- Email: [email protected]
Is the new WHO classification of neuroendocrine tumours useful for selecting an appropriate treatment?
Original article
Annals of Oncology 16: 1374– 1380, 2005 doi:10.1093/annonc/mdi258 Published online 6 June 2005
Is the new WHO classification of neuroendocrine tumours useful for selecting an appropriate treatment? E. Bajetta1*, L. Catena1, G. Procopio1, E. Bichisao2, L. Ferrari3, S. Della Torre1, S. De Dosso1, S. Iacobelli4, R. Buzzoni1, L. Mariani5 & J. Rosai6 1
Medical Oncology Unit 2, 2ITMO Group, 3Nuclear Medicine, 5Department of Statistics, 6Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan; 4Universita` degli Studi ‘G. D’Annunzio’, Chieti, Italy
Received 13 December 2004; revised 18 April 2005; accepted 19 April 2005
Introduction Neuroendocrine tumours (NETs) derive from the neuroendocrine cell system, which is widely distributed in the body, and are a rare and heterogeneous group of neoplasms characterized by embryological, biological and histopathological differences [1–3]. The most frequent sites of NETs are the gastrointestinal
*Correspondence to: Prof. E. Bajetta, Division of Medical Oncology 2, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133 Milano. Tel: + 39-0223-902500; Fax: + 39-0223-902149; E-mail: [email protected] q 2005 European Society for Medical Oncology
tract (70%) and the broncopulmonary system (25%); the distribution of tumours inside the gastrointestinal tract involves the small bowel (28%), appendix (19%) and rectum (13%) [4]. The broad heterogeneity characterizing NETs has always posed problems regarding their correct classification. A distinction between foregut, midgut and hindgut tumours was used to describe carcinoids originating from anterior, medium and posterior bowel, respectively. Subsequently, another functional subclassification related to either the presence or the absence of a syndrome caused by hypersecretion of humoral factors by the NET cells, was proposed (biologically active or inactive NETs).
Downloaded from http://annonc.oxfordjournals.org/ at University of Wisconsin-Oshkosh on June 8, 2015
Background: Neuroendocrine tumours (NETs) are a rare and heterogeneous group of neoplasms. The most recent WHO classification provides clinical tools and indications to make the diagnosis and to suggest the correct treatment in different subgroups of patients. The aim of this trial was to apply the new classification criteria in clinical practice and, accordingly, to choose the most appropriate treatment. Patients and methods: Thirty-one evaluable patients, not previously treated, classified as advanced well differentiated NETs according to the new classification, were given long-acting release octreotide 30 mg every 28 days until evidence of disease progression. The treatment activity was evaluated according to objective, biochemical and symptomatic responses. Safety and tolerability were also assessed. Results: Two partial objective tumour responses were obtained (6%), stabilization occurred in 16 _ 6 months. However, eight patients (52%) and 95% of patients had a disease stabilisation lasting > patients showed rapid disease progression within 6 months of therapy and six patients after 6 months. Biochemical responses, evaluated by changes in serum chromogranine A levels were reported in 20/24 patients (83%). Symptomatic responses were observed in 6/14 patients (43%): a complete syndrome remission in one patient, partial syndrome remission in five patients, no change in four patients and progressive disease in four patients. The median overall survival was not reached, and the median time to disease progression was 18 months (range 1 – 49 months). The treatment was well tolerated, no severe adverse events were observed and no patient withdrew from the study because of adverse events. Conclusions: The WHO classification enables identification of low-grade NET patients who may be suitable for hormonal treatment. Octreotide LAR was seen to be effective in controlling the disease and was well tolerated. However, eight patients failed to respond to the treatment, despite histological evidence of a well differentiated tumour according to the new classification. This suggests that further histological examination should be carried out, especially in patients with visceral metastases and a short disease-free interval. Key words: hormonal treatment, low-grade neuroendocrine tumours, WHO classification
1375 be related to the reduction of tumour growth factors, such as insulin-like growth factor (IGF-I) and epidermal growth factor (EGF), and to the reduction of biologically active substances. On average, somatostatin analogues are able to achieve syndrome control and biochemical changes in 70% and 30 –50% of patients, respectively, but they are associated with a very low rate of objective response ( 10%) [17]. The use of long-acting (LAR) formulations of octreotide has provided a significant improvement in patient compliance by changing the schedule from three daily subcutaneous administrations to one intramuscular administration every 28 days [19]. In light of this evidence, we decided to select patients with low-grade NETs, who had never been treated, using the new WHO classification and, for the reasons mentioned above, to treat them with a somatostatin analogues, with the aim of evaluating the consistency between diagnosis and response rate.
Patients and methods Patients A total of 31 consecutive patients with metastatic or locally advanced well differentiated NETs, who had not previously been treated, entered the study between May 2000 and October 2002. The trial involved two centres and was co-ordinated by the Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. Patient characteristics are summarised in Table 1. The histological diagnosis of well differentiated NET was assessed in 30 patients using the new WHO criteria [5]; a diagnosis of medullary thyroid carcinoma (MTC) was obtained in only one patient. We treated this patient with somatostatin analogues because his clinical condition precluded the use of chemotherapy. Six patients presented with lung primary tumour and three of them had atypical carcinoid. The decision to include these patients in this study was based on the absence of a standard firstline treatment for these neoplasms. Only 12 patients received surgical intervention on the primary tumour; the other 19 patients presented with an inoperable tumours at diagnosis. The following variables were recorded for each patient before starting treatment: sex, age, performance status (<2 ECOG), disease-free interval (DFI), number of metastatic sites, Octreoscanw uptake, bone radiographs, presence or absence of carcinoid syndrome and serum chromogranin A (CgA) and calcitonin (Ct) levels. The study was approved by the local institutional ethical committee. The patients gave their informed written consent before starting the trial.
Somatostatin analogue treatment Treatment consisted of injection of LAR octreotide 30 mg intramuscularly (i.m.) every 28 days until disease progression or toxicity. The treatment schedule was as follows: before starting LAR octreotide, induction therapy with octreotide 0.1 mg s.c. every 8 h for 14 days was performed. At the end of this 14-day period, LAR octreotide was administered and octreotide 0.1 mg s.c. every 8 h was maintained for a further 14 days.
Evaluation of responses The objective, symptomatic and biochemical responses were separately evaluated as previously described by the Italian Trial in Medical Oncology (ITMO] [10]. The first assessment of response was carried out after 3 months of treatment by evaluating the size of the tumour lesions, the presence of syndrome, and the values of tumour markers. The responses were
Downloaded from http://annonc.oxfordjournals.org/ at University of Wisconsin-Oshkosh on June 8, 2015
Recently, a new classification of NETs has been proposed and adopted by the World Health Organization (WHO) [5]. In order to explain the natural history of NETs more adequately, this classification is based on a series of histopathological and biological characteristics: cellular grading, primary tumour size and site, cell proliferation markers, local or vascular invasivity, and the production of biologically active substances. The main categories of tumour are classified as follows: well differentiated endocrine tumours characterised by a low grade of malignancy and well differentiated endocrine carcinomas which are more aggressive because of the presence of metastases; poorly differentiated endocrine carcinomas with a high grade of malignancy and a poor prognosis; mixed exocrine – endocrine tumours. This classification enables neuroendocrine tumours in the gastroenteropancreatic tract to be diagnosed easily, but unfortunately it is not applicable to lung tumours. The classification of lung tumours is currently based on that of Travis et al. [6] who recognised the following categories: typical carcinoid, atypical carcinoid, small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNC). Typical carcinoids have a clinical behaviour similar to that of well differentiated neuroendocrine tumours; SCLC and LCNC are poorly differentiated neuroendocrine carcinomas. Atypical carcinoids are found to be more aggressive than typical carcinoids but less aggressive than small-cell carcinoma (poorly differentiated NETs). Furthermore, a few moderately differentiated tumours with cellular and structural types intermediate between well and poorly differentiated NETs have also been found among gastroenteropancreatic NETs. This observation supports the comments in the introduction to the second edition of the Histological Typing of Endocrine Tumours by Solcia et al. [5] that this was not sufficient to warrant a separate category at these sites or in the general classification of endocrine tumours. However, the new WHO classification provides important clinical features which aid in formulating a diagnosis and a prognosis and, consequently, in suggesting suitable therapeutic programmes for NETs. The poorly differentiated tumours together with SCLC and LCNC have a high proliferation index and can be treated with chemotherapy, although there is not yet a standard combination regimen. Cisplatin plus etoposide and streptozotocin in combination with 5-fluorouracil and doxorubicin are frequently employed [7, 8]. Recently a new combination chemotherapy with doxorubicin, 5-fluorouracil and dacarbazine has demonstrated its activity in the treatment of NETs [9]. In patients with well differentiated neuroendocrine tumours or typical carcinoids, which show a low proliferation index, biotherapy (somatostatin analogues and interferon-a) is the treatment of choice, because of the intense biological activity of these tumours correlated with carcinoid syndrome [10–12]. Somatostatin analogues (octreotide and lanreotide), which bind the somatostatin receptors expressed on neuroendocrine tumour cells, are considered the first-line treatment in low-grade NETs [13–18], although the correlation between somatostin receptor expression and clinical response is still uncertain. The antitumour activity of these agents is likely to
1376 Table 1. Patient characteristics
Table 2. Characteristics of eight patients with disease progression after 3–6 months of treatment
Total patients
31
Median age Gender
57 (28–86) yr
Male Female
23 (74%) 8 (26%)
Performance status (ECOG)1
No. of patients
8/31 (25%)
Median age (range)
58 (28–66) years
Male/female
8/0
Performance status 0
6
1
2
0
27 (87%)
1
4 (13%)
Previous surgery
2
12
Median time between surgery and relapse
2.2 months
6 (2–36) months
Site of primary
Previous surgery Median time between surgery and relapse Site of primary Pancreas Small bowel
4
11 (35%)
Pancreas
1
6 (25%)
Thyroid Unknown
1 2
Lung
6 (20%)
Unknown
5 (17%)
Thyroid
1
Metastases and number of sites
Site of metastases 1 site > _ 2 sites Local advanced disease Metastatic disease
13 (47%) 16 (53%) 2 29 (93%)
Pathological levels of markers CgA Calcitonin
1
Carcinoid syndrome 14 (45%) 17 (55%)
Diarrhoea
11 (79%)
3
Liver and peritoneum
1
Liver and mesentery
1
Liver and bone
1
Liver, lung and bone
1
Liver, lung, pancreas and bone Pathological levels of markers
23 (74%)
Present Absent
Liver only
1
CgA
5
5-HIAA
1
NSE
1
Calcitonin
1
MIB-1a Pt 5
18%
11
Pt 9 Pt 15
Abdominal pain
4 (29%)
Pt 19
3%
Other
11
Pt 29
10%
Flushing
6 (43%)
Cardiac syndrome
2% 2%
Octreoscanw assessed every 3 months thereafter. The change in tumour size was calculated according to the WHO criteria [16]. The symptoms were monitored monthly in the first 3 months of treatment, and then every 3 months until the end of the study. The biochemical response was assessed by measuring serum CgA levels because this biomarker is the most useful indicator for NET monitoring [20–22]. The evaluation of serum Ct levels was also performed for the patient with diagnosis of MTC.
Specimen collection and analytical methods Peripheral blood was collected by venipuncture on the day of octreotide administration and before the drug injection. Plasma and serum separation was achieved by centrifugation (1500 g for 15 min) at room temperature. Finally, the supernatants were divided into aliquots and stored at 608C until the day of the assay. Ct was measured in serum samples by means of immunoradiometric assays purchased from CIS Bio International (Gif sur Yvette Cedex, France), RADIM (Pomezia, Italy), Scantibodies Laboratory Inc (Santee, USA) and Immunotech (Prague, Czech Republic). CgA was determined by an enzyme-linked immunosorbent assay (ELISA) supplied by DAKO A/S (Glostrup, Denmark). All the assessments were performed in duplicate and the tested samples were appropriately diluted if necessary.
Positive
4
Negative
2
Unknown
2
a
Could not be assessed in three patients.
Statistical analysis This was an open non-comparative clinical study in which no null hypothesis was being tested. The major endpoint was to evaluate the consistency between the diagnosis of low-grade NETs and the response rate in patients suitable for hormonal treatment. No formal statistical analysis was planned. Clinical, laboratory and subjective data were reported as mean ( ± standard deviation), median, range or percentage as appropriate. Confidence intervals (95%) were also calculated. Survival and time to progression (TTP) curves were calculated using the Kaplan–Meier method.
Results All of the 31 patients were considered to be evaluable for response and toxicity.
Downloaded from http://annonc.oxfordjournals.org/ at University of Wisconsin-Oshkosh on June 8, 2015
Lung
1377
Confirmation of diagnosis At the end of the study in 2002, we observed that disease had rapidly progressed in eight patients although the results of their histological examination indicated a well differentiated NET. The reasons for this failure in antitumour response were investigated and we concluded that further examination (e.g. proliferative index) would be necessary in order to confirm the histological diagnosis. On the basis of these conclusions, we decided to re-evaluate the histological samples from these patients in an attempt to identify variables of prognostic value. The histological re-examination of all samples was performed by a single pathologist, and the details are reported in the relevant sections.
No complete responses occurred; two partial responses (6%) were observed and disease stabilisation occurred in 16 patients _6 (52%). In 95% of patients disease stabilisation lasted for > months. Thirteen patients (42%) showed a disease progression: eight patients (26%) had an early progression before 3–6 months of treatment, and six patients (19%) progressed after 9 months of treatment. Surgery was carried out in only two of these patients; in the remaining cases the disease was metastatic at diagnosis. It is worth noting that DFI (from surgery to disease relapse) was 2.2 months in the patients who experienced an early progression compared with 6.0 months for all the patients studied. Table 2 summarises the characteristics of the eight patients with disease progression within 6 months. The pattern of clinical responses is in agreement with that observed in other trials [20, 21, 23], because eight patients (26%) were withdrawn from the treatment with LAR octreotide after only three to six administration (two patients after two administrations) because of rapid disease progression. After this treatment failure, these patients were treated with chemotherapy and they experienced prolonged disease control. The histological analyses carried out after the study (Tables 2 and 3) failed to identify any reason for the failure of
Biochemical response Serum CgA levels were evaluable in 24 patients, with an _ 34 U/l. At baseline, increased serum CgA upper normal limit < levels were observed in 23/24 patients (96%), and after 3 months of treatment there was a decrease (>50% compared with the baseline value) in 11/24 patients (46%). These patients showed the following clinical response: two complete responses (18%), three partial responses (27%), four no change (36%) and two disease progressions (19%). Serum CgA levels were assessable in only three patients with rapid disease progression, and dramatically increased compared with baseline values which were already out of normal range. In the patient with diagnosis of medullary thyroid carcinoma, calcitonin was above the normal limit at baseline. The patient experienced an early progressive disease and the new value of the marker was not assessable.
Subjective response The effects of LAR octreotide were evaluated in 14 patients (46%) with carcinoid syndromes. The syndrome disappeared completely in one patient, while a reduction of intensity or frequency of episodes (diarrhoea and flushing) occurred in five patients (35%). In four patients (28%) the symptoms did not change. Five patients experienced symptom progression. Three patients with early disease progression had carcinoid syndrome, but the reduction of symptoms was significant in only one patient.
Overall survival and time to progression The study was closed on 1 January 2003. The median overall survival was not reached and the median TTP was 18 months
Table 3. Characteristics of eight patients with disease progression according to MIB-1, octreoscan and markers Patient no.
Sex
Primary site of disease
Sites of metastases
MIB-1 index
Octreoscanw
Markers
1
M
Unknown
Liver, peritoneum
18%
+
No
2
M
Lung
Liver
2%
ND
CgA
3
M
Unknown
Liver, peritoneum
2%
+
CgA
4
M
Pancreas
Liver
3%
ND
CgA
5
M
Lung
Liver
No
+
CgA
6
M
Thyroid
Liver, bone
ND
+
Calcitonin
7
M
Lung
Lung, liver, pancreas, bone
ND
ND
NSE
8
M
Lung
Lung, liver, bone
10%
+
CgA
ND, not determined.
Downloaded from http://annonc.oxfordjournals.org/ at University of Wisconsin-Oshkosh on June 8, 2015
Tumour response
the hormonal treatment. However, it is worth noting that in these patients the disease progression always occurred in liver with the involvement of other sites. The marker levels were pathological in all the patients; however, MIB-1 (assessable in six patients) was very high in only two patients, who had metastases in liver and peritoneum and in liver, lung and bone, respectively.
1378
(range 1 –49 months). The OS and TTP curves are shown in Figures 1 and 2, respectively.
Tolerability Diarrhoea (7%), steatorrhoea (17%) and abdominal pain (7%) were the most frequent grade 1–2 adverse effects recorded. No adverse NCI-CTC grade 4 events were recorded, and no patient was withdrawn from the study because of adverse effects.
Discussion The carcinoid tumours were described more than 100 years ago and considered to show indolent behaviour compared with typical adenocarcinomas [24]. It is well known that the
Figure 2. Time to progression.
clinical diagnosis of NETs is uncertain, difficult and often occasional, resulting in NETs generally being considered as tumours of low incidence. The difficulty in identifying patients with NETs is compounded by the problem of NET classification and, as consequence, it is difficult to select the appropriate therapeutic approach. Capella et al. [25] published a revised classification suggesting replacement of the term ‘carcinoid tumours’ by the term ‘neuroendocrine tumours’ to include all neuroendocrine tumours. This classification was updated by Solcia and colleagues and adopted by the WHO [5], who suggested the following categories: (1) well differentiated endocrine tumours characterised by a low grade of malignancy and well differentiated endocrine carcinomas which are more aggressive because of the presence of metastases; (2) poorly differentiated endocrine carcinomas; (3) mixed exocrine –endocrine
Downloaded from http://annonc.oxfordjournals.org/ at University of Wisconsin-Oshkosh on June 8, 2015
Figure 1. Overall survival.
1379 although the clinical and prognostic impact of each of these variables remains to be established. We have in progress a clinical study that takes into account these suggestions, and further clinical trials are warranted.
Acknowledgements The authors would like to thank the Italian Trials in Medical Oncology (ITMO) group for technical assistance. We would also like to thank Mrs Barbara Formisano for her assistance with data management.
References 1. Pearse AGE. The diffuse neuroendocrine system and the APUD concept: related ‘endocrine’ peptides in brain, intestine, pituitary, placenta and human cutaneous glands. Med Biol 1977; 55: 115–125. 2. Fontaine J, Le Douarin NM. Analysis of endoderm formation in the avian blastoderm by use of qual-chick chimeras. Fed Proc 1979; 38: 2289–2294. 3. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumours. Cancer 1997; 79: 813–829. 4. Pearse AGE. Genesis of neuroendocrine system. In Frisen SR, Thompson NW (eds): Surgical Endocrinology. Philadelphia, PA: Lippincott 1990; 25–35. 5. Solcia E, Kloppel G, Sobin LH et al. Histologic typing of endocrine tumours. WHO International Histological Classification of Tumours. Heidelberg: Springer Verlag 2000. 6. Travis WD, Colby TV, Corrin B et al. Histological typing of lung and pleural tumours. WHO International Histological Classification of Tumours. Heidelberg: Springer Verlag 1999. 7. Rivera E, Ajani JA. Doxorubicin, streptozotocin, and 5-fluorouracil chemotherapy for patients with metastatic islet-cell carcinoma. Am J Clin Oncol 1998; 21: 36–38. 8. Ridolfi R, Amaducci L, Derni S et al. Chemotherapy with 5-fluorouracil and streptozocin in carcinoid tumors of gastrointestinal origin: experiences with 13 patients. J Chemother 1991; 3: 328–331. 9. Bajetta E, Ferrari L, Procopio G et al. Efficacy of chemotherapy combinations for the treatment of metastatic neuroendocrine tumours. Ann Oncol 2002; 13: 614–621. 10. Bajetta E, Zilembo N, Di Bartolomeo M et al. Treatment of metastatic carcinoid and other neuroendocrine tumours with recombinant interferon alpha-2a. Cancer 1993; 72: 3099– 3100. 11. Oberg K. Interferon in the managment of neuroendocrine GEP tumours. Digestion 2000; 62 (Suppl 1): 92–97. 12. Frank M, Klose KJ, Wied M et al. Combination therapy with octreotide and alfa-interferon: effect on tumour growth in metastatic endocrine gastroenteropancreatic tumours. Gastroenterology 1999; 94: 155–159. 13. Iman H, Eriksson B, Lukinius A et al. Induction of apoptosis in neuroendocrine tumours of the digestive system during treatment with somatostatin analogues. Acta Oncol 1997; 36: 607–614. 14. Oberg K, Norheim I, Theodorsson E. Treatment of malignant midgut carcinoid tumours with a long-acting somatostatin analogue octreotide. Acta Oncol 1991; 30: 503–507. 15. Wymenga AN, Eriksson B, Salmela PI et al. Efficacy and safety of prolonged-release lanreotide in patients with gastrointestinal neuroendocrine tumors and hormone-release symptoms. J Clin Oncol 1999; 17: 1111–1117. 16. Ruszniewski P, Ducreux M, Chayvialle JA et al. Treatment of the carcinoid syndrome with the long-acting somatostatin analogue
Downloaded from http://annonc.oxfordjournals.org/ at University of Wisconsin-Oshkosh on June 8, 2015
tumours. The main difference between poorly differentiated and well differentiated endocrine carcinoma is evaluated by means of histological preparations, and in general it is reasonable to treat the former by chemotherapy and the latter by hormone therapy. In agreement with these recommendations, the current trial was carried out on 31 evaluable patients showing histologically well differentiated NETs with a metastatic disease. All of these patients were treatment naive, a factor which accounts for the low number of recruited subjects. However, there was no bias due to any previous interference with tumour responses by pharmacological treatment. Despite the confirmed presence of a low aggressive tumour, disease progressed rapidly in eight patients although they received the appropriate therapy. In order to explain these results we re-evaluated their histological samples, but unfortunately these tests were unable to suggest or discriminate any predictive value for expected clinical response and prognosis, because no correlation was found between MIB-1, mitotic count, grading, presence of necrosis and vascular and/or lymphatic invasion. These patients showed the clinical picture of the tumour with similar characteristics, because all of them had liver metastases and about 50% suffered from a primary lung tumour: thus a primary neoplasm of the lung and the presence of extensive liver metastatic disease could explain the poor response to therapy. The difference in DFI between nonresponders and responders to the treatment is interesting (2.2 months compared with 6.0 months). However, this evidence was obtained from a small number of patients (two compared with 12 patients). Thus our experience suggests that, while the new classification is a useful tool for a preliminary selection of patients, it has limitations. These data seem to be consistent with the observations of Travis et al. [6] about atypical NETs which can be identified as either well differentiated NETs or poorly differentiated NETs and, interestingly, not only for lung but also for gastroenteropancreatic tract tumours. We would like to highlight the observation that responding patients, i.e those with an appropriate diagnosis, showed prolonged overall survival. This result is consistent with the study by Quaedvlieg et al. [26] who showed an improved survival in patients with metastatic disease diagnosed after 1992, probably because of the use of somatostatin analogues. In our series the median survival time was not reached, whereas it was 43 months in unselected patients at any stage of disease and receiving treatment. Thus the combination of additional examinations could improve the quality of the diagnosis, serving the ultimate purpose of treating patients appropriately. In conclusion we believe that it is feasible to use the new WHO criteria to evaluate the characteristics of the tumour and the prognosis and, considering them jointly with the clinical and biological features of the tumour, to prescribe appropriate treatment. In our experience important characteristics to be taken into account could be the site of the primary tumour, liver involvement, high MIB-1 levels and a long DFI,
1380
17.
18.
19.
20.
22.
23.
24. 25.
26.
acid evaluation in patients with neuroendocrine tumors. Cancer 1999; 86: 858–865. Ferrari L, Seregni E, Bajetta E et al. The biological characteristics of chromogranin A and its role as a circulating marker in neuroendocrine tumours. Anticancer Res 1999; 19: 3415–3428. Seregni E, Ferrari L, Bajetta E et al. Clinical significance of blood chromogranin A measurement in neuroendocrine tumours. Ann Oncol 2001; 12 (Suppl 2): S69–S72. Oberndorfer S. Karzinoide tumoren des dunndarms. Frankf Zschr Pathol 1907; 1: 426–430. Capella C, Heitz PU, Hofler H et al. Revised classification of neuroendocrine tumours of the lung, pancreas and gut. Virchows Archiv 1995; 425: 547–560. Quaedvlieg PFHJ, Visser O, Lamers CBHW et al. Epidemiology and survival in patients with carcinoid disease in the Netherlands. An epidemiological study with 2391 patients. Ann Oncol 2001; 12: 1295–1300.
Downloaded from http://annonc.oxfordjournals.org/ at University of Wisconsin-Oshkosh on June 8, 2015
21.
lanreotide: a prospective study in 39 patients. Gut 1996; 39: 279 –283. Di Bartolomeo M, Bajetta E, Buzzoni R et al. Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors. A study by the Italian Trials in Medical Oncology Group. Cancer 1996; 77: 402– 408. Eriksson B, Renstrup J, Imam H et al. High-dose treatment with lanreotide of patients with advanced neuroendocrine gastrointestinal tumour: clinical and biologic effect. Ann Oncol 1997; 8: 1041–1044. Rubin J, Ajani J, Schirmer W et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol 1999; 17: 600–606. World Health Organization. Handbook for Reporting Results of Cancer Treatment. WHO Offset Publication 48. Geneva: World health Organization 1979. Bajetta E, Ferrari L, Martinetti A et al. Chromogranin A, neuronspecific enolase, carcinoembryonic antigen and hydroxyindoleacetic
Annals of Oncology 16: 1374– 1380, 2005 doi:10.1093/annonc/mdi258 Published online 6 June 2005
Is the new WHO classification of neuroendocrine tumours useful for selecting an appropriate treatment? E. Bajetta1*, L. Catena1, G. Procopio1, E. Bichisao2, L. Ferrari3, S. Della Torre1, S. De Dosso1, S. Iacobelli4, R. Buzzoni1, L. Mariani5 & J. Rosai6 1
Medical Oncology Unit 2, 2ITMO Group, 3Nuclear Medicine, 5Department of Statistics, 6Department of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan; 4Universita` degli Studi ‘G. D’Annunzio’, Chieti, Italy
Received 13 December 2004; revised 18 April 2005; accepted 19 April 2005
Introduction Neuroendocrine tumours (NETs) derive from the neuroendocrine cell system, which is widely distributed in the body, and are a rare and heterogeneous group of neoplasms characterized by embryological, biological and histopathological differences [1–3]. The most frequent sites of NETs are the gastrointestinal
*Correspondence to: Prof. E. Bajetta, Division of Medical Oncology 2, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, 20133 Milano. Tel: + 39-0223-902500; Fax: + 39-0223-902149; E-mail: [email protected] q 2005 European Society for Medical Oncology
tract (70%) and the broncopulmonary system (25%); the distribution of tumours inside the gastrointestinal tract involves the small bowel (28%), appendix (19%) and rectum (13%) [4]. The broad heterogeneity characterizing NETs has always posed problems regarding their correct classification. A distinction between foregut, midgut and hindgut tumours was used to describe carcinoids originating from anterior, medium and posterior bowel, respectively. Subsequently, another functional subclassification related to either the presence or the absence of a syndrome caused by hypersecretion of humoral factors by the NET cells, was proposed (biologically active or inactive NETs).
Downloaded from http://annonc.oxfordjournals.org/ at University of Wisconsin-Oshkosh on June 8, 2015
Background: Neuroendocrine tumours (NETs) are a rare and heterogeneous group of neoplasms. The most recent WHO classification provides clinical tools and indications to make the diagnosis and to suggest the correct treatment in different subgroups of patients. The aim of this trial was to apply the new classification criteria in clinical practice and, accordingly, to choose the most appropriate treatment. Patients and methods: Thirty-one evaluable patients, not previously treated, classified as advanced well differentiated NETs according to the new classification, were given long-acting release octreotide 30 mg every 28 days until evidence of disease progression. The treatment activity was evaluated according to objective, biochemical and symptomatic responses. Safety and tolerability were also assessed. Results: Two partial objective tumour responses were obtained (6%), stabilization occurred in 16 _ 6 months. However, eight patients (52%) and 95% of patients had a disease stabilisation lasting > patients showed rapid disease progression within 6 months of therapy and six patients after 6 months. Biochemical responses, evaluated by changes in serum chromogranine A levels were reported in 20/24 patients (83%). Symptomatic responses were observed in 6/14 patients (43%): a complete syndrome remission in one patient, partial syndrome remission in five patients, no change in four patients and progressive disease in four patients. The median overall survival was not reached, and the median time to disease progression was 18 months (range 1 – 49 months). The treatment was well tolerated, no severe adverse events were observed and no patient withdrew from the study because of adverse events. Conclusions: The WHO classification enables identification of low-grade NET patients who may be suitable for hormonal treatment. Octreotide LAR was seen to be effective in controlling the disease and was well tolerated. However, eight patients failed to respond to the treatment, despite histological evidence of a well differentiated tumour according to the new classification. This suggests that further histological examination should be carried out, especially in patients with visceral metastases and a short disease-free interval. Key words: hormonal treatment, low-grade neuroendocrine tumours, WHO classification
1375 be related to the reduction of tumour growth factors, such as insulin-like growth factor (IGF-I) and epidermal growth factor (EGF), and to the reduction of biologically active substances. On average, somatostatin analogues are able to achieve syndrome control and biochemical changes in 70% and 30 –50% of patients, respectively, but they are associated with a very low rate of objective response ( 10%) [17]. The use of long-acting (LAR) formulations of octreotide has provided a significant improvement in patient compliance by changing the schedule from three daily subcutaneous administrations to one intramuscular administration every 28 days [19]. In light of this evidence, we decided to select patients with low-grade NETs, who had never been treated, using the new WHO classification and, for the reasons mentioned above, to treat them with a somatostatin analogues, with the aim of evaluating the consistency between diagnosis and response rate.
Patients and methods Patients A total of 31 consecutive patients with metastatic or locally advanced well differentiated NETs, who had not previously been treated, entered the study between May 2000 and October 2002. The trial involved two centres and was co-ordinated by the Division of Medical Oncology B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. Patient characteristics are summarised in Table 1. The histological diagnosis of well differentiated NET was assessed in 30 patients using the new WHO criteria [5]; a diagnosis of medullary thyroid carcinoma (MTC) was obtained in only one patient. We treated this patient with somatostatin analogues because his clinical condition precluded the use of chemotherapy. Six patients presented with lung primary tumour and three of them had atypical carcinoid. The decision to include these patients in this study was based on the absence of a standard firstline treatment for these neoplasms. Only 12 patients received surgical intervention on the primary tumour; the other 19 patients presented with an inoperable tumours at diagnosis. The following variables were recorded for each patient before starting treatment: sex, age, performance status (<2 ECOG), disease-free interval (DFI), number of metastatic sites, Octreoscanw uptake, bone radiographs, presence or absence of carcinoid syndrome and serum chromogranin A (CgA) and calcitonin (Ct) levels. The study was approved by the local institutional ethical committee. The patients gave their informed written consent before starting the trial.
Somatostatin analogue treatment Treatment consisted of injection of LAR octreotide 30 mg intramuscularly (i.m.) every 28 days until disease progression or toxicity. The treatment schedule was as follows: before starting LAR octreotide, induction therapy with octreotide 0.1 mg s.c. every 8 h for 14 days was performed. At the end of this 14-day period, LAR octreotide was administered and octreotide 0.1 mg s.c. every 8 h was maintained for a further 14 days.
Evaluation of responses The objective, symptomatic and biochemical responses were separately evaluated as previously described by the Italian Trial in Medical Oncology (ITMO] [10]. The first assessment of response was carried out after 3 months of treatment by evaluating the size of the tumour lesions, the presence of syndrome, and the values of tumour markers. The responses were
Downloaded from http://annonc.oxfordjournals.org/ at University of Wisconsin-Oshkosh on June 8, 2015
Recently, a new classification of NETs has been proposed and adopted by the World Health Organization (WHO) [5]. In order to explain the natural history of NETs more adequately, this classification is based on a series of histopathological and biological characteristics: cellular grading, primary tumour size and site, cell proliferation markers, local or vascular invasivity, and the production of biologically active substances. The main categories of tumour are classified as follows: well differentiated endocrine tumours characterised by a low grade of malignancy and well differentiated endocrine carcinomas which are more aggressive because of the presence of metastases; poorly differentiated endocrine carcinomas with a high grade of malignancy and a poor prognosis; mixed exocrine – endocrine tumours. This classification enables neuroendocrine tumours in the gastroenteropancreatic tract to be diagnosed easily, but unfortunately it is not applicable to lung tumours. The classification of lung tumours is currently based on that of Travis et al. [6] who recognised the following categories: typical carcinoid, atypical carcinoid, small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNC). Typical carcinoids have a clinical behaviour similar to that of well differentiated neuroendocrine tumours; SCLC and LCNC are poorly differentiated neuroendocrine carcinomas. Atypical carcinoids are found to be more aggressive than typical carcinoids but less aggressive than small-cell carcinoma (poorly differentiated NETs). Furthermore, a few moderately differentiated tumours with cellular and structural types intermediate between well and poorly differentiated NETs have also been found among gastroenteropancreatic NETs. This observation supports the comments in the introduction to the second edition of the Histological Typing of Endocrine Tumours by Solcia et al. [5] that this was not sufficient to warrant a separate category at these sites or in the general classification of endocrine tumours. However, the new WHO classification provides important clinical features which aid in formulating a diagnosis and a prognosis and, consequently, in suggesting suitable therapeutic programmes for NETs. The poorly differentiated tumours together with SCLC and LCNC have a high proliferation index and can be treated with chemotherapy, although there is not yet a standard combination regimen. Cisplatin plus etoposide and streptozotocin in combination with 5-fluorouracil and doxorubicin are frequently employed [7, 8]. Recently a new combination chemotherapy with doxorubicin, 5-fluorouracil and dacarbazine has demonstrated its activity in the treatment of NETs [9]. In patients with well differentiated neuroendocrine tumours or typical carcinoids, which show a low proliferation index, biotherapy (somatostatin analogues and interferon-a) is the treatment of choice, because of the intense biological activity of these tumours correlated with carcinoid syndrome [10–12]. Somatostatin analogues (octreotide and lanreotide), which bind the somatostatin receptors expressed on neuroendocrine tumour cells, are considered the first-line treatment in low-grade NETs [13–18], although the correlation between somatostin receptor expression and clinical response is still uncertain. The antitumour activity of these agents is likely to
1376 Table 1. Patient characteristics
Table 2. Characteristics of eight patients with disease progression after 3–6 months of treatment
Total patients
31
Median age Gender
57 (28–86) yr
Male Female
23 (74%) 8 (26%)
Performance status (ECOG)1
No. of patients
8/31 (25%)
Median age (range)
58 (28–66) years
Male/female
8/0
Performance status 0
6
1
2
0
27 (87%)
1
4 (13%)
Previous surgery
2
12
Median time between surgery and relapse
2.2 months
6 (2–36) months
Site of primary
Previous surgery Median time between surgery and relapse Site of primary Pancreas Small bowel
4
11 (35%)
Pancreas
1
6 (25%)
Thyroid Unknown
1 2
Lung
6 (20%)
Unknown
5 (17%)
Thyroid
1
Metastases and number of sites
Site of metastases 1 site > _ 2 sites Local advanced disease Metastatic disease
13 (47%) 16 (53%) 2 29 (93%)
Pathological levels of markers CgA Calcitonin
1
Carcinoid syndrome 14 (45%) 17 (55%)
Diarrhoea
11 (79%)
3
Liver and peritoneum
1
Liver and mesentery
1
Liver and bone
1
Liver, lung and bone
1
Liver, lung, pancreas and bone Pathological levels of markers
23 (74%)
Present Absent
Liver only
1
CgA
5
5-HIAA
1
NSE
1
Calcitonin
1
MIB-1a Pt 5
18%
11
Pt 9 Pt 15
Abdominal pain
4 (29%)
Pt 19
3%
Other
11
Pt 29
10%
Flushing
6 (43%)
Cardiac syndrome
2% 2%
Octreoscanw assessed every 3 months thereafter. The change in tumour size was calculated according to the WHO criteria [16]. The symptoms were monitored monthly in the first 3 months of treatment, and then every 3 months until the end of the study. The biochemical response was assessed by measuring serum CgA levels because this biomarker is the most useful indicator for NET monitoring [20–22]. The evaluation of serum Ct levels was also performed for the patient with diagnosis of MTC.
Specimen collection and analytical methods Peripheral blood was collected by venipuncture on the day of octreotide administration and before the drug injection. Plasma and serum separation was achieved by centrifugation (1500 g for 15 min) at room temperature. Finally, the supernatants were divided into aliquots and stored at 608C until the day of the assay. Ct was measured in serum samples by means of immunoradiometric assays purchased from CIS Bio International (Gif sur Yvette Cedex, France), RADIM (Pomezia, Italy), Scantibodies Laboratory Inc (Santee, USA) and Immunotech (Prague, Czech Republic). CgA was determined by an enzyme-linked immunosorbent assay (ELISA) supplied by DAKO A/S (Glostrup, Denmark). All the assessments were performed in duplicate and the tested samples were appropriately diluted if necessary.
Positive
4
Negative
2
Unknown
2
a
Could not be assessed in three patients.
Statistical analysis This was an open non-comparative clinical study in which no null hypothesis was being tested. The major endpoint was to evaluate the consistency between the diagnosis of low-grade NETs and the response rate in patients suitable for hormonal treatment. No formal statistical analysis was planned. Clinical, laboratory and subjective data were reported as mean ( ± standard deviation), median, range or percentage as appropriate. Confidence intervals (95%) were also calculated. Survival and time to progression (TTP) curves were calculated using the Kaplan–Meier method.
Results All of the 31 patients were considered to be evaluable for response and toxicity.
Downloaded from http://annonc.oxfordjournals.org/ at University of Wisconsin-Oshkosh on June 8, 2015
Lung
1377
Confirmation of diagnosis At the end of the study in 2002, we observed that disease had rapidly progressed in eight patients although the results of their histological examination indicated a well differentiated NET. The reasons for this failure in antitumour response were investigated and we concluded that further examination (e.g. proliferative index) would be necessary in order to confirm the histological diagnosis. On the basis of these conclusions, we decided to re-evaluate the histological samples from these patients in an attempt to identify variables of prognostic value. The histological re-examination of all samples was performed by a single pathologist, and the details are reported in the relevant sections.
No complete responses occurred; two partial responses (6%) were observed and disease stabilisation occurred in 16 patients _6 (52%). In 95% of patients disease stabilisation lasted for > months. Thirteen patients (42%) showed a disease progression: eight patients (26%) had an early progression before 3–6 months of treatment, and six patients (19%) progressed after 9 months of treatment. Surgery was carried out in only two of these patients; in the remaining cases the disease was metastatic at diagnosis. It is worth noting that DFI (from surgery to disease relapse) was 2.2 months in the patients who experienced an early progression compared with 6.0 months for all the patients studied. Table 2 summarises the characteristics of the eight patients with disease progression within 6 months. The pattern of clinical responses is in agreement with that observed in other trials [20, 21, 23], because eight patients (26%) were withdrawn from the treatment with LAR octreotide after only three to six administration (two patients after two administrations) because of rapid disease progression. After this treatment failure, these patients were treated with chemotherapy and they experienced prolonged disease control. The histological analyses carried out after the study (Tables 2 and 3) failed to identify any reason for the failure of
Biochemical response Serum CgA levels were evaluable in 24 patients, with an _ 34 U/l. At baseline, increased serum CgA upper normal limit < levels were observed in 23/24 patients (96%), and after 3 months of treatment there was a decrease (>50% compared with the baseline value) in 11/24 patients (46%). These patients showed the following clinical response: two complete responses (18%), three partial responses (27%), four no change (36%) and two disease progressions (19%). Serum CgA levels were assessable in only three patients with rapid disease progression, and dramatically increased compared with baseline values which were already out of normal range. In the patient with diagnosis of medullary thyroid carcinoma, calcitonin was above the normal limit at baseline. The patient experienced an early progressive disease and the new value of the marker was not assessable.
Subjective response The effects of LAR octreotide were evaluated in 14 patients (46%) with carcinoid syndromes. The syndrome disappeared completely in one patient, while a reduction of intensity or frequency of episodes (diarrhoea and flushing) occurred in five patients (35%). In four patients (28%) the symptoms did not change. Five patients experienced symptom progression. Three patients with early disease progression had carcinoid syndrome, but the reduction of symptoms was significant in only one patient.
Overall survival and time to progression The study was closed on 1 January 2003. The median overall survival was not reached and the median TTP was 18 months
Table 3. Characteristics of eight patients with disease progression according to MIB-1, octreoscan and markers Patient no.
Sex
Primary site of disease
Sites of metastases
MIB-1 index
Octreoscanw
Markers
1
M
Unknown
Liver, peritoneum
18%
+
No
2
M
Lung
Liver
2%
ND
CgA
3
M
Unknown
Liver, peritoneum
2%
+
CgA
4
M
Pancreas
Liver
3%
ND
CgA
5
M
Lung
Liver
No
+
CgA
6
M
Thyroid
Liver, bone
ND
+
Calcitonin
7
M
Lung
Lung, liver, pancreas, bone
ND
ND
NSE
8
M
Lung
Lung, liver, bone
10%
+
CgA
ND, not determined.
Downloaded from http://annonc.oxfordjournals.org/ at University of Wisconsin-Oshkosh on June 8, 2015
Tumour response
the hormonal treatment. However, it is worth noting that in these patients the disease progression always occurred in liver with the involvement of other sites. The marker levels were pathological in all the patients; however, MIB-1 (assessable in six patients) was very high in only two patients, who had metastases in liver and peritoneum and in liver, lung and bone, respectively.
1378
(range 1 –49 months). The OS and TTP curves are shown in Figures 1 and 2, respectively.
Tolerability Diarrhoea (7%), steatorrhoea (17%) and abdominal pain (7%) were the most frequent grade 1–2 adverse effects recorded. No adverse NCI-CTC grade 4 events were recorded, and no patient was withdrawn from the study because of adverse effects.
Discussion The carcinoid tumours were described more than 100 years ago and considered to show indolent behaviour compared with typical adenocarcinomas [24]. It is well known that the
Figure 2. Time to progression.
clinical diagnosis of NETs is uncertain, difficult and often occasional, resulting in NETs generally being considered as tumours of low incidence. The difficulty in identifying patients with NETs is compounded by the problem of NET classification and, as consequence, it is difficult to select the appropriate therapeutic approach. Capella et al. [25] published a revised classification suggesting replacement of the term ‘carcinoid tumours’ by the term ‘neuroendocrine tumours’ to include all neuroendocrine tumours. This classification was updated by Solcia and colleagues and adopted by the WHO [5], who suggested the following categories: (1) well differentiated endocrine tumours characterised by a low grade of malignancy and well differentiated endocrine carcinomas which are more aggressive because of the presence of metastases; (2) poorly differentiated endocrine carcinomas; (3) mixed exocrine –endocrine
Downloaded from http://annonc.oxfordjournals.org/ at University of Wisconsin-Oshkosh on June 8, 2015
Figure 1. Overall survival.
1379 although the clinical and prognostic impact of each of these variables remains to be established. We have in progress a clinical study that takes into account these suggestions, and further clinical trials are warranted.
Acknowledgements The authors would like to thank the Italian Trials in Medical Oncology (ITMO) group for technical assistance. We would also like to thank Mrs Barbara Formisano for her assistance with data management.
References 1. Pearse AGE. The diffuse neuroendocrine system and the APUD concept: related ‘endocrine’ peptides in brain, intestine, pituitary, placenta and human cutaneous glands. Med Biol 1977; 55: 115–125. 2. Fontaine J, Le Douarin NM. Analysis of endoderm formation in the avian blastoderm by use of qual-chick chimeras. Fed Proc 1979; 38: 2289–2294. 3. Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumours. Cancer 1997; 79: 813–829. 4. Pearse AGE. Genesis of neuroendocrine system. In Frisen SR, Thompson NW (eds): Surgical Endocrinology. Philadelphia, PA: Lippincott 1990; 25–35. 5. Solcia E, Kloppel G, Sobin LH et al. Histologic typing of endocrine tumours. WHO International Histological Classification of Tumours. Heidelberg: Springer Verlag 2000. 6. Travis WD, Colby TV, Corrin B et al. Histological typing of lung and pleural tumours. WHO International Histological Classification of Tumours. Heidelberg: Springer Verlag 1999. 7. Rivera E, Ajani JA. Doxorubicin, streptozotocin, and 5-fluorouracil chemotherapy for patients with metastatic islet-cell carcinoma. Am J Clin Oncol 1998; 21: 36–38. 8. Ridolfi R, Amaducci L, Derni S et al. Chemotherapy with 5-fluorouracil and streptozocin in carcinoid tumors of gastrointestinal origin: experiences with 13 patients. J Chemother 1991; 3: 328–331. 9. Bajetta E, Ferrari L, Procopio G et al. Efficacy of chemotherapy combinations for the treatment of metastatic neuroendocrine tumours. Ann Oncol 2002; 13: 614–621. 10. Bajetta E, Zilembo N, Di Bartolomeo M et al. Treatment of metastatic carcinoid and other neuroendocrine tumours with recombinant interferon alpha-2a. Cancer 1993; 72: 3099– 3100. 11. Oberg K. Interferon in the managment of neuroendocrine GEP tumours. Digestion 2000; 62 (Suppl 1): 92–97. 12. Frank M, Klose KJ, Wied M et al. Combination therapy with octreotide and alfa-interferon: effect on tumour growth in metastatic endocrine gastroenteropancreatic tumours. Gastroenterology 1999; 94: 155–159. 13. Iman H, Eriksson B, Lukinius A et al. Induction of apoptosis in neuroendocrine tumours of the digestive system during treatment with somatostatin analogues. Acta Oncol 1997; 36: 607–614. 14. Oberg K, Norheim I, Theodorsson E. Treatment of malignant midgut carcinoid tumours with a long-acting somatostatin analogue octreotide. Acta Oncol 1991; 30: 503–507. 15. Wymenga AN, Eriksson B, Salmela PI et al. Efficacy and safety of prolonged-release lanreotide in patients with gastrointestinal neuroendocrine tumors and hormone-release symptoms. J Clin Oncol 1999; 17: 1111–1117. 16. Ruszniewski P, Ducreux M, Chayvialle JA et al. Treatment of the carcinoid syndrome with the long-acting somatostatin analogue
Downloaded from http://annonc.oxfordjournals.org/ at University of Wisconsin-Oshkosh on June 8, 2015
tumours. The main difference between poorly differentiated and well differentiated endocrine carcinoma is evaluated by means of histological preparations, and in general it is reasonable to treat the former by chemotherapy and the latter by hormone therapy. In agreement with these recommendations, the current trial was carried out on 31 evaluable patients showing histologically well differentiated NETs with a metastatic disease. All of these patients were treatment naive, a factor which accounts for the low number of recruited subjects. However, there was no bias due to any previous interference with tumour responses by pharmacological treatment. Despite the confirmed presence of a low aggressive tumour, disease progressed rapidly in eight patients although they received the appropriate therapy. In order to explain these results we re-evaluated their histological samples, but unfortunately these tests were unable to suggest or discriminate any predictive value for expected clinical response and prognosis, because no correlation was found between MIB-1, mitotic count, grading, presence of necrosis and vascular and/or lymphatic invasion. These patients showed the clinical picture of the tumour with similar characteristics, because all of them had liver metastases and about 50% suffered from a primary lung tumour: thus a primary neoplasm of the lung and the presence of extensive liver metastatic disease could explain the poor response to therapy. The difference in DFI between nonresponders and responders to the treatment is interesting (2.2 months compared with 6.0 months). However, this evidence was obtained from a small number of patients (two compared with 12 patients). Thus our experience suggests that, while the new classification is a useful tool for a preliminary selection of patients, it has limitations. These data seem to be consistent with the observations of Travis et al. [6] about atypical NETs which can be identified as either well differentiated NETs or poorly differentiated NETs and, interestingly, not only for lung but also for gastroenteropancreatic tract tumours. We would like to highlight the observation that responding patients, i.e those with an appropriate diagnosis, showed prolonged overall survival. This result is consistent with the study by Quaedvlieg et al. [26] who showed an improved survival in patients with metastatic disease diagnosed after 1992, probably because of the use of somatostatin analogues. In our series the median survival time was not reached, whereas it was 43 months in unselected patients at any stage of disease and receiving treatment. Thus the combination of additional examinations could improve the quality of the diagnosis, serving the ultimate purpose of treating patients appropriately. In conclusion we believe that it is feasible to use the new WHO criteria to evaluate the characteristics of the tumour and the prognosis and, considering them jointly with the clinical and biological features of the tumour, to prescribe appropriate treatment. In our experience important characteristics to be taken into account could be the site of the primary tumour, liver involvement, high MIB-1 levels and a long DFI,
1380
17.
18.
19.
20.
22.
23.
24. 25.
26.
acid evaluation in patients with neuroendocrine tumors. Cancer 1999; 86: 858–865. Ferrari L, Seregni E, Bajetta E et al. The biological characteristics of chromogranin A and its role as a circulating marker in neuroendocrine tumours. Anticancer Res 1999; 19: 3415–3428. Seregni E, Ferrari L, Bajetta E et al. Clinical significance of blood chromogranin A measurement in neuroendocrine tumours. Ann Oncol 2001; 12 (Suppl 2): S69–S72. Oberndorfer S. Karzinoide tumoren des dunndarms. Frankf Zschr Pathol 1907; 1: 426–430. Capella C, Heitz PU, Hofler H et al. Revised classification of neuroendocrine tumours of the lung, pancreas and gut. Virchows Archiv 1995; 425: 547–560. Quaedvlieg PFHJ, Visser O, Lamers CBHW et al. Epidemiology and survival in patients with carcinoid disease in the Netherlands. An epidemiological study with 2391 patients. Ann Oncol 2001; 12: 1295–1300.
Downloaded from http://annonc.oxfordjournals.org/ at University of Wisconsin-Oshkosh on June 8, 2015
21.
lanreotide: a prospective study in 39 patients. Gut 1996; 39: 279 –283. Di Bartolomeo M, Bajetta E, Buzzoni R et al. Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors. A study by the Italian Trials in Medical Oncology Group. Cancer 1996; 77: 402– 408. Eriksson B, Renstrup J, Imam H et al. High-dose treatment with lanreotide of patients with advanced neuroendocrine gastrointestinal tumour: clinical and biologic effect. Ann Oncol 1997; 8: 1041–1044. Rubin J, Ajani J, Schirmer W et al. Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome. J Clin Oncol 1999; 17: 600–606. World Health Organization. Handbook for Reporting Results of Cancer Treatment. WHO Offset Publication 48. Geneva: World health Organization 1979. Bajetta E, Ferrari L, Martinetti A et al. Chromogranin A, neuronspecific enolase, carcinoembryonic antigen and hydroxyindoleacetic