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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)


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.


PMHx

  • AC joint dissection in 2012

  • IVF x 4C in 2004

  • GORD

  • Sinusitis

  • NKDA

  • Nil regular meds previously


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


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


F/up

  • Urinary 5-HIAA

    • 13/2/11 : 186; 11/8/11: 372H

  • Chromogranin A increased

    • 25/10/12 : 121 ; 9/5/13 : 158


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


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


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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