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

Abstract

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, 1997). Response to chemotherapy in clinical trials is usually reported using the World Health Organization (WHO) criteria, in which an ‘objective tumour’ response is defined as a reduction of at least 50% in the product of the longest measurable tumour diameter (Fig. 4). However, many patients whose NET tumours fail to satisfy the WHO response criteria obtain valuable and sustained relief of symptoms and resolution of humoral secretion, but often with little or no gross reduction of tumour size, at least in the short term (Harris et al., 1990; Hatton & Reed, 1997). Reduction of tumour size, retrosellar (pontine) extension, and cavernous sinus invasion (computed tomography scan) in a patient with a highly aggressive prolactinoma before (a) and after (b) two courses of chemotherapy with CCNU/5-FU. [Reproduced with permission from Kaltsas et al., (1998a) Journal of Clinical Endocrinology and Metabolism, 83, 4233–38.] Health-related quality of life (HRQoL) questionnaires incorporate the extent to which a patient's physical, emotional and social well-being is affected by a disease process or its treatment, and have become an essential outcome measure in the evaluation of treatments for cancer patients (Kaplan & Bush, 1982; Cella, 1995). Knowledge of the HRQoL in patients with NET tumours may help in decision-making, thus avoiding highly toxic treatments with limited impact on survival, provide important information about long-term effects in cancer survivors, and help identify potential adjustment problems (Öberg, 1998). The increasing number of investigative procedures and therapeutic options for both diagnosis and treatment of NET is best dealt with by a multidisciplinary team. Such a team may include physicians with a special interest in NET, such as endocrinologists, gastroenterologists and oncologists, and a nuclear medicine expert (Caplin et. 1998). All conventional and radionuclear imaging procedures should be reviewed and a consensus on the best evidence-based management, including chemo-embolization or repeated surgical procedures, should be agreed. As patients with NET are rare, optimum management should be performed in centres with relevant experience and expertise (Caplin et. 1998). As the majority of NET are slow growing and even patients with disseminated disease may exhibit prolonged survival, early involvement in palliative team programs may be very helpful. In order to evaluate the results of current management, establish guidelines and develop new therapeutic trials in patients with NET, United Kingdom and European NET networks have been established. Neuroendocrine tumours of the GI (Gastroenteropancreatic-GEP) have an estimated incidence of 1–2/100 000 and include both carcinoid and pancreatic islet cell tumours (Öberg, 1993; Table 2). Carcinoids are characteristically serotonin-secreting tumours, of which the great majority (73% in one series) originate from the GI (Modlin & Sandor, 1997). According to their primary localization these tumours originate from the foregut (oesophagus, stomach, duodenum and pancreas), midgut (jejunum, ileum, appendix, right-sided colon) and hindgut (transverse colon, left-sided colon, sigmoid and rectum). About half of these tumours are functionally active and secrete several neurotransmitters leading to the development of characteristic syndromes, while most of them metastasize to the liver (Caplin et al., 1998). A cumulative analysis of 8305 carcinoid tumours indicated that in 45·3% metastases were already evident at the time of diagnosis, whereas the overall 5-year survival rate of all carcinoid tumours regardless of site is 50·4%. However, when the carcinoid syndrome is present overall survival is reported to be less than two years from diagnosis (Modlin et al., 1997). SMS analogues are associated with 70–80% symptomatic and 30–75% hormonal improvement, whereas an objective tumour response is noted in only 10–15% (Eriksson & Oberg 1999). More recently, long-acting SMS analogues have been associated with similar symptomatic and hormonal responses, but there is also evidence in favour of an antiproliferative response, which translates mainly into disease stabilization (Arnold et al. 2000). SMS analogues constitute the treatment of choice for the prevention of the tumour lysis syndrome; however, several patients became resistant after around one year of treatment (Moertel et al., 1994; Eriksson & Oberg 1999). Similarly, α-interferon has been associated with 60% symptomatic, 44% hormonal, and 11% objective tumour responses, and an overall improvement in survival (Öberg, 2000). Both SMS analogues and α-interferon, have been reported to produce survival rates of 36 and 80 months, respectively, with minimal side-effects (Eriksson & Oberg 1999). In addition, the combination of SMS analogues and interferon has been noted to have a synergistic effect, although this awaits confirmation in more extended studies (Öberg, 1998; Arnold et al. 2000). The cumulative experience of using 131I-MIBG in more than 200 patients with carcinoid tumours has revealed that approximately 50% show symptomatic and hormonal improvement with objective tumour responses in almost 10% (Shapiro, 1995; Wiseman & Kvols, 1995; Chatal et al. 2000); however, there is evidence to suggest that patients treated with 1131-MIBG may have a more favourable overall 5 year survival (Mukherjee et al., 2001). The majority of experience in applying single-agent chemotherapy has been gained with the alkylating agent 5-fluorouracil (5-FU) in small numbers of patients, with objective response rates ranging from 18 to 26% (Öberg, 1993; Moertel et al., 1994; Öberg, 1998, 1999). Similarly, doxorubicin has been noted to exert a 21% response rate, dacarbazine 17% and actinomycin D only 5% (Van Hazel et al., 1983; Öberg, 1993); cisplatin has also been shown to exert a low rate of response of 7% when used alone (Moertel et al., 1992; Öberg, 1999). These data show that single-agent chemotherapy of malignant carcinoid tumours is rarely of any significant beneficial value, with low overall and short-lasting response rates, generally lasting less than a year (Öberg, 1993, 1999; Veenhof, 1999). Combination regimens with the nitrogen mustard, streptozotocin, have produced response rates ranging between 9 and 30%; the largest group of patients treated with streptozotocin and 5-FU has shown a response rate of 23% (Öberg, 1993, 1998). In our experience, the combination of another nitrogen mustard, lomustine, with 5-FU has produced similar results (Kaltsas et al., 1998b). Combinations of 3–4 different chemotherapeutic drugs using streptozocin, 5-FU and cisplatinum (Moertel et al., 1991; Rougier et al., 1991), 5-FU, dacarbazine and epirubicin (Di Bartolomeo et al., 1995; Bajetta et al., 1998), or etoposide and cisplatinum, did not produce any significant improvement in the response rates (Moertel, 1983; Öberg, 1993, 1998). Chemotherapy is generally reserved for relapsing or rapidly progressive disease with a high proliferation capacity; tumours derived from the foregut are said to be more chemoresponsive than those from the midgut, where treatment with α-interferon is effective (Faiss et al., 1996). Adverse effects of treatment depend on the regimen used and are dose related; streptozotocin in particular is associated with renal toxicity and emesis, while bone marrow suppression, alopecia and neuropathy are other commonly encountered adverse-effects (Faiss et al., 1996); therefore, the patient's tolerance of these chemotherapeutic agents in terms of their quality of life has to be carefully considered. Systemic chemotherapy has to be initiated after a prolonged observational period related to the frequent slow rate of tumour growth; similarly, response to chemotherapy should be evaluated after 3–6 months or more (Rougier & Mitry 2000). Responses are usually unpredictable, unrelated to endocrine hyperfunction or prior therapy, and often short-lasting. In general, they do not translate into prolongation of survival although long-term lasting responses in individual patients have also been described (Öberg (1993, Harris et al., 1990; Hatton & Reed, 1997). In cases of tumour regression it may be useful to consider the possibility of a secondary resection of the main remaining metastases in an attempt to achieve better long-term control (Rougier & Mitry 2000). The best criteria for initiating chemotherapy appear to be: age < 60 years, good general state, unresectable tumours, and prior failure of chemoembolization and/or biotherapy (Rougier & Mitry 2000). It may be preferable to treat such patients in a research setting using protocols designed to improve the effectiveness of the systemic therapy (Moertel et al., 1994). In anaplastic, poorly differentiated carcinoids, a response rate of 67%, although short-lasting, has been described using a combination of cisplatin and etoposide that is highly active in the related SCLC (Moertel et al., 1991; Mitry et al. 1998); it has therefore been suggested that poorly differentiated carcinomas, originating in typical NET sites (small and large bowel, pancreas and stomach) or of unknown origin, should be evaluated with appropriate immune staining or electron microscopy and treated in a similar way to SCLC (Moertel et al., 1991). A special consideration in managing patients with disseminated NET is the usually dominant involvement of the liver in the metastatic process (Moertel et al., 1994). For selected patients prolonged improvement can be obtained by surgical reduction of large solitary tumour masses or well-localized clusters of metastatic lesions (Moertel et al., 1994; Öberg, 1999). As with other liver metastases the blood supply is arterial not portal, and occlusion of the hepatic artery has been used in treatment. Tumour regrowth from a portal vein supply can occur and the median survival time was found to be 27 months (Moertel et al., 1994). Arterial hypervascularization of liver metastases in GEP argues in favour of chemoembolization (Ruszniewski & Malka, 2000). Hepatic artery chemoembolization using doxorubicin is associated with significant adverse effects and a median overall survival of 24 months (Moertel et al., 1994; Bilchik et al., 1997). Liver-targeted chemotherapy, where treatment with doxorubicin and dacarbazine alternate with streptozotocin and 5-FU, repeated every four to six weeks, then followed by hepatic artery occlusion, produced 19% complete biochemical responses and 57% partial remissions and a median survival of 49 months in 21 patients with malignant carcinoid tumours (Moertel et al. 1994). These results have been confirmed in several recent series (Ruszniewski & Malka, 2000). In addition, the application of loco-regional treatments, e.g. lasertherapy, cryotherapy and radiofrequency, has produced encouraging results with response rates ranging from 35 to 90% (Bilchick et al., 1997). These tumours are usually functional (70% of islet cell tumours) and are found in the duodenum as well as the pancreas (Table 2). SMS analogues should be considered as the initial treatment of choice, with VIPomas showing 80% symptomatic and 70–80% hormonal improvement, glucagonomas 60% clinical improvement, and somatostatinomas 40–80% hormonal improvement; they are also used as an adjunct to proton pump inhibitors in gastrinomas (De Herder et al., 1996; Wermers et al., 1996; Nguyen et al., 1999). Their beneficial effect in insulinomas is based on the presence of type 2 SR which are found in 50% of these tumours (Arnold et al. 2000). As noted above, long-acting SMS analogues also exert antiproliferative properties, which in prospective studies translate to a 36–70% stabilization of tumour growth of 2–60 months duration (Arnold et al. 2000). Treatment with α-interferon has been associated with 75–80% objective biochemical responses, including stabilization, while the combination of octreotide and α-interferon has been reported to exert a synergistic effect (Öberg, 1994, 1998, 2000). 123I-MIBG has demonstrated a relatively poor uptake in these tumours, precluding further treatment with 131I-MIBG in the majority; however, the majority of islet cell tumours express SR and are therefore candidates for treatment with 90Y-octreotide and related targetted therapies (Wiseman & Kvols, 1995; Kaltsas et al. 2001). Pancreatic islet cell tumours comprise the most chemosensitive NET (Öberg, 1993; Rougier & Mitry, 2000). Streptozotocin alone has been reported to show complete and partial remissions in 36% and 42% of patients, respectively, with a median duration of remission of 17 months and of survival of 1·5 years (Oberg, 1993). Similarly, doxorubicin alone generates a 20% partial remission rate with a median duration of 4 months, while dacarbazine has been described as producing a 50% complete or partial remission with a median duration of 30 months (Moertel et al., 1980, 1983; Öberg, 1993, 1998). The combination of streptozotocin and 5-FU has been regarded by many as standard therapy after a multi-institutional randomised study which showed the two-drug scheme to be superior to streptozotocin in terms of response rate, response duration and survival (Moertel et al., 1980). Subsequently, the combination of streptozotocin-doxorubicin was claimed to be superior, although both achieved equivalent remission and survival rates of approximately two years (Moertel et al., 1992). Reports using different combinations of more than two drugs, e.g. dacarbazine, 5-FU and epirubicin have not produced demonstrably better results (Di Bartolomeo et al., 1995), although individual responses have been noted (Hatton & Reed, 1997). Similarly, ‘salvage’α-interferon following suboptimal response to chemotherapy in a group of 17 patients failed to improve the response rate (Zilembo et al., 1993). All of these therapeutic schemes are usually associated with significant adverse effects, which are drug and dose dependent, and treatment should always be considered in the light of such adverse events (Veenhof, 1999). Based on these data, it has been suggested that a chemotherapy combination, particularly streptozotocin and doxorubicin, could be considered in progressive well-differentiated islet cell tumours, but the therapy should be continued only if there is an obvious response and should be discontinued on stabilization of the disease (Veenhof, 1999). More promising results in poorly differentiated pancreatic NET have been published using a combination of etoposide and cisplatin, where response rates of 67% have been obtained compared to 7% in patients with well-differentiated tumours. In addition, the median survival for well-differentiated NET was 15 months compared to 15–19 months in the anaplastic ones (Moertel et al., 1991; Rougier & Mitry, 2000). In general, patients with functioning tumours, particularly insulinomas and VIPomas, respond better than those with nonfunctioning tumours (Moertel et al. 1980, Öberg, 1993, 1998; Soga & Yakuma, 1998, Nguyen et al., 1999). Similarly, as in patients with carcinoid tumours, special attention should be paid to the management of liver deposits: the combination of hepatic artery occlusion with sequenced chemotherapy has produced substantial symptomatic and humoral improvement with a median survival of 35 months (Moertel et al., 1994; Öberg, 1999). Most bronchial carcinoid NET are well-differentiated (90%), but the poorly differentiated (atypical) bronchial carcinoid tumours are associated with increased local–regional disease and have a significantly decreased 5 year survival rate of 57% (Froudarakis et al., 1996). Tumour size independently affected survival in patients with well-differentiated tumours (Gould et al., 1998). Atypical carcinoid tumours behave like SCLC and therefore should be treated aggressively with chemotherapy and radiotherapy, analogous to pulmonary carcinomas (Froudarakis et al., 1996). Carcinoid tumours arizing from the thymus are rare (Economopoulos et al., 1990), and are associated with a large tumour bulk, a high rate of metastasis and low postoperative survival rates (Soga et al., 1999). For poorly differentiated tumours, complete resection, along with radiation and chemotherapy when possible, is the best available treatment (Economopoulos et al., 1990). Approximately 10–13% of phaeochromocytomas are malignant (Goldstein et al., 1999); however, with extended follow-up and with the introduction of scintigraphy with 123I-MIBG this proportion has increased in recent years (Schlumberger et al., 1992). Paragangliomas have been reported to have a higher malignancy rate although the long-term prognosis remains similar (Goldstein et al., 1999). The principal treatment for malignant chromaffin cell tumours is resection and catecholamine blockade (Kebebew & Duh, 1998). Short- or long-term administration of SMS analogues has not shown any clinical benefits, although occasional biochemical responses have been obtained (Plouin et al., 1995; de Herder et al., 1996); however, SMS analogues may still be of value in individual patients (Koriyama et al. 2000). For inoperable tumours, or if there is extensive residual disease after resection, therapeutic 131I-MIBG and chemotherapy are the remaining options. Treatment with high-dose 131I-MIBG is well tolerated, while the overall symptomatic and hormonal response in more than 100 patients with metastatic phaeochromocytomas was 76% and 45%, respectively; partial tumour responses were noted in 30%. However, only a few patients with minimal soft tissue disease showed a complete response (Shapiro, 1995; Chatal et al. 2000). Experience with the use of 131I-MIBG in paragangliomas is more limited, but their responsivity appears to be similar to phaeochromocytomas (Mukherjee et al., 2001). External beam radiotherapy is helpful for palliation of painful metastases, while arterial embolization of metastatic liver disease has produced transient responses (Kebebew & Duh, 1998). Radioiodine-labelled octreotide has been used to treat malignant phaeochromocytoma, although showing only transient symptomatic relief in a few patients (Wiseman & Kvols, 1995). Chemotherapy with either single or a combination of agents has been tried as the last option in patients with malignant chromaffin cell tumours (Schlumberger et al., 1992). Survival data in malignant phaeochromocytomas have shown two subsets of patients; approximately 50% of patients have a more aggressive course and die within 4–5 years, whereas the others have a more indolent course and survive for years even without treatment (Averbach et al., 1988). It has therefore been suggested that early mortality results from progression of the malignancy, rather than hormonal hypersecretion, thus necessitating further aggressive treatment (Averbach et al., 1988). Due to the resemblance of these tumours to neuroblastomas, which have shown an overall response rate of 80% to the regimen of cyclophosphamide, vincristine and dacarbazine (CVD), this regimen has been tried in patients with malignant phaeochromocytomas. The largest series, comprising 14 patients, showed a 79% hormonal and a 57% tumour response with minimal side-effects, mainly bone marrow toxicity and hypotension (Averbach et al., 1988); during chemotherapy CgA can be used to gauge tumour response and relapse (Rao et al. 2000). Several other reports have also confirmed the efficacy of this regimen (Rao et al. 2000); however, most responses were transient without clear effects on long-term survival (Averbach et al., 1988), although occasional individual long-term survivors have been described (Iwabuchi et al., 1999). Medullary thyroid carcinoma is a neoplasm of the calcitonin-secreting parafollicular C cells of the thyroid gland which often metastasizes locally to cervical lymph nodes and mediastinal structures (Heshmati et al., 1997; Giuffrida & Gharib, 1998). Despite dissemination, MTC may behave in a relatively indolent manner, the 5 year survival rate being 65% (Giuffrida & Gharib, 1998). There is no specific medical treatment, and MTC is also relatively resistant to radiotherapy (Giuffrida & Gharib, 1998). Although a few studies have shown some symptomatic and hormonal improvement following treatment with SMS analogues (Mahler et al., 1990), biological or morphological parameters were not significantly improved in a large series of patients treated with octreotide (Modigliani et al., 1992); however, continuous treatment with high-dose octreotide can offer temporary relief in some patients (de Herder et al., 1996). Following reports of a near-complete remission of MTC after treatment with α-interferon, the combination of short and long acting SMS analogues with α-interferon has not produced any objective tumour response, although there was a 40–80% symptomatic and hormonal response with a major impact on the quality of life (Lupoli et al., 1996; Vitale et al. 2000). There is limited experience using 131I-MIBG in patients with MTC which has shown significant symptomatic and hormonal responses, but only 23% objective tumour responses (no complete response) (Chatal et al. 2000; Mukherjee et al., 2001). Chemotherapy remains the main option for 20% of patients with MTC, with initially aggressive, recurrent or progressive disease (Giuffrida & Gharib, 1998). Because of the relative rarity of MTC, there are few prospective reports on the efficacy of chemotherapy for metastatic disease, most of which have produced partial responses (Wu et al., 1994). The most effective agent is doxorubicin, which has partial response rates of up to 30% either alone or in various combinations (Shimaoka et al., 1985; Peturson, 1988; Wu et al., 1994). The combination of doxorubicin and cisplatin produced a partial response in a few patients with MTC (Sridhar et al., 1985). There are isolated reports of complete responses to 5-FU and dacarbazine (Peturson et al., 1988), although the application of this scheme to a larger group of patients was associated with only partial and short-lasting responses or disease stabilization (Orlandi et al., 1994); one partial response to doxorubicin, cisplatin and vindesine has also been described (Di Bartolomeo et al., 1995). Responses have been less impressive in other small series using combination chemotherapy with agents including cisplatinum, methotrexate, cyclophosphamide and dacarbazine (Marsh et al., 1995). Combination chemotherapy with cyclophosphamide, dacarbazine and vincristine has been employed as resistance to the first two agents is not mediated by the overexpression of the MDR-1 or Bcl2 antiapoptotic gene, leading to approximately 40% partial objective responses but with fewer adverse effects (Wu et al., 1994). Chemotherapeutic agents have also been used to enhance the tumoricidal effect of ionizing radiation (Giuffrida & Gharib, 1998). Although these agents appear to have moderate activity, it is difficult to reach firm conclusions regarding their efficacy as most series included only limited number of patients (Marsh et al., 1995; Heshmati et al., 1997). Recently, percutaneous ethanol injection to thyroid lesions and/or metastases has been shown to produce valuable responses and can be used as an alternative approach in patients with refractory disease (Isozaki et al., 1999). Another alternative which is still undergoing phase II trials is the administration of radiolabelled antianticarcinoembryonic antigen (CEA) monoclonal antibody (Juweid et al., 1999). Pituitary tumours are mainly benign but can occasionally become highly aggressive, infiltrating adjacent tissues and recurring repeatedly despite conventional treatment (Kaltsas & Grossman, 1998). Malignant pituitary tumours are diagnosed on the presence of central nervous system (CNS) extension not contiguous to the pituitary fossa or other extracranial systemic metastases; using such criteria as the prevalence of pituitary carcinomas in around 0·1–0·2% of all pituitary tumours (Kaltsas & Grossman, 1998). Although the combination of surgery and radiotherapy is usually effective in controlling pituitary tumours, adjuvant therapy is needed for highly aggressive and malignant tumours (Kaltsas et al., 1998a). Medical therapy with dopamine and SMS analogues has rarely been shown to be effective, being limited to controlling symptoms and hormonal secretion in the short term (Kaltsas & Grossman, 1998); although some pituitary tumours express somatostatin receptors, currently there are no data on the use of 90Y-octreotide. In an attempt to achieve control, chemotherapy has been used but experience is limited to case reports mainly due to the rarity of the disease (Kaltsas & Grossman, 1998). Experience using lomustine (approximately equivalent to streptozotocin) and 5-FU in seven patients was associated with only a 14% objective tumour response; while clinically useful, symptomatic and hormonal responses were noted they were mostly short-lasting (Kaltsas et al., 1998b). In general, patients with malignant pituitary tumours have a poor prognosis, with the majority dying within 6 months; patients with CNS metastases have a better prognosis compared to patients with systemic metastases, and may constitute a group for early chemotherapeutic intervention (Kaltsas et al., 1998a). Successful treatment of neuroendocrine tumours requires a multimodal approach. Radical tumour surgery is a prerequisite as it is the only available curative approach; recently, the surgical approach has been more aggressive including wide resections of metastases, together with enucleation of liver metastases and/or hepatic artery ligation or embolization with adjuvant chemotherapy. If surgical intervention is not possible, biotherapy with somatostatin analogues or α-interferon, alone or in combination should be considered, although our own experience with α-interferon has not shown it to be particularly effective. Treatment with 131I-MIBG is reserved for patients with substantial uptake on 123I-MIBG scanning, while experience with 90Y-octreotide is still limited; treatment with 131I-MIBG is associated with good symptomatic and hormonal improvement, although objective tumour responses are limited and occasionally short-lasting. It remains to be seen whether treatment with α-emitting radiolabelled somatostatin analogues, which should be applicable to the majority of NET, will be more effective. In patients with no uptake to radionuclides and/or progressive disease besides other forms of treatment, chemotherapy should be initiated alone or in conjunction with biotherapy, although such an approach has not been fully investigated and deserves further assessment in controlled clinical trials. Chemotherapy with an alkylating agent and streptozotocin has an established role in the treatment of advanced well-differentiated islet cell carcinoma: anaplastic neuroendocrine tumours, which constitute a separate disease entity with patterns of clinical growth and chemosensitivity more similar to small cell lung carcinoma, responds best to the combination of etoposide and cisplatinum. For patients with metastatic well-differentiated carcinoid tumours, where response rates are lower, a chemotherapeutic trial should be considered in the context of collaborative clinical trials. However, our present policy is to use the combination of lomustine (which is functionally related to streptozotocin) and 5-FU for both islet cell and carcinoid tumours of low grade. Due to their resemblance to neuroblastomas, chromaffin cell tumours have been treated with the combination of cyclophosphamide, vincristine and dacarbazine with useful although usually short-lasting results. Pituitary carcinomas constitute a rare and relatively chemoresistant group of tumours with poor overall prognosis. The efficacy of current chemotherapy programs in medullary thyroid carcinoma is not well established, although doxorubicin appears to be specifically efficacious. In order to improve future treatment and achieve more cures, tumour biology has to be defined in every tumour and treatment should be customised accordingly. Maintaining the quality of life should be sought, and the expected efficacy of treatment should be weighed against possible adverse effects.