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Institut National de la Santé et de la Recherche Médicale, Unité 601 (J.B., F.K.-B., J.-F.C.), F-44000 Nantes, France; Université de Nantes (J.B., F.K.-B., J.-F.C.), F-44000 Nantes, France; and René Gauducheau Cancer Center (L.C.), F-44805 Nantes-St. Herblain, France
Address all correspondence and requests for reprints to: Jacques Barbet, Département de Recherche en Cancérologie, Institut National de la Santé et de la Recherche Médicale, Unité 601, Institut de Biologie, 9 quai Moncousu, 44093 Nantes cedex 1, France. E-mail: Jacques.Barbet{at}nantes.inserm.fr.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Objective: This study assesses the prognostic value of calcitonin and carcinoembryonic antigen (CEA) doubling-times (DT).
Design: This is a retrospective study on 65 MTC patients from 2.9–29.5 yr after surgery.
Setting: Data registered in the database of the French Neuroendocrine Tumor Group were analyzed anonymously.
Patients: All patients had abnormal calcitonin levels after total thyroidectomy and bilateral lymph node dissection.
Intervention: Calcitonin and CEA serum levels were measured during routine disease follow-up.
Main Outcome Measure: To assess DT as prognostic factors, a patient population was extracted from the database.
Results: When calcitonin DT was less than 6 months, 5- and 10-yr survivals were three of 12 (25%) and one of 12 (8%), respectively; when between 6 months and 2 yr, 5- and 10-yr survivals were 11 of 12 (92%) and three of eight (37%), whereas all 41 patients with calcitonin DT greater than 2 yr were alive at the end of the study. Tumor-Node-Metastasis (TNM) stage, European Organization for Research and Treatment of Cancer (EORTC) score, and calcitonin DT were significant predictors of survival by univariate analysis, but only calcitonin DT remained an independent predictor of survival by multivariate analysis (P = 0.002) with a proportion of variance explained (PVE) of 37.4%. Calcitonin DT was a better predictor than CEA (PVE 63.3% and 47.0%, respectively). Calcitonin DT calculated using only the first four measurements was also an independent predictor of survival (P < 0.000001; PVE 40.4%).
Conclusion: Calcitonin DT may be superior to initial clinical staging and among the most powerful prognostic indicators in MTC.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Among the various prognostic parameters that could identify high-, moderate-, and low-risk groups with the aim of defining optimal therapeutic strategies (1, 2, 3, 5, 6, 16, 17) advanced age, advanced stage of the disease, and associated multiple endocrine neoplasia (MEN) 2B appear to be the best commonly accepted factors of poor prognosis. Individual parameters have been associated within different staging systems, and Kebebew et al. (2) concluded that the European Organization for Research and Treatment of Cancer (EORTC) prognostic scoring system (18), which takes into account age, gender, nature, and stage of the disease for all thyroid cancers, had the highest predictive value. Serum kinetics of MTC markers, such as calcitonin and CEA, could be alternative predictors of survival (19), and Miyauchi et al. (20) have proposed calcitonin doubling-times (DT) as a prognostic factor. The purpose of the present study was to evaluate the predictive value of calcitonin and CEA serum kinetics, and especially DT of both markers in a cohort of 65 patients who have been followed for 6 months to 29.5 yr after surgery.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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MTC patients treated in participating centers in France can be registered, after formal agreement, in the database of the French Neuroendocrine Tumor Group (GTE). The history of their disease and routine calcitonin and CEA blood level measurements are then recorded in the database, which is managed according to the regulations of the French "Commission Nationale Informatique et Liberté." Patients who 1) were not operated on by total thyroidectomy and lymph node resection, or 2) were cured by surgery (negative postsurgery calcitonin testing), or 3) had not been measured for serum calcitonin at least four times after surgery, or 4) whose status could not be confirmed at the time of the study were excluded. All other patients entered in the database before February 2003 were included, for a total of 65 patients. Data extracted from the database by the GTE were made anonymous before any analysis.
Calcitonin and CEA serum determination
Calcitonin and CEA measurements were obtained using a single technique for a given patient but, for calcitonin, three assays were used (CT US IRMA, Brahms Diagnostica, Berlin, Germany; IRMA hCT, CIS Bio International, Gif-sur-Yvette, France; Advantage, Nichols Institute Diagnostics, San Juan Capistrano, CA) and, for CEA, a total of 15 different assays from nine different manufacturers were used (Axsym and Architect, Abbott Laboratories, Abbott Park, IL; ACS and Advia Centaur, Bayer Diagnostics, Tarrytown, NY; Vidas, bioMérieux, Marcy l’Étoile, France; Kryptor, Brahms Diagnostica; Elsa 2 and RIAgnost, CIS Bio International; Immunlite and Immunlite 2000, Diagnostic Products Corporation, Los Angeles, CA; IRMA, Immunotech, Marseille, France; Vitros ECI, Ortho-Clinical Diagnostics, Inc., Raritan, NJ; Cobas core, Elecsys 2010 and Modular, Roche Molecular Diagnostics, Pleasanton, CA). This could affect comparisons between patients, but had no influence on the estimation of DT.
Data analysis
Single exponentials were fitted to serum calcitonin and CEA concentrations by nonlinear least square regression. Data were weighted by the inverse of the measured concentrations, and best-fit values were reported as DT for progressive disease or half-life (t1/2) for tumor regression. SD were calculated as asymptotic SE. DT or t1/2 were evaluated after all major therapeutic treatments, such as surgery or external beam radiation therapy, and were not calculated when serum concentrations remained below the normal cut-off value. DT were considered as "stable" when too long to be estimated (one case for calcitonin, two cases for CEA).
Overall survival was calculated from the day of surgery until death of the patient. Cause-specific survival curves for each scoring system were calculated using the method of Kaplan-Meier, and compared using the log-rank test for trend. Deaths from a cause other than MTC, or survival after the end of the observation period, were considered as censoring events.
Age, gender, Tumor-Node-Metastasis (TNM) staging, EORTC score (18), and inverse values of calcitonin and CEA DT were considered as independent variables. Patient age at time of diagnosis and gender and other variables with significant influence in the univariate analysis were further considered in multivariate analysis through forward Cox’s proportional hazard model. The proportion of variance explained (PVE) of the different staging systems was calculated using the Cox proportional hazards model according to the method of Schemper and Stare (21, 22). This measure of the amount of variability in survival times that can be assigned to known prognostic factors and staging has a similar interpretation as R-squared in linear regression.
The inverse values of DT counted positive for progression (1/DT) and of t1/2 counted negative for regression (–1/t1/2) were used in all statistical analyses to avoid the discontinuity problem. For stable cases, 1/DT was set to zero. However, for clarity and easier clinical interpretation, changes in serum marker levels are reported in the Results and Discussion sections as DT (progression) or t1/2 (regression), expressed in years.
Survival analysis was performed using the SAS 8.2 software package (SAS, Inc., Cary, NC). For all tests, a value of P 
0.05 was considered as significant. All P values given are the results of two-sided tests.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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A total of 65 MTC patients with abnormal calcitonin after surgery for whom at least four data points were available to calculate DT were selected in the database by the GTE. Descriptive statistics by age, gender, TNM and EORTC scoring, and calcitonin and CEA DT of the 65-patient population and of the subgroup of patients for whom CEA DT data were available are listed in Table 1
. Six patients had familial MTC, four patients had MEN 2A, and two had MEN 2B. There was no TNM stage I, which is consistent with the fact that all patients considered in this study had abnormal calcitonin levels postsurgery.
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) and their distributions are reported in Table 1
. For only five of the 41 patients (12%) with DT or t1/2 less than 5 yr, the estimated SD (asymptotic SE) was larger than one half the DT. Precision on the estimation of long DT or t1/2 (>5 yr) was lower; for 10 of the 26 patients (42%), SD was more than 0.5 DT or t1/2. These patients were scored as DT more than 2 yr.
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In this subgroup, CEA serum levels increased for 40 patients with DT ranging from 0.07–24.2 yr (median 2.4 yr), were stable for two patients, and decreased for four patients with t1/2 ranging from 1.60–36.2 yr (median, 15.1 yr). Thus, CEA and calcitonin observations were very similar in most patients (Fig. 1). As shown in Fig. 2, the progression rates, measured as the inverses of calcitonin and CEA DT, correlated well (R2 = 0.9611).
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The mean follow-up time was 9.6 yr (median, 8.3 yr). The overall cause specific mortality was 17% at 5 yr and 29% at 10 yr.
All patients with calcitonin DT more than 2 yr (or with stable or regressing disease) survived until the end of the follow-up, whereas all those with DT less than 0.5 yr died within 0.5–13.3 yr, and only four of the 12 patients with intermediate DT (between 0.5 and 2 yr) survived until the end of the study. The patient population was thus stratified into three groups: group 1 (low risk), 41 patients with calcitonin DT more than 2 yr (or with stable or regressing disease); group 2 (intermediate risk), 12 patients with calcitonin DT between 0.5 and 2 yr; and group 3 (high risk), 12 patients with calcitonin DT less than 0.5 yr.
No correlation was found between postsurgery calcitonin or CEA levels and survival. Indeed. if median values were slightly higher in the high-risk group, the differences were very small compared with the range of observed values in all three risk groups: calcitonin, high risk, 438 (18–6629); intermediate risk, 269 (12–3487), low-risk group, 371 (30–9000) pg/ml; CEA, high risk, 35 (2–368); intermediate risk, 11 (2–124), low-risk group, 11 (1–184) ng/ml. Along the same line, absolute levels of calcitonin measured shortly before death varied from 371–488,000 pg/ml, showing that these absolute levels have no predictive value.
Five- and 10-yr survival rates are given in Table 2 for the different TNM and EORTC prognosis groups, as well as for the groups defined on the basis of calcitonin DT. Survival statistics were not different in the subgroup of 46 patients with available CEA data and the whole population.
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In the CEA-subgroup, the overall cause-specific mortality was 18% at 5 yr and 31% at 10 yr, and the survival statistics broken down by TNM, EORTC, or calcitonin DT were quite similar to those of the whole population. Groups defined on the basis of CEA DT, using the same cut-off values of 6 months and 2 yr, also gave a clear delineation of 5- and 10-yr survival: patients still alive at 5 and 10 yr were 27 of 27 and 17 of 18 if CEA DT was more than 2 yr, nine of 12 and two of 10 if CEA DT was between 6 months and 2 yr, and zero of four and zero of four if CEA DT was less than 6 months (Table 2).
Prognostic factors and staging system
The results of the univariate and multivariate analyses of survival data vs. clinical and biological variables are summarized in Table 3. EORTC score and calcitonin DT (analyzed in terms of their inverse values, 1/DT, as explained in Patients and Methods) were significant predictors of survival by univariate analysis.
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and in Fig. 3, the correlation with calcitonin DT was not easy to analyze; there were more TNM stage 4 in the high-risk group (25%) than in the other groups (0 and 10%), and the low-risk group did not look different from the intermediate-risk group. EORTC scoring seems better correlated to calcitonin DT; there were 60% group 4 and 5 in the high-risk group, compared with 8% in the intermediate-risk group and 15% in the low-risk group. Accordingly, the number of patients in EORTC groups 1 and 2 was much lower in the high-risk group, but still there was one EORTC group 1 patient and one EORTC group 2 patient among the 10 high-risk patients. In addition, although MEN 2B is considered to be a bad prognostic factor (23), all patients with familial MTC, and particularly two patients with MEN 2B, were found in the best prognostic group and were alive at the end of the study, 12.3 and 21.7 yr after initial surgery. Thus, calcitonin DT appears to be a good prognostic factor independently of the sporadic or familial type of MTC.
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For the CEA-subgroup, EORTC score, calcitonin and CEA DT were significant predictors of survival by univariate analysis (Table 3), but only calcitonin and CEA DT remained independent predictors of survival by multivariate analysis [HR = 6.50; 95% CI = 2.42–17.41; P = 0.003 and HR = 2.12; 95% CI = 1.07–4.20; P = 0.022, respectively] and they had highest PVE (63.3 and 47.0%, respectively).
Kaplan-Meier survival curves, shown in Fig. 3, illustrate the better correlation of survival with calcitonin doubling-times than with TNM or EORTC staging. Groups defined on the basis of CEA DT, like those defined from calcitonin DT, clearly correlate with survival. Only two patients were not classified in the same groups with calcitonin and CEA. One had a CEA DT of 5.4 yr and a calcitonin DT of 1.1 yr. He died 7.0 yr after surgery. The other had a CEA DT of 1.8 yr and a calcitonin DT of 4.4 yr. He is still alive 12.3 yr after surgery.
Consistency of calcitonin DT estimation
Changes over time in the rate of calcitonin exponential increase or decrease were generally limited, and, in particular, there was no sudden increase in progression rate in terminally ill patients. Curves shown in Fig. 1 are typical in this respect. The DT calculated for patient A was almost identical when only the first four points (0.34 yr) or all data points (0.29 yr) were considered. For patient B, another situation occurred; calcitonin DT estimation increased from 0.70 yr, when calculated considering only the first four points, to 2.54 yr when all available data points were considered (Fig. 4).
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Univariate and multivariate analysis showed than calcitonin DT calculated using only the first four data points was a significant prognostic factor for survival with a PVE of 40.4%, higher than that of the other scoring systems (Table 3). This is also illustrated by the Kaplan-Meyer curve (Fig. 3).
In the high-risk group, the median time required for patient staging was 0.9 yr (range, 0.1–2.0), and all patients were staged within 2 yr, with a median survival after staging of 1.3 yr (range, 0.1–9.7 yr). In the intermediate group (0.5 < DT < 2 yr), the initial staging was obtained within 1.9 yr (median; range, 0.3–3.3 yr, 58% before 2 yr) and the final staging was obtained within 2.3 yr (median; range, 0.9–4.5 yr, 50% before 2 yr). The final staging was obtained 3.3 yr before death or before the end of the study (median; range, 0.4–7.5 yr), and 92% of the patients were alive 1 yr after staging. In the low-risk group, nine patients (24%) were initially scored with a DT between 0.5 and 2 yr, but when more data were taken into account, the right score was reached after a median time of 3.9 yr (range, 1.7–5.6 yr).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The main prognostic indicators identified in large series of patients include age at diagnosis, gender, TNM stage, familiarity, and remote metastases but by multivariate analysis, only age and stage are independent factors (1, 2). Scoring systems such as TNM and EORTC have been evaluated previously, with EORTC staging ranking the highest in terms of the proportion of survival variance explained by the calculated score (PVE of 15.1 vs. 13.1% for TNM) (2).
Recently, Tisell et al. (24) have shown that the tumor cell proliferation index provided by the measure of Ki67 expression is a suitable prognostic marker for MTC. Similarly, prognostic values of calcitonin and/or CEA DT have been evaluated in small series of patients with advanced disease (19, 20, 25). In the present study, we have shown that calcitonin serum level DT is an independent predictor of survival, with a high predictive value. Forty-one patients had calcitonin DT more than 2 yr, including 11 patients showing a decrease of calcitonin serum levels. All these patients were still alive at the end of the study, 2.9–29.5 yr after initial surgery. A second group corresponded to 12 patients with calcitonin DT between 6 months and 2 yr. In this group, eight patients (67%) died of the disease 40 to 189 months after surgery. All 12 patients with calcitonin DT less than 6 months died of the disease 6 months to 13.3 yr after surgery.
DT could be calculated for all patients but one, who was reported as stable, for whom calcitonin level fluctuated between 204 and 387 pg/ml over more than 14 yr. Large SD reflect both the fluctuations in calcitonin serum levels and the fact that, in the present panel of patients, selected retrospectively from the GTE database, available data were not distributed according to any specific schedule designed to optimize such DT determinations. Nevertheless, the fitting process smoothed out the fluctuations.
CEA DT was not as good a predictor. Although there was an overall correlation between calcitonin and CEA DT in a subgroup of 46 patients where both measurements had been performed, 12 patients had elevated calcitonin serum levels but normal CEA levels, and these patients were distributed in all three ranges of calcitonin DT. In addition, two patients were classified in different groups with respect to calcitonin and CEA DT, and in both cases, the correct classification was given by the calcitonin DT. These observations are consistent with those reported earlier by Busnardo et al. (26).
If calcitonin DT is to be used as a prognostic factor, it is important that scoring be possible early after surgery. Here we demonstrate that the accuracy of scoring using a limited number of data points collected relatively soon after surgery is rather good: only two intermediate-risk patients were initially underscored as low risk and one high-risk patient was scored as intermediate risk. The most frequent misclassification was low-risk patients classified as intermediate-risk patients. The reason for that is probably that considered data points span a time interval too short to evaluate a DT in the 2–3 yr range: data show that correct staging of intermediate-risk patients is obtained after 2–3 yr. Accuracy should be increased greatly by using a systematic blood sampling protocol. Altogether, the prognostic value of calcitonin DT calculated from the first four data points was almost as good as that of calcitonin DT calculated from all available data points. This should make possible a prognosis early in the course of the disease after surgery. Even though blood samples were monitored for calcitonin at arbitrary times, 100% of the high-risk patients and 50% of the intermediate-risk patients were scored within 2 yr after surgery and prognostication could be made 1.3 yr (median) before death in the high-risk group.
The kinetics of changes in tumor marker serum levels have been taken into consideration as prognostic indicators in several other tumor types. Good correlations with survival have been found between DT of CA 19–9 in pancreatic cancer (27), CEA in colorectal cancer (28, 29), CA 125 in ovarian carcinoma (30), and prostate-specific antigen in prostate carcinoma (31), even if the usefulness of determining DT of these markers during the monitoring of patients has not yet been validated due to discrepancies between the results of different groups related to methodological and individual factors.
For any new staging system to have universal acceptance, the new prognostic indicator must have a strong independent relationship to prognosis and provide additional prognostic information beyond that of TNM stage, age, and gender. It must also have good reproducibility within and between different clinical observers or laboratories. This study showed that the calcitonin DT appears to be one such new predictive marker. Given the very poor 5- and 10-yr survival rates of patients with DT less than 6 months, aggressive therapeutic regimens should be recommended in this group of patients. Conversely, for patients with DT more than 2 yr, a watch and wait attitude is probably adequate, because the benefit of any treatment, other than symptomatic or palliative, would be difficult to assess, and these patients are most likely to survive for very long periods of time. For patients with intermediate DT, the conclusion is not as strong, but the high death rate (37% 10-yr survival) would warrant treatment, although taking into account the fact that 5-yr survival is in the 90% range.
From a practical point of view, it could be recommended to perform repeated determinations of calcitonin and CEA serum concentrations in the event of persisting abnormal concentrations after total thyroidectomy and bilateral lymph node dissection. DT assessment could be done after a few months and its quality could be measured from the estimated SD. High-risk patients will be rapidly detected and precise DT determination will be possible within the first year of follow-up for rapidly progressing (high-risk) patients. Monitoring should continue for other patients, possibly with a longer time interval between measurements. Then, the most appropriate therapeutic intervention could be decided. For low-risk patients (DT > 2 yr), calcitonin and CEA level monitoring could be continued with a reduced frequency (every 6 months). High-risk patients could be offered several aggressive therapeutic options (surgery, external beam radiotherapy, or experimental approaches such as radioimmunotherapy). These proposed guidelines remain to be validated in prospective studies, and calcitonin DT could also prove useful in the assessment of the response to treatment.
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Acknowledgments |
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Footnotes |
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Abbreviations: CEA, Carcinoembryonic antigen; 95% CI, 95% confidence interval; DT, doubling-time(s); EORTC, European Organization for Research and Treatment of Cancer; HR, hazard ratio; MEN, multiple endocrine neoplasia; MTC, medullary thyroid carcinoma; PVE, proportion of variance explained; TNM, tumor-node-metastasis.
Received January 7, 2005.
Accepted August 1, 2005.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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) were monitored periodically after diagnosis and initial surgery in MTC patients. Data were then fitted to single exponentials by nonlinear least-square analysis (solid lines). Two illustrative examples are shown in the figure. Patient A (calcitonin, A; CEA, B) showed fast progression of both markers; estimated calcitonin and CEA DT (±SD) were 0.29 ± 0.03 and 0.34 ± 0.05 yr, respectively. Patient B (calcitonin, C; CEA, D) showed slower progression (note the change in time scale) of both markers; estimated calcitonin and CEA DT (±SD) were 2.5 ± 0.2 and 3.5 ± 0.3 yr, respectively.
