Post on 22-May-2018
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Adverse events / Toxicitiesduring
Immunotherapy of Cancer
Endocrinopathies Stig Valdemarsson
Skåne University Hospital 2015 12 05
CASE 1 -- 76 ys old female; Radioiodine 15 years ago; no need for thyroxine
• Acral / finger melanoma • Regional and lung metastasis • Temozolamid: progress; TKI – nilotinib – progress
• Ipililumab; 3 cycles given • Presented with severe headache, tiredness; vomiting • High blood pressure !! No focal neurology; visual disturbances ?
• Lab A: P-Na from 141 to 129 – 120; S/U Osmol 258/586 = SIADH !
• Lab B: FSH/LH low for age : 12 (25-135) / 2.7 (7.7-59) – hypopituitarism !
• Lab C: ACTH 6.5 normal; P-kortisol 319 = intermediate
• Lab D: TSH 0.23 Free T4 9 = central hypothyroidism
• Received iv hydrokortison; subsequent high dose prednisolon; later thyroxine
Reference Pituitary MRwithout and with constrast
Case 1 : follow up 3 months later
Pituitary stalk lesion: diagnosis to be considered
• Lymphocytic infundibulo-hypophysitis • Langerhans cell histiocytosis • Wegener’s • Neurosarcoidosis • Inflammatory infiltrations by infectious diseases.
• Germ cell tumours • Pituicytomas and other tumours • Metastases from lymphoma, breast cancer,
melanoma etc
Hypofysitis; middle aged women ( verified at exploration )
50 ys old female; previously op malignant melanoma. Admitted to neurology. MR sella lesion; skeletal destruction.
Progressiv pituitary insufficiency. Transsfenoidal exploration. PAD: metastasis from malignant melanoma
Pituitary endocrine evaluation
• Look for anterior lobe disturbances ✓ pituitary – gonadal hypofunction
✓ secondary adrenal insufficiency
✓ central hypothyroidism
• Look for posterior lobe DI symptoms
✓ polyuria - nocturia - and polydipsia
✓ note thirst and high P-Na !!
Blood sampling – anterior pituitary function ?
F-pre MP Oestradiol + FSH / LH ( low+ inappro. normal/low? ) F-postMP FSH / LH ( not increased ? ) M Testo+SHBG + FSH/LH ( low + inappro. normal/low ?)
F+M P-kortisol + ACTH ( low + not increased ?) P-kortisol < 100 nmol/L substitute 100 – 250 treat if suspected / control soon 250 – 450 control, might be normal > 450 sufficient
F+M Free T4 + TSH ( low + not appropriately increased )
F+M IGF-1 : ( GH deficiency ? – evaluated at follow-up ) F+M Prolaktin – increased ? Pituitary stalk disruption ? Prolaktinoma ? Drugs ?
Diabetes insipidus ?Symptoms: • Polyuria • Thirst Polydipsia --- day and night !! • Note increased P-Na !
Diagnosis: • Increased P-Na + low/ inappropriate low / not
increased osmolality in urin + typical symtoms
• Thirst test in unclear cases
Pituitary insufficiency - substitution
• Hydrocortison iv in acute setting
followed by oral hydrocortison 20 – 30 mg / d
• ( Fludrocortison / aldo / seldom indicated )
• Thyroxin; only after hydrocortison !
• Desmopressin if needed
• Next case
Case 2: Thyroid and pembrolizumab• 59 ys old man ; no previous thyroid disorder
• Malignant melanoma 2007; progress 2014
• Ipililumab from Jan 2015 • Steroids for severe toxocodermia • Progress
• Pembroluzimab from April 24th 2015
• May 13th 2015 abnormal thyroid function tests at regular follow up • Moderate thyreotoxic symptoms • Increased pulse rate • Admitted for evaluation of thyroid disturbance
Thyroid scintigraphy; 99mTc Note low up-take: ---thyroiditis? ---Iodine block after CT contrast
Scintigraphy - information
Normal thyroid structure
Enlargded thyroid • isthmus 9 mm • low ecogenecity
Pembrolizumab and tyreotoxicosis
Right lobe Left lobe
Thyroid and pembrolizumab Conti..
• Thyroid lightly enlargded; diffuse; not tender • TSH suppressed Free T4 67 - 92 ( 12-22 ) Free T3 14 – 18.6 (3.6-6.3) • TSH Rec Ab : neg TPOAb : neg
• 99mTc Scint --- no/low uptake
• Ultrasound -- general hypoecogenicity; moderately enlargded vascularisation not increased --- Thyroiditis ? Autoimmun thyroid disease ?
Conclusion: • probable inflammatory process with hormone release; • no nodes; not Graves´
Beta blocker; discontinue pembrolizumab ?
Follow up: Free T4 max > 99 pmol/L; -- subsequent sponaneously decreasing Free T4; nadir 3.7 with TSH increased to 21
Thyroxin substitution initiated
Thyroiditis – inflammation in thyroid
Autoimmune
-- various manifestationes
-- TPOAk (TgAk) positiv
• Hashimoto
• Atrofisk
• Spontaneous / ”silent”
• Post partum • Fokal
• Juvenil
Non – autoimmune -- various patophysiologies -- TPOAk negativ
• Subakut; de- Quarvain • Bakteriel • Riedel • Iodine - amiodarone • Radioiodine • Trauma
• PD-1 ? CTLA-4 ? • TKI ( sunitinib and other )
Thyroiditis – T4 / T3-typical development over time
Thyroiditis: treatment ?
• Beta – blocker
• Consider steroids
-- local tender symtom ?
-- probably no effect on outcome ( de Quervain )
• Watchful follow- up / 2 – 3 weeks
• Thyroxin if hypothyroid / at least if prolonged
• Anti-thyroid drugs not indicated
Induction of Painless Thyroiditis in Patients ReceivingProgrammed Death 1 Receptor Immunotherapy for
Metastatic Malignancies
…. clinical trial to receive anti-PD-1 mAb therapy (2–10 mg/kg IV infusion over 30 minutes, every 3 weeks) … continued
n=6: Toxic phase 3 – 6 weeks from start; duration 4 weeks before hypotyroid n=4. Hypothyroid 6 – 8 weeks from start
Nivolumab in Resected and Unresectable Metastatic Melanoma:Characteristics of Immune-Related Adverse Events and Association
with Outcomes Morganna Freeman-Keller e al Oct 2015
Adverse effects / FASS / Sweden
Nivolumab
• Pnumonitis • Colitis • Hepatitis • Nephritis • Endocrine -- pituitary -- adrenal -- diabetes type 1 -- thyroid - hypothyroidism - hyperthyroidism - thyroiditis
Pembrolizumab
• Pnumonitis • Colitis • Hepatitis • Nephritis • Endocrine -- pituitary -- adrenal -- diabetes type 1 -- thyroid - hypotyroidism - hypertyroidism - thyroiditis
Tc – scintigrafi; man, sunitinib -- supprimerat TSH höga FT4 och FT3
-- lågt – inget upptag som vid tyreoidit
Lymfocytär tyreoidit / Hashimoto
Subacute tyreoiditis; polynuclear cell
Autoimmun tyreoidit Hashimoto
UL: TSH 30 efter 9 cykler Sutent
Hashimoto’s Thyroiditis
Immunmodulering:CTLA-4: interaktion mellan APC och T-cell
Ipilimumab - YERVOY
• CTLA-4 hämmare
• Melanom – dissiminerat
• Autoimmuna reaktioner – hos 72% ( n=325 ) efter 4 behandlingar - tyreoidea – tyreoidit mest sannolik mekanism hypotyreos; hypertyreos ( mindre vanligt )
- hypofysit ACTH svikt / TSH svikt - primär binjuresvikt / Addison - colit - hepatit
CTLA-4 hämmare och Hypofysit
CTLA-4 i TSH, ACTH och FSH/LH celler
PD-1 interference
+ hormonproducerande follikulär tyreoideacancer
Nyström et al ”Thyroid Disease in Adults” 2011
Follikelcellen
Hormonsyntes
Jodomsättning
Regleras av TSH
Ultrasound; normal thyroid structure ( small size )
Germinom. The most common location is the pineal region or posterior ventricle
followed by the suprasellar region.
65 årig kvinna. Tidigare op malign tumör i lunga och ÖNH. Vid utredning av hypofysinsufficiens påvisas expansiv process med recidivbenägenhet. Så småningom anger PAD kronisk hypofysit.
Inom 1 år efter sista op plötslig progess med ny synnedsättning; regress av suprasellär utbredning efter hög dos steroider
Pituitary stalk met från breast cancer presenting with DI symtoms
Pitutiary stalk lesions contin ..
• The diagnosis of lesions determining pituitary stalk thickness is challenging
• The identification of the underlying condition may require a long-term follow-up.