Monthly Archives: October 2014

Gabapentin

Dose:  
start with 300mg OD, then 300 BID, then 300 TID; titrate up to max 3,600 mg/day
*Doses >1,800 mg usually no greater benefit

Mechanism of Action:
Gabapentin is structurally related to GABA, but does not bind to GABA A or GABA B receptors; does not influence synthesis or uptake of GABA
binds to Gabapentin sites throughout brain (with volatage-gated calcium channels that has the alpha-2-delta-1 subunit – A2D1), located presynaptically, and modulates release of excitatory neurotransmitters that are involved in seizures or pain perception

Dose in renal failure:

Table 5

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Metastatic Brain Cancer Prognosis

Prognostic groups for outcome after palliative treatment of brain metastases by recursive partitioning analysis

Class Prognostic factors Median survival, months
I KPS ≥70 percent 7.1
Age <65 years
Controlled primary site
No extracranial metastases
II All others 4.2
III KPS <70 2.3

Karnofsky performance status scale

Value Level of functional capacity Definition
100 Normal, no complaints, no evidence of disease Able to carry on normal activity and to work; no special care needed
90 Able to carry on normal activity, minor signs or symptoms of disease
80 Normal activity with effort, some signs or symptoms of disease
70 Cares for self, unable to carry on normal activity or to do active work Unable to work; able to live at home and care for most personal needs; various degrees of assistance needed
60 Requires occasional assistance, but is able to care for most needs
50 Requires considerable assistance and frequent medical care
40 Disabled, requires special care and assistance Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly
30 Severely disabled, hospitalization is indicated although death is not imminent
20 Hospitalization is necessary, very sick, active supportive treatment necessary
10 Moribund, fatal processes progressing rapidly
0 Dead

Graded prognostic assessment for brain metastases by diagnosis

Non-small-cell and small-cell lung cancer
Prognostic factor Scoring criteria Patient score
0 0.5 1.0
Age in years >60 50-60 <50
KPS <70 70-80 90-100
Extracranial metastases Present Absent
Number of brain mets (BM) >3 2-3 1
Total:
Median survival (months) by score: 0-1.0 = 3.0; 1.5-2.0 = 5.5; 2.5-3.0 = 9.4; 3.5-4.0 = 14.8
Melanoma
Prognostic factor Scoring criteria Patient score
0 1.0 2.0
KPS <70 70-80 90-100
Number of BM >3 2-3 1
Total:
Median survival (months) by score: 0-1.0 = 3.4; 1.5-2.0 = 4.7; 2.5-3.0 = 8.8; 3.5-4.0 = 13.2
Breast cancer
Prognostic factor Scoring criteria Patient score
0 0.5 1.0 1.5 2.0
KPS ≤50 60 70-80 90-100 n/a
Subtype* Basal n/a Luminal A HER2 Luminal B
Age in years ≥60 <60 n/a n/a n/a
Total:
Median survival (months) by score: 0-1.0 = 3.4; 1.5-2.0 = 7.7; 2.5-3.0 = 15.1; 3.5-4.0 = 25.3
Renal cell carcinoma
Prognostic factor Scoring criteria Patient score
0 1.0 2.0
KPS <70 70-80 90-100
Number of BM >3 2-3 1
Total:
Median survival (months) by score: 0-1.0 = 3.3; 1.5-2.0 = 7.3; 2.5-3.0 = 11.3; 3.5-4.0 = 14.8
Gastrointestinal cancers
Prognostic factor Scoring criteria Patient score
0 1 2 3 4
KPS <70 70 80 90 100
Total:
Median survival (months) by score: 0-1.0 = 3.1; 2.0 = 4.4; 3.0 = 6.9; 4.0 = 13.5

* Basal: triple negative; Luminal A: ER/PR positive, HER2 negative; Luminal B: triple positive; HER2: ER/PR negative, HER2 positive.

Brain Metastasis with Poor Prognosis

Key components:

  1. Control of peritumoral edema and increased ICP with steroids
  2. Treatment of seizures
  3. Management of venous thromboembolic disease

Modalities:

  1. whole brain radiation therapy (WBRT)
  2. surgery
  3. stereotactic radiosurgery (SRS)

Supportive care + corticosteroids – median survival of 1-2 months

WBRT – average survival of 3-6 onths

3 factors determining survival:  performance status, extent of extracranial disease, age

Three prognostic classes:

  1. Class 1 Karnofsky performance score (KPS) 70/+, <65y, controlled primary tumor, no extracranial metastases à median survival 7.1 months
  2. Class 2 KPS 70/+ but with other unfavorable characteristics à2 months
  3. Class 3 KPS <70 à median survival 2.3 months

DS-GPA: (diagnosis-specific graded prognostic assessment) = separate criteria for patients with NSCLC, SCLC, melanoma, RCC, breast cancer, GI cancer

  1. NSCLC or SCLC – all factors were significant
  2. Melanoma or RCC – only KPS and # of brain mets significant factors
  3. Breast CA or GI Ca – KPS only

NOTES:

  • Aggressive treatment not warranted
  • If active treatment – prefer WBRT.
  • SRS and surgery for favorable prognosis
  • 2 exceptions: poor performance status due to mets, SRS associated with improved survival; also lesions <5, SRS instead of WBRT (SRS is 1 day, while WBRT is multiple days)

WBRT:

  • goal is to improve deficits, questionable if survival is improved
  • response rate 40-60% (breast and SCLC responsive, less with melanoma or RCC; small, solid tumors more likely than large, necrotic or cystic)
  • Overall survival determined by activity and extent of extracranial disease rather than control of brain mets; there is a trial that compares WBRT with best supportive care showing no difference I survival between optimal supportive care compared with adding WBRT
  • Most common regimen: total dose 30Gy in 10 daily fractions of 3 Gy
  • Acute toxicity: mild and self-limited; cerebral edema may worsen, so start steroids 48 hours prior
  • Late toxicity: leukoencephalopathy, brain atrophy à dementia, radiation necrosis, NPH, hypothyroidism, cerebrovascular disease

Recurrent brain mets:  surgery, SRS, reirradiation, systemic chemo?

TUMORAL VASOGENIC EDEMA

Pathogenesis:  production of VEGF, glutamate, leukotrienes (increases permeability of tumor vessels) and absence of tight endothelial cell junctions in tumor blood vessels (respond to VEGF and basic fibroblast growth factor)

Gliomas, meningiomas, metastatic tumors à secretes VEGF à binds to VEGFR1 and VEGFR2 (surface of endothelial cells à formation of gaps in endothelium à fluid leakage into brain parenchyma à vasogenic edema à spreads more in white matter (lower resistance than gray matter) à disrupts synaptic transmission, alters neuronal excitability à HA, seizures, focal deficits, encephalopathy, herniation

DEXAMETHASONE

Advantages:  Lack of mineralocorticoid activity, less fluid retention; lower risk of infection and cognitive impairment

Mechanism:  Upregulates Ang-1 (BBB-stabilizing factor) and downregulates VEGF in astrocytes and pericytes; increases clearance of peritumoral edema by facilitating transport of fluid into ventricular system

Dosage:

  • Severe symptoms: 10mg IV loading dose then 4mg QID or 8 mg BID
  • Lower doses (1-2mg QID) may be as effective and less toxic if without impending herniation
  • Long half life to allow BID dosing
  • Improves within hours, maximum benefit within 24-72 hours, neuroimaging may not confirm until at least 1 week
  • If 16mg/day insufficient, may increase up to 100mg/day

Taper:  once improved, taper by 50% every 4 days

Guidelines: 16mg/d or more if severe symptoms due to inc ICP and edema due to brain mets; for milder symptoms, start 4-8mg daily; if asymptomatic, steroids not recommended; taper over 2 week period or longer

Complications:

  • insomnia, essential tremor, hiccups
  • GI complications
  • Steroid myopathy – prox weakness in week 9-12
  • PCP infection – risk increases while tapering steroids; fever and dyspnea and dry cough but can be subtle and nonspecific

Novel treatments: bevacizumab (anti-VEGF monoclonal antibodies); corticotrophin-releasing factor, COX-2 inhibitors?

Hepatic Encephalopathy

JAMA Sept 2014

Polyethyene glycol 4L PO or via NGT single dose over 4 hours vs standard treatment with lactulose – (decreased time to resolution of encephalopathy from 7 to 4 days, achieved lower 24-hour HE score)

Rahimi, R., Singal, A., Cuthbert, J., & Rockey, D. (2014). Lactulose vs Polyethylene Glycol 3350-Electrolyte Solution for Treatment of Overt Hepatic Encephalopathy: The HELP Randomized Clinical Trial. JAMA Internal Medicine.