Week 6 Case Presentation

Neuroendocrine Malignancy

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

• 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 • 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)

CEA levels

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 • Lyrica 75mg - neuropathic pain

• Magmin 500mg

• Avanza 60mg - depression

• Dexamethasone 4mg

• Durogesic patch 25mcg/h

• Endone 5mg

• Seretide Accuhaler

• Zometa

Neuroendocrine Tumours

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

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• 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 • <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 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 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

• Bloods

• 24h Urine 5-HIAA (>9mg/24h)

• Chromogranin A

• Imaging

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

• Symptomatic

• Localised

• Metastatic

• Palliative

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 Mx

• IFNα

• better efficacy than somatostatin analogs

• more acceptable SE profile

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

• 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

• 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

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

• 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• 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 • 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• 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 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 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 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 Disease

• Hepatic artery chemoembolization

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 • 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

Palliative

• RT

• carcinoids are relatively radio resistant - not a means of cure

• mainly used for palliate e.g. bone mets

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 • [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.