Week 6 Case Presentation

1
Week 6 Case Presentation

• Neuroendocrine Malignancy

2
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)

3
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.

4
PMHx

• AC joint dissection in 2012
• IVF x 4C in 2004
• GORD
• Sinusitis
• NKDA
• Nil regular meds previously

5
FHx

• No significant history of cancer in the family

6
Social Hx

• Avid cook, ensures well-balanced meals
• Good social support
• Nil financial issues, on private insurance

7
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

8
F/up

• Urinary 5-HIAA
• 13/2/11 186 11/8/11 372H
• Chromogranin A increased
• 25/10/12 121 9/5/13 158

9
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

10
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 _at_ Peter
  Macallum- require PET octreoscan
• Mets in liver
• pagetic changes detected in left clavicle and
  ilium

11
Mets

• FDG PET/CT GaTate Functional Imaging performed
• Ki-67 lt5
• 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

12
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)

13
CEA levels
14
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

15
Current Medications

• Lyrica 75mg - neuropathic pain
• Magmin 500mg
• Avanza 60mg - depression
• Dexamethasone 4mg
• Durogesic patch 25mcg/h
• Endone 5mg
• Seretide Accuhaler
• Zometa

16
Neuroendocrine Tumours
17
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

18
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

19
MEN Syndromes

• MEN1 TSG _at_ 11q13
• pituitary tumours pancreatic islet cell tumours
  parathyroid tumours
• MEN 2 ret oncogene _at_ 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

20
Carcinoid Tumours

• lt1 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

21
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,
  Cushings syndrome, peptic ulcerations, serum
  calcium abnormalities

22
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, cushings syndrome,
  acromegaly, chronic skin changes
• precipitants emotional stress, alcohol,
  exercise, eating, vigorous palpation of liver
  with mets

23
Investigations

• Bloods
• 24h Urine 5-HIAA (gt9mg/24h)
• Chromogranin A
• Imaging

24
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

25
Management

• Symptomatic
• Localised
• Metastatic
• Palliative

26
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

27
Symptomatic Mx

• IFNa
• better efficacy than somatostatin analogs
• more acceptable SE profile

28
Symptomatic Mx

• Hypotension - mediated by kinins, PG,
  catecholamines
• Avoid ß-adrenergics a-adrenergics
  vasoconstrictive agents are preferred
  methaoxamine / angiotensin
• /- corticosteroids for hypotension prevention
• Flushing -mediated kinins histamines
• Prochloperazine, phenoxybenazmine, prednisone,
  benadryl tagament, methyldopa
• Avoid MAO-I

29
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

30
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

31
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 lt30
• Applicable situations include
• aggressive disease
• high proliferation rates
• aggressive pancreatic NETS - chemosensitive with
  RR 40-70

32
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

33
Streptozocin

• Single agent chemotherapy has insignificant RR
  lt10
• 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

34
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

35
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

36
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

37
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 lt10
• unresectable disease

38
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

39
Metastatic Disease

• Hepatic artery chemoembolization

40
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 _at_ 3-6mth
  intervals
• biochemical response - serial chromograinin A
  titre, urinary 5-HIAA levels
• Symptomatic response
• AE

41
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

42
Palliative

• RT
• carcinoids are relatively radio resistant - not a
  means of cure
• mainly used for palliate e.g. bone mets

43
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. IFNa octreotide
• need ongoing trials prior to approval

44
References

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  Treatment strategy of neuroendocrine tumours
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• 2 Rougier P, Mitry E. Chemotherapy in the
  treatment of neuroendocrine malignant tumours
  (review). Digestion. 2000 62 Suppl 173-8.
• 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 1775-90.
• 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/clinicaltri
  als/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
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  (Review). Turkish Journal of Gastroenterology.
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• 9 Razzore P, Colao A, Baldelli R, Gaia D,
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  months therapy with octreotide versus lanreotide
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• 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/COSANET
  s_guidelines/Radionuclide_Therapy
• 11 Casciato DA, Territo MC, editors. Manual of
  clinical oncology. 7th ed. Philadelphia, USA
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