CNS Germinomas, Diabetes Insipidus, and Chemotherapy: Challenges in Management

1
CNS Germinomas, Diabetes Insipidus, and
Chemotherapy Challenges in Management

• Jeff Bednarski, M.D., Ph.D

2
Case Presentation

• MB is a 17 yo boy who presented with a 1 week
  history of declining vision. Vision was
  initially blurry. Seen by ophthalmologist who
  noted visual field deficits and sent for MRI.
  Awaiting MRI his vision loss progressed to only
  seeing shadows.
• ROS polyuria, polydypsia, occasional headaches,
  no fevers
• PMH treated for hypothyroidism
• FH IDDM in parents, mom with hyperlipidemia and
  HTN
• Exam dry mucus membranes, dysconjugated eye
  movements, lungs and heart normal, remainder of
  neuro exam normal.

3
Studies

• MRI masses in suprasellar cistern and pineal
  region, no spinal lesions
• Urine spec gravity 1.003
• Serum sodium 150
• Serum creatinine 1.8
• TSH 1.60 (nl 0.35 - 5.5)
• T4 8.3 (nl 4.5-12)
• Prolactin 11 (nl 2.1 - 18)
• Cortisol lt 1.5 (nl 4.3 - 22.4)

• Tumor studies
• Frozen path pilocytic astrocytoma
• Final path germinoma
• Serum ?HCG and AFP negative
• CSF ?HCG 7.3 (nl lt 1.5)
• Repeat CSF ?HCG 0.6
• CSF AFP lt 0.5 (nl lt 1.5)

4
Diagnosis and Plan

• Diagnoses
• 1. CNS germinoma vs. non-
• germinomatous germ cell
• tumor
• 2. Central diabetes insipidus
• 3. Hypothyroidism
• 4. Adrenal insufficiency
• 5. Significant visual impairment

• Plan
• 1. Radiation vs. chemotherapy
• radiation
• 2. DDAVP, follow Na, spec grav
• 3. Synthroid
• 4. Hydrocortisone
• 5. Early intervention with semi-
• emergent radiation therapy

5
Germ Cell Tumors

• Intracranial GCTs represent 0.5 - 2.5 of all
  brain tumors
• Usually occur in the second to third decade
• Typically occur in the pineal or neurohypophyseal
  regions of brain
• Synchronous involvement of both sites present in
  2 - 13 of cases
• Hypopituitarism, particularly diabetes insipidus,
  is frequently associated with suprasellar lesions
• Visual symptoms are common presenting complaints

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Germ Cell Tumors

• Germinoma
• Also called seminoma or dysgerminoma
• Less aggressive
• Can secrete ?HCG due to presence of
  syncytiotrophoblasts
• (typically less than 50 mIU/mL)
• Does not make AFP
• Comprise 1/2 - 2/3 of all CNS GCTs
• Non-germinomatous germ cell tumor
• Tends to be more aggressive
• Secrete ?HCG (typically gt 50 mIU/mL)
• High ?HCG seen in choriocarcinoma and embryonal
  carcinoma
• May secrete AFP
• Particularly endodermal sinus tumor and embryonal
  carcinoma

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Treatment Radiation

• Germinomas are exquisitely radiosensitive
• Ogawa, et al (2004) reported 90 overall survival
  rates and 95 cause-specific survival rates at 10
  years
• Typically utilizes 40-50 Gy
• Standard was whole brain or craniospinal
• Localized field therapy has been pursued more
  recently
• Complications
• Neurocognitive impairment
• Endocrine disorders
• Secondary malignancy in radiation field (20 yr
  probability of 12)
• Somatic growth impairments
• Not effective as a sole therapeutic modality for
  NGGCT (20-45 5 year survival)

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Treatment Chemo

• Balmaceda, et al (1996) used carboplatin,
  etoposide and bleomycin in 71 patients
• 2 yr survival 84 for germinoma and 62 for NGGCT
• By 5 yr, 60 of patients had cause-specific
  progression
• Thus, 39 had continuous CR with chemo alone
• If progressed were successfully salvaged with
  radiation ( chemo)
• Kellie, et al (2004) used cisplatin, carboplatin,
  etoposide, cytoxan, bleomycin in 19 patients
• Overall 5-year EFS 47 and OS 68
• Complications ototoxicity, renal toxicity,
  myelosuppression, infection

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Treatment Multimodal Therapy

• Bouffet, et al (1999) - alternating
  etoposide-carboplatin and etoposide-ifosfamide
  with 40 Gy local irradiation (followed for 42
  months)
• 3-yr survival probability 98 and EFS 96
• Aoyama, et al (2002) - etoposide-cisplatin with
  24 Gy local irradiation or ifos-ciplatin-etoposide
  with 40-50 Gy for NGGCT followed for 5 years
• Germinoma OS 100, RFS 86
• NGGCT OS 75, RFS 44
• No significant difference in pre- and
  post-therapy IQ
• Kretschmar, et al (2006) - alternating
  cisplatin-etoposis and vincristine-cytoxan with
  30.6 Gy local irradiation (higher doses given if
  not CR after chemo)
• Germinoma EFS 92, OS 100 at 5 yr.
• NGGCT EFS 79, OS 79 at 5 yr.

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Previous Experience

• BS is 10 yo girl with CNS germinoma (pineal,
  sellar/suprasellar) presented with visual field
  deficit, exotropia, headaches. Clinical course
  c/b CDI, hypothyroid, adrenal insufficiency.
  Treated carboplatin and etoposide x 2 cycles and
  tolerated well. Had moderate tumor response so
  planned for 2 more cycles of cisplatin and
  cytoxan. During first cisplatin developed acute
  renal failure.
• Serum cre increased from 0.8 to 2.7 (max 7 during
  subseq dehydration)
• Serum Na 145 - 152
• Urine spec grav 1.005 to 1.015 during therapy
• I/O day 1 day 2 day 3
• 5.3L/5.8L 3.9L/3.2L 2.8L/3.3L
• __________________________________________________
  ___________
• AG is a 12 yo boy with CNS germinoma (pineal)
  presented with polyuria/polydypsia and
  clumsiness. Clinical course c/b CDI,
  hypothyroidism. Treated with cisplatin-etoposide
  alternating with vincristine-cytoxan. During
  second cycle, developed acute renal failure after
  cisplatin.
• Serum cre increased from 0.4 to 2.1
• Serum Na 147-153

11
Normal regulation of body water
12
Normal regulation of body water
X
Diabetes insipidus
13
Normal regulation of body water
X
X
Diabetes insipidus with impaired thirst
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Treatment of DI

• Fluid replacement
• Requires limiting salt delivery to avoid driving
  up urine output (more later)
• Patients with intact thirst do this well, MDs
  dont always do as well
• DDAVP long acting AVP analog, can get fluid
  overload
• Subcutaneous most potent, 4 mcg/ml
• Nasal 10 fold less potent than SQ, 10 mg/0.1 ml
• Oral 100-200 fold less potent than SQ, 0.1 and
  0.2 mg tablets
• Vasopressin drip
• Very short half life, effect goes away rapidly,
  start at 0.5 mU/kg/hr and titrate up

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Cisplatin Renal Toxicity

• Cisplatin toxicity is to renal tubules,
  particularly proximal. There is minimal to no
  effect on glomeruli.
• Most of drug is excreted in first 3 hours
• Renal toxicity seen at 72 - 96 hours
• Toxicity is result of dose and duration dependent
  apoptosis in renal tubular cells.
• Receptor-mediated apoptosis through Fas and TNF
• Mitochondrial-mediated apoptosis
• End-result is activation of caspases and cell
  death
• Result is inability to concentrate urine
• Clinically, high hydration, large saline supply,
  and mannitol have been proven to reduce renal
  toxicity

16
Cisplatin Renal Toxicity

• Low urine osmolarity as a determinant of toxicity
  (Polycarpe, et al 2004)
• Conclusions
• Low urine osmolarity increases uptake of
  cisplatin into renal cells but not tumor cells.
• Increased uptake of cisplatin results in
  increased cell death of renal tubular cells.
• Urine osmolarity in patients on standard fluid
  regimen remains low.

600 mOsm/L
300 mOsm/L
150 mOsm/L
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Cisplatin Renal Toxicity

• Low urine osmolarity as a determinant of toxicity
  (Polycarpe, et al 2004)
• Increased renal toxicity seen when cisplatin
  given in hypotonic solution
• Interpretation
• Increased osmolarity decreases intracellular
  accumulation of cisplatin
• May be secondary to protective effect of Na or Cl
  ions
• May be secondary to decrease solvent drag
  effect

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Cisplatin Renal Toxicity

• Stress response inhibits toxicity (Hanigan, et al
  2005)
• Conclusions
• Increased osmolarity of cisplatin incubation
  solution is protective
• No changes in intracellular cisplatin
  concentration
• Pre-incubation in hypertonic solution is
  detrimental
• Cellular responses to changes in extracellular
  salt concentration alter toxicity of cisplatin

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Cisplatin Renal Toxicity

• Stress response inhibits toxicity (Hanigan, et al
  2005)
• Conclusions
• High osmolarity solution has protective effect
• Protective effect is independent of cellular
  concentration
• Propose that cellular stress responses to changes
  in osmolarity alter renal tubular cell
  sensitivity to cisplatin

20
Kidney
Cisplatin
AVP or DDAVP
21
Vasopressin Drip and Chemo

• Bryant, et al (1994) look at use of vasopressin
  infusion during cisplatin administration in
  patients with diabetes insipidus
• 3 patients - all had suprasellar germinoma and
  central DI
• 2 patients got vasopressin infusion and 1 patient
  managed with fluids
• All pts got D5 0.45 NS 20 mEq/L KCl at 3
  L/m2/day
• Vasopressin was 0.08 to 0.1 mU/kg/h titrated to
  keep Ur spec grav 1.004 - 1.009

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References

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