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Carcinoid syndrome is a disease that gives less than one percent of all malignancies and the most arise in the gastrointestinal system. Carcinoids syndrome arises from carcinoid tumours which are small, malignant or benign tumours which presents itself in the mucosa layer of the gastrointestinal tract. These tumours were first considered as indolent but this tumour could show malignancy with metatastic spreading capacity which may result in a poor prognosis. Although carcinoid tumours are based in the gastrointestinal tract, there can also develop in the pancreas, kidney, ovaries, testicles and lungs. 'Carcinoid' is usually used to sometime describe carcinoid tumours. Carcinoids are mostly rare, and slow growing tumours that may not show any symptoms for several years. The diagnosis range for carcinoid is based from age 10-93 years with the mean age of 55 years. Most of the cases present are seen in patient over the age of 60. Although carcinoid syndrome is a set of symptom that occurs in patients having carcinoid syndrome some are asymptomatic.1
The World Health Organization (WHO) in 1980 onwards applied the term carcinoid to all tumours of the diffuse system. This is synonym to the amine precursor uptake and decarboxylation (APUD) and neuroendocrine cell system.2 In United States it has been estimated that the overall incidence of carcinoid tumours to be around one to two cases per 100,000 people. The indolent nature of the carcinoid may also mask the true incidence rate for this disease. Besides, based on a Swedish study which monitors the frequency of carcinoid tumours were calculated on the basis of both surgical specimens and autopsies in a single geographic location reported a much higher incidence that is 8.4 cases per 100,000 people. In addition in a study done in Netherlands based on epidemiologic studies reported incidence of carcinoid tumours showed 1.95 per 100,000 populations. 3
The exact incidence of carcinoid tumors is not entirely knows as the tumour differs considerably from different population and different study types. An overall estimated incidence for carcinoid tumour is 1.5 per 100,000 of the population. 4 There was an overall increase in incidence over the past 30 years following data collected from a five-decade analysis of 13,715 carcinoids. 5The values showed of 67.2 percentages of patients having a 5 year rate survival regardless of the location of the carcinoid tumour in the body. Increasing incidence is due to a variation of prognosis of carcinoids based on the location and the stage of the tumour besides, carcinoids more aggressive and showed worse prognosis then thought previously.6 The most possible location of a carcinoid tumour occurs in the gastrointestinal system. Based on an anaylsis in the United States of 2837 cases, based on date collected from the End Results Group (1950-1969) and the Third National Cancer Survey (1969-1971), found that the appendix was the most common site followed by rectum, ileum, lungs and bronchi and stomach to develop in carcinoids.7,8 But recently Surveillance, Epidemiology and End Results (SEER) program of the National Cancer institute between the years 1973 and 1991 studying and analysis of 5468 cases, found that there was an increase in proprortion of pulmonary and gastric carcinoid and a decrease in the appendiceal carcinoids.9 This variation in finding of relative incidence may be related to difference in detection and reporting of carcinoid tumours.
Carcinoid is one type of tumour of the neuroendocrine system where the neoplastic proliferation of cells from the diffuse neuroendocrine system forms this carcinoid tumour. These cells are present throughout the gastrointestinal tract, urogenital tract and bronchial epithelium and are named enterochromaffin or Kulchitsky cells. This tumour present itself deep in the mucosa and this layer extends to the underlying submucosa and mucosal surface which results in formation of small firm nodules. This bulge shaped nodules are present in intestinal lumen and often involve with mesentery. The size of tumour correlates with metastatic potential where tumours smaller than 1.5 cm in diameter rarely result in distant metastases or recurrence.10,11 As mentioned earlier, carcinoid tumours are associated with neuroendocrine system. This carcinoid tumour contains many membrane bounded neurosecretory granules which plays an important role in diagnosing and also treating this disease. These granules secrete a wide variety of hormones and biogenic amines which include serotonin, histamine, corticotrophins, dopamine, substance P, neurotensin, prostaglandin and kallikrein. From all of these secretory materials, the primary concern for carcinoid syndrome is a biogenic amines, serotonin.11 Serotonin synthesized from 5-hydroxytryptophan by enzyme aromatic decarboxylase is excreted in the urine in its metabolised form of 5-hydroxyindoleacetic acid (5-HIAA). This metabolism is catalysed by enzyme monoamine oxidases. The release of serotonin as well as other vasoactive substances through the systemic circulation results in carcinoid syndrome to manifest.4 This 52 years old patient suffering from carcinoid syndrome will be experiencing episodes of flushing, wheezing, watery diarrhea, tachycardia, hypotension, bronchospasm, and eventually right-sided valvular heart disease and right heart failure. Only 10 percent of all patients suffering from carcinoid tumours suffer from carcinoid syndrome and usually occurs as the tumour are metastasizing to the lungs or liver.
Most of the time lesions larger than 2 cm in diameter of tumour cells metastasize. This metastasize cells move to various organs such as liver and kidney. Presence of small metastases cells in the liver is associated with a longer life expectancy. The morbidity of patients suffering from carcinoid tumour is closely related to vasoactive amine production, where the survival rate of a patient depends upon its inverse correlation of daily levels of urinary 5-HIAA excretion. Death is usually due to cardiac or hepatic failure with addition to complication arises from tumour growth. High mortality rate is accosiated with the presence of a series of factors such as high plasma levels of neuropeptide K and chromogranin A, location of the tumour in the large bowel, how advanced is the disease and a concomitant second malignancy. Hence, to diagnose this patient with carcinoid syndrome, his urine tests need to be done to confirm elevation of his 24-hour urinary 5-hydroxyindoleacetic acid levels.2
The treatment options for this patient suffering from carcinoid syndrome will be most likely preferred to be surgical removal of the tumour. But if the tumour cannot be entirely removed, then the treatment will be switched which include debulking the tumour, that is removal of as much tumour as possible, following chemotherapy, biological therapy and including radiation therapy and targeted nuclear treatment. As for a cancer which has metastasized then chemotherapy with or without radiation will be the best treatment to relieve the symptoms the patient is suffering.
Identifying the primary tumour location is important as well as the size and whether or not the tumour has metastasized to treat the disease with the mode of surgery. This allows a planned operative strategy together with follow-up after surgery and chemotherapy be planned for the patient. Surgery is the only curative therapy for carcinoid theray and surgical removal of a carcinoid tumour includes removal of tumour (local excision), removal of tumour following with part of an organ (resection), tumour removal using electric current (fulguration), or removal of tumour by freezing the tissue (cryosurgery). The effectiveness of surgery for these patients depends on the tumour load. This patient need to be carefully assessed and to confirm if his cancer is benign or has metastasized to neighbouring organs especially the liver. There is been little knowledge of liver transplantation for metastatic carcinoids.12 Although in recent review on liver transplants for neuroendocrine tumours, it has been seen to show a survival rate of 69% at 5 years compared to 8% at noncarcinoid neuroendocrine tumour.7 But early detection, selection and pre-transplant work-up of suitable patience are crucial for the patient's survival including detection and management of recurrent disease.14
If the carcinoid in this patient has metastasized to his liver, then the liver can be treated using a hepatic artery ligation or hepatic artery embolization. Cutting and tying off the main artery example the hepatic artery that supplies blood to the liver slows down the tumour growth and is the main mode of hepatic artery ligation. As for hepatic artery embolization (HAI) uses drugs or radiation to reduce or block the flow of blood to the liver hence destroying the cancer cells. HAI used together with an additional regional chemotherapy (trans-arterial chemoembolization, TACE) provides a theoretically more attractive treatment strategy for patients. The symptomatic flushing together with 5-hydroxyindoleacetic acid concentration is seen to decrease in up to 80% of patients. Besides, regression of tumour size and some reports suggest an increase of median survival of up to 2 years seen in patients with this treatment. Compared directly to a surgical resection in the same section, HAI does not improve survival rate although it plays a role in symptom relieve for patient. TACE chemotherapy agents include streptozotocin, doxorubicin or various combinations of cytotoxic regimens. 125 patients from Pittsbrugh placed in the largest single center report to date reported 1-, 5- and 10-year survival 59%, 35% and 19% with a mean of 3.2 years for follow up.15,16 As for TACE compared directly to HAI, the addition of chemotherapy to the procedure does not give any survival benefit than HAI used alone.
Biological therapy at the moment is the core for the medical management of patients showing symptomatic carcinoid syndrome. This therapy is used in patients who have the disease beyond resection with curative option where this therapy revolves around immunotherapy using the body's immune system to fight cancer. 17 % reduction in carcinoid tumour size is seen in patients as well as slowing down the growth of metastatic tumour and prolonged survival rate in carcinoid patients. There are a few biological agents used including somatostatin analogues example octreotide, SandostatinÂ® or lanreotide and interferon, Roferon Â®. The somastostatin analogues octreotide and lanreotide are both given as a depot-long-acting preparation with a regular self injection each day. These somastatin analogues are inhibitory regulators of exocrine secretion. The ability of these analogues to act as a cytostatic agent to tumour cells is very important. This effect is based on inhibition of autocrine, paracrine, neurocrine, or endocrine growth factor by directly binding to SSTRs besides showing antiangiogenesis properties. It is a highly specific targeting drug as nearly 90% of carcinoid tumours have high concentration of somastatin receptors. A strong correlation has been observed between somatostatin receptor status and the ability of therapy response to the analogue treatment.17 Good long term compliance up to 5 years has been reported to provide good symptomatic improvement of patients given octreotide. There is reports of 70-90% improvement in biochemical response of patients reflected from as much as 50% reduction of urinary 5-HIAA levels in 30-70% of tha patients with a temporary stabilization of tumour growth of up to 85% There is no difference found between octreotide and lanreotide crossover evalution when compared between the efficacy, patient acceptability, and tolerance for both drugs.18 Reports has shown carcinoid tumour regression when long-term somatostation analogue was used in the therapy, although caution needs to be taken with this drugs. Treatment with somastotatin generally is well tolerated with a good efficacy in symptoms. However there are some common side effects that is needed to be taken into account are a slight abdominal pain during first few days of treatment, due to malabsoprtion of fatty acidm which is a condition which can be easily overcome with supplementary treatment of pancreatic enzymes. Another side effect is also development of gallstones which however is asymptomatic but frequent test can avoid this circumstances.19,20
Adding an alpha interferon into somatostatin therapy has been reported to be effective in controlling carcinoid symptoms patients who are resistant to the somatostatin therapy. The interferon used in treating carcinoids is human leukocyte interferon, interferon-alpha and interferon-beta. Although the exact mechanisms of action of this interferon are not well known, the most possible action includes direct inhibition of cell proliferation, immune cell-mediated cytotoxicity, inhibiting angiogenesis and induction of differentiation via cell-cycle blocking of the G0/G1 phase.21,22 The use of interferon in therapy is reported to show a decrease in 5-HIAA levels besides controlling the secretion of tumour cell products. An approximately 40% of patients with metastatic neuroendocrine tumour given with low-dose of alpha interferon showed biochemical response. Reports have suggested a combination therapy of octreotide and interferon can reduce risk of tumour progression significantly.23
The use of a short term treatment of a highly selective serotonin receptor antagonist ondansetron can mask certain carcinoid syndrome symptoms. A case study done on 11 carcinoid patients showed improvement in diarrhoea symptom in 6 out of 6 patients while nausea showed an improvement within 3 out of 4 patients. There was also an increasing in gastric emptying with this SSRT antagonist although no change was seen in serotonin levels in the platelet and urinary excretion of 5-hydroxyindoleacetic acid. Hence it was concluded that ondansetron can improve gastrointestinal symptoms in carcinoid patients.24
For cases where the solid cancer formed are inoperable, there is a specific cytotoxic treatment that is selective towards tumour cells with having little or no effect on the surrounding normal host tissue. Due to its unique behaviour, neuroendocrine tumours especially carcinoid gives this therapy a better approach. There are two approaches been evaluated and is based on therapeutic armamentarium; MIBG and radio-labelled somastostation analogues. There is a positive uptake of nearly 50 and 70 % of MIBG for patients with carcinoid tumours. The mechanism of action of MIBG therapy is unclear but is based on its uptake by neuroendocrine tumours mediated by vesicular monoamine transporters and there is an increase in response to 131I-labelled MIBG with pre-treatment with non-labelled MIBG. This improvement has been reported to be cost effective as it shows a good long term symptomatic contron with a decrease in use of somatostatin analogue treatment. This approach provides certain toxicity which includes pancytopaenia, thrombocytopenia, nausea, emesis and hypothyroidism which is a consequence of using radiolabelled 131I MIBG.25,26,27
Cytotoxic chemotherapy has limited contributed in treating patient suffering from metastatic carcinoid tumurs. Chemotherapy is based on using the cytotoxic drug to destroy cancer cells as well as active differentiating cels. Chemotherapy drugs may be either used alone, or in combine therapy and are usually administered intravenously.28 Chemotherapy is reported to reduce symptoms in only less than 30% of metastatic carcinoid tumour cases which is usually for less than a year. Studies on single-agent therapy with 5-fluorouracil, streptozocin, doxorubicin, cisplatin and etoposide have contributed in only over 20% in response rate. In treating metastatic carcinoid tumours, patients given single-agent therapy or combination chemotherapy does not seem to be significantly superior from one another.29
Meanwhile, sunitib (SU11248, Sutent) is an orally active, multitargeted tyrosine kinase inhibitor that plays a role in specifically inhibits the VEGF receptor (VEGFR), which is the platelet-derived growth factor receptor and c-kit. The antitumor efficacy of sunitinib shown in early reports of Phase II study in patients with unresectable carcinoid tumour is good.29
The last form of therapy for carcinoid tumours is radiation therapy. This therapy revolves around using high energy x-rays which is used to destroy cancer cells and shrink tumours. An external radiation beam is shot from the outside of the body or a radioactive "seeds" is placed in the body to provide the radiation to the targeted area of the cancer.
Management of carcinoid tumours can be carried out using the therapies listed above. Surgery would be the primary most important part of carcinoid syndrome management of this patient. Locating, sizing up and knowing the degree of the tumour will play an important role with this patient. Although cytotoxic chemotherapy is often used, but it shows limited benefits compared to use of somatostatin analogous of octreotide and lanreotide in ameliorating symptoms.30, A suggestion on use of radiolabeled somatostatin analogues and MIBG has been an important advancement in management of carcinoid tumours.31,32 Besides, if this patient has metastasized tumour with progressive meanings, radionuclide therapy has shown to provide palliative benefit to this patient. For this patient, the use of somatostatin analagues with addition of interferon can improve patient treatment allowing a prolonged life as well as a better control on the disease for a long period of the time.
The somatostatin analogue octreotide dose given may vary between to 50 to 200 Âµg subcutaneously three times a day and can be adjusted according to clinical needs. This analogue is known to tb ethe best therapy in controlling carcinoid symptoms. Flushing is reduced in more than 70% of patients and diarrhoea is reduced in nearly 60 % of patients. Besides, in a small number of patients on this therapy, there are a several reports indicating prospective trials, of inhibitory effect of octreotide on tumour growth. This patient should be started on small doses of octreotide at 50Âµg three times daily, and gradually increased up to 200 Âµg three times daily, to control the carcinoid symptoms. Another analogue of somatostatin lanreotide with a slow-release formulation can also be administered. This drug can increase compliance as it is an intramuscular injection at a typical dose of 30mg, every 2 weeks. Recently, Sandostatin LAR, another long acting somatostatin analogue licensed for carcinoid tumour and administered as a intramuscular injection at dose of 20 mg, every 4 weeks.33
The addition of interferon to a somatostatin can be used if this patient has carcinoid tumours with lymph node or liver metastases together with carcinoid syndrome. Intron A, interferon alpha used in treating carcinoid tumours including 264 patients with presenting carcinoid tumour predominantly at the mid-gut origin, and with metastasis showed a response in 101 patients, although there was a different criteria response between the cases studied. The response rate for remission of diarrhea and flushing is 70%. There is a suggestion that life expectancy is extended with patients treated for more than one year on interferon than only for a year by the Norwegian Carcinoid Study. IntronA causes certain adverse side effects mainly with "flu-like" symptom, persistent fatigue in 60% of patients, and depression in 10% of patients.34
As if this patient has advanced with/without metastatic renal cell carcinoma, sunitib, an inhibitor of a group closely related to tyrosine kinase receptor is given. Sunitinib is given orally with dosage of 50 mg once daily for four weeks running with a 2 week rest period, giving a 6 week cycle treatment. The dose is adjusted between 25-75 mg with 12.5 mg stepping up. There is a partial tumour reduction size seen with sunitib with 31% compared to interferon alpha 6 % with a p<0.001.35