A Clinical Case Of Midgut Carnioid Tumour

A 59 year old lady is referred to your Endocrine Unit complaining of a 2 year history of flushing. You recognise that the differential diagnosis is wide. No further details are available from the referral letter.

Q1: Describe the key points to determine in the clinical history and examination with explanation. Q2: Outline the differential diagnosis of flushing in a lady of this age.

I will begin my clinical assessment by first outlining the differential diagnoses i.e. answering the question two. This will enable me to know what I have to look for in the 59 year old lady during the historical and physical examination.

Q2: Outline the differential diagnosis of flushing in a lady of this age.

The likely causes of flushing1 in a 59 year old woman could be:

1) Idiopathic flushing

2) Menopausal flushing

3) Alcohol induced flushing

4) Drug induced flushing

5) Post-prandial flushing The malar flush in patients with Rosacea

6) Flushing associated with myeloproliferative disorders Polycythaemia Rubra Vera (PRV)

7) Flushing associated with Macrophage-phagocyte system (MPS) disorders Systemic Mastocytosis

8) Endocrinological flushing • T1DM (with both hypo as well as hyperglycaemia) • Cushing’s syndrome (ACTH secreting Bronchial Ca) • Phaechromocytoma

9) Flushing associated with Neuro-endocrine tumours (NET) See diagram 1 below

Diagram No.1: NETs by anatomic origin2

starextra gastrointestinal NETs that can cause flushing & carcinoid syndrome without liver metastases include (in addition to bronchial carcinoid): Ovarian carcinoid, Medullary Thyroid Carcinoma (MTC) & Retroperitoneal metastases from classic midgut carcinoids3,9,10

starstar NETs may be associated with Multiple Endocrine Neoplasia type 1(MEN1)

Q1: Describe the key points to determine in the clinical history and examination with explanation.

The Clinical history I will attempt to determine the following key points in this 59 year old lady: Presenting complaint & its history Age at onset of the flushing symptoms This lady started to suffer from flushing when she was 57 year old. This makes idiopathic flushing extremely unlikely since idiopathic flushing is usually present since childhood3. Menopausal flushing also seems a remote possibility in our patient because average age of menopause is 51 years and this vasomotor symptom lasts for one to two years after menopause. However, postmenopausal flushing may continue for up to ten years or even longer and therefore could still remain on our differential list1,4 The anatomical distribution of flushing • Is it generalised over whole body? Menopausal flushing, Bronchial carcinoid3 & VIPoma • Is it localised to upper torso including face & neck? Most of the flushing syndromes • Is it localised to nose only? Rosacea

Is flushing transient, recurrent or permanent? Permanent flushing may be a norm for the patient.

If flushing is transient and recurrent then I will ask: a) How long a flushing episode does lasts? Early & late midgut carcinoid flushing lasts one to five minutes while the flushing of Bronchial carcinoid tends to last hours to several days3.

Postmenopausal flushing stays for up to fifteen minutes before vanishing4.

b) Is it spontaneous or unprovoked? Menopausal flushing3

c) Is there any provocative factor? • Spicy food – carcinoid syndrome • Any food – postprandial flushing of rosacea • Alcohol (sherry & wines) – carcinoid and alcohol induced flushing. Flushing does not occur with distilled spirits as these do not contain histamine. • Drugs – Calcium supplement (carcinoid), metronidazole, chlorpopamide, disulfiram, tetmosol1. • Skin trauma – Mastocytosis • Sleep – Menopausal flushing characteristically occurs during sleep4

Are there any associated symptoms (systemic enquiry)? Constitutional symptoms- • Sweating – Menopausal flushing • Lacrimation +/- facial (salivary gland swelling) – Bronchial carcinoid flushing3 • Warmth – nonspecific • Galactorrhoea – associated prolactinoma (MEN1)

Cardiorespiratory- • Shortness of breath (SOB), wheeze – Carcinoid syndrome (due to bronchospasm as well as could be due to right heart failure due to valvular lesions) • Pleuritic pain, haemoptysis – Bronchial carcinoid5 • Palpitations – Carcinoid, Pheochromocytoma • Ankle oedema – Right heart failure in carcinoid syndrome

Gastrointestinal- • Diarrhoea – carcinoid, gastrinoma, VIPoma, Somatostatinoma, Glucagonoma, Mastocytosis • Abdominal pain – Gut carcinoid • Epigastric pain with nausea & vomiting, haematemesis – Gastrinoma

Neurological- • Headaches, palpitations, faints, dizzy spells – Insulinoma

Dermatological- • Skin & mucus membrane lesions – Glucagonoma (Necrolytic Migratory Erythema – NME3)

Past medical history This is to explore medical problems that cause or are associated with flushing either as cause or effect. I will ask specifically for:

• Diabetes both T1DM & T2DM • Heart failure • Hypertension • Peptic ulcer disease • Polycythaemia • Intestinal obstructions with lapartomies

Drug history As stated above in the provocative factor enquiry

Family history A family history of flushing may direct me to the following three potential conditions to look for: • Idiopathic flushing • Carcinoid flushing • MEN1

Social history Alcohol-which alcohol? Distilled or wines

Clinical Examination

I will break my examination steps into general, systemic and the specific dermatological assessment of the flushed skin if any is present at the time of examination. I shall begin from the last.

The specific dermatological assessment of the flushed skin – I will assess the two vital aspects: 1) The distribution of the flush • Generalised, with sweating likely menopausal • Generalised with lacrimation, facial/parotid swelling likely Bronchial carcinoid3,9,10

• Localised Upper trunk, face all common causes of flushing Nose only Rosacea1

2) The colour tinge3 • Erythematous likely carcinoid if upper trunk9,10 • Erythematous whole body could be menopausal or Bronchial carcinoid • Violaceous whole body likely VIPoma7,8 • Bright red ECLoma (enterochromaffin-like) The General examination –

I will look for:

Pallor – gastric carcinoid with Pernicious anaemia

Clubbing – ACTH secreting Bronchial Ca

Skin – • Pellagara lesions in carcinoid • NME • Urticaria Pigmentosa (Darier’s sign) & telengiectasi macularis eruptive persistans of Mastocytosis3

Observations –

Hypertension in:

• MEN1with carcinoid • Glucagonoma • Somatostatinoma

Hypotension (with generalised flushing) in:

• Bronchial carcinoid3 • Mastocytosis3

The Systemic examination –

• Cardio-respiratory5 & Abdomen (see diagram 2 on next page) • Neurological Visual field defects in MEN1 associated carcinoid. Bitemporal hemianopia being the typical one.

Diagram No.2: Possible cardio-respiratory & abdominal findings in a suspected carcinoid patient

Q3: Describe the investigations you would do to help elicit the underlying diagnosis

Most of the clinical conditions that are in the differential list of flushing are in fact diagnoses of exclusion as for example the menopausal, the idiopathic and the drug induced. Therefore I shall request the following initial investigations to rule out the more sinister causes of flushing in this 59 year old lady:

1. Urinary 5-Hydroxyindoleacetic acid (5-HIAA)

2. Serum Chromogranin (CgA)

Two separate 24-hour urine collections are recommended for 5-HIAA9-12.

Both the 5-HIAA & CgA levels are better done together. Why I shall do both is because:

a) These are recommended by the guidelines5

b) CgA is not only a more sensitive marker than 5-HIAA but it is secreted from most of the NETs, so we can pick up most of the NETs with one single screening test12-16

Side by side I will request the following tests for any hidden MEN15: • Serum Prolactin • Thyroid function tests (TFT) • Beta-Human chorionic gonadotrophin (HCG) • Alpha fetoprotein (AFP) • Parathormone (PTH), Calcium • Carcinoembryogenic antigen (CEA) • Calcitonin (Medullary Thyroid Carcinoma - MTC)

Fasting gut hormone screen5, 17: I will consider doing this depending upon the clinical assessment revealing any specific syndrome as I stated above in the clinical examination section. In the UK the routinely performed gut hormones include gastrin, glucagon, somatostatin, pancreatic polypeptide, vasointestinal peptide, and neurotensin. Chromogranin A is done on the same sample when requested. A 10 ml standard heparin bottle with trasylol (aprotinin 0.2 ml, 2000 KIU) is used and is centrifuged prior to freezing17.

One of the investigations that you perform is a 48-hour urine collection for 5HIAA. The results for each 24 hour period are 149 mmol/24 hours and 200 mmol/24 hours (upper limit of normal is 50mmol/24 hours)

Q4: What aspects of the urine collection should you consider as the potential cause for this?

It is very obvious that the above results are strongly positive for carcinoid syndrome. The variation of 51% in the two collections could well mean that our patient is a highly variable hormonal excretor18. Furthermore she may well have followed a variable physical activity over the two collections periods & it is known that increased physical exertion leads to increased 5-HIAA excretion. Finally, this lady may have had an increase in the frequency as well the consistency of the stools across the second 24-hour collection period accounting for the 51 mmol/l increment in this interval18-21.

Q5: What initial radiological investigation would you request and what features would you be looking for?

This 59 year old lady seems to have a carcinoid syndrome either due to a:

• Foregut or midgut carcinoid tumour with hepatic metastases (hindgut tumours don’t cause 5-HIAA elevations3), or

• Foregut or midgut carcinoid tumour with retroperitoneal metastases9, or

• Bronchial carcinoid9,10, or

• Ovarian carcinoid9,10

A primary midgut carcinoid tumour, the commonest site of a carcinoid, is usually missed with conventional imaging modalities like CT & MRI3. Therfore, I would request a:

• Whole body Somatostatin Receptor Scintigram (SSRS)

The primary purpose of doing requesting this scan is to localize the biochemically suspected tumour. Carcinoids and other NETs are rich in somatostatin receptors. Therefore, a SSRS can detect upto 90% of primary carcinoid tumours22-29,30. A SRSS is able to: • Localise a primary tumour • Localise the liver & bone secondaries • Stage the tumour • Pick up other NETs A SSRS could be30:

1) Gamma-based SRSS (Octreoscan®): gives planar images with a gamma camera30. 2) SPECT-based SRSS: especially for liver metastases 3) PET-based SRSS: able to pick up lesions as small as 0.5 cm

The gold standard is the full body Octreoscan®30. Therefore I would request it as the initial imaging investigation and would look for the following: • Physiological uptake in the thyroid, spleen, liver and pituitary (Figure 1) • Normal tracer uptake in the kidneys due to reabsorption of filtered isotope, and bowel uptake secondary to hepatobiliary clearance (Figure 1)

Figure 1: Octreoscan showing physiological uptake in the thyroid, spleen, liver, pituitary, kidneys & urinary bladder30

• Abnormal tracer uptake lesion in the abdominal cavity below the imaged liver for a midgut carcinoid lesion in the 24 hrs and post-24 hrs images31 (Figure 233 & Figure 332).

Figure 2: 111In-DTPA-octreotide scintigraphy, planar imaging, anterior–posterior view of a patient with midgut carcinoid mesenteric metastases33.

Figure 3: A 56-y-old patient with midgut carcinoid with carcinoid syndrome. Whole-body images large tumor of small-bowel mesentery, multiple liver deposits, and local and regional lymph node involvement, with additional right-side mediastinal lymph node involvement seen only with 99mTc-TATE. False-positive uptake in hepatic flexure of colon is seen with 99mTc-TOC (A) but not with 99mTc-TATE (B). mts = metastases32

Q6: What additional investigations (non-radiological and radiological) would you request at the same time as requesting this?

Any additional investigation will depend upon the result of the Octreoscan®.

If the Octreoscan® is positive, then I would request:

a) CT scans of thorax & abdomen including the pelvis to: • Assess the full extent of disease (including staging assisted by the already done SSRS) • Localise any suspected Bronchial carcinoid • Guide tissue biopsy

b) Single photon emission CT (SPECT) to pick up liver metastases if these are not picked up on Octreoscan® (Figure 4)

c) CT guided biopsy for histopathology (Endoscopic ultrasound-EUS may be needed for isolated midgut lesions) Figure 4: SPECT-Octreoscan of a patient with midgut carcinoid, where the primary tumour is detected as well as liver metastases34

The Octreoscan has its limitations and can give false negative results in organs with extreme physiological uptake like liver where the background tracer uptake can hide the hepatic metastases. More importantly, lesions less than half centimeters may be missed3,30.

If the Octreoscan® is negative in this 59 year old female, we still need to rule out a carcinoid. Following are the two major causes of a negative SSRS in a potential carcinoid patient: • Carcinoid lesion less than the maximal spatial resolution of a gamma camera i.e. a tumour less than 0.5 cm3,30 • Carcinoid tumour without any expression of somatostatin receptors (SSRT)

Keeping in mind the above mentioned limitations of the planar gamma-based SSRS in an Octreoscan negative case, I would request: a) Positron emission tomography (PET) based SRSS3 b) Triple-phase 1-mm slice CT scans of thorax & abdomen5 c) Upper & lower GI endoscopy5 D) EUS, if a gastric carcinoid is suspected5

Assuming a carcinoid tumour is now localised, the next step will be to carry out a tissue biopsy. On the biopsied tissue I would request two pathological investigations:

1) Histopathology of biopsied tissue for – • Histological confirmation of the NET • WHO classification of the carcinoid (especially for measuring proliferation index (PI) done by quantifying the antigen Ki-67 expression) (Table 1)

2) Immunohistochemsitry of the tissue – • Staining with anti-CgA, anti-synaptophysin antibody for histopathological confirmation3,5 • Anti-SSRT antibody staining: To predetermine whether somatostatin analogue therapy will be effective or not in our patient5

Upto 30% carcinoids may not express Somatostatin receptors (SSRTs) and therefore will show negative SSRS and also will not respond to somatostatin analogue treatment5.

The WHO classification & the PI are vital for deciding the management line of action. Table 1: World Health Organization classification of neuroendocrine tumors35 Behaviour Metastasis Muscularis propria invasion Differentiation Size (cm) Angioinvasion Ki-67 (%) Hormonal index WHO criteria (gastrointestinal) Benign - - Well-differentiated ≤ 1 - < 2 - Benign/Low-grade malignant - - Well-differentiated 1-2 -/+ < 2 - Low-grade malignant + + Well-differentiated > 2 + 2-20 + High-grade malignant + + Poorly-differentiated Any + > 20 - WHO criteria (pancreas) Benign - - Well-differentiated ≤ 1 - < 2 -/+ Benign/Low-grade malignant - - Well-differentiated > 2 -/+ < 2 -/+ Low-grade malignant + + Well-differentiated > 4 + 2-20 + High-grade malignant + + Poorly-differentiated Any + > 20 -

It transpires that the diagnosis based on all of your findings is likely to be a midgut carcinoid tumour which has already metastasised to the liver. Q7: Current & new treatment options what is their mode of action? And what they can achieve?

Staging of the midgut carcinoid After all the imaging & histopathology investigations confirm the tumour as the midgut carcinoid tumour with liver metastases (MGCT with LM), the vital step before planning the treatment strategy is to get the tumour staged (Table 1 & 236,37).

Table 2: Tumor node metastasis staging of MGCT 36 TNM staging Gastric Duodenum/ampulla/proximal jejunum Pancreas Lower jejunum/Ileum Tx Primary tumour cannot be assessed Primary tumour cannot be assessed Primary tumor cannot be assessed Primary tumor cannot be assessed T0 No evidence of primary tumor No evidence of primary tumor No evidence of primary tumor No evidence of primary tumor Tis In situ tumor/dysplasia (> 0.5 mm) - - - T1 Tumor invades lamina propria or submucosa and 1 cm Tumor invades muscularis propria or > 1 cm Tumor limited to pancreas and size 2-4 cm Tumor invades muscularis propria or size > 1 cm T3 Tumor penetrates serosa Tumor invades pancreas or retroperitoneum Tumor limited to pancreas and size > 4 cm or invading duodenum or bile duct Tumor invades subserosa T4 Tumors invade adjacent structures (for any T, add M for multiple tumors) Tumor invades peritoneum or other structures (for any T, add m for multiple tumors) Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall or large vessels (celiac or superior mesenteric artery) Tumor invades peritoneum/other organs (for any T, add m for multiple tumors) Nx Regional lymph nodes cannot be assessed Regional lymph nodes cannot be assessed Regional lymph nodes cannot be assessed Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis No regional lymph node metastasis No regional lymph node metastasis No regional lymph node metastasis N1 Regional lymph node metastasis Regional lymph node metastasis Regional lymph node metastasis Regional lymph node metastasis Mx Distant metastasis cannot be assessed Distant metastasis cannot be assessed Distant metastasis cannot be assessed Distant metastasis cannot be assessed M0 No distant metastasis No distant metastasis No distant metastasis No distant metastasis M1 Distant metastasis Distant metastasis Distant metastasis Distant metastasis

Table 3: ESMOstar tumor node metastasis clinical classification of MGCT37

Disease stage T N M Gastric, duodenum, ampulla, jejunum, ileum, pancreas Stage I T1 N0 M0 Stage IIa T2 N0 M0 Stage IIb T3 N0 M0 Stage IIIa T4 N0 M0 Stage IIIb Any T N1 M0 Stage IV Any T Any N M1 Appendix Stage I T1 N0 M0 Stage IIa T2 N0 M0 Stage IIb T3 N0 M0 Stage IIIa T4 N0 M0 Stage IIIb Any T N1 M0 Stage IV Any T Any N M1 starEuropean Neuroendocrine Tumor Society

It transpires that the diagnosis based on all of your findings is likely to be a midgut carcinoid tumour which has already metastasised to the liver. Q7: Current & new treatment options what is their mode of action? And what they can achieve?

CURRENT TREATMENT OPTIONS The primary objective of treatment of a midgut carcinoid tumour with liver metastases (MGCT with LM) should be curative where possible. These tumours are extremely slow growing even after resection, with median recurrence times for a clinically detectable lesion ranging from 10 to 25 years5. Therefore patients with these tumours do frequently maintain a good quality of life even with metastases2.

Following categories of treatments are available to manage a MGCT with LM2,4,5: 1. Surgery 2. Biotherapy 3. Chemotherapy 4. Combined Bio & Chemotherapy 5. Radiotherapy – External & Internal 6. Tumour Embolisation 7. Cryotherapy

Choosing the most appropriate treatment modalities from the above list heavily rely upon the following four factors: • Clinical symptoms • Tumour staging • SSRS scan results • Tumour histopathology 1. Surgical treatment Radical (curative) Surgery Curative radical surgery can be performed in situations where MGCT with LM is diagnosed early and this happens especially when such tumours are diagnosed during a laparatomy for with an acute abdomen3. Radical surgery is done either by: • Resection of local disease • Resection of local disease along with regional nodular metastases

The primary MGCT & mesenteric metastases are excised by wedge resection along with removal of metastatic lymph nodes as far as possible (Figure 5).

Figure 5: Stages of MGCT with mesenteric metastases38 (Taken from: Tom WJ Lennard, Endocrine Surgery 4th edition: Saunders Elsevier, 2009 pp. 164) Stage I can be removed by limited ileal resection, Stage IV is inoperable

Q: What this radical surgery can achieve? • 60% 5-year-recurrence free survival6 • 40% 10-year-recurrence free survival6

Palliative Surgery

1) Debulking surgery Debulking hepatic mets which are bilobar with one dominant lesion5

2) Intestinal bypass

Both these procedures can be performed at any time during the treatment course as and when required39-41.

Liver transplantation Liver transplantation has been increasingly shown to be beneficial to the level of near curative mainly because of the unusually slow progression if the MGCT with LM6,42,43.

Liver transplantation is appropriate for the following subgroups of MGCT with LM patients: • Younger patient with age <50 years3 • Life threatening uncontrolled carcinoid during biotherapy3 • Life threatening uncontrolled carcinoid during tumour targeted radiotherapy3 treatment • Patients in whom liver metastatic lesions are inoperable or un-removable44 • Patients in whom liver metastatic lesions are markedly space occupying44 • Patients in whom liver metastatic lesions threaten to cause liver failure44

Before undergoing a liver transplantation all potential patients should be screened to fulfil the following three criteria44: 1) They should have extra hepatic metastases excluded 2) They should have a proliferation index (PI) of <5% 3) They should be free from aggressive tumour markers

Q: What liver transplantation can achieve in MGCT patients? • 69% five-year survival but only 20% - 23% five-year-tumour-free survival5,44

2. Biotherapy a) Somtostatin analogues (SSA) Octreotide, Lantreotide, Vaptreotide3

Mode of action:

• bind to SSTR1, SSTR5, and, with lower affinity, SSTR345-50

• inhibit adenylate cyclase activity, activate phosphotyrosine phosphatases (PTPs), and modulate mitogen-activated protein kinases (MAPKs) 45-50

• Activation of all these pathways inhibits known growth factor production and release and has antiproliferative effects45-50

• Induction of apoptosis has been achieved with high-dose therapy, possibly mediated through activation of SSTR351

Q: What somatostatin analogues can achieve? • Symptomatic control in about 60% to 70% of patients55 by suppressing release of peptides from carcinoid lesions • Symptomatic control especially in those prone to carcinoid crises3 • Tumour size reduction notably by high dose lanreotide (12% as against 5% for the standard dose)52-54

Tachyphylaxis is a major problem with long term treatment with SSA.

b) Interferon-α Interferon alfa-2a, interferon alfa-2b Mode of action: • A direct effect that blocks cell division by blocking cell cycle in the G1/S phase by inhibiting protein and hormone synthesis, and by reducing angiogenesis via inhibition of angiogenic factors bFGF and VEGF

• An indirect effect through immune system augmentation, particularly T cells and natural killer cells56-59

Q: What interferons can achieve? • Symptomatic and biochemical control in upto 40% to 50% of patients60-66 • Significant reduction in tumour size in upto 10% to 20% of the patients60-66 • But at the price of severe adverse effects than with somatostatin analogues including chronic fatigue syndrome, anemia, leukopenia, and thrombocytopenia

c) combined SSA & IFN-α This can be considered for patients with carcinoid syndrome who have not responded to octreotide or IFN-α alone3.

Q: What Combined SSA & IFN-α treatment can achieve?

• symptomatic control equal to SSA alone (70% of patients)3 • Stabilisation of tumour growth in 40% to 50% of patients67,68 • better tolerance of α-interferons when SSA are added • Avoidance of possible SSA tachyphylaxis

3. Chemotherapy Overall the role of chemotherapy in NETs is uncertain5. Chemotherapy seems to give maximal response rates reaching upto 70% for the following NETs: • Those with negative SSRS scans69 (inverse relationship between response rate & tracer uptake) • Poorly differentiated & anaplastic NETs69 • Pancreatic islet cell NETs69

The agents used are cisplatin, etoposide, streptozocin, (or lomustine), dacarbazine, 5-flurouracil & adriamycin but the benefits are short lasting for only a maximum of 10 months with considerable side effects.

Q: What it can achieve?

Midgut carcinoid tumours, unfortunately, respond extremely poorly to chemotherapy with a very disappointing response rate of just upto 10% and that too can be sustained only for 6-8 months. Therefore it is recommended that classic midgut carcinoid tumours with low PI should not be treated with chemotherapy70,71.

4. Combined Bio & Chemotherapy This combination can be used3 but then this has to be the IFN-α not the SSA that can be combined. SSAs influence SSRS positive carcinoids while chemotherapy is mainly effective on SSRS negative lesions69.

5. Radiotherapy

a) External Irradiation external beam radiotherapy – • Limited efficacy • Mainly palliative for bone & brain secondaries72,73

Q: What it can achieve? • Excellent relief of pain from skeletal metastases5 • Debulking effect on hepatic secondaries • Response rate about 30% with I-MIBG74

b) Internal Irradiation SSA based tumour-targeted radioactive treatment It works on the principles that where there is abnormally increased uptake of an imaging agent, give that corresponding radionuclide agent as therapy5.

• Better efficacy • Palliative for bone, brain & liver secondaries

Q: What it can achieve? • In-DTPA-octreotide leads to symptom improvement in 405 patients with tumour stabilisation in 30%75 • 90Y-DOTA-octreotide causes 40% significant tumour reduction76 • 90Y-DOTA-lanreotide has shown to cause disease stabilisation in 41% and regression in 14%77

6. Tumour embolisation embolisation of hepatic artery Indicated for inoperable, multiple & hormonally active lesions.

It works by inducing tumour mass ischaemia resulting in a fall in their hormone output as well causing liquefaction77-83.

There are two types77-83: 1) Particle embolisation Particles of polyvinyl alcohol or gel foam are used

2) Chemoembolisation Chemotherapeutic agents like IFN-α, mitomycin, cisplatin & doxorubicin are introduced because ischemic cells are more sensitive to these3,5.

Q: What it can achieve? • Five year survival of 5—60%77-83 • Symptomatic improvement in 40-80%77-83 lasts upto 12 months but procedure can be repeated

7. Cryotherapy84

NEWER TREATMENT OPTIONS for MGCT

New Biotherapies

1) Tyrosine kinase receptor inhibitors • These have been used, with objective response rates of about 10% to 15%87. This is based on the knowledge that carcinoids are rich in tyrosine kinase receptors. • Imatinib mesylate (Gleevec) is a phenylaminopyrimidine derivative that is shown to inhibit protein tyrosine kinases, abl, platelet-derived growth factor (PDGF) receptor (PDGFR)86 in vitro and has a modest clinical activity in carcinoid patients.

2) Inhibitors of the mammalian Target of Rapamycin (mTOR) • mTOR signaling pathway is shown to be active in carcinoid tumours. mTOR is a 289-kDa serine/threonine protein kinase88. Inhibitors of mTOR are drugs that block the mTOR signalling pathway. • One such agent is Everolimus. Everolimus alone or in combination with octreotide has been shown to achieve objective response rates of 15% to 20%89. A randomized, double-blind, placebo-controlled, phase 3 study showed that using Everolimus in conjunction with octreotide improved progression-free survival in patients with low-grade and intermediate-grade advanced neuroendocrine tumors90

3) Anti-serotonin Vaccines5

• Generic cancer vaccines are recombinant tumour antigen proteins that have the potential of inducing specific anti-tumour CD8+ T cell responses. NGcGM3/VSSP Montanide ISA 51 is one such vaccine is use in current research92.

• NGcGM3/VSSP Montanide ISA 51 vaccination in combination with IFN-α has been shown to stabilise the disseminated ganglioside positive bronchial carcinoid after third relapse for upto five years91.

New Radiotherapy Radiofrequency ablation of hepatic metastases85 • The percutaneous approach is used more frequently as it is least invasive, cheap, and carries the safety of CT or MRI guidance.

• The laparoscopic approach has the benefit of intraoperative ultrasound support, which is can detect tiny tumours but does require considerable skill.172 Ablation can be used to reduce hormone secretion and/or to reduce tumour burden93.

Q: How you would approach the management of this patient & explain your answer with reasoning?

Prioritising Rx for this 59 year old lady

This patient has a midgut tumour that has metastasised to liver. In spite of this I would adopt a forward looking, proactive and aggressive approach for planning the treatment strategy for this patient because:

• At 59 she seems relatively fit at age

• Female gender and younger age are associated with a better prognosis3

• She has symptoms of flushing only and that too of just two years duration with no constitutional features & we know that MGCT are extremely slow growing5.

• Between 5% and 10% of patients with carcinoids are at increased risk for simultaneous adenocarcinoma of the large intestine. Occurrence of a second malignancy is associated with a worse prognosis94,95. Therefore early surgery is better.

Other factors that correlate with impaired survival are high CgA level at diagnosis and high proliferation index (Ki-67) but we are not aware of there presence or absence at this time in relation to our patient.

The Management Plan:

1) In depth consultation with patient with full explanation, reassurance & consents

2) Initiation of biotherapy with somatostatin analogues (SSA)

3) Radical surgical removal of the primary midgut lesion

4) Follow up of the hepatic metastases for delayed safe surgery or ablation

I will refer the patient to endocrine surgical team for initiating the surgical plan for the primary tumour. At the same time I shall start her on SSA therapy (Figure 6).

The SSA therapy is the first step of treatment and it is aimed to:

• Control symptoms & therefore to improve quality of life55 • To debulk the primary & secondary lesions for safe surgical removal later52-54 • To prevent carcinoid crises, both unprovoked as well as perioperatively3

SSA Rx consists of two stages: 1. Stabilisation phase I shall start this lady on subcutaneous injections 50-100 mg of short acting octreotide two to three times a day. This shall continue for 10 to 28 days96. I shall monitor the success of this phase against clinical improvement & by requesting a serum CgA level97,98

2. Maintenance phase Once stabilised clinically & biochemically, I shall switch the patient to the long acting preparation, Sandostatin LAR that is given once monthly subcutaneously. This will further improve the patient’s quality of life. The extra SSA cover to prevent a crisis I would document on this lady’s notes and will notify all care staff concerned about the top-up octreotide cover the lady may need in instances of stress viz. surgery, anaesthesia, and any intercurrent illness. This extra cover consists of intravenous infusion of short acting octroetide 50 µg/h administered 24 hours prior to, during, and for 48 hours after the stress is over99. I would make sure that the patient be provided with a warning bracelet & a card that she will be advised to carry at all times.

Surgical removal of the primary midgut lesion Resection of the primary and extensive resection of associated mesenteric nodes is indicated early38 because:

• It may cure the disease

• It can delay progression that would otherwise endanger the small bowel

• It provides the tissue for Ki-67 scoring that helps plan future management

Nodal metastases cause sclerosis around mesenteric vessels leading to vascular compromise of the associated small bowel that result in pain, malabsorption, and even death. Resection of mesenteric metastases may alleviate symptoms dramatically, and possibly prolong survival5.

Addressing the hepatic metastases An initial period of SSA therapy allows time for observation and makes surgery or ablation of liver disease safer38. This lady can be later considered for liver surgery, ablation, embolisation or radiation if her MDGT shows high differentiation with a Ki-67 of <5%38.

Figure 6: Therapeutic algorithm for treatment of metastatic carcinoid tumor. DOTATOC, DOTA-octreotide Dox, doxorubicin 5FU, 5-fluorouracil IFN, interferon NET, neuroendocrine tumor RAD001, everolimus STZ, streptozotocin WHO, World Health Organization classification3.

Monitoring treatment Treatment is monitored by: Assessment of clinical improvement Improvement in biochemical profile CgA levels Reduction in tumour size SSRS, PET 7 CT/MRI

Prognosis • Localized MGCT: 5-year survival is about 65% (not essentially higher than that for patients with regional metastases). • MGCT with distant metastases: the 5-year survival rate is 39%100 • The relative 5-, 10-, and 15-year survival rates for those with MGCTare 67%, 54%, and 44%, respectively101