Annals of Oncology Advance Access originally published online on December 19, 2005
Annals of Oncology 2006 17(3):461-466; doi:10.1093/annonc/mdj113
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© 2005 European Society for Medical Oncology
Long-term clinical outcome of somatostatin analogues for treatment of progressive, metastatic, well-differentiated entero-pancreatic endocrine carcinoma
1 Department of Digestive and Liver Disease; 2 Department of Radiology; 5 Department of Public Health; 7 Department of Surgery, II School of Medicine, University ‘La Sapienza’, Rome; 3 Nuclear Medicine Division, National Tumor Institute ‘Regina Elena’, Rome; 4 Department of Pathology and Laboratory Medicine, University of Parma; 6 Department of Surgery, University of Verona, Italy
* Correspondence to: Dr G. Delle Fave, Department of Digestive and Liver Disease, II School of Medicine, University ‘La Sapienza’, Ospedale Sant'Andrea, via di Grottarossa 1035, 00189 Rome, Italy. Tel: +39 06 80345691; Fax: +39 06 80345001; E-mail: Gianfranco.dellefave{at}uniroma1.it
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Abstract |
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Background: Knowledge of factors able to predict the clinical outcome of homogenous series of entero-pancreatic endocrine tumours treated with somatostatin analogues is poor. This study was aimed at identifying predictors for efficacy of somatostatin analogues at inhibiting tumour growth and modifying patients' survival during long-term follow-up.
Patients and methods: 31 patients with entero-pancreatic well-differentiated endocrine carcinoma received long-acting somatostatin analogues. All had progressive, metastatic disease (87% liver metastases, 38.7% distant extra-hepatic metastases).
Results: Response rate after 6 months of treatment was 45.2% (all disease stabilisation: 27.8% of pancreatic vs. 81.8% of intestinal tumours, P = 0.007). The predictors for non-response were: pancreatic tumour (OR 5.8), no previous surgery (OR 6.7), and the presence of distant extra-hepatic metastases, the latter being also confirmed by multivariate analysis (OR 10.0). Responders maintained stabilisation for 26.5 months, and none died during follow-up. Different survival curves were observed for patients, responding at 6 months compared to non-responders (P = 0.004), 3-year survival rate being 100% and 52.3%, respectively.
Conclusions: Distant extra-hepatic metastases are the major predictor of poor efficacy of somatostatin analogues in progressive, metastatic, well-differentiated entero-pancreatic endocrine carcinomas. Patients achieving response after 6 months of treatment, maintain it throughout a long-term follow-up. Non-responders after 6 months of treatment, have a worse survival, and should be considered for alternative treatments.
Key words: carcinoids, metastases, neuroendocrine tumours, pancreatic endocrine tumours, somatostatin analogues, treatment
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introduction |
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Entero-pancreatic endocrine tumours (EP ETs) are a rare disease, occurring in two cases/100 000 persons/year [1
]. They are heterogeneous tumours, in terms both of clinical and biological features, as they originate from the pancreas [pancreatic endocrine tumours (PETs)] or intestinal tract (commonly known as intestinal carcinoids). They may be associated with a specific syndrome due to hormone hypersecretion, which differentiates ‘functioning’ from ‘non-functioning’ tumours, in which symptoms are related to the mass-effect derived from tumour growth only [2]. Patient survival is affected by several prognostic factors, including the site of the primary tumour, the degree of tumour differentiation, and the presence of metastases [3–5]. Although surgery is widely accepted as first-choice treatment, since a large proportion of patients already present metastases at diagnosis [5], medical treatment also plays a major role, when surgery is not feasible, or when there is evidence of residual disease after surgery. Since some 85% of EP ETs express somatostatin receptors (sstr) [6], somatostatin analogues are most frequently used in these tumours. These drugs have been demonstrated to decrease hormone hypersecretion, control symptoms in functioning tumours, and, in some cases, inhibit tumour growth [7, 8]. Over the last few years, the efficacy of the long-acting analogues, octreotide-acetate long-acting release (LAR) and lanreotide slow-release (SR) has been demonstrated to be comparable to that of subcutaneous analogues, and to have a similar safety profile [9, 10]. However, an analysis of the literature on the efficacy of these drugs in EP ETs is influenced by several elements, such as the site and differentiation of the tumour, the presence of metastases, and the different spontaneous behaviour before commencing the treatment (stable or progressive disease). This latter feature plays a crucial role in the natural history of these diseases. In fact, in some patients, the tumour may remain unchanged for a long period, even without treatment, whereas in others the tumour grows rapidly regardless of anti-proliferative treatment [11].
Most previous studies have not used the above-mentioned prognostic factors as inclusion criteria for selecting patients, and, therefore, evaluations refer to series of tumours with a different behaviour and prognosis. Furthermore, determination of predictors for tumour response to treatment has rarely been performed [12–14], and thus it is difficult to identify those patients more likely to benefit from the antitumour effects of the analogues, before the onset of treatment.
The present prospective study has been performed in a set of patients, specifically selected on the basis of: (i) evidence of progressive disease before treatment; (ii) histological diagnosis of a well-differentiated endocrine carcinoma; (iii) presence of metastases, and (iv) positive somatostatin receptor scintigraphy (SRS). In this uniform subset of patients, we aimed at identifying factors able to predict the efficacy of long-acting somatostatin analogues at inhibiting tumour growth and modifying the patients' outcome during a long-term follow-up.
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patients and methods |
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patients
A total of 44 EP ET outpatients with progressive disease (spontaneous tumour growth) documented by imaging procedures during the 3 months prior to starting treatment, in accordance with WHO criteria, were referred to the Digestive and Liver Disease Unit, University ‘La Sapienza’, Rome, Italy. If during this period a >50% increase in tumour size had been observed, the tumour would have been defined as ‘rapidly progressive’, otherwise, it was considered ‘slowly progressive’.
Among these 44 patients, we selected those with well-differentiated endocrine carcinoma (EC), according to the WHO classification [15] (all diagnoses were reviewed by an expert pathologist (CB) by the histological/immunohistochemical examination of the primary tumour or liver metastases), and positive SRS. The availability of a follow-up period of at least 6 months was also required.
Based on these inclusion criteria, 31 patients (18 male, 13 female; median age 50 years, range 24–75) were enrolled in this prospective single-centre study. Twenty patients (64.5%) had no associated syndrome (non-functioning tumours). Overall, tumours were localized in the pancreas and in the intestine in 18 (58%) and 11 (35.5%) patients, respectively, while in the remaining two (6.5%) patients, the site of the primary tumour was unknown (Table 1). Ki67 value was available in 27 patients (it was assessed in 16 patients on primary tumour samples, and in 11 on liver metastases), the median value being 2.5% (range 1–30%). All patients had metastatic disease, hepatic metastases being present in 27 patients (87%), and advanced disease with extra-hepatic but no liver lesions in four patients (13%). Overall, 12 patients (38.7%) had distant extra-hepatic metastases which were located in the bone (nine patients), lung (four patients), and peritoneum (two patients). The rate of growth was assessed in 25 patients (the remaining six patients had undergone radical surgery, and it was, therefore, impossible to calculate the proportion of increase in tumour size, due to the absence of visible disease at the initial observation). Of these, 22 (88%) had a slowly progressive disease. A total of 29 patients (93.6%) had a Karnofsky score 
80.
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Somatostatine analogues was the first line treatment for all patients other than four, which had been pre-treated by systemic chemotherapy (one of them in combination with chemoembolisation) >1 year prior to the initiation of the analogues. Furthermore, one patient had been treated by chemoembolisation of liver metastases together with radiofrequency. Overall, 20 patients (64.5%) had undergone surgery prior to medical treatment. Of these, six (30%) had had radical surgery. They were treated with somatostatine analogues due to disease recurrence, which occurred after a median interval of 14.5 months (range 8–60 months) from initial radical surgery. The remaining 14 patients (70%) had undergone non-radical surgery.
study design
All the 31 eligible patients were treated with long-acting somatostatin analogues. As the primary aim of the study was not to compare the efficacy of the two analogues, either Octreotide LAR 30 mg (Sandostatine LAR 30, Novartis Farma, Italy) or Lanreotide SR 60 mg (Ipstyl 60, Ipsen, Italy) were administered as intramuscular injection every 28 days, in 21 and 10 patients, respectively. Median duration of treatment was 18 months (range 6–60 months).
The following variables were investigated as possible predictors of response to treatment: patients' age and sex, functional status, primary tumour site and size, Ki67 value, disease extension, previous surgery, plasma Chromogranin A (CgA) levels.
Tumour response was assessed by helical computed tomography and SRS [16], 3–6 months after the beginning of treatment (early follow-up), and then every 6 months during the subsequent period (late follow-up), and defined as follows: positive response if disease regression (DR) (>50% reduction in tumour size) or disease stabilization (DS) (<50% reduction or <25% increase in tumour size), calculated as the sum of the products of the largest perpendicular diameters of measurable lesions; no response, if disease progression (DP) defined as >25% increase in tumour size, or development of new tumour lesions, was maintained. Positive response was considered ‘sustained’ if maintained over a period of at least 12 months. CgA levels were assessed by immunoradiometric assay on plasma obtained from blood samples withdrawn in fasting conditions, as previously described [17]. The value of 90 ng/ml was used as cut-off level.
Fully informed consent was obtained from all patients before entering the study, which was approved by the local Ethics Committee.
statistical analysis
Univariate and multivariate analyses were performed to evaluate the effects of variables on response to treatment using a logistic regression model. The main outcome variable was the lack of response to treatment at early follow-up.
Actuarial survival probabilities were calculated using the Kaplan–Meier method and comparisons were made using the log rank test. The duration of progression-free survival was calculated from the beginning of the documented positive response (DS or DR) to the date of documented DP (in patients who presented DP after positive response), or to the last observation during follow-up (in patients not presenting DP after initial positive response).
Unpaired Wilcoxon test was used to compare variables in the subgroups of patients. Fisher exact test was used to compare percentages. A P value < 0.05 was considered statistically significant.
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response to treatment at early follow-up
At early follow-up, 45.2% of patients (n = 14) showed a positive response to treatment, i.e. DS in all these cases. No tumour regression was observed. The remaining 54.8% of patients (n = 17) maintained DP. The two analogues showed similar efficacy, response being observed in 47.6% (10/21) and 40% (4/10) of patients treated with Octreotide LAR and Lanreotide SR, respectively.
predictors for treatment efficacy
A lower proportion of PETs responded in comparison with intestinal carcinoids, DS being observed in 27.8% (5/18) and in 81.8% (9/11) of patients, respectively (P = 0.007). The remaining two patients with an unknown primary tumour site did not respond to treatment.
As far as concerns the functional status, similar response rates were obtained in patients with or without associated syndrome, DS being observed in 45.4% (5/11) and 45% (9/20) of patients, respectively (P = n.s.).
When compared to responders, patients not responding included a higher proportion of PETs (76.5%), and of tumours with distant extra-hepatic metastases (58.8%) (P = 0.032, and P = 0.024, respectively). On the contrary, no difference was observed between the two groups, in terms of age at time of treatment start, sex, size of primary tumour, Ki67. As far as the number of liver metastases is concerned, we observed a higher, although not statistically significant, proportion of patients with more than five liver lesions in the group of non responders, when compared to responders (64.7% vs 35.7%, respectively; P = 0.054). Furthermore, different plasma CgA levels were observed in the two groups of patients, median values being 402 ng/ml and 785 ng/ml in patients who responded or not to treatment, although statistically significance was not reached in this analysis (P = 0.061) (Table 2).
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The following variables were significantly predictive for non response, at univariate analysis (Table 3): pancreatic tumour (OR 5.8), presence of distant extra-hepatic metastases (OR 8.5), and no previous surgery (OR 6.7). The multivariate analysis confirmed these findings, although a statistically significant risk was reached only for the presence of distant extra-hepatic metastases, confirming that this is the major predictor for negative response to somatostatin analogues (Table 3).
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side effects
No patient had serious side effects that resulted in discontinuation of treatment. Minor side effects (abdominal pain, diarrhoea, nausea) developed in 16.1% of patients. Two patients (6.4%) had evidence of gallstones, without symptoms.
response to treatment during long-term follow-up
The 14 patients responding at the early follow-up, maintained DS during a median of 26.5 months after the initial documented response (range 6–60 months). During this period, these patients were treated by the monthly injection of the analogue only. With regard to the duration of response, nine of the 14 responders were observed for 2 years, DS being maintained throughout this period in 88.8% of them. A total of six responders reached a follow-up period 3 years, DS being confirmed at the last observation in 50% of them. Of note, one patient experienced DS for 5 years.
Of the responders, four patients (28.6%) showed DP at a median interval of 30 months (range 20–76) after initial response. Overall, the 3-year progression-free survival probability was 74.1%. DP was confirmed during long-term follow-up in all non-responders, at early follow-up.
survival of patients
Overall, 3-year survival rate was 75%. A total of seven patients (22.5%) died of the disease, at a median interval of 9.5 months (range 6–18) from the beginning of treatment. All these patients had been considered non-responders at early follow-up. Of these, 57.1% were PETs, and 57.1% had distant extra-hepatic metastases. Of note, all the three patients with rapidly progressive tumour before treatment died of disease during follow-up.
None of the responders at early follow-up died of the disease. Thus, a statistically significant difference was observed in survival curves for patients, responders or not, to treatment (P = 0.004), 3-year survival rate being 100% and 52.3%, respectively (Figure 1).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingReferences |
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This study shows that, in a homogeneous series of patients with progressive, metastatic, well-differentiated entero-pancreatic endocrine carcinomas, the presence of distant extra-hepatic metastases, together with the pancreatic site of the primary tumour, and the absence of previous surgical treatment, is the major predictor for poor response to treatment with long-acting somatostatin analogues.
The availability of these predictors may be useful to select those patients more likely to benefit from the treatment, and to distinguish them from other groups of patients which might be suitable for different therapeutic approaches. Only a few studies have investigated the role of predictors of tumour response to somatostatin analogues, suggesting the importance of the Karnofsky status index and the slope of tumour progression, before treatment [12, 13]. This latter finding was also observed in malignant gastrinomas by Shojamanesh et al. [14], which showed a lower response rate to subcutaneous octreotide in patients with rapidly progressive compared with slow progressive tumours. Our study, however, includes 88% of patients with slowly progressive tumour, and 93.6% of patients with Karnofsky score 80. Thus, these variables could not be analysed as predictors. However, it is of interest to note that all the three patients with rapidly progressive tumour did not respond to treatment, and died of the disease. In this homogeneous set of patients we found that the presence of distant metastases is the major predictor for poor response (OR 10.0 at multivariate analysis), and thus for negative outcome during long-term follow-up, non-responders showing a significantly lower survival probability, when compared with responders (P = 0.004). As far as concerns the role of CgA, an increased risk for non response to treatment was observed for each two-fold increase of CgA levels (OR 1.6, P = 0.057). This finding suggests, as previously reported [18], that the presence of high levels of CgA may be a useful predictor for negative prognosis, and lack of response to treatment with the analogues.
Another interesting finding regards the high rate of sustained response maintained during the long-term follow-up, in those patients responding during the first 6 months. In fact, these patients maintained this response throughout a median period of treatment of 26.5 months. In this group, the treatment was able to modify the course of the disease, as showed by the higher survival rate compared with non-responders (P = 0.004, Figure 1). Few studies investigated the ability of the somatostatin analogues to modify patients' survival. Shojamanesh et al. [14] observed that patients with malignant progressive gastrinomas who respond to octreotide have a higher, although non significant, survival rate when compared to non-responders. This finding was recently confirmed by Arnold et al. [19] who evaluated the efficacy of octreotide, alone or in combination with 
-IFN, in a large series of progressive EP ETs. However, in this latter study, the influence of treatment on survival was evaluated by analysing together both patients who received the analogue alone, and those who were treated by the association of octreotide and -IFN.
A recent report by Bajetta et al. [20] showed that including the tumour in a histological subgroup of the WHO classification [15] is useful, but not sufficiently satisfactory when selecting the appropriate treatment strategy. Our data support this conclusion, suggesting that, in addition to the histological subtype, the presence of distant extra-hepatic metastases, the pancreatic tumour site, and the absence of previous surgical treatment should be taken into account before deciding the optimal therapeutic approach. In this subset of patients, a treatment based on somatostatin analogues only seems inappropriate.
The reported rate of response to somatostatin analogues in progressive EP ETs ranges from 18–57% [12–14, 19, 21–23], a figure in keeping with the overall 45% of our study. However, analysing these findings in relationship with the tumour localisation, we observed that 81.8% of intestinal carcinoids and only 27.8% of PETs responded (P = 0.007). This result, which is in agreement with other studies [12, 13, 21], confirms that progressive PETs respond to somatostatin analogues in some 25% of patients only.
No differences, in tumour response, were observed between patients with or without an associated syndrome, thus confirming that the ‘functional’ status, not only is not a prognostic factor in the natural history of EP ETs [5], but does not affect the probability of response to somatostatin analogue.
One limit of this study concerns the relatively small number of enrolled patients, due both to the rarity of the disease and to the strict inclusion criteria used. These aspects should always be taken in mind when interpreting results of studies on treatment of EP ETs, which, as already mentioned, present with a particular heterogeneity, displaying substantial differences in terms of phenotype and relative behaviour [24]. Thus, the results obtained with each therapeutic strategy should be interpreted, as far as possible, for each specific type of tumour rather than for the overall large family of EP ETs.
In conclusion, this study shows that the presence of distant extra-hepatic metastases, together with the pancreatic tumour site and the absence of previous surgical treatment, is the major negative predictor for efficacy of somatostatin analogues in patients with progressive, metastatic, well-differentiated EP EC expressing sstr. If the patient achieves tumour response 6 months after the beginning of treatment, it is likely that a sustained response will be maintained also throughout the long-term follow-up. In patients non-responders after 6 months of treatment, which have a worse prognosis and a higher mortality rate, alternative therapeutic strategies should be considered.
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funding |
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This is an independent work granted by the Italian Ministry for the University (MIUR) (2003063877_002), the Italian Ministry of Health, and by the University of Roma ‘La Sapienza’ (C26A044873). No support was provided by the pharmaceutical industry.
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Acknowledgements |
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Authors are grateful to Mrs Marian Shields for help with English style.
Received for publication September 25, 2005. Revision received November 18, 2005. Accepted for publication November 21, 2005.
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References |
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