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Week 6 Case Presentation. Neuroendocrine Malignancy. Introduction.

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week 6 case presentation
Week 6 Case Presentation
  • Neuroendocrine Malignancy
introduction
Introduction
  • JR, 51 F previously working at Marketing division in Monash Uni, presented for r/v prior to her monthly Zometa (Zoledronic Acid) infusions for metastatic bronchial carcinoid tumour which was diagnosed in Mar 2010 following worsening non-productive cough and dyspnoea, and 20kg LOW. No significant past medical or family history of cancer was noted, and JR is a life-long non-smoker and has NKDA. She is currently well and ambulating, but experiences moderate fatigue limiting her ADLs (ECOG performance status 2)
slide3
HOPC
  • Feb 2010
    • Worsening non-productive cough over a few months associated with LOW of 20kg over 4 mths, worsening dyspnoea and LOA.
    • Nil chest pain, haemoptysis, fever / flushing, NS, chills/shakes, lumps felt, change in bowel or urinary habits
    • Sought medical assistance in Feb 2010
    • CT scan arranged - highly vascularised lesion in the left lower lobe.
slide4
PMHx
  • AC joint dissection in 2012
  • IVF x 4C in 2004
  • GORD
  • Sinusitis
  • NKDA
  • Nil regular meds previously
slide5
FHx
  • No significant history of cancer in the family
social hx
Social Hx
  • Avid cook, ensures well-balanced meals
  • Good social support
  • Nil financial issues, on private insurance
slide7
Plan
  • Referred for bronchoscopy
    • Histopathology consistent with a bronchial carcinoid tumour
  • Urinary 5-HIAA : 110 H
  • HRCT scan - highly vascularised, non-spiculated mass in the left lower lobe. 4.4 x 3.2 x 5 cm. 2 small left posteroinferior
  • Dx: Bronchial carcinoid tumour AJCC Stage I/B (T2 N1 M0)
  • Referred to surgeon for VATS minimally invasive thorascopically assisted left lower lobectomy
  • Nuclear medicine octreotide study - Normal
  • Refer to Medonc for further management
    • commence on Somatulin (Lanreotide) 120mg
slide8
F/up
  • Urinary 5-HIAA
    • 13/2/11 : 186; 11/8/11: 372H
  • Chromogranin A increased
    • 25/10/12 : 121 ; 9/5/13 : 158
slide9
Mets
  • 18 Jun 2012
    • P/W worsening (L) hip pain during routine r/v
    • XR showed radiolucent area in (L) acetabular region
    • whole body bone scan performed subsequently - mets to (L) hip
    • Repeat urinary 5-HIAA and chromagranin - both elevated
  • Plan :
    • RT + Commence on Zometa + continue on Somatulin
slide10
Mets
  • 15 Feb 2013
    • c/o tenderness over skull and (L) shoulder
    • CT brain, skull, chest - multiple liver mets
  • Plan
    • Liver Biopsy - consistent with mets from bronchial carcinoid tumour
    • LFTs - normal
    • Refer for IV radionuclide therapy @ Peter Macallum- require PET octreoscan
      • Mets in liver
      • pagetic changes detected in left clavicle and ilium
slide11
Mets
  • FDG PET/CT & GaTate Functional Imaging performed
    • Ki-67 <5%
    • low somatostatin expression at sites of disease in abdomen and pelvis - more de-differentiated disease
    • ineligible for IV radionuclide therapy - recommend commencement of IV ChemoRx
    • Recommend cessation of Somatulin due to low somatostatin expression
chemotherapy
Chemotherapy
  • Commenced of 6C CBDCA / Etoposide
    • Experienced recurrent anaemia requiring multiple transfusions post-chemo, profound fatigue, anorexia, n/v, cancer-related pain and multiple episodes of neutropaenia requiring admissions
    • Developed depression - commence on mirtazapine; referral to psycho-oncologist
    • ChemoRx was poorly tolerated - only 5C were completed
  • MRI showed stable disease as of 27/8/13
  • Commence of monthly Zometa (Zoledronic Acid)
current issues
Current issues
  • Moderate fatigue - unable to work but ADLs remain relatively good
  • Social isolation
  • Residual (L) shoulder pain - commence on Lyrica (pregabalin)
  • Depression - mirtazapine 60mg
  • Poor appetite - commence on dexamethasone 4mg for motivation / energy / appetite
current medications
Current Medications
  • Lyrica 75mg - neuropathic pain
  • Magmin 500mg
  • Avanza 60mg - depression
  • Dexamethasone 4mg
  • Durogesic patch 25mcg/h
  • Endone 5mg
  • Seretide Accuhaler
  • Zometa
introduction1
Introduction
  • neoplasms that arise from the cells of the endocrine and nervous system
  • Classification : well-differentiated, low grade malignancy, high grade malignancy
  • Types
    • GEP-NETs - 2/3 of all GEP-NETs carcinoid, 1/3 PNET
    • Lung (SCLC, carcinoid, LCNEC)
    • Pituitary, Thymus, Parathyroid, Thyroid, EPSCC, adrenal, phaeochromocytomas, peripheral nervous system, breast, GU tract
introduction2
Introduction
  • Expresses unique syndromes & biochemical markers
    • Steroids - usually by adrenal cortex / gonads
    • Peptide hormones & catecholamines
      • APUD - 5HT, NA/Adr, Histamines, Kinins
      • Peptide hormones
      • GI hormones
    • MEN syndrome
men syndromes
MEN Syndromes
  • MEN1 [TSG @ 11q13]
    • pituitary tumours + pancreatic islet cell tumours + parathyroid tumours
  • MEN 2 [ret oncogene @ 10q11]
    • MEN2A - medullary CA of thyroid + Bilateral phaeochromocytoma + parathyroid hyperplasia / adenoma
    • MEN 2B - medullary CA of thyroid + bilateral phaeochromocytoma + multiple mucosal ganglioneuromas
    • Cushing syndrome may develop as a consequence of ectopic ACTH production
carcinoid tumours
Carcinoid Tumours
  • <1% of all tumours
  • may be in association with MEN1
  • Primary tumour usually an APUD - small, commonly located in the small intestine but may also be found in stomach / colorectal / lung / ovary
  • Mets
    • liver mets are common; may result in liver failure with replacement of functional liver tissue with tumour
    • bone mets are usually osteoblastic
    • desmoplastic response - mesenteric fibrosis causing bowel obstruction
carcinoid tumours1
Carcinoid tumours
  • 30-50% of tumours are hormonally-active - carcinoid syndrome
    • Rare without liver mets [unless ovarian]
    • usually associated with malignancy
    • may exhibit niacin deficiencies, acromegaly, Cushing’s syndrome, peptic ulcerations, serum calcium abnormalities
carcinoid tumours2
Carcinoid tumours
  • Symptoms
    • Endocrinologically inactive
      • Cough, haemoptysis, pulmonary infections, chest pain, pain from direct compression of the liver from mets
    • Endocrinologically-active
      • Hormonal : flushing, diarrhoea, hypotension, light-headedness, bronchospasm, HF, abdominal cramping, peripheral oedema, heart palpitations
      • Ex: HF, Hepatomegaly, cushing’s syndrome, acromegaly, chronic skin changes
      • precipitants : emotional stress, alcohol, exercise, eating, vigorous palpation of liver with mets
investigations
Investigations
  • Bloods
  • 24h Urine 5-HIAA (>9mg/24h)
  • Chromogranin A
  • Imaging
anaesthesia
Anaesthesia
  • increased risk of flushing, bronchospasm and hypotension during surgery
  • minimise use of adrenergics and hypotensives [morphine, curare]
  • pre-op : octreotide 100mg SC tds 2/52 prior
  • peri-op : octreotide IV 50mcg/h prior to anaesthesia, increase if hypotensive
  • post-op : taper over 1/52
management
Management
  • Symptomatic
  • Localised
  • Metastatic
  • Palliative
symptomatic mx
Symptomatic Mx
  • Somatostatin analogs
    • decrease production of 5-HIAA
    • ameliorate symptoms in 90% of patients
    • tumouristatic with increase in PFS
  • Octreotide is able to induce an earlier reduction in IGF-1 levels and more marked reduction in GH levels cf. lanreotide
  • However, lanreotide dosing schedule does not require induction with daily octreotide (Short-acting) 14d prior to starting on octreotide LAR
    • recommend octreotide for ST pre-surgical treatment
    • recommend lanreotide for chronic therapy to boost compliance
symptomatic mx1
Symptomatic Mx
  • IFNα
    • better efficacy than somatostatin analogs
    • more acceptable SE profile
symptomatic mx2
Symptomatic Mx
  • Hypotension - mediated by kinins, PG, catecholamines
    • Avoid β-adrenergics; α-adrenergics & vasoconstrictive agents are preferred [methaoxamine / angiotensin]
    • +/- corticosteroids for hypotension prevention
  • Flushing -mediated kinins & histamines
    • Prochloperazine, phenoxybenazmine, prednisone, benadryl + tagament, methyldopa
    • Avoid MAO-I
symptom management
Symptom management
  • Bronchospasm - mediated by histamine : aminophylline
  • Diarrhoea - mediated by serotonin : imodium, lomotil, zofran, cyproheptadine
  • Bowel obstruction - NGT + IV therapy
  • Pellagra - daily niacin
  • Right Ventricular failure - avoid valve replacement. manage with diuretics, refer
localised disease
Localised disease
  • Surgery remains the mainstay of treatment for cure and increase in overall survival with debulking
  • Partial Hepatectomy may be performed if liver mets are confined to an area of the liver
chemotherapy1
Chemotherapy
  • In general NETS do not show high degree of sensitivity to chemotherapy
    • low mitotic rates
    • presence of high levels of bcl-2
    • increased expression of multi-drug resistance gene
  • Response rate <30%
  • Applicable situations include
    • aggressive disease
    • high proliferation rates
    • aggressive pancreatic NETS - chemosensitive with RR ~40-70%
metastatic disease
Metastatic Disease
  • Pancreatic NET
    • Typical : Streptozocin-based chemotherapy, Everolimus, Sunitinib
      • Everolimus + octreotide LAR showed a 5mth delay in tumour progression c.f. octreotide alone
    • Atypical - As with GI-NET
streptozocin
Streptozocin
  • Single agent chemotherapy has insignificant RR <10%
  • STZ has shown to have a better survival outcome for unresectable pancreatic NETS
  • In combination with 5FU / Adriamycin, RR increased drastically
    • STZ + FU : RR 45%
    • STZ + Doxorubicin : RR 69%, PFS 20mths (vs. 6.9) , oS 2.2 yrs (vs. 1.4); more drug-related toxicitiies
metstatic disease
Metstatic Disease
  • GI-NET
    • cisplatin + etoposide
      • more signficant nausea, neurotoxicity and nephrotoxicity
    • carboplatin + etoposide
      • more significant haematological toxicities
      • used for patients with poor renal function
cisplatin etoposide
Cisplatin + Etoposide
  • 67% of patients with poorly differentiated NETS achieved overall regression of the tumour
  • median survival of 19mths
  • No significant benefit seen in well-differentiated tumours
  • Carboplatin often substituted in place of cisplatin due to nephrotoxicity
metastatic disease1
Metastatic Disease
  • High response rate to cisplatin + etoposide for patients with high grade NET of colon and rectum
  • Marginal anti-tumor activitiy and relatively severe toxicity for hepatobiliary or pancreatic poorly differentiated neuroendocrine carcinoma
metastatic disease2
Metastatic Disease
  • IV Radionuclide therapy
    • Lutetium-177 Octreotate radiopeptide therapy
    • Patient selection
      • sufficient uptake of 111In-Octreotide or 68Ga-labelled somatostatin analogues
      • disseminated, hitopathologically proven relatively well-differentiated NET
      • Ki67 score <10%
      • unresectable disease
metastatic disease3
Metastatic Disease
  • IV Radionuclide therapy
    • more effective as an early stage disease progression
    • chemotherapy is not a pre-requisite for radiopeptide therapy
    • cease LAR octreotide 6/52 prior to increase receptivity to radiopeptide therapy. short-acting octreotide may be used for symptomatic control in patients with debilitating symptoms
metastatic disease4
Metastatic Disease
  • Hepatic artery chemoembolization
metastatic disease5
Metastatic Disease
  • IV Radionuclide Therapy
    • 4 cycles with intervals of 6-8 weeks
    • response determined at 6/12 post-completion
      • metabolic response - comparative 177Lu-octreotate timor uptake on 24h scintiscancs post-therapy administration
      • objective response - CT/MRI studies @ 3-6mth intervals
      • biochemical response - serial chromograinin A titre, + urinary 5-HIAA levels
      • Symptomatic response
      • AE
palliative
Palliative
  • Hepatic Artery embolisation
    • palliate endocrine symptoms / pain
    • regression of symptoms in 4/12 in 60% of patients
    • tumour shrinkage up to 80%
    • SE: pyrexia, nausea, LFT abnormalities
    • improved duration of response when used in conduction with chemotherapy
palliative1
Palliative
  • RT
    • carcinoids are relatively radio resistant - not a means of cure
    • mainly used for palliate e.g. bone mets
future
Future
  • Bevacizumab
    • carcinoids tend to be highly vascularised
    • shown a rapid and sustained decrease in tumour blood flow with disease stabilisation / partial response achieved when used in conjunction with octreotide [c.f. IFNα + octreotide]
    • need ongoing trials prior to approval
references
References
  • [1] Ducreux m, Baudin E, Schlumberger M. Treatment strategy of neuroendocrine tumours (review). Revue du Practicin. 2002 Feb 1; 52(3):290-6.
  • [2] Rougier P, Mitry E. Chemotherapy in the treatment of neuroendocrine malignant tumours (review). Digestion. 2000; 62 Suppl 1:73-8.
  • [3] Kosmidis PA. Treatment of carcinoid of the lung. Current Opinion in Oncology. 2004 Mar; 16(2):146-9.
  • [4] Strosberg JR, Nasir A, Hodul P, Kwols L. Biology and treatment of metastatic gastrointestinal neuroendocrine tumours. Gastrointestinal Cancer Research. 2007 Dec 14; 2(3):113-125.
  • [5] Basu Bristi, Sirohi Bhawna, Corrie P. Systemic therapy for neuroendocrine tumors of gastroenteropancreatic origin. Endocrine-related cancer. 2010; 17:75-90.
  • [6] National Cancer Institute. Treatment for advanced carcinoid tumours [Internet]. USA: Yao J; 2008 [updated 2008 Jun 24; cited 2014 Mar 4]. Available from : http://www.cancer.gov/clinicaltrials/featured/trials/swog-s0518
  • [7] National Cancer Institute. MD anderson study find everolimus prolongs progression-free survival for patients with neuroendocrine tumours [Internet]. USA: NCI Cancer Center News; 2011 [updated 2011 Nov 30; cited 2014 Mar 4]. Available from : http://www.cancer.gov/newscenter/cancerresearchnews/2011/MDAndersonEverolimusStudy
  • [8] Demirkan BH, Eriksson b. Systemic treatment of neuroendocrine tumours with hepatic metastases (Review). Turkish Journal of Gastroenterology. 2012; 23(5) : 427-37.
  • [9] Razzore P, Colao A, Baldelli R, Gaia D, Marzullo P, Ferretti E et al. Comparison of six months therapy with octreotide versus lanreotide in acromegalic patients: a retrospective study. Clinical Endocrinology. 1999 Aug; 51(2):159-164.
  • [10] Clinical Oncological Society of Australia. Guidelines for the diagnosis and management of gastroenteropancreatic neuroendocrine tumours (GEP NETs) [Internet]. Australia: COSA; 2010 [updated Nov 2010; cited 2014 Mar 4]. Available from: http://wiki.cancer.org.au/australia/COSA:NETs_guidelines/Radionuclide_Therapy
  • [11] Casciato DA, Territo MC, editors. Manual of clinical oncology. 7th ed. Philadelphia, USA: Lippincott Williams & Wilkins. 2012. Chapter 15, Endocrine Neoplasm.; p. 408-414.
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