The role of chemotherapy in the nonsurgical management of malignant neuroendocrine tumours

Malignant neuroendocrine tumours (NET) are a rare and heterogeneous group of tumours derived from cells that belong to the so-called diffuse neuroendocrine system (DNES) (Capella et al., 1995). Neuroendocrine tumours are programmed to adopt a neuroendocrine phenotype and exert multipotential secretory capacities producing distinct clinical syndromes (Faiss et al., 1996). Although NET generally show indolent growth, they may be diagnosed late with humoral symptoms and/or metastases to the liver, and it is known that this is associated with a less favourable prognosis (Öberg, 1993). The initial management of NET comprises surgical excision of the primary tumour (aimed at reducing as much as possible of the tumour mass); additionally, in patients who are not cured by surgery alone, medical therapy is used for the control of symptoms and humoral syndromes with agents such as somatostatin analogues and/or α-interferon. Specific therapy with radiopharmaceuticals using radio-labelled substances such as meta-iodobenzylguanidine (MIBG) or somatostatin analogues appears promising for some tumours which show diagnostic uptake, and is the first-line systemic management for sensitive cases. Hepatic artery ligation and/or chemoembolization is also used in patients with excessive hepatic tumour load and uncontrollable symptoms. The control of tumour growth with chemotherapeutic agents is currently mainly reserved for patients with recurrent and/or progressive disease and where other therapeutic modalities have failed. Chemotherapy may be particularly helpful for selected cases of advanced NET, especially pancreatic or poorly differentiated NET. This review deals with the general role of chemotherapy in the management of malignant NET, its integration with other modes of therapy, and the specific protocols which have been used. Neuroendocrine tumours are relatively rare tumours considered to be embryologically derived from the neural crest or the endoderm, notably in the digestive and respiratory tracts (Capella et al., 1995). The specific features of neuroendocrine cells are detected by refined morphological techniques for endocrine granules (chromogranin A [CgA], synaptophysin or neurone-specific enolase [NSE]), histochemical techniques for secretory peptides, and electron microscopy demonstrating secretory granules; the cell-specific characterization of NET may require hormone immunohistochemistry (Fig. 1) (Solcia et al., 1999). Based upon the presence of CgA, the most sensitive and reliable immunohistochemical marker for NET, a simple classification of NET tumours is shown in Table 1 (Eriksson et al. 2000). While immunohistochemical staining for amine and peptide hormones may help to define the origin of the tumour, they provide less information concerning its biological behaviour and prognosis (Solcia et al. 2000). Taking into consideration tumour size and location, angio-invasion, hormone production, histological grade and proliferative index, NET may be divided into both well- and poorly-differentiated tumours (Capella et al., 1995; Solcia et al. 2000). The majority of NET are well-differentiated; these tumours are composed of monomorphic cells with low cytological atypia, express the markers of neuroendocrine differentiation (in particular CgA), and exhibit low mitotic and proliferative status as assessed by nuclear Ki-67 expression (Fig. 1) (Solcia et al., 1999, 2000). Poorly differentiated (anaplastic) tumours express mainly cytosolic markers, e.g. NSE and synaptophysin, and are associated with abundant necrosis, a high degree of cellular atypia, a high mitotic index and a high proliferative status by Ki-67 expression (Fig. 2a & b) (Solcia et al., 1999, 2000; Rindi et al. 2000). Well-differentiated neuroendocrine tumour (typical carcinoid tumour), showing positive immunohistochemistry for chromogranin A (CgA); neoplastic cells are uniform and arranged in trabeculae. Poorly differentiated neuroendocrine tumour (atypical carcinoid tumour), showing positive immunohistochemistry for neurone specific enolase (NSE), but negative for chromogranin A (CgA); neoplastic cells exhibit a high degree of cellular atypia. The histological degree of differentiation of NET relates to their proliferative rate, and is an important determinant of response to treatment and in particular chemosensitivity (Solcia et al., 1999). The behaviour of well-differentiated tumours is rather unpredictable and depends on the type of hormonal secretion, tumour size, functioning status and the degree of nearby tissue invasion (Rindi et al. 2000). Anaplastic-NET define an increasingly recognized group of NET that show histological similarity to small-cell lung cancer (SCLC). Such tumours behave aggressively, with rapid growth and early metastasis, but also exhibit a relatively high response rate to chemotherapy (Solcia et al., 1999). The basis for therapy in NET is not only curative elimination or reduction of tumour mass but also amelioration of clinical syndromes and maintaining and improving quality of life; different means of treatment have to take into consideration the stage of the disease and tumour biology (Öberg, 1998). Currently, pharmacological (nonsurgical) treatment of NET consists of: SMS exerts a major inhibitory role in exocrine and endocrine secretion, intestinal motility and cellular proliferation through binding to specific somatostatin receptors (SR); five types (1–5) of SR have been identified (Lamberts et al., 1991). SMS analogues are synthetic analogues of the native peptide, with a prolonged half-life (2·5–3 h) and thus increased biological activity; SMS analogues available for clinical use include octreotide and lanreotide, with the newer vapreotide soon to be available (Arnold et al. 2000). As the majority of NET express SR, SMS analogues have been very effective in inhibiting hormonal secretion, improving clinical syndromes and the quality of life in many patients with NET tumours (Öberg, 1999). In addition, SMS analogues also exert antiproliferative effects, which translates mainly as stabilization of tumour growth, by inhibiting the G1 phase of the cell cycle and angiogenesis and/or inducing apoptosis, though this is mainly seen at higher doses (Öberg, 1999). Recently, long-acting formulations have been developed, increasing the intervals of administration. Somatostatin® LAR® (Novartis, Basel, Switzerland) is rather slow in onset, but once therapeutic levels have been achieved injections every 4–6 weeks may retain effectiveness. Somatulin LA (Ipsen, Paris, France) is faster in onset but has to be administered every 7–14 days; a very new gel formation of lanreotide may last longer and be easier to administer. Adverse effects of SMS analogues are usually minimal, mainly mild diarrhoea or abdominal pain, with only very few patients discontinuing treatment (Arnold et al. 2000). α-INF has been shown to possess some therapeutic efficacy in metastatic NET; this action is thought to be mediated through inhibitory effects on oncogene expression, DNA replication, and protein synthesis (Lupoli et al., 1996). Tumour cell division is mainly blocked in the G1-S phase, but a definite cytotoxic effect has not yet been demonstrated; control can also be indirect through activation of the immune system and by inhibiting angiogenesis. Side-effects, which are dose related, include flu-like symptoms, chronic fatigue, weight loss, anaemia, depression and increased liver enzymes (Öberg, 2000). Such adverse effects may occasionally be unpleasant and persistent; this limits the usefulness of this agent which in our experience has not been particularly effective (Papamichael et al., 1998). NET retain multipotent differentiation capacities as the possession of neuroamine uptake mechanisms and/or the expression of specific receptors, e.g. SR, at the cell membrane (Wiseman & Kvols, 1995). Meta-iodobenzylguanidine (MIBG) is structurally similar to noradrenaline, and through the amine precursor uptake mechanism is incorporated into neurosecretory granules (Shapiro, 1995). When a β-emitting radioisotope is coupled to MIBG or an SMS analogue, it specifically targets tumour cells and delivers an effective radiation dose to the involved cell and neighbouring tissue to within a few millimeters or so, thus selectively sparing nontumour tissue (Wiseman & Kvols, 1995). 131I-MIBG has been mainly used for the treatment of chromaffin cell tumours and other NET with minimal side-effects; while complete tumour regression is unusual, current data suggest that there may be considerable symptomatic improvement and possible extension of survival (Fig. 3) (Mukherjee et al., 2001). Experience with 90Y-octreotide or 90Y-lanreotide, although still limited, appears promising due to the wider expression of SR by NET (Kaltsas et al. 2001). Post-therapy scan in a patient with a metastatic phaeochromocytoma. The top panel shows an anterior view (left) with uptake in the mediastinum and left shoulder, while in the posterior view (right) scattered ‘hot spots’ in the spine and ribs are visible. In the middle panel the anterior view of the lower abdomen and pelvis (left) demonstrates metastases in the right pelvis and femur, while metastases in the left pelvis and femur are shown in the posterior view (right). The lower panel of the abdomen and lower thorax shows further bone metastases and patchy liver uptake of 131I-mIBG in both anterior (left) and posterior (right) views. [Reproduced with permission from Mukherjee et al., (2001) Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with 131I-MIBG. Clinical Endocrinology, 55, 47–60.] Neuroendocrine tumours are not highly chemosensitive, this may be due to their generally low rate of mitosis, the target of many cytotoxic drugs, and also to their biological properties (Faiss et al., 1996; Arnold, 1997; Veenhof, 1999; Öberg, 1993, 1998, 1999). Neuroendocrine tumours show high expression of the multidrug resistance (MDR-1) gene, involved in hormonal efflux, and are able to extrude a variety of anticancer drugs resulting in resistance to them (Marty-Ane et al., 1995). In addition, NET show constitutively high levels of expression of the antiapoptotic gene Bcl-2, which contributes further to their intrinsic resistance to chemotherapeutic agents (Wang, 1999). Chemotherapy has been widely used for the treatment of disseminated NET, but assessing response to chemotherapy may be difficult as these tumours exhibit long phases of spontaneous tumour standstill, sudden explosive growth or even spontaneous regression (Arnold et al. 2000). In addition, many reports in the literature are retrospective, involving small numbers of patients and tumours with different biological behaviour (Öberg, 1993, 1998; Arnold, to chemotherapy in clinical is usually using the in which an response is as a reduction of at in the of the tumour (Fig. many patients NET tumours to the response and of symptoms and of humoral secretion, but with or reduction of tumour size, at in the et al., & of tumour size, and invasion in a patient with a highly and of chemotherapy with [Reproduced with permission from et al., of Clinical and quality of life the to which a and is by a disease or its and have an in the of for cancer patients & 1995). of the in patients with NET tumours may help in thus highly with on provide important information effects in cancer and help (Öberg, 1998). The increasing of and therapeutic for both and treatment of NET is with by a Such a may include with a in NET, such as and and a nuclear 1998). and be and a on the or surgical be As patients with NET are management be in with experience and 1998). As the majority of NET are slow and even patients with disseminated disease may exhibit prolonged early in may be very In to the of current and new therapeutic in patients with NET, and NET have been Neuroendocrine tumours of the have an of and include both carcinoid and pancreatic cell tumours (Öberg, Table are tumours, of which the majority in from the & to their primary these tumours from the and and and of these tumours are and to the of while most of them to the liver et al., 1998). A of carcinoid tumours that in metastases at the of the survival rate of carcinoid tumours of is the carcinoid is survival is to be less from et al., SMS analogues are associated with symptomatic and hormonal an tumour response is in only (Eriksson & 1999). long-acting SMS analogues have been associated with similar symptomatic and hormonal but there is also in of an antiproliferative which translates mainly into disease stabilization (Arnold et al. 2000). SMS analogues the treatment of for the of the tumour patients of treatment et al., & 1999). has been associated with and tumour and an improvement in survival (Öberg, 2000). SMS analogues and have been to survival of and with minimal (Eriksson & 1999). In addition, the of SMS analogues and has been to have a although this in (Öberg, 1998; et al. 2000). The experience of using 131I-MIBG in patients with carcinoid tumours has that show symptomatic and hormonal improvement with tumour in (Shapiro, 1995; & Kvols, 1995; et al. there is to suggest that patients with may have a favourable survival (Mukherjee et al., 2001). The majority of experience in chemotherapy has been with the agent in small numbers of with response from to (Öberg, et al., Öberg, 1998, 1999). has been to exert a response rate, and only et al., Öberg, has also been shown to exert a low rate of response of used et al., Öberg, 1999). data show that chemotherapy of malignant carcinoid tumours is of with low and response generally less a (Öberg, 1993, 1999; Veenhof, 1999). with the have response and the group of patients with and has shown a response rate of (Öberg, 1993, 1998). In our the of with has similar (Kaltsas et al., of different chemotherapeutic drugs using and et al., et al., and et al., 1995; et al., or and not improvement in the response Öberg, 1993, 1998). Chemotherapy is generally reserved for or progressive disease with a high proliferation tumours derived from the are to be from the where treatment with is effective (Faiss et al., 1996). Adverse effects of treatment on the used and are dose in particular is associated with and while bone and are other (Faiss et al., the of these chemotherapeutic agents in of their quality of life has to be chemotherapy has to be a prolonged to the slow rate of tumour response to chemotherapy be or & 2000). are usually to endocrine or therapy, and In they not into of survival although in patients have also been et al., & In cases of tumour regression it may be to the of a of the metastases in an to control & 2000). The for chemotherapy to general tumours, and of chemoembolization and/or & 2000). may be to such patients in a using protocols to the of the systemic therapy et al., In poorly differentiated a response rate of although has been using a of and that is highly in the et al., et al. it has been that poorly differentiated in NET and and or of be with immune staining or electron microscopy and in a similar to et al., 1991). A consideration in patients with disseminated NET is the usually of the liver in the metastatic et al., selected patients prolonged improvement can be by surgical reduction of tumour or of metastatic et al., Öberg, 1999). As with other liver metastases the is not and of the hepatic artery has been used in Tumour from a can and the survival to be et al., of liver metastases in in of chemoembolization & 2000). Hepatic artery chemoembolization using is associated with adverse effects and a survival of et al., et al., where treatment with and with and every to by hepatic artery complete and and a survival of in patients with malignant carcinoid tumours et al. have been in & 2000). In addition, the of e.g. and has with response from to et al., tumours are usually of cell and are in the as as the SMS analogues be considered as the initial treatment of with showing symptomatic and hormonal clinical and hormonal they are also used as an to in et al., 1996; et al., 1996; et al., 1999). effect in is on the presence of type SR which are in of these tumours (Arnold et al. 2000). As long-acting SMS analogues also exert antiproliferative which in to a stabilization of tumour growth of (Arnold et al. 2000). Treatment with has been associated with while the of octreotide and has been to exert a effect (Öberg, 1998, 2000). has a relatively uptake in these tumours, further treatment with 131I-MIBG in the the majority of cell tumours express SR and are for treatment with 90Y-octreotide and (Wiseman & Kvols, 1995; et al. 2001). cell tumours the most NET (Öberg, & 2000). has been to show complete and in and of with a of of and of survival of 1993). a rate with a of while has been as producing a complete or with a of et al., Öberg, 1993, 1998). The of and has been by many as therapy a which the to be to in of response rate, response and survival et al., the of to be although both achieved and survival of et al., using different of drugs, e.g. and have not et al., although have been & response to chemotherapy in a group of patients to the response rate et al., 1993). of these therapeutic are usually associated with adverse effects, which are and dose and treatment be considered in the of such adverse 1999). Based on these it has been that a chemotherapy particularly and be considered in progressive well-differentiated cell tumours, but the therapy be only there is an response and be on stabilization of the disease 1999). promising in poorly differentiated pancreatic NET have been using a of and where response of have been to in patients with well-differentiated In addition, the survival for well-differentiated NET to in the et al., & 2000). In patients with functioning tumours, particularly and with tumours et al. Öberg, 1993, 1998; & 1998, et al., 1999). as in patients with carcinoid tumours, be to the management of liver the of hepatic artery with chemotherapy has symptomatic and humoral improvement with a survival of et al., Öberg, 1999). carcinoid NET are well-differentiated but the poorly differentiated carcinoid tumours are associated with increased disease and have a survival rate of et al., 1996). Tumour size survival in patients with well-differentiated tumours et al., 1998). carcinoid tumours behave and be with chemotherapy and to et al., 1996). tumours from the are rare et al., and are associated with a tumour a high rate of and low survival et al., 1999). poorly differentiated tumours, complete with radiation and chemotherapy is the available treatment et al., of are malignant et al., with and with the of with this has increased in et al., have been to have a higher rate although the prognosis similar et al., 1999). The treatment for malignant chromaffin cell tumours is and & 1998). or of SMS analogues has not shown clinical although have been et al., 1995; et al., SMS analogues may still be of in patients et al. 2000). tumours, or there is disease therapeutic 131I-MIBG and chemotherapy are the Treatment with 131I-MIBG is while the symptomatic and hormonal response in patients with metastatic and tumour in only a few patients with minimal tissue disease a complete response (Shapiro, 1995; et al. 2000). Experience with the use of 131I-MIBG in is limited, but their appears to be similar to (Mukherjee et al., 2001). is helpful for of while of metastatic liver disease has & 1998). octreotide has been used to malignant phaeochromocytoma, although showing only symptomatic in a few patients (Wiseman & Kvols, 1995). Chemotherapy with or a of agents has been as the last in patients with malignant chromaffin cell tumours et al., data in malignant have shown of of patients have a and within the have a indolent and for even treatment et al., has been that early from of the rather hormonal thus further treatment et al., to the of these tumours to which have shown an response rate of to the of and this has been in patients with malignant The a hormonal and a tumour response with minimal mainly bone and et al., chemotherapy can be used to tumour response and et al. 2000). other reports have also the efficacy of this et al. most effects on survival et al., although have been et al., 1999). thyroid carcinoma is a of the cells of the thyroid which to and et al., 1997; & 1998). may behave in a relatively indolent the survival rate & 1998). is specific medical and is also relatively to & 1998). Although a few have shown some symptomatic and hormonal improvement treatment with SMS analogues et al., biological or morphological not in a of patients with octreotide et al., treatment with octreotide can in some patients et al., 1996). reports of a of treatment with the of and long SMS analogues with has not tumour although there a symptomatic and hormonal response with a major on the quality of life (Lupoli et al., 1996; et al. 2000). is experience using 131I-MIBG in patients with which has shown symptomatic and hormonal but only tumour complete et al. 2000; Mukherjee et al., 2001). Chemotherapy the for of patients with with recurrent or progressive disease & 1998). of the of there are few reports on the efficacy of chemotherapy for metastatic most of which have et al., The most effective agent is which has response of to or in et al., et al., The of and a response in a few patients with et al., are reports of complete to and et al., although the of this to a group of patients associated with only and or disease stabilization et al., response to and has also been et al., 1995). have been less in other small using chemotherapy with agents and et al., 1995). chemotherapy with and has been as resistance to the agents is not mediated by the of the or antiapoptotic gene, to but with adverse effects et al., agents have also been used to the effect of radiation & 1998). Although these agents to have it is difficult to their efficacy as most only of patients et al., 1995; et al., Recently, to thyroid and/or metastases has been shown to and can be used as an in patients with disease et al., 1999). which is still phase is the of et al., 1999). tumours are mainly but can occasionally highly and treatment (Kaltsas & 1998). Malignant tumours are diagnosed on the presence of system extension not to the or other systemic using such as the of in of tumours (Kaltsas & 1998). Although the of surgery and is usually effective in tumours, therapy is for highly and malignant tumours (Kaltsas et al., therapy with and SMS analogues has been shown to be to symptoms and hormonal in the (Kaltsas & although some tumours express somatostatin receptors, currently there are data on the use of In an to chemotherapy has been used but experience is to reports mainly due to the of the disease (Kaltsas & 1998). Experience using to and in patients associated with only a tumour while symptomatic and hormonal they (Kaltsas et al., In patients with malignant tumours have a with the majority within patients with metastases have a prognosis to patients with systemic and may a group for early chemotherapeutic (Kaltsas et al., treatment of neuroendocrine tumours a tumour surgery is a as it is the only available curative the surgical has been of with of liver metastases and/or hepatic artery ligation or with surgical is not with somatostatin analogues or or in be although our experience with has not shown it to be particularly Treatment with 131I-MIBG is reserved for patients with uptake on while experience with 90Y-octreotide is still treatment with 131I-MIBG is associated with symptomatic and hormonal although tumour are and occasionally to be seen treatment with somatostatin which be to the majority of NET, be In patients with uptake to and/or progressive disease other of chemotherapy be or in with although such an has not been and further in clinical Chemotherapy with an agent and has an role in the treatment of advanced well-differentiated cell neuroendocrine tumours, which a disease with of clinical growth and chemosensitivity similar to small cell lung to the of and patients with metastatic well-differentiated carcinoid tumours, where response are a chemotherapeutic be considered in the of clinical our is to use the of is to and for both cell and carcinoid tumours of low to their to chromaffin cell tumours have been with the of and with although usually a rare and relatively group of tumours with The efficacy of current chemotherapy in medullary thyroid carcinoma is not although appears to be specifically In to treatment and tumour biology has to be in every tumour and treatment be the quality of life be and the efficacy of treatment be possible adverse