week 6 case presentation
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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
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)
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
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
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 • 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 • 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.
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