Carcinoid syndrome is a collection of symptoms that is associated with carcinoid tumours. Carcinoid is a cancer of the neuroendocrine system; neuroendocrine cells are spread throughout the body in organs such as the small intestine, appendix, colon, rectum, bronchi, pancreas, ovaries,Â testes, bile ducts,Â liver, as well as other organs. 1, 2, 9 Neuroendocrine cells are known to be able to produce many types of hormones, for instance, histamine, serotonin, dopamine and tachykinins.Â Carcinoid tumours are rare, and they are generally slow growing thus it may take years before the symptoms appear and the tumour is diagnosed. 7,9,10 Carcinoid tumours are mostly found in the mucosa of the gastrointestinal tract. Not all patients with carcinoid tumours will develop carcinoid syndrome, the syndrome occurs when hormones and vasoactive substances such as serotonin, bradykinin, histamine and chromogranin A are being overproduced by carcinoid tumors and being released to the blood stream, resulting in the dilation of the blood vessels, increased heart rate, diarrhea, wheezing, abdominal pain and so on. 2, 7, 9, 10 The symptoms of the carcinoid syndrome vary depending on which hormones are released by the tumors. Carcinoid syndrome occurs in about 1 in 10 people with carcinoid tumors, usually after the tumour has spread to the liver or lung.
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Flushing is the most common symptom being experienced by those who have carcinoid syndrome. Over 90% of the patient will experience flushing some time during their illness. Flushing is being presented as an intense blush, redness or purple discolouration of face and neck which is accompanied by a warm or unpleasant sensation.7, 10 The flush might also appear on other sites such as the upper body and leg as well. Episodes of flushing normally occur in a sudden, it can be brought on either spontaneously or by trigger factors such as emotions, physical stress, eating, drinking alcohol, or hot liquids. Dilation of the blood vessels at the affected areas causes flush and it can last from minutes to hours. The length of flushing can be determined by the stage of carcinoid syndrome you are normally in. 1,7,10Telangiectasia also may occur from prolonged flushing, it is characterised by reddish spots or veins that appear most often on the face, chest or arms. Flushing in carcinoid syndrome is characterised to be "dry" flushing instead of "wet" flushing because it is not accompanied by sweating. Flushing also often comes with palpitations and low blood pressure. The possible hormones which are responsible for causing flushing are serotonin, substance P and bradykinin.7, 10
An estimated of about 75% of the patients who have carcinoid syndrome will experience diarrhea, which often occurs together with flushing but also can occur by itself. Diarrhea causes dehydration and electrolyte loss, which leads to improper digestion and resulting in weight loss, weakness and fatigue. Patient who experience severe diarrhea can have their daily life interfered. 9, 10 There are also patients who report having nocturnal diarrhea as well. Overproduction of serotonin hormone is most likely the main cause of diarrhea in carcinoid syndrome. Obstruction of the small intestine by local tumour also can result in diarrhea as well.
Exposure of the heart to high levels of hormones and vasoactive substances released by the carcinoid tumour causes heart valvular lesions (injuries to the heart valves cause by excess amount of serotonin), endocardial damage, and heart failure. This leads to carcinoid heart disease, which occurs in over 50% of the patients with carcinoid syndrome. 2,9,10 Scarring and stiffness of the tricuspid and pulmonic valves of the right side of the heart decreases the ability of the heart to pump blood from the right ventricle to the lungs and to the rest of the body. Right ventricular failure is a major cause of morbidity and mortality in carcinoid heart disease.3,4 Cardiac involvement is detected by echocardiography in more than 50% of patients with carcinoid syndrome 3,4.
An estimated of about 10% of the patients who have carcinoid syndrome suffers from wheezing. Wheezing is caused by the overproduction of hormones from the carcinoid tumours, which can cause the blood vessels to constrict, and thus narrowing the airway passages and making it difficult to breathe, wheezing is often being mistaken for asthma.7, 10 Abdominal pain and cramping often occurs in patients with carcinoid syndrome and it may be due to the metastases of the tumour in the liver, tumour obstructing bowel movements, and tumour invading tissues and organs nearby. 7,10Patients who have carcinoid syndrome also experiences symptoms such as peripheral edema, cyanosis (bluish skin spots that appears due to lack of oxygenated blood circulation in affected areas), pellagra (disease of nutritional deficiency that causes symptoms such as skin rash because of the lack of niacin). Patients with carcinoid syndrome are also found to be more likely to develop arthritis compared to normal healthy population. 2, 7,9,10 Carcinoid crisis may occur at the time of surgery and accounts for high mortality rate. It is characterised by a sudden drop of blood pressure causing shock, accompanied by an abnormally fast heart rate, high blood glucose, and severe bronchospasm. It is best to treat patients with somatostatin analogues before surgery begins to prevent carcinoid crisis.
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Many of the early symptoms of carcinoid syndrome are difficult to diagnose, many people live with the symptoms for years before learning what the problem is. Identifying the symptoms of carcinoid syndrome early is a benefit in fighting the condition.
Carcinoid tumour is a very rare type of tumour and it has a low incidence rate of 1.9 per 100,000 people. Approximately 1200 people are diagnosed with carcinoid tumours each year in the UK, and they are usually adults over the age of 60.1,3,9 However, the exact cause of the cancer is remained unknown. People who carry a rare family syndrome which is known as Multiple Endocrine Neoplasia 1 (MEN1) have a slightly higher risk of developing carcinoid tumour. 1,3,4 Carcinoid tumors are more common among African Americans than whites. Outcomes are also not as good for African Americans. Researchers do not yet know why. Carcinoid tumors are also slightly more common in women than men. Smoking may double the risk of getting a carcinoid tumor of the small intestine, according to a recent European study. But further research is needed to confirm this.1 The increasing use of proton pump inhibitors is also being identified as a major contributory factor to that increased incidence. The carcinoid syndrome is very rare and it only occurs in about 1 in 10 people with carcinoid tumour.1,3,9 Carcinoid tumours normally do not produce hormones, and the minorities of those which do release hormones into the blood circulation often have their hormones destroyed by the liver before they reach the general circulation to cause symptoms. Carcinoid syndrome only occurs when the carcinoid tumours are able to release the hormones directly into the general circulation and bypassing the portal veins which pass through the liver. Thus, carcinoid syndrome normally only occurs when the tumour has already metastasized to the liver since the tumour will be able to release the hormones directly into the circulation that way.2,3,4,10 Another rare example is carcinoid tumors of the bronchial airways. Carcinoid tumors in the bronchial airways can release hormones directly into the general circulation via the pulmonary veins without passing through the liver.
Carcinoid tumours can be benign or malignant, malignant tumours are typically large (>2cm) at the time of diagnosis. Many small carcinoid tumors produce no symptoms and are not fatal, they are found incidentally at autopsy. Even patients with larger, malignant carcinoid tumors (with or without metastasis) can survive years or decades with a good quality of life.9 This is especially true with modern treatments to control the carcinoid syndrome and to control the growth of the carcinoid tumours. Distant metastases may be evident at the time of diagnosis in 12.9% of patients, but better diagnostic techniques have contributed to improved survival ratesÂ .Evolution in diagnostic methods and in medical and surgical therapies has led in recent years to more active care and a more favourable prognosis for patients. A five-decade analysis of 13,715 carcinoid tumours showed an overall 5-year survival rate of 67.2%, with the best survival rates being recorded for patients with rectal (88.3%), bronchopulmonary (73.5%), and appendiceal (71.0%) carcinoidsÂ . 14
Carcinoid tumours can be diagnosed using barium small intestinal study, capsule enteroscopy, MIBG Scintigraphy, CT and MRI scans and Indium 111 octreotide scans. Another way of diagnosing carcinoid tumour is by diagnosing the carcinoid syndrome first, and then by searching for the primary tumour and its metastases. Biochemical tests such as Chromogranin A testing, 5-Hydroxyindoleacetic Acid (5-HIAA) testing, and Somatostatin Receptor Scintigraphy (SRS) [OctreoScanÂ®] testing can be used to determine the presence of carcinoid syndrome by checking the levels of related biochemical markers in the body. Patients with carcinoid syndrome have elevated Chromogranin A, 5-HIAA and somatostatin receptors. Since carcinoid syndrome is difficult to diagnose because there are few if any symptoms, there may be a delay of approximately 5-7 years in correctly diagnosing carcinoid syndrome. This emphasizes the need for early recognition of the symptoms of carcinoid syndrome, and continued testing for the disease.
Once the carcinoid syndrome is diagnosed, the next step will be to determine the stage of the carcinoid tumour which is responsible for producing the carcinoid syndrome, and then the cancer care team will suggest treatment plans for the patients to consider. The treatment will be planned according to where the carcinoid started, whether it has spread, the presenting symptoms, how the cells look under a microscope, patient's general health and whether the patient have carcinoid syndrome. 1,9However, most of the time when carcinoid syndrome is present, it would suggest that the tumour has already metastasized into the liver. People often need a combination of treatments for carcinoid. The first choice in treating carcinoid tumour is often destruction or removal of the functioning tumour via surgery or drug therapy, this aims to cure the cancer. However if the tumour cannot be completely removed, then the treatment is generally aimed at reducing the tumour size and relieving the symptoms, and thus improving quality of life of the patient.7,10
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Surgery can be used to remove the tumour completely, to relief the symptoms such as small intestinal obstruction or intestinal bleeding, and to reduce the size of the tumours that are not resectable (debulking). 16,17Patients can only have surgery when they are generally well (performance status 0 or 1). Rate of success of removing the tumour if it is localized is generally high, however if the tumour is too advanced to be removed completely, cytoreductive surgery should be carried out as soon as possible provided that if it is technically feasible and clinically appropriate, in order to achieve cure or maximal debulking and reduction of symptoms. 16,17Surgical approach such as liver resection also can be carried out to reduce the tumour size or to remove the tumour that has already metastasized into the liver.
Hepatic artery embolization, cryotherapy( cryoablation), percutaneous ethanol injection and radiofrequency ablation are all useful for debulking unresectable tumours which already metastasized into the liver. 14 Effective debulking can improve the carcinoid syndrome and also prolong the survival of the patient. Hepatic artery embolization works by blocking the arterial blood supply to carcinoid tumour in the liver followed by chemotherapy to debulk the remaining tumours.3, 4, 7 The objective response rates have varied between 30% and 70% significant tumour reductions.3 It is recommended to patient who cannot have surgery to remove the liver tumour and when the tumour is producing a lot of hormones. Hepatic artery embolization helps to relief the symptom for 6 months or sometimes up to a year.1,3,7 Patients who are receiving cyrotherapy and percutaneous ethanol injection will have a probe that freeze by injecting liquid nitrogen (cryotherapy) or deliver concentrated ethanol (percutaneous ethanol injection) inserted into the liver to debulk the liver of metastases from carcinoid tumours.1,4 Radioactive ablation uses high-energy radio waves to vibrate and heat up the tumour inside the liver, resulting in the destruction of the tissue around the probe.3
Cytotoxic chemotherapy uses anti-cancer drug to kill tumours, it aims to shrink the tumour and to reduce the symptoms. It has wide area of distribution and it can be taken via oral, intramuscular or intravenously.3, 4, 7 Unfortunately, carcinoid tumours often do not respond to chemotherapy because they are low-proliferating (10-30% respond rate). Chemotherapy is generally used only for carcinoid tumours that have already spread to other organs, and does not respond to other medications.7 Patient may receive chemotherapy pre -surgery to reduce the size of the tumour or post -surgery to remove the remaining tumour as well. Some of the chemotherapy drugs that are being used include doxorubicin, streptozotocin, cisplatin, 5-fluorouracil and cyclophosphamide.3, 4, 14 Chemotherapy can be given via combination and the type of chemotherapy given depends on where in the body the carcinoid started. Chemotherapy drugs kill cancer cells but also damage some normal cells, which can cause some side effects such as myelosupression, nausea and vomiting, constipation, hair loss and kidney damage.7 Nephrotoxicity is the dose-limiting factor for most cytotoxic chemotherapy. Cytotoxic agents exert their anti-tumour effect by damaging the cellular DNA of the cell.1,3,4 Due to the bizarre side effects that cytotoxic chemotherapy can induce, anti-emetic drugs are often being prescribed along to cope with the nausea and the vomiting of the patient; laxatives are also oftenly prescribed to cope with the constipation as well. Patient who receive chemotherapy are also often at risk of infection because of the immunosuppresion side effect from cytotoxic drugs.
RadiotherapyÂ treats cancer by using high-energy x-rays to destroy cancer cells, while doing as little harm as possible to normal cells. It may be given externally from a radiotherapy machine (external beam radiotherapy), or internally by placing radioactive material close to the tumour. 3,15However, carcinoid tumours are considered to be relatively radio-resistant. External radiations usually is not effective in treating tumors within the liver, and are only used to treat symptoms such as pain, if the tumour has spread to the bones.4 Conventional external radiation therapy is recommended only for bone and brain metastases. Tumour-targeted radioactive treatment with 111 Indium DOTA octreotide or 90Yttrium DOTA octreotide, and 177 Lutetium DOTA octreotate has generated significant interest during the last few years. The response rates with standard WHO criteria reported have been around 20-25% significant tumour shrinkage, with biochemical and clinical responses in 40-50% patients.3,4 The precise role of tumour-targeted radioactive treatment is not yet defined but future randomized trials will give us more information on how to use this kind of treatment. 131 MIBG has been attempted, mainly in classical midgut carcinoids, with some beneficial effect with biochemical responses in 30-40% of the patients and tumour responses in about 20%.3,4 Some people have side effects such as stomach ache or feel sick with the treatment but this can be relieved with medication. Patient also experience fatigue, and side effects such as immunosuppression and myelosuppression also increase the risk of bleeding and infection. For most people side effects don't last long and they recover quite quickly.
The somatostatin analogues such as lanreotide and octreotide have been in clinical use for treatment of carcinoid tumours since the early 1980s. They are synthetic somatostatin derivatives with the structure and activities similar to those of the hypothalamic release - inhibiting hormone somatostatin.3,13 Compared to somatostatin, they have longer half-life and duration of action. Somatostatin is a protein made naturally in the body which slows down the production of many hormones, including autocrine, paracrine, neuracrine and endocrine growth factors. Â It exerts its action by binding to specific receptors on the membranes of cells that produce and release hormones and chemical substances.4,13 More than 90% of carcinoid tumors have high concentrations of somatostatin receptors. Somatostatin analogues significantly reduce the symptoms of carcinoid syndrome and help to reduce flushing, wheezing, and diarrhea.3,4,11,13 While this class of drug rarely shrinks tumours, it stops or slows their growth, thus improving quality of life of the patient. Octreotide are given as subcutaneous injection (100 to 500mcg) up to three times a day. A longer-acting octreotide injection may be given once the symptoms are well controlled, and they are given as 10 to 60mg 4 weeks apart intramuscularly.3,4 Immediate-release octreotide may also be given to prevent breakthrough symptoms and carcinoid crisis from occurring with procedures such as chemoembolization or surgery. The dose of the slow-release lanreotide ranges from 60 mg to 120 mg every 4 week. With somatostatin analogues, symptomatic relief is achieved in more than 70% of patients, usually during first week of the treatment.3,4 Significant reduction in tumour size is also seen in 5-10% of patients. Tumour stabilization has also been observed in 36-70% of the patients who have progressive disease. The main side effects of somatostatin analogues are loss of appetite, fatigue, diarrhea, abdominal pain, nausea, vomiting and headache.4,13 Octreotide causes sludging of bile in the gallbladder which can lead to gallstones. Up to 60% of patients under long-term treatment may develop sludge in gallbladder but less than 10% develop clinically significant gallstones.1,3,11 It can also result in insulin resistance that can make pre-existing diabetes more difficult to control. Adverse effects rarely result in discontinuation of treatment.
Interferons are natural substances that are made by the body a part of the immune system. Interferon works in several ways, it directly interferes with how cells grow and multiply. Inteferons also stimulate the immune system by encouraging T-cells to attack cancer cells, and encouraging cancer cells to produce chemicals that attract immune system cells.11, 13 Alpha-interferon inhibits protein and hormone synthesis in tumour cells, inhibits angiogenesis, and stimulates the immune system. Alpha-interferon is sometimes helpful in shrinking or slowing the growth of metastatic neuroendocrine cancers and improving symptoms of carcinoid syndrome. It is a primary choice for treating low-proliferating tumours, either alone or in combination with somatostatin analogues.12, 13 The dose of alpha-interferon should be individually titrated in each patient based on the leucocyte count. The usual dose of alpha-interferon is 3-5 million units (MU) 3-5 times per week subcutaneously. The average response rate achieved by treating patient with alpha-interferon is a symptomatic response of 40-60%, biochemical response of 30-60%, tumour size reduction in 10-15% of the patient and tumour stabilization is also noted in 40-60% of patients with progressing tumour.12, 13, 14 The main side effects of alpha-interferon are flu-like symptoms such as chills and fever, aching joints and tiredness, however these side effects usually wears off after a few weeks. The most severe and dose-limiting toxicity is the chronic fatigue, mental depression and neurological disorders. 1, 2, 4
There are a few other new treatment that are being tested, among them everolimus, sunitinib, and bevacizumab shows promising results. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor which works similary to sirolimus and expresses immunosuppressant and antitumour activity.8 In a large, phase III, randomized placebo-controlled trial with advanced pancreatic neuroendocrine tumour patients, everolimus 10 mg daily demonstrated a significant improvement in progression-free survival.8 Bevacizumab is a humanized monoclonal antibody targeting VEGF. In a Phase II trial, bevacizumab was associated with a sustained decrease in tumor perfusion by functional CT.14 Sunitinib is an orally active, multitargeted tyrosine kinase inhibitor that specifically inhibits the VEGF receptor (VEGFR) and the platelet-derived growth factor receptor. Antitumor efficacy associated with sunitinib was suggested in a preliminary report of a Phase II study in patients with unresectable carcinoid tumors.14
Patients with carcinoid syndrome should take vitamin supplements, especially nicotinic acid, since carcinoid tumors can cause a deficiency of nicotinic acid. In some patients, diarrhea caused by the carcinoid syndrome may respond to Imodium, Lomotil, ondansetron (Zofran), or cyproheptadine (Periactin). 3, 12, 14 Patients also should avoid alcohol, spicy foods, physical stress, and ephedrine-containing medications such as nasal decongestants in order to avoid the precipitation of carcinoid syndrome by the release of hormones and chemical substances from the tumor.1, 3, 14 Patients with chronic diarrhea should take minerals supplements as well as vitamins since any cause of chronic diarrhea can lead to deficiencies of minerals.
In this scenario, the best treatment for the patient would be combining alpha-interferon and octreotide. According to a study, an objective biochemical response rate of 72% lasting for 10 months was seen, with 22% stabilised and only 6% of the patients have their disease progressed, indicating at least an additive effect of alpha-interferon. 11,13Furthermore there does not seem to be any 'cross-resistance' between the two drugs. The combination of alpha-interferon with somatostatin analogues has found to be synergistic as alpha-interferon upregulates the expression of somatostatin receptors while somatostatin analogues reduce the side effects of alpha-interferon.11, 13 The addition of alpha-interferon resulting in an additional year of control in the carcinoid disease. The adverse reactions noted to octreotide were few and quite easy to manage. Alpha-interferon might cause more severe adverse reactions and might not be as well tolerated as octreotide, but there is no additive or synergistic toxicity and therefore the patients tolerated the combination quite well. 11, 12,13The combination of octreotide and alpha-interferon might be of beneficial value for long-term management of this disease. Patient should also be prescribed vitamin supplements and other medication such as anti-emetics, pain management medications, laxatives and such to counteract the side effects of the treatment.