Prognostic factors influencing survival from metastatic (stage IV) gastroenteropancreatic well-differentiated endocrine carcinoma

in Endocrine-Related Cancer

Survival of metastatic gastroenteropancreatic well-differentiated endocrine carcinoma (GEP WDEC) is not well characterized. We evaluated the long-term outcome and prognostic factors for survival in 118 patients with distant metastases from GEP WDEC. Inclusion criteria were 1) pathological review by a single pathologist according to the present WHO criteria, 2) absence of previous therapy apart from surgery, 3) complete morphological evaluation within 3 months including somatostatin receptor scintigraphy, and 4) follow-up at Gustave-Roussy Institute until death or study's end. Clinical, biological marker, and pathological parameters were analyzed in univariate and multivariate statistical models. Survival after the first complete imaging work-up of the metastatic disease was determined using Kaplan–Meier method. Overall, survival for 5 years after the diagnosis of metastatic disease was 54%. In multivariate analysis, age (hazard ratio (HR): 1.05, 95% confidence interval (CI): 1.01–1.08, P=0.01), the number of liver metastases (HR: 3.4, 95% CI: 1.4–8.3, P=0.01), tumor slope (HR: 1.1, 95% CI: 1.0–1.1, P=0.001), and initial surgery (HR: 0.3, 95% CI: 0.1–0.8, P=0.01) were predictive of survival. Five-year survival was 100%, 91% (95% CI, 51–98%), 62% (95% CI, 37–83%), and 9% (95% CI, 6–32%) when patients had 0, 1, 2, 3 or more poor prognostic features respectively. This study enables the stratification of metastatic GEP WDEC patients into distinct risk groups. These risk categories can be used to tailor therapeutic approaches and also to design and interpret clinical trials.

Abstract

Survival of metastatic gastroenteropancreatic well-differentiated endocrine carcinoma (GEP WDEC) is not well characterized. We evaluated the long-term outcome and prognostic factors for survival in 118 patients with distant metastases from GEP WDEC. Inclusion criteria were 1) pathological review by a single pathologist according to the present WHO criteria, 2) absence of previous therapy apart from surgery, 3) complete morphological evaluation within 3 months including somatostatin receptor scintigraphy, and 4) follow-up at Gustave-Roussy Institute until death or study's end. Clinical, biological marker, and pathological parameters were analyzed in univariate and multivariate statistical models. Survival after the first complete imaging work-up of the metastatic disease was determined using Kaplan–Meier method. Overall, survival for 5 years after the diagnosis of metastatic disease was 54%. In multivariate analysis, age (hazard ratio (HR): 1.05, 95% confidence interval (CI): 1.01–1.08, P=0.01), the number of liver metastases (HR: 3.4, 95% CI: 1.4–8.3, P=0.01), tumor slope (HR: 1.1, 95% CI: 1.0–1.1, P=0.001), and initial surgery (HR: 0.3, 95% CI: 0.1–0.8, P=0.01) were predictive of survival. Five-year survival was 100%, 91% (95% CI, 51–98%), 62% (95% CI, 37–83%), and 9% (95% CI, 6–32%) when patients had 0, 1, 2, 3 or more poor prognostic features respectively. This study enables the stratification of metastatic GEP WDEC patients into distinct risk groups. These risk categories can be used to tailor therapeutic approaches and also to design and interpret clinical trials.

Introduction

Gastroenteropancreatic neuroendocrine tumors (GEP NET), recently renamed endocrine tumors, are a group of tumors defined by the expression of a set of structural proteins and hormonal products common to neurons and endocrine cells (Plöckinger et al. 2004, Baudin 2007).

Defining prognostic factors for survival is a critical objective in oncology to evaluate therapeutic results, to tailor therapeutic trials and the aggressiveness of treatment. This is particularly true in GEP tumors that can be associated with a diverse natural history. Epidemiological studies of GEP NET have reported increase age as a major prognostic feature (Quaedvlieg et al. 2001, Zar et al. 2004, Lepage et al. 2007) but conflicting results regarding the prognostic effect of gender (Beasley et al. 2000, Quaedvlieg et al. 2001, Modlin et al. 2003, Zar et al. 2004, Tomassetti et al. 2006, Lepage et al. 2007). Additionally, in previous multivariate analysis from tertiary referral centers, pathological differentiation and stage at diagnosis have been identified as the strongest prognostic features of GEP NET. Indeed, differentiation of GEP NET classified as poorly compared with well-differentiated (WD) carcinoma (Johnson et al. 1986, Greenberg et al. 1987, Madeira et al. 1998, Travis et al. 1998, Rindi et al. 1999, Lim et al. 2005, Panzuto et al. 2005, Asamura et al. 2006, Faggiano et al. 2007, Lepage et al. 2007, Pape et al. 2008) and stage (Lo et al. 1996, Pelosi et al. 1996, Burke et al. 1997, Madeira et al. 1998, Kirshbom et al. 1999, Rindi et al. 1999, Shebani et al. 1999, Onaitis et al. 2000, Quaedvlieg et al. 2001, Rigaud et al. 2001, Solorzano et al. 2001, Hochwald et al. 2002, Plöckinger et al. 2004, Panzuto et al. 2005, Tomassetti et al. 2006, Baudin 2007, Pape et al. 2008) as long been recognized the strongest prognostic parameters before the primary location. More recently, lymph node metastases (Hellman et al. 2002, Cardillo et al. 2004, Lim et al. 2005, Tomassetti et al. 2005, Baudin 2007, García-Yuste et al. 2007, Rea et al. 2007, Pape et al. 2008) and proliferative index have emerged as major determinant of prognosis in GEP tumors of the lung (Travis et al. 1998, Beasley et al. 2000, Lim et al. 2005, Asamura et al. 2006, Baudin 2007) stomach and pancreas (Chaudhry et al. 1992, Pelosi et al. 1996, Rindi et al. 1999, Rigaud et al. 2001, Hochwald et al. 2002). At the end, a new classification emphasizing the role of TNM (Tumor, Nodes, Metastases) classification and proliferative index has emerged (Rindi et al. 2006, 2007, Bettini et al. 2008, Fischer et al. 2008).

The vast majority of previous studies but one has focused on GEP tumors of various stages. However, progress in subgroup of GEP NET patients characterized by a given differentiation and stage is expected since these two parameters are the strongest prognostic parameters of GEP NET and since each stage of GEP NET carries a specific set of clinical characteristics.

We therefore conducted a single-center, retrospective multivariate analysis of previously untreated, metastatic (stage IV), GEP WD endocrine carcinoma (WDEC), 1) to identify prognostic factors related to survival not affected by the therapy at the time of definition and 2) to evaluate the prognostic value of morphologically defined tumor burden slope.

Materials and methods

Patients

Two hundred and fifteen consecutive patients referred to Gustave-Roussy Institute between January 1994 and June 2001 for treatment of a metastatic GEP well-differentiated endocrine carcinoma (GEP WDEC) was included in a retrospective analysis. Inclusion criteria were: 1) pathological diagnosis of metastatic GEP WDEC (stage IV) according to WHO and TNM classification diagnostic criteria and confirmed by a single pathologist (PD; n=11 patients excluded, because tumor samples were not available: Solcia et al. 2000, Heitz et al. 2004, Travis et al. 2004, Rindi et al. 2006, 2007); in the absence of a solid or diffuse histologic architectural pattern and/or presence of necrosis, a mitotic index >10 or a Ki-67 score >10% was not considered sufficient as a single criteria to classify the tumor as poorly differentiated; 2) initial visit including no prior treatment for GEP WDEC, except for surgery (n=53 patients excluded); 3) distant metastatic disease analyzed by complete morphological evaluation, including somatostatin receptor scintigraphy performed within 3 months of study entry (n=13 patients excluded); and 4) diagnostic work-up and follow-up in a single institution (Gustave-Roussy Institute; n=20 patients excluded). All of the patients who met the inclusion criteria for this study underwent a clinical examination and biological and morphological testing at the time of initial visit and every 3–6 months until the end of the study (October 31, 2004) or death.

Treatment given for GEP WDEC after enrolment in the study is presented in Table 1. Results of these therapies have been previously published (Mitry et al. 1999, Aparicio et al. 2001, Elias et al. 2003, Roche et al 2003, 2004, Delaunoit et al. 2004).

Table 1

Therapeutic management of gastroenteropancreatic well-differentiated endocrine carcinoma (GEP WDEC)

Type of treatmentaNumberPercent
Treatments before study initiation5244
  Primary tumor surgery4639
  Liver metastases surgery815
  Others metastases surgery1223
Treatments after study initiation11682
  Primary tumor surgery3026
  Liver metastases surgery2421
  Others metastases surgery1614
  Systemic chemotherapy7060
Number of chemotherapy regimens
     12739
     22333
     ≥32028
  Chemoembolization4438
  Radiotherapy2421
  Somatostatin analogs7766
  Interferon1210
  Peptide receptor radionuclide therapy11

Treatments were not mutually exclusive.

Pathological, biological, and morphological work-up

Initial evaluation included a careful interview history and physical examination. Clinical, laboratory, imaging, and histologic data were collected prospectively and analyzed by skilled pathologist and radiologist specialists (PD, CD). During the course of study, chromogranin A (CGA) measurement and liver magnetic resonance imaging (MRI) became part of routine clinical practice in 1998 and September 2000 respectively, and incorporated into the study protocol.

Tumoral tissue was obtained from the primary tumor (n=74; 63%) or metastases (n=44; 37%), by either surgical resection (n=75; 64%) or biopsy (n=43; 36%) allowing proliferative index assessment. At least 10 high-power fields (HPFs) were examined on hematoxylin and eosin section to determine the mitotic index using a Zeiss Axioplan microscope (40×/0.7 objective, 10× ocular was used; each field corresponding to a surface of 0.33 mm2). Ki-67 score was assessed using MIB1 (mindbomb homolog 1) stains (clone MIB1, Dako A/S, Glostrup, Denmark).

Laboratory investigations included serum gastrin, pancreatic peptides, urinary 5-hydroxyindoleacetic acid (5-HIAA) levels in patients with pancreas, ileum or lung endocrine tumors according to a standard clinical practice (Plöckinger et al. 2004, Baudin et al. 2007). Finally, serum glucose, serum calcium, neuron specific enolase or CGA were measured in all patients as previously described (Baudin et al. 1998, 1999, Baudin 2007).

To determine the extent of metastatic disease during the initial evaluation, patients underwent conventional imaging studies. Abdominal and chest computed tomography (CT) scan was performed with a conventional scanner and after 1998 with a spiral scanner; images were obtained before and after i.v. injection of iodinated contrast material. CT of the brain was performed, if clinical symptoms were suggestive of brain metastases. Liver MRIs were performed with a 1.5-T whole-body imager, and included both T1-weighted and fat-suppressed T2-weighted sequences but also dynamic contrast-enhanced MRIs as previously described (Dromain et al. 2005). Furthermore, all patients underwent somatostatin receptor scintigraphy after i.v. injection of 170–220 MBq of indium-111-DTPA-phel-octreotide (Dromain et al. 2005). Only lesions larger than 1 cm in diameter were taken into account to determine the number of lung metastases on CT. Bone involvement was quantified by specifying the number of metastases detected by somatostatin receptor scintigraphy. Bone-related clinical events (pain, spinal cord compression, and/or fractures) were also recorded. All liver CTs and MRIs were reviewed to determine the number of liver metastases and tumor slope. Indeed, in a subgroup of patients, in whom a second imaging work-up was carried out in our institution, spontaneous tumor slope was evaluated by performing a CT scan or MRI 3–6 months after initial assessment. Results of tumor slope were normalized per month to allow comparison between patients. Comparison of the sum of the longest diameters of target lesions at two imaging and/or, appearance of one or more new lesions were analyzed to classify the tumor slope as progressive (whatever the rate of progression) or stable (Therasse et al. 2000). Patients were either untreated or in the case of functioning GEP tumors, had received somatostatin analogs at the time of tumor slope assessment.

Statistical analysis

The following clinical information extracted from patients charts was recorded in all patients: gender, age (≤65 or >65 years), embryologic origin of the primary tumor (foregut, midgut or hindgut), anatomical location of the primary tumor (lung, pancreas or ileum), presence or absence of hormone-related symptoms (≤3 episodes/day = no; >3 episodes/day = yes), time elapsed between diagnosis of primary tumor and diagnosis of metastatic disease (synchronous; metachronous), liver involvement (yes/no), lung involvement (yes/no), bone involvement (yes/no), number of lung metastases (<5, 5–9, or ≥10), bone metastases (<3, 3–5 or >5), number of organs involved with metastatic tumor (1, 2 or ≥ 3). Surgery before study entry and treatment given during the course of the study were also recorded.

Tumor mitotic count (<2, 2–10, or >10 per 10 HPF) was available for 82 cases, Ki-67 index (<2, 2–10, or >10%) for 50 cases, and 86 patients had either tumor mitotic count or Ki-67 index. Very few tumors expressed mitotic counts above 20 or Ki-67 index above 20% explaining why these cut off values were not selected despite recent recommendations (34, 35). 5-HIAA or CGA (<2, 2–4 or ≥5) levels or at least one of these measurements were found in 60, 89, and 101 cases respectively. Eighty-five patients had information on the number of metastatic liver lesions (<10, ≥10). Tumor slope (0, if non-progressive or >0, if progressive) was determined over a 3–6 month period in 66 patients, including 19 patients receiving somatostatin analogs at the time of tumor slope assessment.

Overall, survival rates and 95% confidence intervals (CIs) were estimated using the Kaplan–Meier method (Kaplan & Meier 1958). Rates were computed with life-table analysis. The log-rank test (Lee 1986) was used to compare survival curves. Univariate and multivariate analysis of survival were performed with follow-up starting at the time of first complete imaging work-up, as described above, after diagnosis of distant metastasis. Univariate analysis included the above-mentioned variables. Multivariate analysis included only variables that were significant in the univariate analysis and was performed with a backward variable selection technique. The risk of death was computed as hazard ratio (HR). The effect of the variables that were significant in the multivariate analysis was evaluated using a stepwise Cox proportional-hazards regression model from the time of diagnosis of the first tumor metastasis to the end of the study or the patient's death (Cox 1972). For all analyses, two-sided tests were employed and the 0.05 level of significance was used. Ninety-five percent CIs were calculated for the HR estimated from the Cox proportional hazard regression analysis. All analyses were performed using SAS software (version 9.1, SAS Institute, Cary, NC, USA).

Results

Characteristics of patients at discovery of distant metastases

The characteristics of the 118 remaining patients enrolled into this retrospective study are listed in Table 2. Briefly, the study population included 60 men (51%) and 58 women (49%). The mean age was 57 years (s.d.: 13 years; range: 12–90 years) at the time of first complete imaging work-up of metastatic disease. The mean follow-up was 4.6 years (s.d.: 2.9 years; median: 4 years; range: 0.2–14 years) from the time of first complete imaging work-up of metastatic disease.

Table 2

Characteristics of patients with metastatic well-differentiated endocrine carcinoma (WDEC). Univariate and multivariate analysis of overall survival

VariablesNumber of patientsNumber of deathsFive-year survival (%)Univariate analysisMultivariate analysis
Total1186654Unadjusted HR95% CIPaAdjusted HRb95% CIPc
GenderMale603946
Female5827630.70.4–1.10.11___
Age≤65854360
>653323411.71.1–2.90.032.81.4–5.40.002
ForegutdNo431865
Yes5837471.91.1–3.30.030.90.4–2.40.9
MidguteNo623849
Yes3917640.60.3–1.10.09___
HindgutfNo975454
Yes41750.30.1–2.60.3___
Pulmonary primaryNo844652
Yes179690.70.3–1.50.33___
Pancreatic primaryNo663265
Yes3523362.11.2–3.60.011.60.8–3.30.18
Ileum primaryNo683952
Yes3316620.70.4–1.20.21___
FlushingNo1076052
Yes116530.80.5–1.20.22___
DiarrheaNo1005258
Yes1814371.50.8–2.70.21___
Mitotic countg<2452556
2–102912710.70.4–1.50.41
>1085371.80.7–4.60.2___
Ki-67 indexh<212767
2–102911600.70.6–1.50.3
>1095441.90.7–5.40.2___
CGA leveliNormal28874
2–4 USR122820.60.2–2.30.46
≥5 USR2015302.61.3–5.00.002___
5-HIAANormal512753
2–4 USR2110620.90.5–1.50.69
≥5 USR1713461.41.0–2.10.09___
Metastasis discoverySynchr965553
Metachr2211610.90.8–1.00.09___
Liver metastasesNo10467
Yes10862531.80.6–4.90.3___
Number of liver metastases<10502075
≥103524362.11.2–3.90.012.41.3–4.60.005
Lung metastasesNo1095856
Yes98221.80.8–3.80.12___
Bone metastasesNo924958
Yes2315431.30.7–2.30.5___
Number of organs with metastases1733857
24126511.20.9–1.70.25
342501.00.3–2.60.94___
Tumoral progressionj0371477
≥12921392.81.4–5.60.0032.91.3–6.60.01
Previous surgerykNo664342
Yes5223690.40.2–0.7<0.0010.40.2–0.70.002
Previous surgery for primary tumorNo724544
Yes4621700.40.2–0.70.0020.90.2–3.90.8

Abbreviations: CGA, Chromogranin A; 5HIAA, 5 hydroxyindolacetic acid; HR, Hazard risk; USR, Upper superior range; Synchr, Synchronous; Metachr, Metachronous.

P value univariate.

Adjusted HR: multivariate analysis was performed within three steps according to the variables categories which are respectively: clinical variables, the slope progression, and variables related to the treatment. We first computed adjusted risks in a multivariable model including clinical parameters that were significant in the univariate analysis, then in a second step, we added the slope variable to this first model. The third step consisted to generate a multivariate model with treatment variables that were significant in the univariate analysis.

P value for the multivariate analysis.

Foregut included pancreas (n=35), thymus (n=3), larynx (n=1), stomach (n=1), duodenum (n=1) and lung (n=17).

Midgut included ileum (n=33), appendix (n=4), and right colon (n=2).

Hindgut included rectum (n=4).

The mitotic index was determined in 59 (72%) primary or 23 (28%) metastatic tumor specimens, and in 59 (72%) surgical or 23 (28%) biopsy samples.

The Ki-67 score was determined in 33 (66%) primary or 17 (34%) metastatic specimens, and in 38 (76%) surgical or 12 (24%) biopsy samples.

Because of the small number of patients with information regarding CGA levels, this parameter was not included in the multivariate analysis.

Percentage increase per month after a 3–6 month period of follow-up.

Primary tumor and/or initial metastases surgery, before study entry.

Concerning primary, 58 (57%) arose from the foregut, most from the pancreas (35 patients) and 39 (39%) arose from the midgut, most from the ileum (33 patients); four (4%) arose from the hindgut, all arising from the rectum (Table 2) and 17 (14%) remained unknown. Clinical symptoms related to hormonal overproduction included cutaneous flushing and or diarrhea in 24 (20%) patients. Multiple endocrine neoplasia type 1 (MEN1) were diagnosed in three patients.

Mitotic counts above 2 or 10 was observed in 35 and 10% of patients respectively, while Ki-67 index values above 2 or 10% was observed in 58 and 18% of patients respectively.

An increase (≥5 the high upper limit) in at least one hormonal marker was observed in 32 of 101 patients (32%), including CGA and or 5-HIAA in 20 (33%) and 17 (19%) patients respectively.

Synchronous or metachronous metastases were observed in 96 (81%) or 22 (19%) patients respectively. In the latter case, the first metastasis was diagnosed after a mean (±s.d.) period of 6.1±6 years (range 1–26 years) from the time of primary tumor diagnosis. At study entry, the majority of patients had liver metastases (n=108; 92%). Among the 85 patients for whom the number of liver metastases could be properly determined, 31 (37%) had 1–4 metastases, 19 (22%) had 5–9 metastases, and 35 (37%) had 10 or more. Extra-hepatic metastatic sites were seen in 49 of the study subjects (Table 3). Only three patients experienced bone pain; spinal cord compression or fractures were not observed. The spread of metastases involved one organ site in 73 (62%) patients, two in 41 (35%) and three in four (3%). Among the 29 (44%) patients who experienced a tumor progression, 11 (38%) and 18 (62%) patients experienced a tumor rate of progression below or above 20% respectively. Results were not significantly different when patients receiving therapy with somatostatin analogs were excluded form analyses. Patients in whom spontaneous tumor slope was analyzed differed for primary location (higher prevalence of non-pancreatic foregut primary; P<0.01) and frequency of surgery (higher prevalence of patients who underwent surgery before study entry; P<0.01) among parameters listed in Table 2.

Table 3

Site of metastatic disease according to site of primary tumor

Location of metastases
Site of primary GEP WDECLiver number (%)Lung number (%)Bone number (%)Othera number (%)
Foregut
 Pancreas35 (100)2 (6)8 (23)4 (12)
 Lung16 (94)2 (12)8 (47)4 (24)
 Thymus–larynx1 (33)2 (50)2 (50)2 (50)
 Stomach–duodenal2 (100)000
Midgut
 Ileum 31 (94)02 (6)9 (27)
 Colon–appendix5 (83)003 (59)
Hindgut
 Colon–rectum4 (100)01 (25)0
Unknown14 (82)3 (18)2 (12)4 (24)
Total108 (65%)9 (5%)23 (14%)26 (16%)

Other sites included: peritoneum, adrenal gland, ovary, skin, spleen and cerebellum.

Prognostic factors of survival

At the end of the study, 64 (54%) patients died. Deaths were related to tumor progression in 61 (95%) cases. Therefore, overall survival was studied. The 5- and 10-year overall survival rates from the time of detection of metastases were 54% (95% CI 45–63%) and 22% (95% CI 11–37%) respectively (Fig. 1A).

Figure 1
Figure 1

(A) Overall, patient survival since metastases diagnosis. Number of patients: 118. Five-year overall survival rate: 54% (95% CI:45–63%). Ten-year overall survival rate: 22% (95% CI:11–37%). (B) Survival rate according to the number of poor prognostic factor.

Citation: Endocrine-Related Cancer 16, 2; 10.1677/ERC-08-0301

The following parameters were associated with a significant decrease in overall survival in the univariate analysis: age at the time of first complete imaging work-up of metastases discovery, foregut embryological origin, pancreatic primary site, more than 10 liver metastases, tumor-progression slope, increased CGA >5 levels, absence of surgery before study entry and absence of surgery for the primary tumor (Table 2). Owing to the small number of patients with information regarding CGA levels, this parameter was not included in the multivariate analysis.

In multivariate analysis (Table 4), an older age at diagnosis of metastases (HR:1.05; 95% CI 1.01–1.08) and the number of liver metastases over 10 (HR:3.4; 95% CI 1.4–8.3) were found to be predictors of decreased survival. When tumor slope and therapeutic modalities given during the course of the disease were introduced in the multivariate analysis, the significance of the two former criteria did not change and two new predictors were found: tumoral progression slope (HR:1.1; 95% CI 1.0–1.1) and initial surgery (HR:0.3; 95% CI 0.1–0.8). No other therapeutic options given during the course of the disease was found to alter the statistical analysis (details given in Table 5).

Table 4

Predictors for overall survival in patients with metastatic gastroenteropancreatic well-differentiated endocrine carcinoma (GEP WDEC; multivariate analysis)

Variables (characteristics)Adjusted HRa95% CIP
Age at diagnosis of metastasesb1.051.01–1.080.01
Number of liver metastasesc3.41.4–8.30.01
Tumoral progression slope (%)1.11.0–1.10.001
Previous surgery (no/yes)d0.30.1–0.80.02

Each risk estimate is adjusted for all risk factors shown in the table.

Per additional year of age.

Less than 10 vs 10 or more liver nodules.

Primary tumor and/or initial metastases surgery, before study entry.

Table 5

Therapeutic management of gastroenteropancreatic well-differentiated endocrine carcinoma (GEP WDEC) after study initiation according to the number of poor prognostic factors

Number of poor prognostic factors
Treatments after study initiationa0 (n=10)1 (n=12)2 (n=19)≥3 (n=15)
Primary tumor surgery1 (10%)4 (33%)6 (32%)4 (27%)
Liver metastases surgery3 (30%)2 (17%)3 (16%)3 (20%)
Others metastases surgery2 (20%)1 (8%)2 (11%)0
Systemic chemotherapy2 (20%)5 (42%)11 (58%)13 (87%)
Number of chemotherapy regimens
     12 (20%)1 (8%)5 (26%)6 (40%)
     202 (17%)4 (21%)3 (20%)
     ≥302 (17%)2 (11%)4 (27%)
Chemoembolization3 (30%)2 (17%)10 (53%)5 (33%)
Radiotherapy03 (25%)4 (21%)2 (13%)
Somatostatin analogs6 (60%)8 (67%)15 (79%)11 (73%)
Interferon01 (8%)2 (11%)4 (27%)
Peptide receptor radionuclide therapy0000
None001 (5%)0
Number of treatments (%)b17 (12%)26 (19%)53 (38%)42 (31%)

 The number of treatments has been evaluated in the subgroup of 56 patients in whom all the prognostic parameters identified in the multivariate analysis were available (age at diagnosis of metastases; number of liver metastases; tumoral progression slope; previous surgery).

 Percentage over the total number of treatments performed after the study initiation.

Using the four prognostic parameters identified in the multivariate analysis (age above 65 years, number of liver metastases above or equal to 10, a progressive tumor slope and absence of previous surgery), a subgroup of 56 patients with all these parameters available was identified. The survival significantly decreased with increasing numbers of risk factors: 100%, 91% (95% CI 51–98%), 65% (95% CI 37–83%), and 9% (95% CI 6–32%) 5-year survival was observed when patients had 0 (10 patients (18%)), 1 (12 patients (21%)), 2 (19 patients (34%)) or ≥3 (15 patients (27%)) poor prognostic features. The risk of death significantly rose moving from patients with one risk factor (HR:2.1; 95% CI:0.9–4.7; P=0.15) to patients with two or more risk factors (HR:4.8, 95% CI 1.5–15.3; P=0.008) and patients with three risk factors or more (HR:19.2, 95% CI 5.3–70.0; P<0.0001; Fig. 1B).

Finally, we analyzed tumor progression as a function of the number of liver metastases, Ki-67 and pancreatic location: tumor progression was observed in 10 out of 32 (18%) subjects with less than 10 liver metastases but in 14 out of 24 (58%) of those with 10 or more liver metastases (P=0.04); tumor progression was observed in 9 out of 23 (30%) subjects with Ki-67 less than 10% but in 7 out of 7 (100%) of those with Ki-67 equal or above 10% (P=0.005; Fig. 2). No relationship was found with the primary.

Figure 2
Figure 2

Ki-67 index as a function of tumor slope, defined by the percentage increase per month after a 3–6 month period of follow-up (correlation coefficient 43%, P=0.016).

Citation: Endocrine-Related Cancer 16, 2; 10.1677/ERC-08-0301

Discussion

Until now, very few studies have focused on metastatic WD GEP tumors, and to the best of our knowledge, this is only the second study that includes multivariate analysis in the study of these patients. Previously, Clancy et al. (2006) first found age and alkaline phosphatase level, probably as a surrogate marker of liver tumor burden, to be important prognostic parameters in patients with metastatic GEP tumors; gender, primary location, CGA level, and presence of liver metastases were not found to be predictive. Our study includes a comprehensive list of detailed prognostic parameters considered to be important in previous studies including pancreatic primary (Onaitis et al. 2000, Panzuto et al. 2005), extra-hepatic metastases (Yu et al. 1999, Panzuto et al. 2005), extent of liver metastases (Weber et al. 1995, Lo et al. 1996, Yu et al. 1999, Chamberlain et al. 2000, Solorzano et al. 2001), level of serum biological markers (Janson et al. 1997, Onaitis et al. 2000, Turner et al. 2006), presence of a functioning tumor (Pellikka et al. 1993), and also the spontaneous tumor burden slope (Madeira et al. 1998, Arnold et al. 2005).

The main issue regarding the prognostic stratification of GEP tumors relies in the heterogeneity of the study populations. Our aim was to focus the analysis on a homogeneous subgroup of chemotherapy-naïve GEP WDEC patients regarding the stage and differentiation, subsequently treated with classical therapeutic options. All tumors samples and imaging were revised by single experienced specialists (PD, CD). Our analysis carries the limitation of retrospective studies but remains the most detailed to date in this specific subgroup of patients.

The clinical characteristics of patients with metastatic WDEC warrant comment. The 5-year survival of 54% we report is within the range of that reported by others in referral center-based studies (Weber et al. 1995, Janson et al. 1997, Madeira et al. 1998, Solorzano et al. 2001, Panzuto et al. 2005, Pape et al. 2008), but higher than rates published in cancer registries (Quaedvlieg et al. 2001, Modlin et al. 2003). Death related to disease progression accounted for nearly all deaths in patients with metastatic GEP tumors in contrast to studies of GEP patients with non-metastatic disease (Greenberg et al. 1987, Yu et al. 1999, Söreide et al. 2000). We evaluated various primary tumor sites because primary location is a weaker prognostic parameter than differentiation and stage. Finally, mainly sporadic GEP WDEC analyzed before any systemic therapeutic intervention were enrolled making the role of mitotic index or tumor slope evaluable. In accordance with previous results, the majority of WDEC patients with metastatic disease had liver metastases of varying extent, followed by bone metastases (Gibril et al. 1998, Madeira et al. 1998, Hellman et al. 2002, Modlin et al. 2003, Plöckinger et al. 2004, Panzuto et al. 2005, Tomassetti et al. 2006, Baudin 2007, Pape et al. 2008).

Our study identifies age, the number of liver metastases, spontaneous tumor slope, and initial surgery as major predictors for overall survival in patients with metastatic GEP tumors. Advanced age has been found to be related to worse overall survival as well as disease-specific and relative survival in multiple studies (Greenberg et al. 1987, Janson et al. 1997, Gibril et al. 1998, Quaedvlieg et al. 2001, Solorzano et al. 2001, Zar et al. 2004, Asamura et al. 2006, Clancy et al. 2006, Lepage et al. 2007, Rea et al. 2007). Our study does not allow for discriminating the putative roles of co-morbid conditions, tolerance to therapy and/or tumor aggressiveness associated to increased age. Our study also suggests a prognostic role of the number of liver metastases at diagnosis in contrast to either metastatic disease at other sites or the number of organs with metastatic involvement. The less significant prognostic effect of bone metastases, also evidenced by the low number of bone-related morbid events, may be explained by increased bone mineral density associated with these lesions. Interestingly, CGA, a well-known surrogate marker of both tumor burden and/or functional activity of endocrine tumors (Baudin et al. 1998), was found to positively correlate with overall survival in univariate analysis and remains to be evaluated in multivariate analysis.

We demonstrate an independent statistical correlation between tumor slope before and survival of metastatic GEP tumors. Indeed, in our study, this parameter was found to better reflect tumor aggressiveness than disease-free interval or proliferative index. Interestingly, stable disease without aggressive therapy was observed in 56% of GEP tumors over a 6 month time frame. Previous studies report the occurrence of spontaneous disease stabilization ranging from 13% of 31 and 26% of 65 evaluable patients (Arnold et al. 1996, Madeira et al. 1998, Clancy et al. 2006). Since tumor slope assessment is not yet standardized in the field of endocrine tumors, a comparison with previous studies is difficult. Our results suggest that tumor slope assessment improves prognostic classification of GEP tumors. However, it should be stressed that the period of time required for slope assessment delayed the prognostic classification and was frequently considered stressful by patients. Some other limitations of tumor slope assessment in our study should be mentioned. First, tumor slope was assessed in 56% of total patients, among which a higher frequency of midgut GEP tumors and previous surgery was noted. Second, somatostatin analog therapy was given to 28% of these patients who complained of symptoms attributed to functioning tumor. Finally, caution should be exercised when treating patients with high tumor burden, (e.g. more than 10 liver metastases), or high Ki-67 index (above or equal to 10%). Indeed, 58 or 100% of these subgroups of patients were found to have progressive disease. In our series, previous surgery but not other therapies given during the course of the disease was associated with a favorable outcome as similarly reported by others (Lo et al 1996, Madeira et al. 1998, Solorzano et al. 2001, Asamura et al. 2006). However, the design of our study preclude definite conclusion regarding the influence of therapies given during the course of our study on our results even if, major disequilibrium between each therapeutic option was not observed between prognostic subgroup (Table 5).

Several parameters analyzed in this study deserve further comment. First, the primary location of the tumor was not found to be a major prognostic factor in metastatic WD GEP tumors even if pancreatic location was associated with a poorer outcome at univariate analysis. Second, our study does not confirm a main role of mitotic index to lead the therapeutic strategy in metastatic GEP tumors as already found by others (Burke et al. 1997, Van Eeden et al. 2002, Panzuto et al. 2005), but not all (Pape et al. 2008). Remarkably, our results suggest a good correlation between positive slope and Ki-67 equal or above 10% but heterogeneous results in case of Ki-67 below 10%. Both tissue heterogeneity, cut-off levels of mitotic index used in this study but also various impact of mitotic index as a function of primary location may explain this result in stage IV GEP WDEC. Third, presence of a functioning WDEC should no more be considered as a major prognostic indicator thanks to progress in control of functioning symptoms including somatostatin analog therapy. Association of a GEP tumor as part of a MEN1 could not be evaluated in our study.

By combining the prognostic indicators described in our study, different outcome can be predicted. For patients with no risk factor, a ‘wait-and-see’ policy or low-toxicity profile therapy should be scheduled. On the other hand, among the 25% of our study population expressed at least three poor prognostic factors, 5-year disease-specific survival was only 9% (95% CI 0.6–33%), which suggests the use of early therapeutic approaches. Finally, in case of one negative prognostic feature (which account for 39% of our study population), or two negative prognostic features (which account for 36% of our study population), the 5-year disease-specific survival was 95% (95% CI 71–99%) or 62% 5-year survival (95% CI 35–80%) respectively additional studies are required. However, we suggest close monitoring of patients with more than 10 liver metastases or Ki-67 above 10%.

In conclusion, our study highlights prognostic indicators associated with survival in patients with metastatic WDEC. Number of liver metastases together with age and tumor progression slope may serve to divide what is a heterogeneous population of patients into more homogeneous subgroups to whom therapeutic interventions, including therapeutic trials, might be tailored.

Declaration of interest

The authors have no conflict of interest to disclose.

Funding

This research was supported (in part) by the Intramural Research Program of the NIH and the National Cancer Institute.

Acknowledgements

The authors thank Diane Prestone for reviewing and constructive remarks. Houda Boukheris had a fellowship from the International Agency for Research on Cancer (IARC). Present address: National Cancer Institute, Division of Cancer Epidemiology and Genetics, Radiation Epidemiology Branch, Bethesda, MD, USA.

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    (A) Overall, patient survival since metastases diagnosis. Number of patients: 118. Five-year overall survival rate: 54% (95% CI:45–63%). Ten-year overall survival rate: 22% (95% CI:11–37%). (B) Survival rate according to the number of poor prognostic factor.

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    Ki-67 index as a function of tumor slope, defined by the percentage increase per month after a 3–6 month period of follow-up (correlation coefficient 43%, P=0.016).

References

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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
  • ArnoldRRinkeAKloseKJMüllerHHWiedMZamzowKSchmidtCSchade-BrittingerCBarthPMollR2005Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: a randomized trial. Clinical Gastroenterology and Hepatology3761771.

    • Search Google Scholar
    • Export Citation
  • AsamuraHKameyaTMatsunoYNoguchiMTadaHIshikawaYYokoseTJiangSXInoueTNakagawaK2006Neuroendocrine neoplasms of the lung: a prognostic spectrum. Journal of Clinical Oncology247076.

    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
  • BaudinEGigliottiADucreuxMRopersJComoyESabourinJCBidartJMCailleuxAFBonacciRRuffiéP1998Neuron-specific enolase and chromogranin A as markers of neuroendocrine tumours. British Journal of Cancer7811021107.

    • Search Google Scholar
    • Export Citation
  • BaudinEBidartJMRougierPLazarVRuffiéPRopersJDucreuxMTroalenFSabourinJCComoyE1999Screening for multiple endocrine neoplasia type 1 and hormonal production in apparently sporadic neuroendocrine tumors. The Journal of Clinical Endocrinology and Metabolism846975.

    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
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    • Search Google Scholar
    • Export Citation
  • CardilloGSeraFDi MartinoMGrazianoPGiuntiRCarboneLFaccioloFMartelliM2004Bronchial carcinoid tumors: nodal status and long-term survival after resection. Annals of Thoracic Surgery7717811785.

    • Search Google Scholar
    • Export Citation
  • ChamberlainRSCanesDBrownKTSaltzLJarnaginWFongYBlumgartLH2000Hepatic neuroendocrine metastases: does intervention alter outcomes?Journal of the American College of Surgeons190432445.

    • Search Google Scholar
    • Export Citation
  • ChaudhryAObergKWilanderE1992A study of biological behavior based on the expression of a proliferating antigen in neuroendocrine tumors of the digestive system. Tumour Biology132735.

    • Search Google Scholar
    • Export Citation
  • ClancyTESenguptaTPPaulusJAhmedFDuhMSKulkeMH2006Alkaline phosphatase predicts survival in patients with metastatic neuroendocrine tumors. Digestive Diseases and Sciences51877884.

    • Search Google Scholar
    • Export Citation
  • CoxDR1972Regression models and life-tables. Journal of the Royal Statistical Society Series B34187220.

  • DelaunoitTDucreuxMBoigeVDromainCSabourinJCDuvillardPSchlumbergerMde BaereTRougierPRuffieP2004The doxorubicin–streptozotocin combination for the treatment of advanced well-differentiated pancreatic endocrine carcinoma; a judicious option?European Journal of Cancer40515520.

    • Search Google Scholar
    • Export Citation
  • DromainCde BaereTLumbrosoJCailletHLaplancheABoigeVDucreuxMDuvillardPEliasDSchlumbergerM2005Detection of liver metastases from endocrine tumors: a prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging. Journal of Clinical Oncology237078.

    • Search Google Scholar
    • Export Citation
  • Van EedenSQuaedvliegPFTaalBGOfferhausGJLamersCBVan VelthuysenML2002Classification of low-grade neuroendocrine tumors of midgut and unknown origin. Human Pathology3311261132.

    • Search Google Scholar
    • Export Citation
  • EliasDLasserPDucreuxMDuvillardPOuelletJFDromainCSchlumbergerMPocardMBoigeVMiquelC2003Liver resection (and associated extrahepatic resections) for metastatic well-differentiated endocrine tumors: a 15-year single center prospective study. Surgery133375382.

    • Search Google Scholar
    • Export Citation
  • FaggianoASabourinJCDucreuxMLumbrosoJDuvillardPLeboulleuxSDromainCColaoASchlumbergerMBaudinE2007Pulmonary and extrapulmonary poorly differentiated large cell neuroendocrine carcinomas: diagnostic and prognostic features. Cancer110265274.

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