- Email: [email protected]
Carcinoid tumors: Analysis of prognostic factors and survival in 301 patients from a referral center
Annals of Oncology 8: 685-690, 1997. (;) 1997 Kluwer Academic Publishers. Primed in the Netherlands
Original article Carcinoid tumors: Analysis of prognostic factors and survival in 301 patients from a referral center E. T. Janson,' L. Holmberg.i M. Stridsberg," B. Eriksson,' E. Theodorsson.i E. Wilander 4 &
K.Oberg l Departments of Ilnlernal Medicine, 2 Surgery, 3 Clinical Chemistry, "Pathology, University Hospital, Uppsala University, Uppsala, Sweden; of Clrnical Chemistry. University Hospital, Linkbping University. Linkiiping, Sweden
5 Department
Summary
Introduction
According to the site of origin, carcinoid tumors have been divided into foregut (bronchus, stomach, proximal duodenum and pancreas), midgut (distal duodenum to the mid-transverse colon) and hindgut (descending colon and rectum) tumors [I]. The incidence of these rare neoplasms is 0.5-1.5/100,000 [2]. Midgut, and sometimes foregut carcinoid tumors, may be associated with the carcinoid syndrome which comprises diarrhea, flush, carcinoid heart disease with right heart failure, and bronchial constriction [3]. The syndrome usually becomes overt in patients with liver metastases and has been attributed to hormones produced by the tumor, for example serotonin and tachykinins, such as neuropeptide K. The biochemical marker most commonly employed to monitor therapy in midgut carcinoid tumors is the urine serotonin metabolite 5-hydoxyindoleacetic acid (U-5HIAA) [4]. We have previously reported that chromogranin A may be a more sensitive marker in early cases and can thus be used for the primary detection of the disease [5]. Studies from the 1960s and 1970s have reported fiveyear survival rates of 21% in patients with liver metastases, 38% in patients with inoperable nodal or peritoneal metastases [6], and 54% in midgut carcinoid pa-
Key words: carcinoid tumor, chromogranin, prognostic factor, survival, U-5HIAA
tients including all stages of the disease [7]. Recently, McDermott et al. reported a five-year survival of 25% in patients with gastrointestinal carcinoid tumor and liver metastases and 45% in patients with lymph node metastases [8]. They also found by multivariate analysis that female gender was accompanied by a favorable prognosis while the presence of metastases at the time of diagnosis was a bad prognostic factor. In another study the likelihood of death in gastrointestinal carcinoid tumors was found to be related independently to increasing age, advanced stage, location within the large intestine and the occurrence of another malignancy [9]. None of these studies included an analysis of the prognostic value of elevation of the biochemical markers used for diagnosis and monitoring therapy. The aim of this study was to characterize clinical features in untreated patients in a large cohort of patients with carcinoid tumors consecutively referred to one center for diagnosis, treatment and follow-up. Special emphasis was placed on presenting symptoms, hormone production and the distribution of metastases. Survival analyses were performed for the different tumor groups. In midgut carcinoid tumors, the largest group, survival and prognostic factors were also adjusted for tumor burden and correlated to tumor marker levels.
Downloaded from http://annonc.oxfordjournals.org/ at University of Texas at Austin on June 6, 2015
Background: Little is known about factors related to prognosis in patients with carcinoid disease. In this study we have tried to identify such factors. Patients and methods: We have evaluated 301 consecutive carcinoid patients (256 midgut, 39 foregut and six hindgut) referred during 15 years for medical treatment with respect to tumor distribution, hormone production, prognostic factors and survival. Results: Survival was significantly shorter in midgut carcinoid patients with ~ 5 liver metastases or with high levels of urinary 5-hydroxyindoleacetic acid, plasma chromogranin A or neuropeptide K. By univariate analysis, these variables together with the presence of carcinoid syndrome were related to a higher risk of dying. In multivariate analyses, performed
in the 71 patients with full information on all variables, advanced age and plasma chromogranin A > 5000 Ilg/l were independent predictors of overall survival. Conclusions: Poor prognostic factors for midgut carcinoid patients were multiple liver metastases, presence of carcinoid syndrome and high levels of the tumor markers studied. In this study the only independent predictors of bad prognosis in midgut carcinoid patients were advanced age, which however is inherently related to overall survival, and plasma chromogranin A > 5000 Ilg/l. Thus, chromogranin A may prove to be an important prognostic marker for patients with carcinoid tumors.
686 Tab/e 1. Patient characteristics at the time of referral related to the site of the primary tumor.
Site
Midgut Foregut Bronchial Gastric Thymic Hindgut
No.
256 39 23 13 3 6
Males/females
Median age (range) (years)
1331123 17/22
62 (20--85) 57 (18-77)
4/2
68 (54-73)
Tab/e 3. Clinical symptoms in 301 carcinoid patients at referral.
Symptom
No. of patients
%
F1ush a/o diarrhea Abdominal pain Carcinoid heart disease Bronchial cons triction Cough/pneumonia
219 40 35 6 3
74 13 12 2 I
tion including chemotherapy, and 12 received a somatostatin analogue simultaneously. Thirteen patients remained untreated.
Table2. Surgical treatment before start of medical treatment. Methods No. of patients
Resection of primary midgut tumor Laparotomy By-pass of intestinal tumor Total or partial pulmectomy Resection of rectal tumor Total or partial gastrectomy Liver resection Resection of thymic tumor Resection of ovarian tumor
141 21 19 17 6 6 4
3
U-5HIAA was determined in 290 patients according to a method described earlier [15], and calculated as the mean of two 24-hour collections. Plasma levels of chromogranin A [4] and neuropeptide K [16] were measured in 108 and 173 patients, respectively. Pulmonary X-ray, computerized tomography and/or ultrasound investigations were used to evaluate the distribution of metastases. A bonescan was performed if bone metastases were suspected from medical history and an echocardiography was performed in patients with symptoms of a carcinoid heart disease.
3 Statistics
Patients and methods Patients This study includes 301 consecutive carcinoid patients referred to the Department of Internal Medicine, the Endocrine unit, for medical treatment, between January 1978 and June 1993. The study includes all patients treated at the unit during the study period. The inclusion criteria was a histopathologically verified carcinoid tumor. Tumor specimens obtained at operation or by ultrasound-guided biopsy (1.2 mm) were subjected to histological examination and stained with the argyrophil method of Grimelius and the argentaffin method of Masson. Immunohistochemical staining with different antiserum against relevant hormones was also performed [10]. Gender distribution was 154 males and 147 females. There were 256 patients with midgut, 39 patients with foregut and SIX patients with hindgut carcinoid tumors. The median age at diagnosis was 62 years with a range of 18-85 years. For patient characteristics of the different tumor groups see Table 1. Altogether 216 patients (72%) had been operated upon before medical treatment was initiated, for details see Table 2. At referral 147 patients suffered from flush and 189 had diarrhea. A total of 219 patients (74%) had a carcinoid syndrome with flush and/or diarrhea, while only 14% of the midgut carcinoid patients had a carcinoid heart disease detected by echocardiography at the first visit. Symptoms at referral are summarized in Table 3. There were also single patients with nausea, dyspnea, coughing, perspiration, pain from bone metastases and acromegaly. Medical records were reviewed and only data collected at the first visit to the center was analyzed. After the initial data collection, patients received treatment according to different protocols with either interferon-«, somatostatin analogues or chemotherapy [11-14]. Chemotherapy was the only medical treatment used before 1982 while interferon-a and somatostatin analogues have been more used later in this study. A total of 55 patients (including 45 with midgut tumors) received chemotherapy (usually streptozotocin alone or together with 5-fluorouracil or doxorubicin), 47 patients (including 40 with midgut tumors) received a somatostatin analogue (usually octreotide) and 212 (including 172 with midgut tumors) received interferon-a as first-line treatment. Of the interferon-a-treated patients 14 received a combina-
Non-parametric analyses (Kruskal-Wallis and Mann-Whitney) were used for comparison of hormone levels between different groups. Survival from time of diagnosis and initiation of treatment was calculated according to the Kaplan-Meier analysis with death from any cause as outcome, and comparison of survival curves was performed using the Mantel-Cox log-rank test. Survival was also calculated, adjusted for presence of carcinoid heart disease, the extent of disease and for categorized levels of tumor markers including U-5HIAA, chromogranin A and neuropeptide K with the same categories as in the Cox proportional Hazards Model, see below. Calculations were performed using the StatView computer program (Abacus Concepts,
Inc.). The association between different covariates and the risk of dying were evaluated in the Cox proportional Hazards Model. All deaths irrespective of cause were considered an event. Continuous variables were categorized and represented with dummy variables in the models to avoid building assumptions about linear relationships into the models. Plasma chrornogranin A was dichotomized at 5000 ug/l. U-5HIAA was dichotomized at 300 Ilmols/24 hours and neuropeptide K at a level of 16 pmol/1. Patients were categorized into age groups according to quartiles, using patients younger than 53 years of age as the reference category. Stage of disease was divided into patients with no radiological signs of disease (reference group), those WIth lymph node metastases, patients with < 5 liver lesions and patients with ;l: 5 liver metastases. A variable representing the number of months between primary diagnosis and initiation of treatment was included in continuous form to adjust for duration of disease before systemic treatment. Results are represented as Relative Hazards with 95 percent confidence intervals. For age and hormone levels the medians and ranges are given.
Results Tumor staging
The distribution of metastases is summarized in Table 4. Of the 301 patients 103 still had the primary tumor present at admittance. In 253 patients (84%) metastases
Downloaded from http://annonc.oxfordjournals.org/ at University of Texas at Austin on June 6, 2015
Operation
687 Table 4. The distribution of metastases in 301 patients at referral according to the site of the primary tumor. Each patient may have more than one metastatic location.
Lymph nodes
Site
Liver
Bone
CNS'
Skin
Midgut (n : 256) 67 (26%) 194 (76%) 2 (1%) - Foregut, (n: 39)-Bronchial (n : 23) 4 (22%) 17 (74%) 8 (35%) 3 (15%) 2 (9"10) Gastric (n : 13) 3 (23%) 6 (46%) Thymic (n : 3) 2 (67%) 1(33%) Hindgut (n : 6) 4 (67%) 6 (100%) • Abbreviation: CNS - central nervous system.
Tumor
Tumor marker
No. elevated I no. tested
Median
Range'
Midgut
U-5HlAA b Chromogranm Neuropeptide K U-5HIAA Chromogranin Neuropeptide K U-5HIAA Chromogranin Neuropeptide K
187/246 75/86 69/149 12/39
285 2325 13 85 847 7.8 33 727 7.8
3-3182 155-100,000 6-810 18-1428 130-20,000 7.8-1,000 12-70 380-900 7.8-7.8
Foregut
Hindgut
15/19
2/22 015 3/3 0/2
t----------~
• Reference ranges: Urinary 5-hydroxyindoleacetic acid < 80 umol per 24 hours; chromogranin < 350 ug per liter; neuropeptide K < 16 pmol per liter. b Urinary 5-hydroxyindoleacetic acid.
could be detected by computerized tomography and/or ultrasound at referral. Of these 223 (74%) had liver metastases. In 48 patients no tumor could be detected by conventional radiology. However, only 27 of these were considered to be cured by surgery. In the remaining 21 patients either metastases had been detected during surgery but could not be confirmed by postoperative radiology, or elevated biochemical markers indicated the presence of tumor tissue. Tumor markers
The levels of the different tumor markers and reference levels are summarized in Table 5. U-5HIAA was increased in 76% of the patients with midgut and in 48% of the patients with bronchial carcinoid tumors in whom this was measured. One patient with a gastric carcinoid tumor also presented with a borderline increase of U-5HIAA of 87 ~mo1/24 hours. The method for determining plasma chromogranin A levels was not available until 1987, and therefore the number of patients investigated is limited. In 86 midgut carcinoid patients plasma chromogranin A levels were measured and of these 87% had elevated levels while 79% of 19 the patients tested with foregut carcinoid
~,CI '_Y
Figure I. Plasma chromogranin A levels were significantly higher in
midgut patients with ;l: 5 (median 8374 ug/I) as compared to those with < 5 liver metastases (median 959 ug/I) or lymph node metastases (median 451 /lg/l) (P < 0.001). Logarithmic scale. Median values are indicated by horizontal bars and the upper reference range by the horizontal lme.
tumors showed increased values. The plasma chromogranin A levels were significantly higher among patients with multiple (~5) liver metastases, median 8374 ~g/l (range 450-100,000 ug/I), as compared to those with only few [1-4] liver metastases, 959 ug/I (range 18014,200 ug/I), or lymph node metastases, 451 ug/I (range 155-11,200 ug/I), P < 0.001 (Figure 1). Plasma neuropeptide K was measured in all patients from 1986 and onwards giving a total of 149 patients with midgut carcinoid tumors tested, and an increase was seen in 46%. Only two of 22 patients (9%) with foregut carcinoid tumors displayed elevated plasma neuropeptide K. In patients with midgut carcinoid tumors those with a carcinoid heart disease present at referral had significantly higher levels of U-5HIAA, mean 814 as compared to 441 J.llllo1/24 hours, P < 0.001. There was no significant difference in plasma chromogranin A or neuropeptide K levels between these two groups. Survival analyses and prognostic/actors
A total of 157 patients died during follow-up. There were 96 carcinoid-related deaths while 16 patients died from other known causes such as cardiovascular events. In 45 patients no autopsy was performed and the cause of death was assessed as unknown.
Downloaded from http://annonc.oxfordjournals.org/ at University of Texas at Austin on June 6, 2015
Table 5. Levels and ranges of tumor markers according to the site of the primary tumor.
688
1
-~
j ~
1 () 1L.,-----.--~_,____.__,____.___,____.__,_____,__,___..______,__.....___,____.,..______,_ f
i
•
i
(j
51)
l'jl.1
1"'-1)
21(,
=
-ir~1
,(,1,
~)(J
4)1)
Figure 3. There was a significant difference in survival between patients with few liver metastases (1, n =48) and those with lymph node metastases or a primary tumor (2, n =23) as compared to those with> 5 liver metastases (3, n =138). P < 0.001. FIve-year survival in patients with lymph node metastases was 73%, in patients with few liver lesions 79% and in patients with massive liver involvement 47%.
ease present at referral the median survival from diagnosis was 46 months as compared to 94 months for those without this complication. This difference was, however, not significant, P =0.09. In the univariate analyses the risk of dying increased rapidly with age, Table 6. There was also a higher risk associated with extensive liver involvement (Relative Hazard 3.0), the presence of carcinoid syndrome (Relative Hazard 2.9) and U-5HIAA > 300 Ilmol/24 hours (Relative Hazard 1.8). High levels of plasma chrornogranin A and neuropeptide K were associated with higher risk of dying in the 83 and 146 patients, respectively, that could be analyzed regarding these parameters. Sex and duration of disease prior to systemic treatment were not clearly related to prognosis. In the multivariate model excluding plasma chromogranin A and neuropeptide K as variables in patients with midgut carcinoid tumors, only age was clearly statistically related to prognosis (Table 6). There were still estimates of Relative Hazard above 1.0 tied to advanced metastatic disease of the liver, to the presence of carcinoid syndrome and to high U-5HIAA levels but none of the Relative Hazards were above 2.0 and none reached statistical significance. On multivariate analysis in the 71 patients for whom information was present on all variables including plasma chromogranin A and neuropeptide K, the pattern was essentially the same but the estimate for liver involvement rose to 4.8 (P =0.2) and the Relative Hazard for plasma chromogranin A > 5000 J,lgll was 4.4 (P 0.02).
=
Discussion In this series only 9% of the patients were considered to have been cured by surgery at referral. This is a low frequency as compared to other series [6, 17, 18], but
Downloaded from http://annonc.oxfordjournals.org/ at University of Texas at Austin on June 6, 2015
For midgut carcinoid patients the median survival was 92 months from diagnosis, for patients with foregut carcinoid tumors 80 months and for patients with hindgut tumors 64 months, Figure 2. Five-year survival was 63% for midgut carcinoid patients and 60% for the foregut carcinoid group. The median survival from the start of treatment was 67 months in the midgut carcinoid group and differed significantly from the median survival of 26 months for patients with malignant foregut carcinoid tumors (P < 0.001). The median survival from start of treatment in the six hindgut carcinoid patients was 22 months. In univariate analyses the relative hazard for death in patients with foregut or hindgut tumors was 2.2 (95% confidence interval 1.4-3.3) as compared to midgut carcinoid patients (P < 0.001). In midgut carcinoid patients survival was also calculated stratified according to the distribution of disease, Figure 3. Patients with only a primary tumor and/or lymph node metastases had a median survival of 108 months (five-year survival 73%), while the median survival from diagnosis in patients with few (1-4) liver metastases was 159 months (five-year survival 79%). In patients with extensive hepatic disease (five or more metastases) the median survival was 53 months (fiveyear survival 47%) which was significantly shorter as compared with the other two groups (P < 0.001). The median survival in midgut carcinoid patients with U-5HLAA > 300 llmol/24 hours was significantly shorter, 45 months, than the 72 months in patients with lower levels, P 0.001. Patients with plasma chromogranin A levels < 5000 ug/I had a significantly longer median survival (57 months) as compared to those with higher levels (33 months), P < 0.001. Analyses of survival performed with respect to neuropeptide K levels at referral showed that patients with normal levels ( < 16 pmolll) had a significantly longer median survival (72 months) as compared to those with increased levels (55 months), P =0.04. In midgut carcinoid patients with carcinoid heart dis-
1 ,'
\L'nlh--
, M(jfitns
Figure 2. Survival from the time of diagnosis. No sigmficant difference In survival was detected; I = midgut; 2 = foregut; five-year survival was 63% in midgut carcinoid patients and 60% among foregut carcinoid patients.
:'1
689 Table 6. Relative Hazards with 95% confidence intervals obtained in Cox proportional hazards models of overall survival in patients with midgut carcinoid tumors.
Variable
Univariate RH (95% CI)
Multivariate RH (95% CI)
Multivariate"
1.0 referent 3.8 (2.0-7.I)b
1.0 referent 4.2 (2.1-8.4)b 5. n2~6-9 .9)~ 8.8 (4.3-17.9)b 0.9 (0.6-1.3) 1.0 (0.9-1.1) 1.0 referent 1.1 (0.4--2.8) 0.7 (0.3-1.6) 1.7 (0.8-3.6) 1.9 (0.8-4.3)
1.0 referent 8.2 (1.3-51.5t '[0(0.5-28.9) 15.4 (2.I-lll.5)b 2.3 (0.8-6.5) 1.0 (0.9-1.1) 1.0 referent 0.3 (0.02-4.1) 4.8 (0.4--51.9) 1.9 (0.2-19.1) 1.5 (0.3-8.0)
Age
4.8V·~b
7.7 (4.1-14.5)b 0.8 (0.6-1.2) 1.0 (0.9-1.1) 1.0 referent 1.5 (0.6-3.8) 1.3 (0.6-2.7) 3.0 (1.6-5.9)b 2.9 (1.4-6.0)b 1.8 (1.2-2.5)b 4.5 (2.1-9.5)b 1.7 (I 0-2.7t
I 3 (0.9-2.0)
0.9 (0.3-3.2) 4.4 (1.3-15.4)C 1.0 (0.3-3.3)
Abbreviations: RH - relative hazard; CI - confidence interval. • In the multivariate analysis including all factors, complete information was available on 71 patients. b p < 0.05. C P < 0.01.
may depend on our center being a national referral center for medical treatment of carcinoid tumors. Patients who have been successfully operated upon with resection of all visible tumor are seldom referred for further evaluation, and there is therefore a predominance of patients with malignant disease with an advanced stage in this study. There are few patients with carcinoid heart disease in this study. However, we have only reported patients with a confirming echocardiography study performed at the first visit to our department, and thus there may be more patients included in the material with this complication to the disease. In other studies higher numbers of patients with carcinoid heart disease have been reported, but these studies include patients at different stages of the disease, that is the carcinoid heart disease may be diagnosed several years after medical treatment was initiated [19, 20]. We found that levels of U-5HIAA were significantly higher among patients with as compared to those without carcinoid heart disease. We were not able to find any difference in the group with carcinoid heart disease as compared to midgut carcinoid patients without this feature in terms of impaired survival or difference in other hormone levels. However, we had low power to determine the importance of such factors. At referral 74% of the patients presented with liver and 27% with lymph node metastases. The relatively low frequency of lymph node metastases detected may depend on surgical removal in a high number of patients, but also on the low sensitivity of computerized tomography and ultrasound investigations to detect abdominal lymph node metastases. In the future new investigation methods including somatostatin receptor scintigraphy and positron emission tomography may prove to be more sensitive and give a better staging of the disease [21-23].
U-5HIAA is currently used to monitor therapy in midgut carcinoid patients, since the correlation between increased levels and symptoms of the carcinoid syndrome is strong. It has been proposed that plasma chromogranin A levels reflect tumor size [24]. Plasma chromogranin A levels were increased in 87% of the patients with midgut carcinoid tumors while U-5HIAA was increased in 76%. A combination of these two tumor markers may be an option to diagnose and monitor therapy in midgut carcinoid patients. High levels of all the tumor markers studied, could be associated with shorter duration of survival and an increased Relative Hazard in the univariate analysis. Plasma chromogranin A was significantly higher in patients with widespread disease and levels > 5000 ug/l emerged as an independent factor predicting death in the multivariate analysis. This might reflect a more advanced disease with a larger tumor burden but massive liver involvement did not reach a statistical significance in the multivariate model. However, there were only 71 patients included in the multivariate analysis and these results will have to be confirmed in future studies. Survival data showed a median survival from diagnosis in patients with midgut tumors of > 7 years. However, if tumor burden was taken into account, median survival from diagnosis in patients with ~ 5 liver metastases at referral was about four years, while those with few liver metastases or only lymph node metastases had an estimated median survival of more than 13 and nine years, respectively. The reason for the longer survival in patients with a limited number of liver metastases as compared to those with lymph node metastases is not completely clear. However, remaining lymph node metastases can cause intestinal obstruction and entrapment of the intestinal blood supply. This
Downloaded from http://annonc.oxfordjournals.org/ at University of Texas at Austin on June 6, 2015
< 53 years 53-62 years 63=-69 years ~ 70 years Sex (males vs. females) -Duration of disease No metastases Lymph node metastases Few liver metastases > 5 liver metastases Carcinoid syndrome (yes vs, no) Urinary 5-hydroxyindoleacetic acid (> 300 vs. < 300 umol per 24 hours) P-chromogranin A ( > 5000 vs. < 5000 IJg per hter) P-neuropeptide K (> 16 vs. < 16 pmol per liter)
690
5.
6. 7. 8.
9.
10. II.
12.
13.
14.
15.
16.
17. 18. 19.
20.
21.
22.
23.
24.
References I. Williams ED, Sandler M. The classification of carcinoid tumours. Lancet 1963; I: 238-9. 2. Norheim I, Oberg K, Theodorsson-Norheim E et al. Malignant carcinoid tumors: An analysis of 103patients with regard to tumor localization, hormone production and survival. Ann Surg 1987; 206: 115-25. 3. Grahame-Smith DG. The Carcinoid Syndrome. Am J Cardiol 1968;21: 376-7. 4. Feldman JM and O'Dorisio TM. Role of neuropeptides and
serotonin in the diagnosis of carcinoid tumors. Am J Med 1986; 81:41-8. Eriksson B, Amberg H, Oberg K et aL A polyclonal antiserum against chromogranin A and B - a new sensitive marker for neuroendocrine tumours. Acta Endocrinol1990; 122: 145-55. Moertel CG, Sauer WG, Dockerty MB et al. Life history of the carcinoid tumor of the small intestine. Cancer 1961;14: 901-12. Godwin JD. Carcinoid tumors. An analysis of 2837cases. Cancer 1975; 36: 560-9. McDermott EWM, Guduric B, Brennan ME Prognostic variables in patients with gastrointestinal carcinoid tumours. Br J Surg 1994;81:1007-9. Greenberg RS, Baumgarten DA, Clark WS et al. Prognostic factors for gastrointestinal and bronchopulmonary carcinoid tumors. Cancer 1987;60: 2476-83. Wilander E, Lundqvist M, Oberg K. Gastrointestinal carcinoid tumours. Progr Histochem Cytochem 1989; 19:1-85. Oberg K, Funa K, Aim G. Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med 1983; 309: 129-33. Oberg K, Norheim I, Lundqvist G et al. Cytotoxic treatment in patients with malignant carcinoid tumors. Response to streptozocin - alone or in combination with 5-FU. Acta Oncol 1987;26: 429-32. Janson ET, Ronnblom L, Ahlstrom H et aLTreatment with alphainterferon versus alpha-interferon in combination with streptozocin and doxorubicin in patients with malignant carcinoid tumors: A randomized trial. Ann OncoI1992; 3: 635-8. Janson ET, Ahlstrom H, Andersson T et aL Octreotide and interferon alfa: A new combination for the treatment of malignant carcinoid tumors. Eur J Cancer 1992;28A: 1647-50. Wahlund KG, Edlen B. Simple and rapid determination of 5-hydroxyindole-3-acetic acid in urine by direct injection on a liquid chromatographic column. Clin Chim Acta 1981; 110: 71-6. Theodorsson-Norheim E, Norheim I, Oberg K et aL Neuropeptide K: A major tachykinin in plasma and tumor tissues from carcinoid patients. Biochem Biophys Res Comm 1985; 131: 77-83. Moertel CG. An odyssey in the land ofsmall tumors. J Clin Oncol 1987; 5: 1503-22. Hajdu SI,Winawer SJ, Myers WPL. Carcinoid tumors. A study of 204 cases. Am J Clin Patho11974; 61: 521-8. . Pellikka PA, Tajik AI, Khandheria BK et aL Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients. Circulation 1993;87: 1188-96. Lundin L. Norheim I. Landelius J et al, Carcinoid heart disease: Relationship od circulating vasoactive substances to ultrasound detectable abnormalities. Circulation 1988;77: 264-9. Krenning EP, Bakker WH, Kooij PPM et aL Somatostatin receptor scintigraphy with [lllIn-DTPA-D-Phelj-octreotide in man: Metabolism s . dosimetry and comparison with [123I-Tyr3j-octreotide. J Nucl Med 1992;33: 652-8. Westlin JE, Janson ET, Amberg H et aL Somatostatin receptor scintigraphy of carcinoid tumours using the [lllIn-DTPA-DPhelj-octreotide. Acta Onco11993; 32: 783-,.6. Eriksson B, Bergstrom M, Lilja A et al. Positron emission tomography (PET) in neuroendocrine gastrointestinal tumors. Acta Onco11993;32: 189-96. Hsiao R, Seeger RC, Yu AL et al. Chromogranin A in children with neuroblastoma. Serum concentration parallels disease stage and predicts survival. J Clin Invest 1990; 85: 1555-9.
Received 14April 1997;accepted 10June 1997.
Correspondence to: E. T. Janson, MD, Dr Med Sc Dept of Internal Medicine University Hospital S-751 85 Uppsala Sweden
Downloaded from http://annonc.oxfordjournals.org/ at University of Texas at Austin on June 6, 2015
should be compared to the rather indolent course of a few liver metastases which may be successfully medically treated. Although there was a tendency towards a higher Relative Hazard inpatients with advanced liver involvement it was not statistically significant. The five-year survival of those with the most extensive disease was 47% which may be compared with a five-year survival of 25% in patients with liver metastases in a recently published report [8], or 38% in Moertel's material [6]. The difference may be due to several factors which are impossible to disentangle in a retrospective case-study: different selection of cases (i.e., referral hospital vs. other); earlier diagnosis in later years (i.e., lead time bias); improved surgical results due to both improved techniques and more appropriate selection of cases; or improved medical treatment (c-interferon, somatostatin analogues). Gender did not emerge as a predictive factor. In a previous study females showed a better prognosis while age did not influence the survival [8]. Such differences might reflect differences in the group of patients analyzed, with our material consisting almost exclusively of patients with malignant carcinoid tumors. Since overall survival was studied, age was inherently related to prognosis and should be seen as a co-variate in the multivariate analyses. To study age in relation to tumor progression, disease specific survival has to be analyzed. In our series, however,45 cases had deaths with unknown causes (although many of these probably had a carcinoid related death cause) and the 16cases with cardiovascular events are difficult to classifyas dependent or independent from the carcinoid disease. Thus, an analyses of disease specific survival would suffer from misclassification of the end-point. In conclusion we have found that the median survival in foregut carcinoid patients after start of therapy was signifianctly shorter as compared to patients withmidgut carcinoid. We also found a correlation of plasma chromogranin A levels to tumor burden. In the multivariate .analyses, plasma chromogranin A > 5000 ·lJ.gll and advanced age were found to be independent predictors of survival. Although the prognosis is generally good for patients with carcinoid tumors, patients with extensive liver involvement or high plasma chromogranin A levels do worse and in this group future efforts should be made to improve therapy.
Original article Carcinoid tumors: Analysis of prognostic factors and survival in 301 patients from a referral center E. T. Janson,' L. Holmberg.i M. Stridsberg," B. Eriksson,' E. Theodorsson.i E. Wilander 4 &
K.Oberg l Departments of Ilnlernal Medicine, 2 Surgery, 3 Clinical Chemistry, "Pathology, University Hospital, Uppsala University, Uppsala, Sweden; of Clrnical Chemistry. University Hospital, Linkbping University. Linkiiping, Sweden
5 Department
Summary
Introduction
According to the site of origin, carcinoid tumors have been divided into foregut (bronchus, stomach, proximal duodenum and pancreas), midgut (distal duodenum to the mid-transverse colon) and hindgut (descending colon and rectum) tumors [I]. The incidence of these rare neoplasms is 0.5-1.5/100,000 [2]. Midgut, and sometimes foregut carcinoid tumors, may be associated with the carcinoid syndrome which comprises diarrhea, flush, carcinoid heart disease with right heart failure, and bronchial constriction [3]. The syndrome usually becomes overt in patients with liver metastases and has been attributed to hormones produced by the tumor, for example serotonin and tachykinins, such as neuropeptide K. The biochemical marker most commonly employed to monitor therapy in midgut carcinoid tumors is the urine serotonin metabolite 5-hydoxyindoleacetic acid (U-5HIAA) [4]. We have previously reported that chromogranin A may be a more sensitive marker in early cases and can thus be used for the primary detection of the disease [5]. Studies from the 1960s and 1970s have reported fiveyear survival rates of 21% in patients with liver metastases, 38% in patients with inoperable nodal or peritoneal metastases [6], and 54% in midgut carcinoid pa-
Key words: carcinoid tumor, chromogranin, prognostic factor, survival, U-5HIAA
tients including all stages of the disease [7]. Recently, McDermott et al. reported a five-year survival of 25% in patients with gastrointestinal carcinoid tumor and liver metastases and 45% in patients with lymph node metastases [8]. They also found by multivariate analysis that female gender was accompanied by a favorable prognosis while the presence of metastases at the time of diagnosis was a bad prognostic factor. In another study the likelihood of death in gastrointestinal carcinoid tumors was found to be related independently to increasing age, advanced stage, location within the large intestine and the occurrence of another malignancy [9]. None of these studies included an analysis of the prognostic value of elevation of the biochemical markers used for diagnosis and monitoring therapy. The aim of this study was to characterize clinical features in untreated patients in a large cohort of patients with carcinoid tumors consecutively referred to one center for diagnosis, treatment and follow-up. Special emphasis was placed on presenting symptoms, hormone production and the distribution of metastases. Survival analyses were performed for the different tumor groups. In midgut carcinoid tumors, the largest group, survival and prognostic factors were also adjusted for tumor burden and correlated to tumor marker levels.
Downloaded from http://annonc.oxfordjournals.org/ at University of Texas at Austin on June 6, 2015
Background: Little is known about factors related to prognosis in patients with carcinoid disease. In this study we have tried to identify such factors. Patients and methods: We have evaluated 301 consecutive carcinoid patients (256 midgut, 39 foregut and six hindgut) referred during 15 years for medical treatment with respect to tumor distribution, hormone production, prognostic factors and survival. Results: Survival was significantly shorter in midgut carcinoid patients with ~ 5 liver metastases or with high levels of urinary 5-hydroxyindoleacetic acid, plasma chromogranin A or neuropeptide K. By univariate analysis, these variables together with the presence of carcinoid syndrome were related to a higher risk of dying. In multivariate analyses, performed
in the 71 patients with full information on all variables, advanced age and plasma chromogranin A > 5000 Ilg/l were independent predictors of overall survival. Conclusions: Poor prognostic factors for midgut carcinoid patients were multiple liver metastases, presence of carcinoid syndrome and high levels of the tumor markers studied. In this study the only independent predictors of bad prognosis in midgut carcinoid patients were advanced age, which however is inherently related to overall survival, and plasma chromogranin A > 5000 Ilg/l. Thus, chromogranin A may prove to be an important prognostic marker for patients with carcinoid tumors.
686 Tab/e 1. Patient characteristics at the time of referral related to the site of the primary tumor.
Site
Midgut Foregut Bronchial Gastric Thymic Hindgut
No.
256 39 23 13 3 6
Males/females
Median age (range) (years)
1331123 17/22
62 (20--85) 57 (18-77)
4/2
68 (54-73)
Tab/e 3. Clinical symptoms in 301 carcinoid patients at referral.
Symptom
No. of patients
%
F1ush a/o diarrhea Abdominal pain Carcinoid heart disease Bronchial cons triction Cough/pneumonia
219 40 35 6 3
74 13 12 2 I
tion including chemotherapy, and 12 received a somatostatin analogue simultaneously. Thirteen patients remained untreated.
Table2. Surgical treatment before start of medical treatment. Methods No. of patients
Resection of primary midgut tumor Laparotomy By-pass of intestinal tumor Total or partial pulmectomy Resection of rectal tumor Total or partial gastrectomy Liver resection Resection of thymic tumor Resection of ovarian tumor
141 21 19 17 6 6 4
3
U-5HIAA was determined in 290 patients according to a method described earlier [15], and calculated as the mean of two 24-hour collections. Plasma levels of chromogranin A [4] and neuropeptide K [16] were measured in 108 and 173 patients, respectively. Pulmonary X-ray, computerized tomography and/or ultrasound investigations were used to evaluate the distribution of metastases. A bonescan was performed if bone metastases were suspected from medical history and an echocardiography was performed in patients with symptoms of a carcinoid heart disease.
3 Statistics
Patients and methods Patients This study includes 301 consecutive carcinoid patients referred to the Department of Internal Medicine, the Endocrine unit, for medical treatment, between January 1978 and June 1993. The study includes all patients treated at the unit during the study period. The inclusion criteria was a histopathologically verified carcinoid tumor. Tumor specimens obtained at operation or by ultrasound-guided biopsy (1.2 mm) were subjected to histological examination and stained with the argyrophil method of Grimelius and the argentaffin method of Masson. Immunohistochemical staining with different antiserum against relevant hormones was also performed [10]. Gender distribution was 154 males and 147 females. There were 256 patients with midgut, 39 patients with foregut and SIX patients with hindgut carcinoid tumors. The median age at diagnosis was 62 years with a range of 18-85 years. For patient characteristics of the different tumor groups see Table 1. Altogether 216 patients (72%) had been operated upon before medical treatment was initiated, for details see Table 2. At referral 147 patients suffered from flush and 189 had diarrhea. A total of 219 patients (74%) had a carcinoid syndrome with flush and/or diarrhea, while only 14% of the midgut carcinoid patients had a carcinoid heart disease detected by echocardiography at the first visit. Symptoms at referral are summarized in Table 3. There were also single patients with nausea, dyspnea, coughing, perspiration, pain from bone metastases and acromegaly. Medical records were reviewed and only data collected at the first visit to the center was analyzed. After the initial data collection, patients received treatment according to different protocols with either interferon-«, somatostatin analogues or chemotherapy [11-14]. Chemotherapy was the only medical treatment used before 1982 while interferon-a and somatostatin analogues have been more used later in this study. A total of 55 patients (including 45 with midgut tumors) received chemotherapy (usually streptozotocin alone or together with 5-fluorouracil or doxorubicin), 47 patients (including 40 with midgut tumors) received a somatostatin analogue (usually octreotide) and 212 (including 172 with midgut tumors) received interferon-a as first-line treatment. Of the interferon-a-treated patients 14 received a combina-
Non-parametric analyses (Kruskal-Wallis and Mann-Whitney) were used for comparison of hormone levels between different groups. Survival from time of diagnosis and initiation of treatment was calculated according to the Kaplan-Meier analysis with death from any cause as outcome, and comparison of survival curves was performed using the Mantel-Cox log-rank test. Survival was also calculated, adjusted for presence of carcinoid heart disease, the extent of disease and for categorized levels of tumor markers including U-5HIAA, chromogranin A and neuropeptide K with the same categories as in the Cox proportional Hazards Model, see below. Calculations were performed using the StatView computer program (Abacus Concepts,
Inc.). The association between different covariates and the risk of dying were evaluated in the Cox proportional Hazards Model. All deaths irrespective of cause were considered an event. Continuous variables were categorized and represented with dummy variables in the models to avoid building assumptions about linear relationships into the models. Plasma chrornogranin A was dichotomized at 5000 ug/l. U-5HIAA was dichotomized at 300 Ilmols/24 hours and neuropeptide K at a level of 16 pmol/1. Patients were categorized into age groups according to quartiles, using patients younger than 53 years of age as the reference category. Stage of disease was divided into patients with no radiological signs of disease (reference group), those WIth lymph node metastases, patients with < 5 liver lesions and patients with ;l: 5 liver metastases. A variable representing the number of months between primary diagnosis and initiation of treatment was included in continuous form to adjust for duration of disease before systemic treatment. Results are represented as Relative Hazards with 95 percent confidence intervals. For age and hormone levels the medians and ranges are given.
Results Tumor staging
The distribution of metastases is summarized in Table 4. Of the 301 patients 103 still had the primary tumor present at admittance. In 253 patients (84%) metastases
Downloaded from http://annonc.oxfordjournals.org/ at University of Texas at Austin on June 6, 2015
Operation
687 Table 4. The distribution of metastases in 301 patients at referral according to the site of the primary tumor. Each patient may have more than one metastatic location.
Lymph nodes
Site
Liver
Bone
CNS'
Skin
Midgut (n : 256) 67 (26%) 194 (76%) 2 (1%) - Foregut, (n: 39)-Bronchial (n : 23) 4 (22%) 17 (74%) 8 (35%) 3 (15%) 2 (9"10) Gastric (n : 13) 3 (23%) 6 (46%) Thymic (n : 3) 2 (67%) 1(33%) Hindgut (n : 6) 4 (67%) 6 (100%) • Abbreviation: CNS - central nervous system.
Tumor
Tumor marker
No. elevated I no. tested
Median
Range'
Midgut
U-5HlAA b Chromogranm Neuropeptide K U-5HIAA Chromogranin Neuropeptide K U-5HIAA Chromogranin Neuropeptide K
187/246 75/86 69/149 12/39
285 2325 13 85 847 7.8 33 727 7.8
3-3182 155-100,000 6-810 18-1428 130-20,000 7.8-1,000 12-70 380-900 7.8-7.8
Foregut
Hindgut
15/19
2/22 015 3/3 0/2
t----------~
• Reference ranges: Urinary 5-hydroxyindoleacetic acid < 80 umol per 24 hours; chromogranin < 350 ug per liter; neuropeptide K < 16 pmol per liter. b Urinary 5-hydroxyindoleacetic acid.
could be detected by computerized tomography and/or ultrasound at referral. Of these 223 (74%) had liver metastases. In 48 patients no tumor could be detected by conventional radiology. However, only 27 of these were considered to be cured by surgery. In the remaining 21 patients either metastases had been detected during surgery but could not be confirmed by postoperative radiology, or elevated biochemical markers indicated the presence of tumor tissue. Tumor markers
The levels of the different tumor markers and reference levels are summarized in Table 5. U-5HIAA was increased in 76% of the patients with midgut and in 48% of the patients with bronchial carcinoid tumors in whom this was measured. One patient with a gastric carcinoid tumor also presented with a borderline increase of U-5HIAA of 87 ~mo1/24 hours. The method for determining plasma chromogranin A levels was not available until 1987, and therefore the number of patients investigated is limited. In 86 midgut carcinoid patients plasma chromogranin A levels were measured and of these 87% had elevated levels while 79% of 19 the patients tested with foregut carcinoid
~,CI '_Y
Figure I. Plasma chromogranin A levels were significantly higher in
midgut patients with ;l: 5 (median 8374 ug/I) as compared to those with < 5 liver metastases (median 959 ug/I) or lymph node metastases (median 451 /lg/l) (P < 0.001). Logarithmic scale. Median values are indicated by horizontal bars and the upper reference range by the horizontal lme.
tumors showed increased values. The plasma chromogranin A levels were significantly higher among patients with multiple (~5) liver metastases, median 8374 ~g/l (range 450-100,000 ug/I), as compared to those with only few [1-4] liver metastases, 959 ug/I (range 18014,200 ug/I), or lymph node metastases, 451 ug/I (range 155-11,200 ug/I), P < 0.001 (Figure 1). Plasma neuropeptide K was measured in all patients from 1986 and onwards giving a total of 149 patients with midgut carcinoid tumors tested, and an increase was seen in 46%. Only two of 22 patients (9%) with foregut carcinoid tumors displayed elevated plasma neuropeptide K. In patients with midgut carcinoid tumors those with a carcinoid heart disease present at referral had significantly higher levels of U-5HIAA, mean 814 as compared to 441 J.llllo1/24 hours, P < 0.001. There was no significant difference in plasma chromogranin A or neuropeptide K levels between these two groups. Survival analyses and prognostic/actors
A total of 157 patients died during follow-up. There were 96 carcinoid-related deaths while 16 patients died from other known causes such as cardiovascular events. In 45 patients no autopsy was performed and the cause of death was assessed as unknown.
Downloaded from http://annonc.oxfordjournals.org/ at University of Texas at Austin on June 6, 2015
Table 5. Levels and ranges of tumor markers according to the site of the primary tumor.
688
1
-~
j ~
1 () 1L.,-----.--~_,____.__,____.___,____.__,_____,__,___..______,__.....___,____.,..______,_ f
i
•
i
(j
51)
l'jl.1
1"'-1)
21(,
=
-ir~1
,(,1,
~)(J
4)1)
Figure 3. There was a significant difference in survival between patients with few liver metastases (1, n =48) and those with lymph node metastases or a primary tumor (2, n =23) as compared to those with> 5 liver metastases (3, n =138). P < 0.001. FIve-year survival in patients with lymph node metastases was 73%, in patients with few liver lesions 79% and in patients with massive liver involvement 47%.
ease present at referral the median survival from diagnosis was 46 months as compared to 94 months for those without this complication. This difference was, however, not significant, P =0.09. In the univariate analyses the risk of dying increased rapidly with age, Table 6. There was also a higher risk associated with extensive liver involvement (Relative Hazard 3.0), the presence of carcinoid syndrome (Relative Hazard 2.9) and U-5HIAA > 300 Ilmol/24 hours (Relative Hazard 1.8). High levels of plasma chrornogranin A and neuropeptide K were associated with higher risk of dying in the 83 and 146 patients, respectively, that could be analyzed regarding these parameters. Sex and duration of disease prior to systemic treatment were not clearly related to prognosis. In the multivariate model excluding plasma chromogranin A and neuropeptide K as variables in patients with midgut carcinoid tumors, only age was clearly statistically related to prognosis (Table 6). There were still estimates of Relative Hazard above 1.0 tied to advanced metastatic disease of the liver, to the presence of carcinoid syndrome and to high U-5HIAA levels but none of the Relative Hazards were above 2.0 and none reached statistical significance. On multivariate analysis in the 71 patients for whom information was present on all variables including plasma chromogranin A and neuropeptide K, the pattern was essentially the same but the estimate for liver involvement rose to 4.8 (P =0.2) and the Relative Hazard for plasma chromogranin A > 5000 J,lgll was 4.4 (P 0.02).
=
Discussion In this series only 9% of the patients were considered to have been cured by surgery at referral. This is a low frequency as compared to other series [6, 17, 18], but
Downloaded from http://annonc.oxfordjournals.org/ at University of Texas at Austin on June 6, 2015
For midgut carcinoid patients the median survival was 92 months from diagnosis, for patients with foregut carcinoid tumors 80 months and for patients with hindgut tumors 64 months, Figure 2. Five-year survival was 63% for midgut carcinoid patients and 60% for the foregut carcinoid group. The median survival from the start of treatment was 67 months in the midgut carcinoid group and differed significantly from the median survival of 26 months for patients with malignant foregut carcinoid tumors (P < 0.001). The median survival from start of treatment in the six hindgut carcinoid patients was 22 months. In univariate analyses the relative hazard for death in patients with foregut or hindgut tumors was 2.2 (95% confidence interval 1.4-3.3) as compared to midgut carcinoid patients (P < 0.001). In midgut carcinoid patients survival was also calculated stratified according to the distribution of disease, Figure 3. Patients with only a primary tumor and/or lymph node metastases had a median survival of 108 months (five-year survival 73%), while the median survival from diagnosis in patients with few (1-4) liver metastases was 159 months (five-year survival 79%). In patients with extensive hepatic disease (five or more metastases) the median survival was 53 months (fiveyear survival 47%) which was significantly shorter as compared with the other two groups (P < 0.001). The median survival in midgut carcinoid patients with U-5HLAA > 300 llmol/24 hours was significantly shorter, 45 months, than the 72 months in patients with lower levels, P 0.001. Patients with plasma chromogranin A levels < 5000 ug/I had a significantly longer median survival (57 months) as compared to those with higher levels (33 months), P < 0.001. Analyses of survival performed with respect to neuropeptide K levels at referral showed that patients with normal levels ( < 16 pmolll) had a significantly longer median survival (72 months) as compared to those with increased levels (55 months), P =0.04. In midgut carcinoid patients with carcinoid heart dis-
1 ,'
\L'nlh--
, M(jfitns
Figure 2. Survival from the time of diagnosis. No sigmficant difference In survival was detected; I = midgut; 2 = foregut; five-year survival was 63% in midgut carcinoid patients and 60% among foregut carcinoid patients.
:'1
689 Table 6. Relative Hazards with 95% confidence intervals obtained in Cox proportional hazards models of overall survival in patients with midgut carcinoid tumors.
Variable
Univariate RH (95% CI)
Multivariate RH (95% CI)
Multivariate"
1.0 referent 3.8 (2.0-7.I)b
1.0 referent 4.2 (2.1-8.4)b 5. n2~6-9 .9)~ 8.8 (4.3-17.9)b 0.9 (0.6-1.3) 1.0 (0.9-1.1) 1.0 referent 1.1 (0.4--2.8) 0.7 (0.3-1.6) 1.7 (0.8-3.6) 1.9 (0.8-4.3)
1.0 referent 8.2 (1.3-51.5t '[0(0.5-28.9) 15.4 (2.I-lll.5)b 2.3 (0.8-6.5) 1.0 (0.9-1.1) 1.0 referent 0.3 (0.02-4.1) 4.8 (0.4--51.9) 1.9 (0.2-19.1) 1.5 (0.3-8.0)
Age
4.8V·~b
7.7 (4.1-14.5)b 0.8 (0.6-1.2) 1.0 (0.9-1.1) 1.0 referent 1.5 (0.6-3.8) 1.3 (0.6-2.7) 3.0 (1.6-5.9)b 2.9 (1.4-6.0)b 1.8 (1.2-2.5)b 4.5 (2.1-9.5)b 1.7 (I 0-2.7t
I 3 (0.9-2.0)
0.9 (0.3-3.2) 4.4 (1.3-15.4)C 1.0 (0.3-3.3)
Abbreviations: RH - relative hazard; CI - confidence interval. • In the multivariate analysis including all factors, complete information was available on 71 patients. b p < 0.05. C P < 0.01.
may depend on our center being a national referral center for medical treatment of carcinoid tumors. Patients who have been successfully operated upon with resection of all visible tumor are seldom referred for further evaluation, and there is therefore a predominance of patients with malignant disease with an advanced stage in this study. There are few patients with carcinoid heart disease in this study. However, we have only reported patients with a confirming echocardiography study performed at the first visit to our department, and thus there may be more patients included in the material with this complication to the disease. In other studies higher numbers of patients with carcinoid heart disease have been reported, but these studies include patients at different stages of the disease, that is the carcinoid heart disease may be diagnosed several years after medical treatment was initiated [19, 20]. We found that levels of U-5HIAA were significantly higher among patients with as compared to those without carcinoid heart disease. We were not able to find any difference in the group with carcinoid heart disease as compared to midgut carcinoid patients without this feature in terms of impaired survival or difference in other hormone levels. However, we had low power to determine the importance of such factors. At referral 74% of the patients presented with liver and 27% with lymph node metastases. The relatively low frequency of lymph node metastases detected may depend on surgical removal in a high number of patients, but also on the low sensitivity of computerized tomography and ultrasound investigations to detect abdominal lymph node metastases. In the future new investigation methods including somatostatin receptor scintigraphy and positron emission tomography may prove to be more sensitive and give a better staging of the disease [21-23].
U-5HIAA is currently used to monitor therapy in midgut carcinoid patients, since the correlation between increased levels and symptoms of the carcinoid syndrome is strong. It has been proposed that plasma chromogranin A levels reflect tumor size [24]. Plasma chromogranin A levels were increased in 87% of the patients with midgut carcinoid tumors while U-5HIAA was increased in 76%. A combination of these two tumor markers may be an option to diagnose and monitor therapy in midgut carcinoid patients. High levels of all the tumor markers studied, could be associated with shorter duration of survival and an increased Relative Hazard in the univariate analysis. Plasma chromogranin A was significantly higher in patients with widespread disease and levels > 5000 ug/l emerged as an independent factor predicting death in the multivariate analysis. This might reflect a more advanced disease with a larger tumor burden but massive liver involvement did not reach a statistical significance in the multivariate model. However, there were only 71 patients included in the multivariate analysis and these results will have to be confirmed in future studies. Survival data showed a median survival from diagnosis in patients with midgut tumors of > 7 years. However, if tumor burden was taken into account, median survival from diagnosis in patients with ~ 5 liver metastases at referral was about four years, while those with few liver metastases or only lymph node metastases had an estimated median survival of more than 13 and nine years, respectively. The reason for the longer survival in patients with a limited number of liver metastases as compared to those with lymph node metastases is not completely clear. However, remaining lymph node metastases can cause intestinal obstruction and entrapment of the intestinal blood supply. This
Downloaded from http://annonc.oxfordjournals.org/ at University of Texas at Austin on June 6, 2015
< 53 years 53-62 years 63=-69 years ~ 70 years Sex (males vs. females) -Duration of disease No metastases Lymph node metastases Few liver metastases > 5 liver metastases Carcinoid syndrome (yes vs, no) Urinary 5-hydroxyindoleacetic acid (> 300 vs. < 300 umol per 24 hours) P-chromogranin A ( > 5000 vs. < 5000 IJg per hter) P-neuropeptide K (> 16 vs. < 16 pmol per liter)
690
5.
6. 7. 8.
9.
10. II.
12.
13.
14.
15.
16.
17. 18. 19.
20.
21.
22.
23.
24.
References I. Williams ED, Sandler M. The classification of carcinoid tumours. Lancet 1963; I: 238-9. 2. Norheim I, Oberg K, Theodorsson-Norheim E et al. Malignant carcinoid tumors: An analysis of 103patients with regard to tumor localization, hormone production and survival. Ann Surg 1987; 206: 115-25. 3. Grahame-Smith DG. The Carcinoid Syndrome. Am J Cardiol 1968;21: 376-7. 4. Feldman JM and O'Dorisio TM. Role of neuropeptides and
serotonin in the diagnosis of carcinoid tumors. Am J Med 1986; 81:41-8. Eriksson B, Amberg H, Oberg K et aL A polyclonal antiserum against chromogranin A and B - a new sensitive marker for neuroendocrine tumours. Acta Endocrinol1990; 122: 145-55. Moertel CG, Sauer WG, Dockerty MB et al. Life history of the carcinoid tumor of the small intestine. Cancer 1961;14: 901-12. Godwin JD. Carcinoid tumors. An analysis of 2837cases. Cancer 1975; 36: 560-9. McDermott EWM, Guduric B, Brennan ME Prognostic variables in patients with gastrointestinal carcinoid tumours. Br J Surg 1994;81:1007-9. Greenberg RS, Baumgarten DA, Clark WS et al. Prognostic factors for gastrointestinal and bronchopulmonary carcinoid tumors. Cancer 1987;60: 2476-83. Wilander E, Lundqvist M, Oberg K. Gastrointestinal carcinoid tumours. Progr Histochem Cytochem 1989; 19:1-85. Oberg K, Funa K, Aim G. Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome. N Engl J Med 1983; 309: 129-33. Oberg K, Norheim I, Lundqvist G et al. Cytotoxic treatment in patients with malignant carcinoid tumors. Response to streptozocin - alone or in combination with 5-FU. Acta Oncol 1987;26: 429-32. Janson ET, Ronnblom L, Ahlstrom H et aLTreatment with alphainterferon versus alpha-interferon in combination with streptozocin and doxorubicin in patients with malignant carcinoid tumors: A randomized trial. Ann OncoI1992; 3: 635-8. Janson ET, Ahlstrom H, Andersson T et aL Octreotide and interferon alfa: A new combination for the treatment of malignant carcinoid tumors. Eur J Cancer 1992;28A: 1647-50. Wahlund KG, Edlen B. Simple and rapid determination of 5-hydroxyindole-3-acetic acid in urine by direct injection on a liquid chromatographic column. Clin Chim Acta 1981; 110: 71-6. Theodorsson-Norheim E, Norheim I, Oberg K et aL Neuropeptide K: A major tachykinin in plasma and tumor tissues from carcinoid patients. Biochem Biophys Res Comm 1985; 131: 77-83. Moertel CG. An odyssey in the land ofsmall tumors. J Clin Oncol 1987; 5: 1503-22. Hajdu SI,Winawer SJ, Myers WPL. Carcinoid tumors. A study of 204 cases. Am J Clin Patho11974; 61: 521-8. . Pellikka PA, Tajik AI, Khandheria BK et aL Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients. Circulation 1993;87: 1188-96. Lundin L. Norheim I. Landelius J et al, Carcinoid heart disease: Relationship od circulating vasoactive substances to ultrasound detectable abnormalities. Circulation 1988;77: 264-9. Krenning EP, Bakker WH, Kooij PPM et aL Somatostatin receptor scintigraphy with [lllIn-DTPA-D-Phelj-octreotide in man: Metabolism s . dosimetry and comparison with [123I-Tyr3j-octreotide. J Nucl Med 1992;33: 652-8. Westlin JE, Janson ET, Amberg H et aL Somatostatin receptor scintigraphy of carcinoid tumours using the [lllIn-DTPA-DPhelj-octreotide. Acta Onco11993; 32: 783-,.6. Eriksson B, Bergstrom M, Lilja A et al. Positron emission tomography (PET) in neuroendocrine gastrointestinal tumors. Acta Onco11993;32: 189-96. Hsiao R, Seeger RC, Yu AL et al. Chromogranin A in children with neuroblastoma. Serum concentration parallels disease stage and predicts survival. J Clin Invest 1990; 85: 1555-9.
Received 14April 1997;accepted 10June 1997.
Correspondence to: E. T. Janson, MD, Dr Med Sc Dept of Internal Medicine University Hospital S-751 85 Uppsala Sweden
Downloaded from http://annonc.oxfordjournals.org/ at University of Texas at Austin on June 6, 2015
should be compared to the rather indolent course of a few liver metastases which may be successfully medically treated. Although there was a tendency towards a higher Relative Hazard inpatients with advanced liver involvement it was not statistically significant. The five-year survival of those with the most extensive disease was 47% which may be compared with a five-year survival of 25% in patients with liver metastases in a recently published report [8], or 38% in Moertel's material [6]. The difference may be due to several factors which are impossible to disentangle in a retrospective case-study: different selection of cases (i.e., referral hospital vs. other); earlier diagnosis in later years (i.e., lead time bias); improved surgical results due to both improved techniques and more appropriate selection of cases; or improved medical treatment (c-interferon, somatostatin analogues). Gender did not emerge as a predictive factor. In a previous study females showed a better prognosis while age did not influence the survival [8]. Such differences might reflect differences in the group of patients analyzed, with our material consisting almost exclusively of patients with malignant carcinoid tumors. Since overall survival was studied, age was inherently related to prognosis and should be seen as a co-variate in the multivariate analyses. To study age in relation to tumor progression, disease specific survival has to be analyzed. In our series, however,45 cases had deaths with unknown causes (although many of these probably had a carcinoid related death cause) and the 16cases with cardiovascular events are difficult to classifyas dependent or independent from the carcinoid disease. Thus, an analyses of disease specific survival would suffer from misclassification of the end-point. In conclusion we have found that the median survival in foregut carcinoid patients after start of therapy was signifianctly shorter as compared to patients withmidgut carcinoid. We also found a correlation of plasma chromogranin A levels to tumor burden. In the multivariate .analyses, plasma chromogranin A > 5000 ·lJ.gll and advanced age were found to be independent predictors of survival. Although the prognosis is generally good for patients with carcinoid tumors, patients with extensive liver involvement or high plasma chromogranin A levels do worse and in this group future efforts should be made to improve therapy.