1, 2, 3, 4, 5

RT Dose for Non Germinomas• British Oncology Society 2011

• Non-metastatic disease (negative CSF-cytology, negative spinal MRI)

• 24Gy /15# @1.6 to WVRT

• Primary tumor bed additional boost to 54Gy

• Metastatic disease (positive CSF-cytology and / or positive spinal MRI)

No Of # Dose/# Total dose (Gy)

Duration (weeks)

Brain 20 1.5 30 4

Spinal cord 20 1.5 30 4

Boost CNS +15 1.6 24 +3

Boost SC +10 1.6 16 +2

Total 35 54 To CNS46 To S. mets30 to CSI

7

Stem Cell Rescue

• 12 patients treated with induction chemo f/b CSI and pineal region boost(36Gy CSI,59.4Gy boost)

• F/b high dose chemo and stem cell transplant

• 9/12 pts remained disease free iclu 1 who didn’t receive rt

• Overall survival at 4 years was 71%

• Still investigational

Case 1• 10 year old

• Vp shunting done

• MRI-lesion inpineal regon

• Tumor decompression done

• HPR-Germinoma

• 4 cycles of CT carbo+Eto

• 24 Gy/15# at 1.6 Gy/# panventricular

• f/b preop dis + margin

• 1cm CTV

• 3mm PTV

• Tumor bed boost 10.5 Gy/6 # @1.75Gy/#

2nd Case

• 20 year old male

• MRI sol in pineal region

• AFP-2.34,BHCG<1.2

• GTR at Paras Hospital

• HPR-Pineoblastoma Gd IV

• CSI with concurrent CDDP

• F/b Adjuvant chemo

• CSI 36Gy/20#@ 1.8Gy/#

• Post fossa boost to 54Gy

Japanese Pediatric Brain Tumor Study Group Classification

Prognostic Group• Good

• Germinoma, pure

• Mature teratoma

• Germinoma with syncytiotrophoblastic giant cells

• Intermediate

• Immature teratoma

• Mixed tumors mainly composed of germinoma or teratoma

• Poor

• Teratoma with malignant transformation

• Choriocarcinoma

• Embryonal carcinoma

• Mixed tumors composed of choriocarcinoma, yolk sac tumor, or embryonalcarcinoma

• Yolk sac tumor

Side effects of RT

• Acute Side Effect (1-6 months after Treatment)

• Skin Burns

• Hair Loss

• Fatigue

• Occasional Worsening of Neurological Symptoms

• Headaches

• Nausea / Vomiting

• Hearing Loss

• Dry Eyes

• Late Side Effects(6-24 months after Treatment)

• Ataxia,

• Urinary Incontinence

• Hearing Loss

• Dry Eyes

• Endocrine Disorders

• 10-20% risk of cognitive change, which include memory loss and apathy

Follow -UP• Schedule Frequency

• Years 0–2 Annually every 3–6 months

• Year 3–5 Every 6–12 months

• Year 6 and beyond Annually

• Examination

• Complete history and physical examination

• Formal visual field testing

• Imaging study MRI 1st at 3 momths then every 6 months in the first 2 years, then annually

• Laboratory tests

• Endocrine tests are recommended every 6 months

• Tests include GH, TSH/T3/T4, gonadal function and adrenal function tests, and hypersecreted hormone

• Serum markers AFP,BHcg for GCT