**2.4 Treatment**

#### **2.4.1 Surgery**

Surgery remains the only curative treatment of insulinomas. Long-term remission can be achieved by surgery in 95% of patients according to a recent study (Zhao et al. 2011). Two different types of surgery can be performed : minimal resection i.e. either tumour enucleation whenever it is possible or central pancreatectomy, or a more extended resection, i.e. left-sided pancreatectomy or pancreatico-duodenectomy. The type of surgery depends on the size and the location of the tumour and of its proximity with specific anatomical structures (pancreatic duct, vessels, adjacent organs). The improvement in the pre-operative imaging techniques enables the surgeon to have an accurate pre-operative topographic assessment and to decide the surgical approach pre-operatively. However intra-operative bidigital palpation and ultrasound remain valuable (Fendrich et al. 2009).

Whenever it is possible, tumour enucleation is to be chosen (Crippa et al. 2007). It allows to cure the patient in most cases with minimized risks of post-operative pancreatic exocrine deficiency and diabetes mellitus. It must be performed only to remove small tumours on the surface of the pancreas, with a distance of more than 2-3 mm between the

Diagnosis and Treatment of Insulinomas in the Adults 157

A medical treatment must be given to insulinoma patients in order to control the hypoglycaemia while the patient is awaiting surgery. A long-term medical treatment is

In some patients a medical treatment can result in controlling the hypoglycaemia. Evaluation of the occurrence of hypoglycaemia could probably be improved by continuous glucose monitoring (Munir et al. 2008). However sudden occurrence of severe hypoglycaemic spells cannot be ruled out, so that even if medications seem to be effective, surgery must not be delayed or cancelled when a surgical cure is possible. Dietary advice is useful but generally not sufficient to avoid hypoglycaemia. The patient must be advised regarding the symptoms suggesting hypoglycaemia, and what must be done when such symptoms occur. Self monitoring of glucose levels is recommended in order to detect asymptomatic episodes of hypoglycaemia and to prevent occurrence of hypoglycaemic spells, by treating asymptomatic abnormal lowering of glucose levels. The patients should be advised regarding everyday personal safety, to avoid possible consequences of dizziness

Diazoxide (a benzothiazide) allows direct suppression of insulin secretion by beta cells through its effect on K-ATP channel. It stimulates hepatic gluconeogenesis and lowers glucose utilization by muscle cells (Altszuler et al. 1977). It can be given bid or tid at a total daily dose of 150-400 mg in most cases. It can control symptomatic hypoglycaemia in 50- 60% of the patients (Stefanini et al. 1974). Adverse effects have been reported in about half of the patients. They comprise mainly fluid retention with oedemas, hypokalemia, digestive intolerance with nausea, cutaneous rashes and hirsutism. Diuretics may be added to treatment with diazoxide in order to control oedemas, and thiazides are known to potentiate the anti-hypoglycemic effects of diazoxide, but may induce electrolytic disorders or cause

Somatostatin analogues can achieve normalization of plasma glucose levels in 50-60% of the patients (Vezzosi et al. 2008). There are only few adverse effects, mostly digestive intolerance with diarrhoea and steatorrhea. We did not observe a tachyphylaxis phenomenon when using somatostatin analogues in insulinoma patients. The dose of octreotide that was found to control the hypoglycaemia had to be determined on an individual basis, since the doses varied between 50 and 2000 µg per day. Somatostatin analogues inhibit insulin secretion mainly through their effects on sst2A and sst5 receptors, which were found in 70% of insulinomas (Bertherat et al. 2003). A short 100 µg octreotide test, not Octreoscan uptake, was predictive of the long-term efficacy of octreotide treatment on hypoglycaemia. This could be explained by the differing affinities of Octreoscan and octreotide for sst2 receptor (Reubi et al. 2000; Vezzosi et al. 2008). Worsening of hypoglycaemia after administration of somatostatin analogues has been reported (Healy et al. 2007). Such phenomenon could be explained by glucagon suppression by somatostatin analogues. It has not been observed in all series (Vezzosi et

Glucocorticoids may be used to normalize plasma glucose levels in insulinoma patients (Novotny et al. 2005). They decrease insulin secretion and increase peripheral insulin resistance. They are associated with several well-known adverse effects and they cannot be recommended as a first-line medication or for long-term use. Other medications have been employed with variable results, e.g. calcium channel blockers like verapamil (Stehouwer et al. 1989), and also phenytoin and propanolol. To date, m-TOR inhibitors have only been

used in metastatic malignant insulinomas (see below).

given only if surgery is technically impossible or contra-indicated.

**2.4.2 Medical treatment** 

and loss of consciousness.

worsening of hypokalemia.

al. 2008).

tumour and the pancreatic duct (Finlayson & Clark 2004). Providing that the tumour present with the above mentioned characteristics, and that surgery is performed by experienced surgeons, the risk of pancreatic fistula is not higher than that observed in larger resections of the pancreas (Kooby et al. 2008). When tumour enucleation is not possible, central pancreatectomy for a tumour in the pancreatic neck or adjacent body is preferred by several groups (Muller et al. 2006; Crippa et al. 2007; Zhao et al. 2011), in order to preserve a functional pancreatic gland, and to reduce the risks of post-operative pancreatic exocrine deficiency and diabetes mellitus (Crippa et al. 2007; Hirono et al. 2009). A larger pancreatic resection, i.e. left-sided pancreatectomy, ideally spleenpreserving, or pancreatico-duodenectomy, is preferred when the insulinoma is in close proximity to the pancreatic duct in order to lower the risk of pancreatic fistula (Carrere et al. 2007; Nikfarjam et al. 2008). If a plane between the tumour capsule and the pancreatic parenchyma cannot be easily identified, resection is indicated instead of enucleation (Fendrich et al. 2009). A large resection is also preferable for big invasive insulinomas that are suspected to be malignant.

When enucleation is possible, or even when left-sided pancreatectomy is to be performed, laparoscopy is now employed (Crippa et al. 2007). It reduces the duration of the stay in the hospital and improves the post-operative quality of life (Zhao et al. 2011). It must be performed only by experienced surgeons. It can be employed only if the insulinoma has been accurately localized preoperatively. It does not allow intra-operative bi-digital palpation of the pancreas. Laparoscopic ultrasound can be now performed in many expert centres and can localize the insulinoma and evaluate its proximity with the pancreatic duct and the possibility of performing tumour enucleation.

When no insulinoma was found intra-operatively, blind distal pancreatectomy had been recommended several years ago, but to date, such procedure must not be performed (Hirshberg et al. 2002), due to its short-term and long-term morbidity and its frequent failure to achieve a cure of the disease. If no insulinoma is found, it is recommended to stop the operation, then to perform new investigations in order to localize the insulinoma, including invasive techniques.

Morbidity and mortality depend on the type of surgery. Mortality is almost 0% for enucleation, but may reach 1-2% for left-sided pancreatectomy and up to 4-5% for pancreaticoduodenectomy. The most frequent short-term complication of pancreatic surgery is pancreatic fistula. Pancreatic fistulae are more frequent after enucleation or left-sided pancreatectomy, but their consequences are more severe after pancreaticoduodenectomy, due to infectious or haemorrhagic complications. They occur globally in 3-60% of cases, depending on the definition (Pannegeon et al. 2006; Yoshioka et al. 2010; Zhao et al. 2011). Most of them are asymptomatic and no additional treatment is necessary. The clinical prevalence of pancreatic fistulae is about 14% (Zhao et al. 2011). Other complications are intra-abdominal abscess (6.6%), pulmonary infections (3.7%), wound infection (2.5%), delayed gastric emptying (2.2%), abdominal bleeding (1.3%) acute pancreatitis (0.6%) and pulmonary embolism (0.6%) (Zhao et al. 2011). Long-term complications also depend on the type of surgery. Pancreatic exocrine deficiency and diabetes mellitus almost never occur after enucleation or central pancreatectomy. Pancreaticoduodenectomy results in exocrine pancreatic deficiency in 60% of cases, and left-sided pancreatectomy may lead to 5-10% diabetes mellitus. Therefore, limited pancreatic resection such as tumour enucleation or central pancreatectomy are preferred whenever they are technically possible.

#### **2.4.2 Medical treatment**

156 Basic and Clinical Endocrinology Up-to-Date

tumour and the pancreatic duct (Finlayson & Clark 2004). Providing that the tumour present with the above mentioned characteristics, and that surgery is performed by experienced surgeons, the risk of pancreatic fistula is not higher than that observed in larger resections of the pancreas (Kooby et al. 2008). When tumour enucleation is not possible, central pancreatectomy for a tumour in the pancreatic neck or adjacent body is preferred by several groups (Muller et al. 2006; Crippa et al. 2007; Zhao et al. 2011), in order to preserve a functional pancreatic gland, and to reduce the risks of post-operative pancreatic exocrine deficiency and diabetes mellitus (Crippa et al. 2007; Hirono et al. 2009). A larger pancreatic resection, i.e. left-sided pancreatectomy, ideally spleenpreserving, or pancreatico-duodenectomy, is preferred when the insulinoma is in close proximity to the pancreatic duct in order to lower the risk of pancreatic fistula (Carrere et al. 2007; Nikfarjam et al. 2008). If a plane between the tumour capsule and the pancreatic parenchyma cannot be easily identified, resection is indicated instead of enucleation (Fendrich et al. 2009). A large resection is also preferable for big invasive insulinomas

When enucleation is possible, or even when left-sided pancreatectomy is to be performed, laparoscopy is now employed (Crippa et al. 2007). It reduces the duration of the stay in the hospital and improves the post-operative quality of life (Zhao et al. 2011). It must be performed only by experienced surgeons. It can be employed only if the insulinoma has been accurately localized preoperatively. It does not allow intra-operative bi-digital palpation of the pancreas. Laparoscopic ultrasound can be now performed in many expert centres and can localize the insulinoma and evaluate its proximity with the pancreatic duct

When no insulinoma was found intra-operatively, blind distal pancreatectomy had been recommended several years ago, but to date, such procedure must not be performed (Hirshberg et al. 2002), due to its short-term and long-term morbidity and its frequent failure to achieve a cure of the disease. If no insulinoma is found, it is recommended to stop the operation, then to perform new investigations in order to localize the insulinoma,

Morbidity and mortality depend on the type of surgery. Mortality is almost 0% for enucleation, but may reach 1-2% for left-sided pancreatectomy and up to 4-5% for pancreaticoduodenectomy. The most frequent short-term complication of pancreatic surgery is pancreatic fistula. Pancreatic fistulae are more frequent after enucleation or left-sided pancreatectomy, but their consequences are more severe after pancreaticoduodenectomy, due to infectious or haemorrhagic complications. They occur globally in 3-60% of cases, depending on the definition (Pannegeon et al. 2006; Yoshioka et al. 2010; Zhao et al. 2011). Most of them are asymptomatic and no additional treatment is necessary. The clinical prevalence of pancreatic fistulae is about 14% (Zhao et al. 2011). Other complications are intra-abdominal abscess (6.6%), pulmonary infections (3.7%), wound infection (2.5%), delayed gastric emptying (2.2%), abdominal bleeding (1.3%) acute pancreatitis (0.6%) and pulmonary embolism (0.6%) (Zhao et al. 2011). Long-term complications also depend on the type of surgery. Pancreatic exocrine deficiency and diabetes mellitus almost never occur after enucleation or central pancreatectomy. Pancreaticoduodenectomy results in exocrine pancreatic deficiency in 60% of cases, and left-sided pancreatectomy may lead to 5-10% diabetes mellitus. Therefore, limited pancreatic resection such as tumour enucleation or central pancreatectomy are preferred whenever they are technically

that are suspected to be malignant.

including invasive techniques.

possible.

and the possibility of performing tumour enucleation.

A medical treatment must be given to insulinoma patients in order to control the hypoglycaemia while the patient is awaiting surgery. A long-term medical treatment is given only if surgery is technically impossible or contra-indicated.

In some patients a medical treatment can result in controlling the hypoglycaemia. Evaluation of the occurrence of hypoglycaemia could probably be improved by continuous glucose monitoring (Munir et al. 2008). However sudden occurrence of severe hypoglycaemic spells cannot be ruled out, so that even if medications seem to be effective, surgery must not be delayed or cancelled when a surgical cure is possible. Dietary advice is useful but generally not sufficient to avoid hypoglycaemia. The patient must be advised regarding the symptoms suggesting hypoglycaemia, and what must be done when such symptoms occur. Self monitoring of glucose levels is recommended in order to detect asymptomatic episodes of hypoglycaemia and to prevent occurrence of hypoglycaemic spells, by treating asymptomatic abnormal lowering of glucose levels. The patients should be advised regarding everyday personal safety, to avoid possible consequences of dizziness and loss of consciousness.

Diazoxide (a benzothiazide) allows direct suppression of insulin secretion by beta cells through its effect on K-ATP channel. It stimulates hepatic gluconeogenesis and lowers glucose utilization by muscle cells (Altszuler et al. 1977). It can be given bid or tid at a total daily dose of 150-400 mg in most cases. It can control symptomatic hypoglycaemia in 50- 60% of the patients (Stefanini et al. 1974). Adverse effects have been reported in about half of the patients. They comprise mainly fluid retention with oedemas, hypokalemia, digestive intolerance with nausea, cutaneous rashes and hirsutism. Diuretics may be added to treatment with diazoxide in order to control oedemas, and thiazides are known to potentiate the anti-hypoglycemic effects of diazoxide, but may induce electrolytic disorders or cause worsening of hypokalemia.

Somatostatin analogues can achieve normalization of plasma glucose levels in 50-60% of the patients (Vezzosi et al. 2008). There are only few adverse effects, mostly digestive intolerance with diarrhoea and steatorrhea. We did not observe a tachyphylaxis phenomenon when using somatostatin analogues in insulinoma patients. The dose of octreotide that was found to control the hypoglycaemia had to be determined on an individual basis, since the doses varied between 50 and 2000 µg per day. Somatostatin analogues inhibit insulin secretion mainly through their effects on sst2A and sst5 receptors, which were found in 70% of insulinomas (Bertherat et al. 2003). A short 100 µg octreotide test, not Octreoscan uptake, was predictive of the long-term efficacy of octreotide treatment on hypoglycaemia. This could be explained by the differing affinities of Octreoscan and octreotide for sst2 receptor (Reubi et al. 2000; Vezzosi et al. 2008). Worsening of hypoglycaemia after administration of somatostatin analogues has been reported (Healy et al. 2007). Such phenomenon could be explained by glucagon suppression by somatostatin analogues. It has not been observed in all series (Vezzosi et al. 2008).

Glucocorticoids may be used to normalize plasma glucose levels in insulinoma patients (Novotny et al. 2005). They decrease insulin secretion and increase peripheral insulin resistance. They are associated with several well-known adverse effects and they cannot be recommended as a first-line medication or for long-term use. Other medications have been employed with variable results, e.g. calcium channel blockers like verapamil (Stehouwer et al. 1989), and also phenytoin and propanolol. To date, m-TOR inhibitors have only been used in metastatic malignant insulinomas (see below).

Diagnosis and Treatment of Insulinomas in the Adults 159

hypoglycaemia. Controlling the hypoglycaemia must not be neglected, since uncontrolled

Regarding the tumour process, 10 year-survival is about 30% in patients with metastatic insulinomas (Service et al. 1976), with very heterogeneous courses. Some patients may present a very slow progression rate, even with a metastatic disease, and have long-term survival, whereas other patients present with rapid tumour progression and poor shortterm survival rate. Predictive factors for rapid tumour progression remain to be established. They could be similar to those found for endocrine bronchial or digestive carcinomas, which comprise the presence of extra-hepatic metastases, the number of liver metastases, the proliferative index Ki67, the spontaneous progression of tumour volume in 3-6 months (Greenberg et al. 1987; Pape et al. 2004; Lepage et al. 2007). The anti-tumour strategy will not be detailed. Since malignant insulinomas are rare, there is no specific prospective study on this particular topic, so that the therapeutic strategy is similar to that of non secreting pancreatic endocrine carcinomas. Whenever it is possible, surgery must aim at totally removing the detectable lesions. However even in selected patients, post-operative complementary treatments are necessary, due to a frequent underestimation of liver metastases. In addition, even when total removal of the tumour has been performed with a R0-resection, recurrence is frequent (about 60% after a follow-up of 3 years) and the recurrence-free median survival is 5 years (Danforth et al. 1984). Treatments other than surgery combine local or regional treatments such as intra-arterial chemotherapy or chemoembolization of liver metastases (Roche et al. 2003) and radiofrequency (Berber et al. 2002), and systemic treatments such as radionuclide systemic administration (Ong et al. 2010), cytotoxic chemotherapy (traditional combination of streptozotocin, doxorubicin and 5-fluoro-uracil and more recently, capecitabine and temozolomide) (Moertel et al. 1992; Strosberg et al. 2008; Strosberg et al. 2011), or targeted therapies (Kulke et al. 2006; Dimou et

Symptomatic treatment of insulinomas aims at achieving short-term control of the hypoglycaemia while awaiting the effects of anti-tumour treatment or when anti-tumour treatments do not prove to be effective. Surgical removal of the tumour and its metastases is valuable in order to control the hypoglycaemia. Even a reduction of the tumour volume may result in reduction or transient subsiding of symptoms of hypoglycaemia (Sarmiento et al. 2002). A medical treatment is performed if there is no possible surgical cure, or as a complementary therapeutic approach. One should choose as first-line therapies medications that can achieve short-term control of hypoglycaemic spells, and do not jeopardize (by their possible adverse effects) the following use of other treatments. A few recent studies have addressed the issue of the control of severe hypoglycaemic spells in patients with inoperable malignant insulinomas (Bourcier et al. 2009; Ong et al. 2010; Maiza et al. 2011). All the medications used to treat hypoglycaemia in benign insulinomas can be employed, but in most cases, a combination of several hyperglycaemic medications is necessary (Vezzosi et al. 2008). Diazoxide or somatostatin analogues (2-3 subcutaneous injections daily, or long-acting forms, or continuous subcutaneous administration with a portable pump) may result in reduction or disappearance of hypoglycaemic spells in patients with metastatic insulinomas. Radiolabelled somatostatin analogues (especially the Lutetium labelled derivative of octreotide) may prove helpful in long-term control of hypoglycaemia and tumour progression in some patients (Ong et al. 2010). Calcium channel blockers like verapamil gave disappointing results (Stehouwer et al. 1989). Glucocorticoids were found to be effective on hypoglycaemia in malignant insulinomas, and some patients were improved even on doses as low as 2.5 mg of

hypoglycaemia results in increased morbidity and mortality.

al. 2010)(Raymond et al. 2011;Yao et al. 2011).
