Neuroendocrine tumours

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Neuroendocrine tumours ¨ Dan Granberg ∗ , Kjell Oberg Department of Endocrine Oncology, University Hospital, S-751 85 Uppsala, Sweden

a r t i c l e

i n f o

a b s t r a c t

Keywords:

Neuroendocrine tumours can be divided into endocrine neoplasms occurring in the lungs,

Neuroendocrine tumours

thymus, gastrointestinal tract and pancreas. Most neuroendocrine tumours are slowly grow-

Carcinoid

ing neoplasms, but some of them are highly malignant and show an aggressive behaviour. A

Endocrine pancreatic tumour

special feature of neuroendocrine tumours is the ability to produce peptides or hormones,

Hormone production

for example, serotonin, histamine, ACTH, VIP, insulin, proinsulin, glucagon or calcitonin,

Carcinoid syndrome

thereby giving rise to disabling endocrine syndromes such as the carcinoid syndrome,

Alpha-interferon

an atypical carcinoid syndrome, ectopic Cushing’s syndrome, the WDHA-syndrome, the

Somatostatin analogs

insulinoma syndrome or the glucagonoma syndrome. The treatment of patients with neu-

Chemotherapy

roendocrine tumours consists of surgery, radiotherapy, biotherapy, chemotherapy and local

Targeted irradiation therapy

ablative treatments such as liver embolization and radiofrequency ablation. Nearly all patients should be considered for surgery, which is the only curative treatment but may also be used for debulking of metastases. Radiotherapy may either be given as conventional radiotherapy, usually against bone or brain metastases, or as targeted irradiation therapy with

111

Indium-,

90

Yttrium- or

177

Lutetium-labelled somatostatin analogues. Bio-

therapy traditionally consists of alpha-interferon and somatostatin analogues, which may show antitumoural activity and relieve endocrine symptoms. Today, several new biological agents have been introduced such as tyrosine kinase inhibitors, mTOR inhibitors and antiangiogenic agents. Various chemotherapy combinations are used in patients with endocrine pancreatic tumours, lung and thymic carcinoids and in patients with highly aggressive neuroendocrine tumours. Most patients with neuroendocrine tumours have a relatively good prognosis with long expected survival, but the prognosis in patients with poorly differentiated neuroendocrine tumours is poor. © 2007 Elsevier Ltd. All rights reserved.

1.

Introduction

According to the old classification system, neuroendocrine tumours can be divided into carcinoids and endocrine pancreatic tumours, depending on the localisation of the primary tumour. Carcinoids are further subdivided into foregut, midgut and hindgut depending on the embryological origin [1]. Lung, thymic, gastric and duodenal carcinoids encompass the foregut carcinoids, midgut carcinoids originate from the appendix, jejunum, ileum and proximal colon, while hindgut

∗

Corresponding author. Tel.: +46 18 611 00 00; fax: +46 18 55 39 43. E-mail address: [email protected] (D. Granberg). 1872-115X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.uct.2007.04.001

carcinoids are localised in the distal colon and rectum. Midgut carcinoids, often called classical carcinoids, produce serotonin and may give rise to the carcinoid syndrome with flushing, diarrhea, right-sided heart disease and asthma. The carcinoid syndrome is predominantly seen when liver metastases are present. Foregut carcinoids rarely produce serotonin. Instead, they may secrete histamine, resulting in an atypical carcinoid syndrome with generalized flushing, diarrhea, periorbital oedema, lacrimation and asthma. Hindgut carcinoids do not produce biologically active hormones and

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thus do not cause endocrine symptoms. Endocrine pancreatic tumours, which also belong to the foregut group of neuroendocrine tumours, may also secrete various hormones. These tumours are subdivided according to their hormone production into gastrinomas, insulinomas, glucagonomas, VIPomas, somatostatinomas and non-functioning tumours. Endocrine pancreatic tumours may change their hormone production over time, and secretion of multiple hormones is common. Occasionally, endocrine pancreatic tumours as well as lung carcinoids can secrete other hormones such as ACTH or CRF resulting in ectopic Cushing’s syndrome, growth hormone releasing hormone causing acromegaly, or calcitonin. Most neuroendocrine tumours are relatively slowly growing neoplasms. There are, however, a subgroup of poorly differentiated, fast growing, neuroendocrine tumours with high proliferative activity. These tumours, which are called neuroendocrine carcinomas, are usually unable to produce hormones and endocrine symptoms are rare in these patients. A new classification of endocrine tumours has recently been introduced, where the tumours are classified according to size, proliferation, localisation, differentiation and hormone production. The main categories are well-differentiated endocrine tumours (functioning or non-functioning), welldifferentiated endocrine carcinomas (functioning or nonfunctioning) and poorly differentiated endocrine carcinomas (usually non-functioning). Since special emphasis is put on prognosis, this classification may aid in choosing the optimal treatment for the individual patient [2]. In addition, a consensus has recently been obtained regarding a TNM classification of foregut neuroendocrine tumours [3]. A similar consensus regarding TNM classification of other endocrine tumours is being elaborated.

2.

Carcinoid tumours

The incidence of carcinoids was previously 1.2–2.2 per 100,000 depending on sex and race [4–6]. During the last decade, the incidence has increased to 2.5–4.5 per 100,000. The highest incidence, 4.5 per 100,000, is seen in black males [6]. Carcinoids are most frequently localised in the gastrointestinal tract (74%) and bronchopulmonary system (25%). The most common sites are within the gastrointestinal tract, the small bowel and the appendix [5]. Midgut carcinoids most often originate from the terminal ileum. Metastases are common at diagnosis, in particular to the regional lymph nodes and the liver. These tumours frequently secrete serotonin and tachykinins, giving rise to the classical carcinoid syndrome. In addition, most midgut carcinoids secrete chromogranin A, which can be used as a marker for treatment monitoring. Lung carcinoids may secrete chromogranin A, but production of chromogranin B is also frequently seen in these tumours. Although many lung carcinoids show positive immunostaining for serotonin, elevation of urinary 5 HIAA and the carcinoid syndrome is rare among these patients, possibly due to the relatively low frequency of liver metastases. Carcinoids in the appendix are usually found en passant at appendectomy or at autopsy. They rarely develop metastases and their prognosis is excellent. Rectal carcinoids are usually benign tumours that do not secrete hormones. Endocrine symptoms are rare in this group.

The prognosis is best among patients with rectal and appendix carcinoids, 5-year survival being 72–88% and 71–86%, respectively [5,6]. The treatment of choice for all carcinoids is radical surgery. The majority of lung and rectal carcinoid patients, as well as nearly all patients with carcinoids in the appendix, are cured by surgery. Surgery should also be performed in patients with midgut carcinoids, even in the presence of liver metastases. Debulking of the liver metastases, resulting in reduction of the hormone levels and relief of the carcinoid syndrome, could be achieved either by surgery, radiofrequency ablation or by liver embolization with gel-foam or tris-acryl-gelatin microspheres. Chemoembolization of liver metastases is another option.

2.1.

Lung carcinoids

The etiology of lung carcinoids is unknown, but patients with multiple endocrine neoplasia type 1 (MEN1) have an increased risk. Many tumours present deletion on chromosome 11q13 and the MEN1 gene. Lung carcinoids are divided into typical, which are the most frequent, and atypical carcinoids. Typical carcinoids, although potentially malignant, have a good prognosis and can usually be cured by surgery even when local lymph node metastases are present. Atypical lung carcinoids are more malignant; metastases are seen in up to 70% of these patients [7]. Many of theses patients are asymptomatic and detected on chest X-ray for unrelated causes, while other present with respiratory symptoms such as cough, hemoptysis, breathlessness, wheezing or recurrent pneumonias. The diagnostic procedures include CT scan, bronchoscopy with biopsy, octreoscan, positron emission tomography (PET) and measurement of plasma chromogranin A and B. The main treatment is surgery. During the operation, a thorough lymph node dissection, aided by the use of frozen sections, is mandatory and as much lung parenchyma as possible should be spared. The treatment of metastatic lung carcinoids is disappointing. Cisplatin or carboplatin in combination with etoposide has produced reduction of tumour size for limited periods of time; an alternative is doxorubicin combined with paclitaxel or streptozotocin [8]. In a recent paper, describing 11 lung carcinoid patients harbouring distant metastases, 2 partial responses were observed: 1 of these patients (with a typical carcinoid) received cisplatin + etoposide alternating with cyclophosphamide + vincristine + doxorubicin and the other patient (with an atypical carcinoid) was treated with cisplatin + etoposide + paclitaxel [9]. Another study with temozolomide as monotherapy in 13 patients with progressive lung carcinoids resulted in partial response in 4 patients (31%) and stabilization of the disease in another 4 patients, yielding a beneficial effect in 62% of the patients [10]. Lung carcinoids may secrete various hormones, giving rise to a carcinoid syndrome, an atypical carcinoid syndrome or rarely Cushing’s syndrome or acromegaly. Alphainterferon, with or without somatostatin analogues, may produce symptomatic relief in patients with the carcinoid syndrome, and in addition stabilize the tumour disease in a limited number of patients [8]. In patients with high uptake on octreoscan, targeted radiotherapy with 90 Yttrium-DOTAoctreotide or 177 Lutetium-DOTA-octreotate may be an option.

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Ten-year survival after surgery in patients with typical carcinoids is between 90% and 100% [11], while atypical carcinoid patients have a considerably lower 10-year survival, 40–50% [12,13].

2.2.

Thymic carcinoids

Thymic carcinoids may be seen as sporadic tumours or in association with MEN1. They are often locally aggressive with a high risk of recurrence after surgery. Approximately, 30–40% have distant metastases [14]. Except for local symptoms such as cough, chest pain, dyspnea and superior vena cava syndrome, systemic symptoms such as fatigue, fever and night sweats are common. Endocrine symptoms, especially Cushing’s syndrome but also acromegaly or SIADH, occur in roughly 30% of the patients, but association with the carcinoid syndrome has not been described. Non-endocrine syndromes associated with thymic carcinoids include polymyositis, polyarthritis and pericarditis. The biochemical diagnosis should encompass measurements of urinary cortisol and plasma ACTH and chromogranin A and B. CT is the preferred diagnostic imaging investigation, but MRI may also be considered and may detect pericardial or large vessel invasion, thereby guiding the surgical treatment procedure. In addition, scintigraphy with 111 In-octreotide is valuable. Surgery is the treatment of choice. The primary tumour should be removed together with affected intrathoracic lymph nodes. Postoperative radiotherapy should be given in case the resection is not radical, and may also be considered as adjuvant treatment if lymph node metastases are present and as symptomatic relief of a superior vena cava syndrome. Various chemotherapy regimens have been tried, including carmustine (BCNU), cisplatin + etoposide, streptozotocin + doxorubicin, ifosfamide + etoposide. The response rates are usually poor. In our experience, the best responses are obtained with a combination of cisplatin or carboplatin + etoposide [15]. A recent study suggested temozolomide as monotherapy to have effect, resulting in stabilization of the disease in 5/7 patients (71%) [10]. In case of high uptake on scintigraphy with 111 In-octreotide, targeted radiotherapy with 90 Yttrium-DOTA-octreotide or 177 Lutetium-DOTA-octreotate may be considered in patients with metastatic or incompletely respectable tumours. The prognosis is poor. One study reported 60% overall mortality [16]. Patients with MEN1 or Cushing’s syndrome have a worse prognosis [14].

2.3.

Gastric carcinoids

Gastric carcinoids are divided into four types. The first three types originate from enterochromaffin-like cells in the gastric mucosa. Type 1 are gastrin-dependent tumours, associated with chronic atrophic gastritis (CAG), hypergastrinemia and pernicious anemia. Type 2 are also gastrin-dependent. These tumours are seen in patients with MEN1 and the ZollingerEllison syndrome. Type 3 carcinoids are solitary tumours without association to elevated serum gastrin. Type 4 tumours are poorly differentiated neuroendocrine carcinomas [17]. There is also a fifth type of gastric carcinoid or hyperplasia developed from antral G-cells with gastrin production.

2.3.1.

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Type 1 gastric carcinoids

Type 1 carcinoids are located in the body or fundus and are mainly multiple. The tumour cells stain positively for chromogranin A and may occasionally secrete histamine. The diagnosis is made at gastroscopy because of nausea, vomiting, epigastric pain or pernicious anemia. These tumours are usually benign, but metastases do occur, most often to regional lymph nodes but also distant to the liver. Overall frequency of metastases is 9–23% and liver metastases have been reported in 3–5% of patients [18–21]. There is no complete consensus regarding the treatment of type 1 gastric carcinoids [22]. Spontaneous resolution has been reported [23]. Small polyps, <1 cm, could be removed endoscopically [24] while larger tumours should be surgically excised. The role of concomitant antrum resection, aimed at reducing the serum gastrin level, has not been clarified. After polyp removal, endoscopic surveillance with multiple biopsies is recommended at 6-monthly intervals, since recurrences are not infrequent [24,25]. In metastatic type 1 carcinoids, regression of liver metastases has been reported after gastric surgery followed by medical treatment with alpha-interferon combined with octreotide [26,27].

2.3.2.

Type 2 gastric carcinoids

These tumours are, like type 1 gastric carcinoids, gastrindependent and often multifocal. They are, however, more malignant than type 1 tumours. The recommended treatment is surgery. In case of distant metastases, alpha-interferon and octreotide may be administered. Somatostatin analogues have demonstrated long-term remission of gastric polyps in type 2 patients [28]. Chemotherapy with streptozotocin and 5-FU is the preferred treatment of metastatic endocrine pancreatic tumours, both sporadic and MEN1 related. It is not clear if this treatment will also retard the growth of concomitant type 2 gastric carcinoids. However, complete resolution of type 2 gastric carcinoids have been described following surgical resection of all gastrinomas, leading to normogastrinemia, in MEN1 patients with the Zollinger-Ellison syndrome [29]. The long-term prognosis is to a large extent dependent on the endocrine pancreatic tumour.

2.3.3.

Type 3 gastric carcinoids

Type 3 gastric carcinoids are solitary, non-gastrin-dependent tumours, originating from enterochromaffin-like (ECL) cells in the gastric mucosa [30]. There is no relation to chronic atrophic gastritis or the Zollinger-Ellison syndrome. These tumours have a high malignancy potential and are often metastatic at the time of diagnosis. Metastatic rates between 60% and 82% have been reported [30,31]. They may secrete histamine and give rise to an atypical carcinoid syndrome with generalized flushing, lacrimation, periorbital swelling and diarrhea. The most common presenting symptom is abdominal pain [26]. Recently, these tumours have been described to secrete ghrelin [32], which is a 28-amino acid peptide hormone that stimulates secretion of growth hormone and inhibits secretion of insulin, thereby leading to hyperglycemia. The treatment of choice is radical surgery [31], which is the only curative treatment. Chemotherapy has been tried with different drug combinations in cases of distant metastases, usually with poor response and for only limited periods of time [26]. Stable disease has been observed during

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treatment with cisplatin or carboplatin combined with etoposide. Other possible therapeutic measures include octreotide, liver embolization, 111 In-octreotide, liver transplantation [33] and alpha-interferon. Five-year survival is generally less than 50% for sporadic non-gastrin-dependent gastric carcinoids, but reached 55% in one study [31].

2.3.4.

Type 4 gastric carcinoids

These tumours consist of poorly differentiated neuroendocrine carcinomas and mixed exocrine-endocrine carcinomas. Their proliferative rate is high and distant metastases are common at the time of diagnosis. Chemotherapy, preferably with platinum-containing combinations may be attempted. The prognosis is poor and the expected survival is less than 12 months [30].

2.4.

Midgut carcinoids

Midgut carcinoids are most frequently localised to the terminal part of the ileum, but may also be found in the proximal half of the colon and in other parts of the small bowel. The metastatic rate is around 70% [5]. Metastastic spread occurs most frequently to the mesenteric lymph nodes and the liver. The patient may present with abdominal pain, bowel obstruction, diarrhea, malabsorption, palpable mass or right sided heart failure. Diagnostic procedures include computerized tomography, ultrasound, ultrasound-guided biopsy, capsule endoscopy and somatostatin-receptor scintigraphy with 111 Inoctreotide. PET with 5-hydroxy-tryptophan is a novel method, which is more sensitive than octreotide scintigraphy and computerized tomography [34]. It is important to check for carcinoid heart disease with echo-cardiography. Measurements of plasma chromogranin A and urinary 5 HIAA represent the biochemical diagnostic measures. Surgery of the primary tumour with removal of mesenteric lymph node metastases is recommended even in cases with liver metastases [35] to avoid problems with bowel ischemia and strangulation. Surgical resection of liver metastases may be indicated when all visible intra- and extrahepatic tumours can be safely resected [36]. The standard medical treatment of midgut carcinoids is alpha-interferon and somatostatin analogues. Alphainterferon in doses of 3–5 million units s.c. 3–5 times/week decreases hormone levels in 50% of the patients, offers relief of the carcinoid syndrome, may retard the tumour growth and improve survival. Decrease of the metastases is seen in 15% of patients [37–39]. The interferon dose is titrated according to the leucocyte count, which should be decreased to <3000 mm−3 . Alpha-interferon acts by inducing a cell cycle block in the S phase, which is mediated via an up-regulation and phosphorylation of Stat proteins and an up-regulation of p21 and p27. Other contributing anti-tumour mechanisms are anti-angiogenesis and an immunomodulating effect by induction of cytotoxic T-cells and natural killer cells [40,41]. In recent years, a sustained release interferon has been used, PegIntron (Peginterferon alpha), which is administered in doses of 50–100 ␮g s.c. once weekly. Interferon gamma has been tried in patients with metastatic carcinoids without producing any significant antitumour effects [42]. Somatostatin analogues are an important part of the medical treatment of midgut carcinoids. Somatostatin analogues

offer symptomatic relief and reduction of hormones, including U-5 HIAA, which is seen in more than 60% of cases. Reduction of tumour size, however, occurs only in about 5–10% [43]. Previously, octreotide was the only drug available, which had to be administered s.c. two to four times daily. Nowadays there are two long-acting drug formulations, Sandostatin LARTM (long-acting octreotide) which is given in doses of 20–30 mg i.m. every third to fourth week and Somatuline AutogelTM (prolonged-release lanreotide), of which 60–120 mg is given s.c. every fourth week. Both these drugs provide good long-term symptomatic control and improved quality of life in midgut carcinoid patients, are well tolerated and are preferred by the patients to the daily injections [44,45]. Resistance to treatment with one somatostatin analogue need not disqualify the patient from trying another. Raderer et al. described a patient who progressed during alpha-interferon + lanreotide. After the treatment was switched to Sandostatin LARTM , the symptoms disappeared and the tumour decreased [46]. Chemotherapy is of little value in patients with midgut carcinoids. Streptozotocin, alone or in various combinations, seldom yields responses in these patients [47,48]. In one study with paclitaxel 250 mg/m2 every third week, only 1/14 midgut carcinoid patients had a partial response lasting just one course [49], and in a recent study with docetaxel 75 mg/m2 every third week, none of seven patients with midgut carcinoids responded [50]. Neither gemcitabine for 4-week cycles (3 weekly infusions of 1000 mg/m2 followed by a 1-week break) in seven patients with small bowel carcinoids [51], nor topotecan 1.5 mg/m2 for 5 days every third week in 13 carcinoid patients and 9 patients with endocrine pancreatic tumours [52] produced any objective responses. Hepatic artery embolization can be of value for tumour debulking, reduction of hormones and amelioration of a disabling carcinoid syndrome in some patients with gross liver involvement. Embolization with gel foam powder (SpongostanTM ) produces an overall objective response in 50–80% of patients with midgut carcinoids and results in control of the carcinoid syndrome [53–55]. During the last year, we have used tris-acryl gelatin microspheres, 300–500 ␮m in diameter, for liver embolization of patients with metastatic midgut carcinoids and endocrine pancreatic tumours. An objective response (partial remission or occurrence of necroses) was seen after 11/23 embolizations, which is similar to previous results with gel-foam [56]. Chemoembolization with doxorubicin in Lipiodol, immediately followed by gelatin sponge particles may offer symptomatic relief and objective responses in 60–90%. Long-term palliation, more than 8 years, may be possible in individual cases [57,58]. Another regimen, using cisplatin, doxorubicin and mitomycin-C combined with either viscous collagen agent or ethiodol and polyvinyl alcohol particles in suspension, produced improvement of clinical symptoms in 10 and radiologic response in another 5 of 20 patients with neuroendocrine tumours [59]. In a study with streptozotocin as a single drug, an objective response was achieved in 8/15 patients, of whom 7 were carcinoids and 8 were endocrine pancreatic tumours. Median response duration was 10 months. The carcinoid syndrome disappeared for about a year in 3/5 patients [60]. In another study of chemoembolization with doxorubicin 20–40 mg in lipiodol followed by gel-foam or PVA microspheres, no symptomatic

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response was seen. One of 12 patients showed decrease in tumour burden [61]. Doxorubicin 20–120 mg in Lipiodol followed by Gelatin sponge in nine patients with midgut carcinoids produced symptomatic response in six patients, partial and minor objective responses in three and four patients, respectively, stable disease in one patient while the last patient progressed [57]. One recent study indicated that particle embolization is more effective in patients with midgut carcinoids, while chemoembolization might have better effect on liver metastases from endocrine pancreatic tumours. The objective response rates for particle embolization were 81% in carcinoid and 25% in endocrine tumour patients, respectively, while chemoembolization yielded an objective response rate of 44% in patients with carcinoids and 50% in patients with endocrine pancreatic tumours [55]. Marrache et al. studied 67 patients with neuroendocrine tumours subjected to chemoembolization with streptozotocin or doxorubicin. The objective response rate according to RECIST criteria was 37%, while 36% had stable disease. Predictors for treatment efficacy were body mass index and arterial phase enhancement on abdominal CT. Their conclusion was that chemoembolization should be performed with streptozotozin in order to save anthracyclines for systemic chemotherapy [62]. Radiofrequency ablation is a novel method for destruction of liver metastases. The procedure can be performed either percutaneously or intraoperatively during open surgery. In the latter case, it can be combined with surgical resection of the contralateral liver lobe. There are generally few complications to the ablation and most of the treated metastases are completely destroyed [63]. Relief of the carcinoid syndrome and decrease in urinary 5 HIAA may be obtained [64]. A study has been started to evaluate the long-term results on survival. The only effective treatment for carcinoid heart disease (fibrous involvement of the tricuspid and pulmonary valves resulting in stenosis and regurgitation) is valve replacement surgery which should be considered for patients with cardiac symptoms whose carcinoid tumour disease and symptoms of carcinoid syndrome are well controlled. In order to assess the degree of the carcinoid heart disease and decide the optimal timing for cardiac surgery, echocardiography and clinical monitoring is necessary [65]. The prognosis in patients with midgut carcinoids is influenced by the presence of lymph node metastases and the extent of liver metastases. Plasma chromogranin A level has also been found to be a predictor of survival. In patients with extensive liver metastases, a median survival of 53 months (5-year survival 47%) was reported, while patients with few liver metastases had a median survival of 159 months (5-year survival 79%) and patients with only lymph node metastases lived for a median of 108 months (5-year survival 73%) [66]. Other authors have found a 5-year survival of 52–61% for small intestinal carcinoids and 42% for carcinoids in the colon, with the exclusion of the appendix (all stages) [5,6].

2.5.

Hindgut carcinoids

Hindgut carcinoids usually do not produce clinically active hormones. Rectal or colonic carcinoids may present with bleeding, constipation or diarrhea. Rectal tumours are usually small and benign, and can be radically resected. In some

45

cases, however, lymph node or liver metastases are already present at the time of diagnosis [67]. Colonic carcinoids are often of the small cell type and malignant with poor prognosis. Using chemotherapy or alpha-interferon, we have observed tumour stabilisation in individual cases with metastatic disease, but there are no reported clinical trials regarding the medical treatment of these patients.

3.

Endocrine pancreatic tumours

Endocrine tumours of the pancreas are divided according to the main hormone secreted. Patients harbouring gastrin-producing tumours suffer from the Zollinger-Ellison syndrome with multiple peptic ulcers and diarrhea, induced by the high acid output. About 20% of patients with Zollinger-Ellison syndrome have MEN1 [68], which encompasses primary hyperparathyroidism, pituitary tumours and adrenal cortical hyperplasia. Gastrinomas are often small, and about 30% are located outside the pancreas, most often in the duodenal wall. Gastrinomas can primarily be found in lymph nodes, adrenals and the heart. About two-third of the patients have localised disease at the time of presentation. Metastases most often occur to regional lymph nodes and the liver. Surgery with curative intent should always be considered if no liver metastases are detected. Insulinomas produce insulin or proinsulin, giving rise to hypoglycemia. Most insulinomas are benign and can be cured by surgery, but 5–10% are malignant. These patients may present with massive liver involvement and severe hypoglycemic symptoms. Glucagonomas secrete glucagon, which cause a certain rash named necrolytic migratory exanthema, mucositis, diabetes mellitus, weight loss, anemia and elevated erythrocyte sedimentation rate. These tumours are often malignant with detectable metastases at the time of presentation. VIPomas are also usually malignant and can be found outside the pancreas in the lung or ganglioneurons. These tumours produce vasoactive intestinal polypeptide, leading to the VernerMorrison syndrome. This syndrome consists of profuse watery diarrhea, up to 30 times per day, and hypokalemia. Somatostatinomas are rare tumours presenting with gallstones and diabetes mellitus. These tumours, although presenting with metastases, may have an indolent course. In rare cases, endocrine pancreatic tumours may produce ACTH or CRF leading to an ectopic Cushing’s syndrome, PTH-related-peptide causing hypercalcemia or calcitonin. Neurotensin and ghrelin have also been found in endocrine pancreatic tumours. More than one-third of patients with malignant endocrine pancreatic tumours have no endocrine symptoms (nonfunctioning). It is also important to know that the tumours can change their hormone production over time, and that several different hormones can be secreted at the same time, making the patient suffer from a mixture of endocrine symptoms. The biochemical diagnosis of an endocrine pancreatic tumour consists of measurements of serum gastrin, pancreatic polypeptide, calcitonin, insulin, C-peptide and proinsulin, plasma chromogranin A and B, glucacon and VIP. The radiological diagnostic tools encompass ultrasonography, endoscopic ultrasonography, CT, MRI, octreoscan and PET.

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Unless surgical resection of the tumour is possible, chemotherapy with streptozotocin combined with 5-FU is usually chosen as first-line medical treatment [69]. When streptozotocin was combined with doxorubicin, a somewhat longer survival was obtained [70]. However, the cardiac toxicity of doxorubicin limits the number of cycles that can be administered. A liposomal formulation of doxorubicin, claimed to have less cardiac toxicity, is being attempted in combination with streptozotocin, but no results are yet available. In two recent papers, conflicting results were obtained with streptozotocin + doxorubicin [71,72]. The addition of 5FU to streptozotocin and doxorubicin has not resulted in any improved response rate or survival advantage [73]. The combination of cisplatin and etoposide has produced radiological and/or biochemical responses in 7/14 patients with endocrine pancreatic tumours. Median duration of response was 9 months. No difference in response was seen between patients with well differentiated or poorly differentiated endocrine pancreatic carcinoma [15]. In previous studies, however, only 2/27 and 1/11 patients, respectively, with well differentiated neuroendocrine tumours showed partial responses on this combination [74,75]. A combination of dacarbazine (DTIC), 5-FU and epirubicin resulted in complete response in 1/15 and partial response in 3/15 patients with endocrine pancreatic tumours. Median duration of response was 10 months [76]. In a more comprehensive study of dacarbazine, 5-FU and epirubicin, 8/32 (25%) patients with foregut neuroendocrine tumours showed objective response lasting a median of 38 months [77]. A recent evaluation of seven patients treated with temozolomide as monotherapy showed one partial response and five (71%) stable disease [10]. Temozolomide combined with capecitabine in 17 patients with metastatic neuroendocrine tumours of the pancreas yielded a complete radiological response according to RECIST criteria in 1 (6%)

and a partial radiologic response in 9 (53%) patients, with a median duration of partial response of 284 days (range 85–364 days) [78]. In a study with paclitaxel, 1/9 patients with endocrine pancreatic tumours experienced a partial biochemical response, but no radiological responses were seen [49]. No objective responses have been observed in endocrine pancreatic tumour patients with either topotecan [52], or gemcitabine [51]. Biotherapy with alpha-interferon and/or somatostatin analogues may be used either alone or in combination with streptozotocin and 5-FU. Alpha-interferon alone produced a radiological response in 7/57 patients (12%) lasting a median of 20 months, and stable disease in 14/57 patients (25%) lasting 16 months [79]. In one study where alpha-interferon was combined with either octreotide or lanreotide, radiological response was obtained in 3/16 patients (19%) lasting a median of 23 months, and biochemical response in 10/16 patients (62.5%) [80]. A summary of the medical treatment of neuroendocrine tumours is given in Table 1. Hepatic artery embolization with gel foam powder or trisacryl gelatin microspheres, or chemoembolization can be used for debulking of liver metastases and symptomatic relief in patients with endocrine pancreatic tumours [53,58–61]. The results are similar to those obtained in carcinoids. A recent study suggested chemoembolization, resulting in an objective response rate of 50%, to be more effective than particle embolization, yielding 25% objective responses in patients with endocrine pancreatic tumours [55]. Some authors recommend surgical resection of the liver metastases as first-line treatment. Chemoembolization is suggested in case of numerous, unresectable metastases in the liver. The pancreatic tumour should be completely resected even if the liver metastases are not resectable [81]. Radiofrequency ablation for destruction of liver metastases is possible in patients with

Table 1 – Summary of medical treatment for patients with neuroendocrine tumours Treatment IFN IFN + octreotide Octreotide, lanreotide Streptozotocin + 5-FU Streptozotocin + doxorubicin Cisplatin + etoposide DTIC + 5-FU + epirubicin Temozolomide Temozolomide + capecitabine Temozolomide + thalidomide Temozolomide + bevacizumab Paclitaxel Docetaxel Topotecan Gemcitabine Sunitinib Temsirolimus Bortezomib Endostatin

Disease EPT, carcinoids EPT EPT, carcinoids EPT EPT EPT, foregut carcinoids EPT EPT, carcinoids EPT EPT, carcinoids, pheo EPT, carcinoids EPT, carcinoids Carcinoids EPT, carcinoids EPT, carcinoids EPT, carcinoids EPT, carcinoids EPT, carcinoids EPT, carcinoids

Total no of patients 168 16 175 64 97 33 15 36 17 29 29 24 21 22 18 93 37 16 42

Objective responsea 12–15% 19% 0–6% 35–45% 6–69% 33–39% 27% 17% 59% 25% 14% 4% 0 0 0 10% 5% 0 0

IFN, alpha-interferon; EPT, endocrine pancreatic tumours; pheo, pheochromocytoma. NE, not evaluated. a

Including complete and partial responses.

Biochemical responsea 47–50% 63% 32–77% 48% NE 22–33% 20% 19% 86% 40% 20% 4% 31% 0 0 NE NE 0 6%

References [79,110,111] [80] [79,112–115] [70,79] [70–72] [15] [76] [10] [78] [104] [105] [49] [50] [52] [51] [106] [109] [102] [103]

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endocrine pancreatic tumours as well as in carcinoid patients [63,64,82]. Liver transplantation has been tried in selected patients with metastatic neuroendocrine tumours. In one series of 12 patients, 4 with carcinoids and 8 harbouring endocrine pancreatic tumours, 2 patients died of transplantation-related complications and 4 patients developed tumour recurrences. Three of these four patients underwent surgical resection of the recurrences, and one has been treated with 177 Lu-DOTATyr3 -octreotate. Altogether, 10 of the 12 patients are alive, 7 of them without evidence of disease, after a mean followup of 30 months (range 1–66 months) [83]. In another study of 11 patients with neuroendocrine tumours (7 of whom had endocrine pancreatic tumours, 1 each had an ileal, appendix and rectal carcinoid and the last patient an unidentified primary tumour), 5 patients died of recurrences, 3 died in the postoperative period and 3 are alive after more than 5 years observation, yet only 1 of them is free of disease. One-year survival was 73% and 5-year survival was 36% [84]. Liver transplantation may be an option in highly selected patients with metastatic neuroendocrine tumours. Good control of endocrine symptoms and long disease-free intervals as well as potential cure may be obtained.

3.1.

els of insulin or proinsulin are diagnostic. Most insulinomas are benign, metastases occurring in less than 10% of patients. The tumours are often small, and pre-operative localisation before curative surgery may be difficult. Before the operation, it is necessary to keep the blood glucose at a normal level by glucose infusion, glucagon injections and corticosteroids. In malignant insulinomas, the same chemotherapy is used as for gastrinomas, i.e. streptozotocin + 5-FU or doxorubicin. Liver embolization is also possible in these patients. Chemoembolization with streptozotocin as a single drug caused significant decrease of the hypoglycaemic attacks in a patient with insulinoma [60]. Repeated chemoembolizations with epirubicin and 5-FU combined with monthly injections of long-acting octeotide have induced complete remission in a patient who developed liver metastases 12 years after resection of an insulinoma [88]. Only about half the patients with insulinoma express somatostatin receptors. Treatment with octreotide should thus always be preceded by an octreoscan. Since the response is variable despite the presence of somatostatin receptors, some patients show improved insulin and glucose levels while others experience further deterioration of the blood glucose, initiation of octreotide therapy should always be performed in hospital with close monitoring [89].

Gastrinomas 3.3.

Patients harbouring gastrin-producing tumours suffer from the Zollinger-Ellison syndrome due to acid hypersecretion. This syndrome consists of multiple gastric and duoudenal ulcers, reflux oesophagitis and diarrhea. The diagnosis is made by elevated serum gastrin, abnormal secretin test and measurement of basal and maximum (pentagastrinstimulated) gastric acid secretion. Previously, total gastrectomy was often necessary to prevent the ulcer bleedings, but nowadays the gastric acid hypersecretion can be well controlled with proton-pump inhibitors, e.g. omeprazole, lanzoprazole or pantoprazole [68]. High doses of these drugs are, however, often necessary, and in patients with upper gastrointestinal bleeding, parenteral administration can be used [85]. The effectiveness of the proton-pump inhibitors makes the use of somatostatin analogues controversial for relief of symptoms. In patients with metastatic or non-resectable tumours, chemotherapy with streptozotocin and 5-FU or doxorubicin should be considered as first-line treatment [69,70,86]. Alpha-interferon has produced biochemical and/or radiological responses in 60% of gastrinoma patients [86], and 3/3 patients showed stable disease during 10–24 months on combination therapy with alpha-interferon and octreotide [80]. In another patient with MEN1 and multiple liver metastases from a gastrinoma, stable disease was obtained for 7 years by alphainterferon [87].

3.2.

47

Insulinomas

The diagnosis of an insulinoma is primarily biochemical. The patient is fasting for 48–72 h while continuous measurements are made of plasma glucose and serum insulin, C-peptide and proinsulin. Symptoms of hypoglycaemia in combination with low blood glucose values and unsuppressed or elevated lev-

Glucagonomas

These patients are primarily embarrassed by the skin lesions and mucositis, which are not correlated with plasma glucagon. Both symptoms respond to treatment with somatostatin analogues, the skin rash showing a dramatic improvement within days in 90% of the patients. The long-acting variant of octreotide has also been effective in abolishing the rash and reducing the glucagon level. No decrease in tumour size was obtained, however [90]. If radical surgery is not possible, alphainterferon or chemotherapy with streptozotocin and 5-FU is recommended. Since the recurrence rate is high, adjuvant treatment should be considered if metastases are present at surgery, even in cases where surgery was macroscopically radical.

3.4.

VIPomas

VIPomas usually arise in the pancreas, although a minority are located in the duodenum. Plasma VIP should be measured when the diagnosis is suspected; VIP levels >70 pmol/L give secretory diarrheas. These patients may present with severe dehydration and electrolyte disturbances. The tumours are usually metastatic at presentation. Treatment with somatostatin analogues has symptomatic effect in 80% of patients with reduction of diarrhea and improved electrolyte balance and general condition. Antitumoural treatment includes chemotherapy with streptozotocin combined with 5-FU and biotherapy with alpha-interferon. Alpha-interferon has yielded objective responses (more than 50% reduction in tumour markers or tumour size) in 7/7 patients with VIPomas [91]. In one study, the combination of alpha-interferon with streptozotocin and 5-FU resulted in objective response in two patients [86]. One patient who progressed on conventional chemotherapy responded with tumour regression and clinical

48

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improvement on combination therapy with alpha-interferon and 5-FU [92].

3.5.

Somatostatinomas

Somatostatin-producing tumours are rare, and only sporadic cases are reported in the literature. The biochemical diagnosis is made by analysis of plasma somatostatin. Octreotide has been successfully used for treatment, with improvement of diabetes mellitus and diarrhea and reduction of plasma somatostatin levels [93]. This indicates that therapy with longacting somatostatin analogues may be beneficial for these patients. Long-time survival has been described even in cases with liver metastases [94]. Some of the somatostatinomas might be non-functioning tumours.

3.6.

Non-functioning tumours

These tumours secrete hormones such as somatostatin, PYY, pancreatic polypeptide, HCG␣ and chromogranin A. Chemotherapy with streptozotocin combined with 5-FU or doxorubicin is recommended as first-line therapy for this large group of patients with endocrine pancreatic tumours [69,70]. Another possibility is alpha-interferon and somatostatin analogues [80]. Hepatic artery embolization can be used as well in these patients [53,58,59]. In cases with more malignant tumours, cisplatin + etoposide should be chosen as the initial treatment.

4. Poorly differentiated neuroendocrine carcinomas Poorly differentiated neuroendocrine carcinomas are rapidly growing tumours with a high proliferative rate (Ki-67 index >20%) usually displaying multiple metastases at the time of diagnosis. Immunohistochemical staining for chromogranin A is often negative or only weakly positive but synaptophysin and NSE might be positive, and the tumour cells may not contain large dense core secretory granules. Most of these tumours are unable to secrete hormones and endocrine symptoms are rare. Biotherapy with alpha-interferon or somatostatin analogues has no proven effect in these patients. In those few cases displaying endocrine symptoms, e.g. an ectopic Cushing’s syndrome, somatostatin analogue treatment may provide symptomatic relief. Chemotherapy with cisplatin and etoposide has resulted in objective responses in 41–67% of patients with poorly differentiated neuroendocrine carcinomas, but the median response duration is only about 9 months and the toxicity is considerable [74,75]. Close surveillance at short intervals is thus necessary in order to avoid treating patients who do not respond.

5.

Targeted irradiation therapy

Targeted radiotherapy is a new approach for patients with metastatic neuroendocrine tumours, developed during recent years. In one report using 131 I-MIBG in a single dose of 7.4 GBq, 7/12 patients with the carcinoid syndrome had complete

disappearance of symptoms during a mean of 15 months, and another three patients obtained short-lasting, incomplete clinical responses. Reduction of tumour burden occurred in only two patients [95]. In a recent, more comprehensive study of high-dose 131 I-MIBG, median 402 (77–1076) mCi administered in one to three doses, symptomatic response was obtained in 49%, biochemical response in 37% and radiological response in 15% of carcinoid patients, respectively. Prolonged survival was observed in those patients who had symptomatic response and in those who received an initial 131 I-MIBG dose of >400 mCi, but biochemical or radiological response did not correlate to improved survival [96]. Most reported studies on somatostatin analogue based tumour targeting treatment have used 111 In-labelled somatostatin analogues. In one review, 21 patients with progressive neuroendocrine tumours who had received a total cumulative dose of 20 GBq or more of [111 In-DTPA0 ]octreotide were evaluated. Six of the patients had tumour shrinkage on CT or MRI and another eight patients showed stable disease. There were no major clinical side effects observed except for transient decline in platelet and white blood cell count. No clinically relevant kidney damage occurred [97]. In another study, 16 patients harbouring disseminated neuroendocrine tumours who had been treated with 111 In-pentetreotide in cumulative doses of up to 36 GBq were evaluated. 70% had some benefit for at least 6 months and 31% had sustained benefit for at least 36 months. No significant toxicity was noted [98]. 90 Y-DOTATOC has been studied in 39 patients with progressive neuroendocrine gastroenteropancreatic and bronchial tumours. Four doses of 7.4 GBq/m2 were administered at 6 weeks’ intervals. The overall objective response rate was 23%, while for endocrine pancreatic tumours (n = 13) the response rate was 38%. Complete response was found in 5%, partial remissions in 18% and stable disease in 69%. Persistent renal toxicity occurred in only a single patient (3%) [99]. Recently, the effect of 177 Lu-octreotate, given in repeated doses of 100–200 mCi with intervals of 6–9 weeks up to a final cumulative dose of 600–800 mCi was investigated in 131 patients with neuroendocrine gastroenteropancreatic tumours. Complete remission was seen in 2%, partial remission in 26%, minor response in 19%, stable disease in 35% and progressive disease in 18%. Tumour response was positively correlated with a high uptake on octreoscan and limited number of liver metastases. Median time to progression in patients with either tumour regression or stable disease was more than 3 years. One patient developed renal insufficiency and hepatorenal syndrome was seen in another patient [100]. The shorter range in tissues for 177 Lu may indicate that this isotope is better for treatment of smaller tumours, while 90 Y might be more suitable for larger ones [101]. Since metastases often are of varying size, the best option may be to combine 117 Lu- and 90 Y-labelled somatostatin analogues. Another kind of targeted irradiation therapy is selective internal radiation therapy (SIRT), which means hepatic arterial embolization with 90 Y-labelled resin microspheres (SIR-SpheresTM ) or glass microspheres. This method has been

u p d a t e o n c a n c e r t h e r a p e u t i c s 2 ( 2 0 0 7 ) 41–52

used in patients with primary hepatocellular cancer and metastatic colorectal cancer, and has recently been tried in patients with neuroendorine tumours. Preliminary results are encouraging, but further studies are warranted.

6.

New treatments

Novel principles for treating cancer patients have been developed during recent years, for example, inhibition of angiogenesis or molecular targeting of growth factor receptors. In a recent paper bortezomib, a proteasome inhibitor, was tried in 16 patients altogether, 12 with carcinoids and 4 harbouring endocrine pancreatic tumours. No objective responses were obtained, although 11 patients (69%) showed stable disease after median 12 (3–24) weeks [102]. Human endostatin, which inhibits angiogenesis, was tried in a study encompassing 42 patients with advanced neuroendocrine tumours. No toxicity occurred, but among 40 evaluable patients no one experienced a radiologic response according to WHO criteria [103]. In another study with a combination of temozolomide, a cytotoxic drug, and thalidomide, which has antiangiogenic activity by interfering with the VEGF and bFGF pathways, a radiologic response rate of 25% was obtained (45% among patients with endocrine pancreatic tumours, 33% among patients with pheochromocytomas and 7% among carcinoid patients). The median duration of response was 13.5 months [104]. Temozolomide has also been combined with bevacizumab, inhibiting the VEGF pathway. A partial radiologic response was obtained in 4/17 (24%) patients with endocrine pancreatic tumours, while 12 (70%) had stable disease. No radiologic responses were seen in carcinoid patients, but 11/12 (92%) showed stable disease. The side effects were generally mild [105]. Sunitinib, an oral tyrosine kinase inhibitor with antiangiogenic and antitumour effect that inhibits VEGFR, PDGFR and c-kit, was studied in 91 patients with unresectable neuroendocrine tumours, 52 with endocrine pancreatic tumours and 39 with carcinoids. A partial response was observed in 7 (13.5%) patients with endocrine pancreatic tumours and 2 (5.1%) carcinoid patients, while stable disease was seen in 40 (77%) patients with endocrine pancreatic tumours and 36 (92.3%) patients with carcinoid tumours. The drug was generally well tolerated. More comprehensive studies to evaluate the efficacy of sunitinib in patients with neuroendocrine tumours are warranted [106]. Imatinib, another tyrosine kinase inhibitor selectively inhibiting bcr-abl, PDGFR and c-kit was tried in patients harbouring various neuroendocrine tumours without any objective responses, though causing significant toxicity [107]. Poor results were also observed in a study with gefitinib, acting on the EGFR. None of the patients with endocrine pancreatic tumours and 1/40 (2.5%) patients suffering from carcinoid had a partial response [108]. Temsirolimus, acting on mTOR, which participates in the regulation of cell growth, appeared to have little activity in 37 patients with advanced neuroendocrine carcinomas. Two patients (5%), one with a carcinoid and another with an endocrine pancreatic tumour, had partial radiologic responses. Median time to progression in the study population was 6 months [109].

49

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