Background: Medullary thyroid carcinoma (MTC) is a malignant tumor with low incidence. Currently, most studies have focused on the prognostic risk factors of MTC, whatever, time kinetic and risk factors related to calcitonin normalization (CN) and biochemical persistence/recurrence (BP) are yet to be elucidated. Methods: A retrospective study was conducted for 190 MTC patients. Risk factors related to calcitonin normalization (CN) and biochemical persistence/recurrence (BP) were analyzed. The predictors of calcitonin normalization time (CNT) and biochemical persistent/recurrent time (BPT) were identified. Further, the prognostic roles of CNT and BPT were also demonstrated. Results: The 5- and 10-year DFS were 86.7% and 70.2%, respectively. The 5- and 10-year OS were 97.6% and 78.8%, respectively. CN was achieved in 120 (63.2%) patients, whereas BP was presented in 76 (40.0%) patients at the last follow up. After curative surgery, 39 (32.5%) and 106 (88.3%) patients achieved CN within 1 week and 1 month. All patients who failed to achieve CN turned to BP over time and 32/70 of them developed structural recurrence. The median time of CNT and BPT was 1 month (1 day to 84 months) and 6 month (3 day to 63months), respectively. LNR > 0.23 and male gender were independent predictors for CN and BP. LNR > 0.23 (Hazard ratio (HR), 0.24; 95% CI,0.13–0.46; P < 0.01) and male gender (HR, 0.65; 95% CI, 0.42–0.99; P = 0.045) were independent predictors for longer CNT. LNR > 0.23 (HR,5.10; 95% CI,2.15–12.11; P < 0.01) was still the strongest independent predictor followed by preoperative serum Ctn > 1400ng/L (HR,2.34; 95% CI,1.29–4.25; P = 0.005) for shorter BPT. In survival analysis, primary tumor size > 2 cm (HR, 5.81; 95% CI,2.20-15.38; P < 0.01), CNT > 1 month (HR, 5.69; 95% CI, 1.17–27.61; P = 0.031) and multifocality (HR, 3.10; 95% CI, 1.45–6.65; P = 0.004) were independent predictor of DFS. Conclusion: Early changes of Ctn after curative surgery can predict the long-term risks of biochemical and structural recurrence, which provide a useful real-time prognostic information. LNR significantly affect the time kinetic of biochemical prognosis. Tumor burden and CNT play a crucial role in MTC survival, the intensity of follow-up must be tailored accordingly.
Keywords: Medullary thyroid carcinoma; Calcitonin; Biochemical persistence; Biochemical recurrence; Structural recurrence
Fengli Guo, Guiming Fu and Fangxuan Li contributed equally to this work.
Medullary thyroid carcinoma (MTC) is a malignancy subtype originating from C cells of the thyroid gland, characterized with secreting calcitonin (Ctn) and carcinoembryonic antigen (CEA). Despite its low prevalence, MTC demonstrates a aggressive clinical course and is susceptible to lymph node involvement and distant metastases. Ctn is a highly sensitive biochemical marker indicating residual, recurrence or metastasis long prior to tumor localization can be visualized by imaging [[
Previous studies have reported that the serum Ctn levels declined rapidly within hours [[
Therefore, the present study was conducted to establish the time frame of calcitonin normalization (CN) and biochemical persistence/recurrence (BP) in patients with MTC, and to explore the associated clinical and pathological factors. Furthermore, we identified the independent predictors of calcitonin normalization time (CNT), biochemical persistent/recurrent time (BRT) and disease-free survival (DFS). To our knowledge, this is the first study covering both the CNT and BPT and long-term prognosis.
A total of 190 patients who were first diagnosed with MTC and underwent curative surgery in Tianjin medical university cancer institute and hospital between February 2015 and February 2020 was included in present study. The medical records of the patients were retrospectively reviewed and followed up in the years. All patients were performed with total thyroidectomy and central node dissection. Lymph node dissection in the lateral neck was performed according to the neck ultrasound preoperative and evidence intro-operative. Patients with preoperative Ctn records and continuous postoperative Ctn monitoring were included in the study. Patients with preoperative Ctn ≤ 2 ng/L, those without thyroid or neck dissection and those loss follow-up as well as pediatric patients, were excluded. Postoperative pathological stage was classified according to the 8th revision of the American Joint Committee of Cancer (AJCC) TNM classification. Data regarding demographics, epidemiological, clinical and pathological, as well as preoperative and postoperative laboratory values were retrieved from electronic medical records.
Ctn was measured using Immulite 2000® Siemens with a sex dependent reference range (male < 2-8.5 ng/L, female < 2–5 ng/L) and a detection limits: <2.0 ng/L and > 2,000 ng/L. CN, as serum Ctn normalization, was defined as serum Ctn levels decreased to < 5 ng/L for male and < 8.5 ng/L for female. CNT was calculated since the time from the last surgery to the time when serum Ctn normalization achieved. For patients who failed to achieve CN and had persistent or elevated serum Ctn, the time was calculated since last surgery to last follow-up. BP, was defined as serum Ctn never decreased, or raised from nadir for patients who failed to achieve CN, and exceeded 5ng/L or 8.5 ng/L for patients who achieved CN. BPT was calculated since last surgery to the time of serum Ctn raised for patients who failed to achieve CN and exceed upper limitation for patients who achieved CN. For patients without BP, the time was calculated from last surgery to the last follow-up.
Lymph node metastases ratio (LNR) defined as the number of lymph node involvement divided by the total number of dissected.
Follow-up was performed early after surgery. The postoperative serum Ctn levels were measured within 3 days and a week in partial patients and 1 month in all patients, and repeated every 1–3 months intervals according to the results. The end of the surveillance period for each patient was considered the date of last follow-up or structural recurrence. Patients who underwent the initial and second operations within 3 months for curative intent were considered to be a single sequence and the serum Ctn levels after last operation were taken into account.
This study was approved by the ethics committee of Tianjin Medical University Cancer Institute and Hospital (EK2022260).
Data were analyzed using SPSS software (SPSS for Windows, version 22.0). Continuous data were presented as means and standard deviations or median values with ranges, and analyzes with non-parametric test and t test for differences between groups. Discrete variables were described with rated (%) and analyzed by x
The study included 108 females and 92 males. The median age was 52 years (range 19–74) with a median follow-up period of 67 months (range 18–127). Multifocality presented in 55 patients (28.9%). According to 8th AJCC TNM classification, there were 58 (30.5%) patients in stage I, 22 patients in stage II, 25 patients in stage III and 85 patients in stage IV. Structural recurrence occurred in 35 (18.4%) patients at the last follow up. The distant organs most commonly affected by systemic spread were, in descending order, lung, bone and liver.
At the last follow-up, 120 (63.2%) patients achieved CN, whereas 70 (36.8%) patients failed. For patients who achieved long term biochemical cure, the serum Ctn levels decreased sharply in several days after curative surgery. The time-dependent curve of cumulative rates of CN decreased rapidly, eventually leveling off more than 1 month, and 21 (17.5%), 18 (15.0%), 67 (55.8%), 14 (11.7%) patients achieved CN within 3 days, 1 week, 1 week to 1 month, more than 1 months after surgery, respectively. Only 6 patients had a slow decline in serum Ctn as long as more than 6 months or even more than a year, up to 84 months. The median time of CNT was 1 month with a range of 1d − 84 months. Of 120 patients, 95.0% (
Graph: Fig. 1 Cumulative rates of calcitonin normalization (CN) (a) and biochemical cure (b) of 190 MTC patients
There were 76 (40.0%) patients developed BP including 6 patients previously achieved CN. Postoperative Ctn decreased to varying degrees, and then rises from nadir at different points of time. Consequently, all patients who failed to achieve CN all progressed to BP over time. The median time of CNT was 6 months with a range of 3 days − 63 months. The time-dependent curve of cumulative rates of BP advanced steadily up to 2 years, eventually leveling off more than 2 years. There were 20 (26.3%), 12 (15.8%), 19 (25.0%), 17 (22.4%) and 8 (10.5%) patients developed recurrence within 1 month, 1 to 3 months, 3 to 6 months and 6 months to 2 years and longer than 2 years, with the longest time being 63 months. About 42.1% (32/76) patients with BP progressed to structural recurrence at the last follow-up and 65.0% (13/20) patients recurrent within 1 month, including 8 patients nearly without decrease in Ctn presenting structural recurrence after short-term follow-up. Nearly half of(32/70)patients failed to achieve CN progressed to structural recurrence. The distributions of CNT and BPT with structural recurrence were presented in Fig. 2.
Graph: Fig. 2 The distribution of calcitonin normalization time (CNT) (a) and biochemical persistent/recurrent time (BPT) (b) with structural recurrence. *d, day/days; m, month/months; y, year/years
To calculate the cutoff values of preoperative serum Ctn levels and LNR for the CN and BP, the patients were grouped into CN (n = 120) and failure (n = 70), BP (n = 76) and biochemical cure (n = 114), respectively.
The cut-off value of preoperative Ctn levels and LNR were identified by ROC cure analysis. When Youden index was the largest, the preoperative serum Ctn level and LNR were both 1400ng/L and 0.23 based on CN and BP, respectively. Accordingly, the cut-off value of preoperative Ctn level and LNR was set as 1400ng/L and 0.23, respectively (Fig. 3).
Graph: Fig. 3 Identification of the optimal cutoff values of preoperative Ctn and LNR based on CN and BP via ROC curve analysis. The optimal cutoff values of preoperative Ctn (a) and LNR (b) based on CN were 0.23 and 1400 pg/L, respectively. The optimal cutoff values for preoperative serum Ctn (c) and LNR (d) based on BP were 0.23 and 1400 pg/L, respectively
The clinicopathological factors associated with CN and BP were analyzed. Male gender, multifocality, extrathyroid invasion, primary tumor size > 2 cm, advanced T stage (T3/T4) and N stage (N1a/N1b), advanced clinical stage, LNR > 0.23, preoperative serum Ctn > 1400ng/L were all related to CN and BP significantly (P < 0.05). Table 1 listed clinical, pathological and biological factors related to CN and BP.
Table 1 The clinical, pathological and biological factors associated with Calcitonin normalization (CN) and Biochemical recurrence (BR).
Characteristic CN BR Yes ( No ( x2 No ( Yes ( x2 Gender 18.71 < 0.01 18.87 < 0.01 Female 80 (76.9) 24 (23.1) 77 (74.0) 27 (26.0) Male 40 (46.5) 46 (53.5) 37 (46.0) 49 (57.0) Age (year) 0.28 0.596 0.75 0.385 ≤ 50 76 (61.8) 47 (38.2) 71 (57.7) 52 (42.3) > 50 44 (65.7) 23 (34.3) 43 (64.2) 24 (35.8) Multifocality 17.84 < 0.01 15.35 < 0.01 Solitary 98 (72.6) 37 (27.4) 93 (68.9) 42 (31.1) Multiple 22 (40.0) 33 (60.0) 21 (38.2) 34 (61.8) Extrathyroid invasion 23.56 < 0.01 20.76 < 0.01 No 101 (73.7) 36 (26.3) 96 (70.1) 41 (29.9) Yes 19 (35.8) 34 (64.2) 18 (34.0) 35 (66.0) Primary tumor size (cm) 17.57 < 0.01 12.05 < 0.01 ≤ 2 91 (74.0) 32 (26.0) 85 (69.1) 38 (30.9) > 2 29 (43.3) 38 (56.7) 27 (43.3) 38 (56.7) T stage 19.31 < 0.01 14.68 < 0.01 T1/T2 104(71.7) 41 (28.3) 98 (67.6) 47 (32.4) T3/T4 16 (35.6) 29 (64.4) 16 (35.6) 29 (64.4) N stage 55.85 < 0.01 56.63 < 0.01 0 74 (90.2) 8 (9.8) 72 (87.8) 10 (12.2) N1a 19 (67.9) 9 (32.1) 18 (64.3) 10 (35.7) N1b 27 (33.8) 53 (66.2) 24 (30.0) 56 (70.0) Clinical stage 46.87 < 0.01 47.59 < 0.01 I/II 73 (91.3) 7 (8.8) 71 (88.8) 9 (11.3) III/IV 47 (42.7) 63 (57.3) 43 (39.1) 67 (60.9) LNR 68.12 < 0.01 62.63 < 0.01 ≤ 0.23 93 (89.4) 11 (10.6) 89 (85.6) 15 (14.4) > 0.23 27 (31.4) 59 (65.9) 25 (29.1) 61 (70.9) Preoperative serum Ctn(ng/L) 36.98 < 0.01 29.30 < 0.01 ≤ 1,400 97 (75.8) 31 (24.2) 91 (71.1) 37 (28.9) > 1,400 15 (27.8) 39 (72.2) 15 (27.8) 39 (72.2)
Logistic analysis was performed to analyze the independent factors for CN and BP. LNR > 0.23 (Odd ratio (OR),15.06; 95% Confidence interval (CI),4.27–53.09; P < 0.01) and male gender (OR, 2.67; 95% CI,1.08–6.58; P = 0.034) were independent predictors for CN. LNR > 0.23 (OR,9.78; 95% CI,3.20-29.92; P < 0.01) and male gender (OR, 2.52; 95% CI,1.09–5.82; P = 0.030) were independent predictors for BP. The results were listed in Table 2.
Table 2 Logistic analysis of the clinical, pathological and biological factors of Calcitonin normalization (CN) and Biochemical recurrence (BR).
Characteristic CN BR OR 95% CI OR 95% CI Male 2.67 1.08–6.58 0.034 2.52 1.09–5.82 0.030 Multifocality 2.58 0.97–6.83 0.057 1.95 0.78–4.88 0.151 Extrathyroid invasion 3.18 0.95–10.71 0.062 2.68 0.87–8.23 0.086 Primary tumor size > 2 cm 2.02 0.64–6.39 0.231 1.43 0.48–4.24 0.519 T3/T4 1.16 0.29–4.68 0.835 1.03 0.27–3.86 0.970 N stage 0.182 0.095 N1a 0.28 0.01–7.82 0.454 0.31 0.02–6.53 0.452 N1b 0.79 0.03–21.79 0.890 1.02 0.05–20.54 0.992 III/IV stage 1.51 0.07–33.39 0.795 1.65 0.10-28.74 0.730 LNR > 0.23 15.06 4.27–53.09 < 0.01 9.78 3.20-29.92 < 0.01 Preoperative serum Ctn > 1,400 ng/L 2.77 0.91–8.48 0.073 2.24 0.76–6.58 0.144
For patients who achieved CN and failed, male gender, multifocality, primary tumor size > 2 cm, advanced T stage (T3T/4 vs. T1/T2), N stage (N0 vs. N1a/1b, N1a vs. N1b) and clinical stage (III/IV vs. I/II), LNR > 0.23, preoperative serum Ctn > 1400ng/L were significant predictors for longer CNT (P < 0.05) in univariate analysis. In the adjusted multivariate analysis, LNR > 0.23 (HR, 0.24; 95% CI,0.13–0.46; P < 0.01) and male gender (HR, 0.65; 95% CI, 0.42–0.99; P = 0.045) were independent predictors for longer CNT. The results were listed in Table 3.
Table 3 Univariate and multivariate analysis of clinical, pathological and biological predictors of calcitonin normalization time (CNT).
Characteristic Univariate Kaplan-Meier analysis Multivariate COX analysis ¯x ± SD x2 HR HR 95.0% CI Gender 20.81 < 0.01 Female 27.35 ± 4.70 Male 64.35 ± 6.31 0.65 0.42–0.99 0.045 Age (year) 0.18 0.669 ≤ 50 46.08 ± 5.16 > 50 40.75 ± 6.63 Multifocality 15.93 < 0.01 Solitary 33.75 ± 4.51 Multiple 69.80 ± 7.58 0.66 0.40–1.09 0.105 Extrathyroid invasion 19.55 < 0.01 No 30.98 ± 4.32 Yes 76.88 ± 7.23 0.66 0.36–1.23 0.191 Primary tumor size (cm) 15.98 < 0.01 ≤ 2 32.18 ± 4.65 > 2 65.60 ± 4.91 0.84 0.50–1.44 0.530 T stage 15.20 < 0.01 T1/T2 34.48 ± 4.40 T3/T4 74.43 ± 8.14 0.91 0.47–1.76 0.775 N stage 64.22 < 0.01 0 12.39 ± 3.87 0.053 N1a 39.89 ± 9.90 2.09 0.54–8.03 0.283 N1b 77.33 ± 6.01 0.95 0.26–3.48 0.936 Clinical stage 57.58 < 0.01 I/II 11.21 ± 3.73 III/IV 66.94 ± 5.38 0.90 0.27–3.02 0.858 LNR 71.17 < 0.01 ≤ 0.23 13.56 ± 3.56 > 0.23 79.96 ± 5.70 0.24 0.13–0.46 < 0.01 Preoperative serum Ctn(ng/L) 35.43 < 0.01 ≤ 1,400 29.94 ± 4.46 > 1,400 83.96 ± 7.00 0.54 0.29–1.03 0.063
*P < 0.05, CNT, calcitonin normalization time; Ctn, calcitonin; LNR, lymph node metastasis ratio; SD, standard deviation; HR, hazard ratio; CI, confidence interval
Since the patients who failed to achieve CN all progressed to BP, the biochemical failures and BP were almost identical, with the exception of 6 individuals switching from normalization to recurrence. Subsequently, all the predictors for longer CNT were predictors for BPT in univariate analysis. After multivariate COX analysis, LNR > 0.23 (HR,5.10; 95% CI,2.15–12.11; P < 0.01) was still the strongest independent predictors followed by preoperative serum Ctn > 1400ng/L (HR,2.34; 95% CI,1.29–4.25; P = 0.005) for shorter BPT. The results were listed in Table 4.
Table 4 Univariate and multivariate analysis of clinical, pathological and biological predictors to biochemical persistent/recurrent time (BRT).
Characteristic Univariate Kaplan-Meier analysis Multivariate COX analysis ‾x ± SD x2 HR HR 95.0% CI Gender 20.24 < 0.01 Female 95.68 ± 5.10 Male 56.70 ± 6.17 1.58 0.93–2.67 0.088 Age (year) 0.91 0.341 ≤ 50 76.03 ± 5.32 > 50 81.54 ± 6.68 Multifocality 19.04 < 0.01 Solitary 89.66 ± 4.72 Multiple 41.65 ± 6.01 1.43 0.88–2.33 0.151 Extrathyroid invasion 24.31 < 0.01 No 90.93 ± 4.65 Yes 43.67 ± 7.08 1.37 0.78–2.40 0.280 Primary tumor size (cm) 16.04 < 0.01 ≤ 2 87.39 ± 4.71 > 2 58.06 ± 7.32 1.09 0.56–2.13 0.800 T stage 21.02 < 0.01 T1/T2 85.50 ± 4.12 T3/T4 48.48 ± 8.67 1.17 0.61–2.25 0.638 N stage 63.49 < 0.01 0 111.84 ± 4.32 0.072 N1a 75.07 ± 8.78 0.20 0.03–1.64 0.136 N1b 39.57 ± 5.57 0.44 0.06–3.24 0.419 Clinical stage 46.90 < 0.01 I/II 113.09 ± 4.18 III/IV 49.76 ± 5.02 3.29 0.43–24.96 0.250 LNR 72.37 < 0.01 ≤ 0.23 109.79 ± 3.98 > 0.23 36.94 ± 5.05 5.10 2.15–12.11 < 0.01 Preoperative serum Ctn(ng/L) 47.70 < 0.01 ≤ 1,400 88.25 ± 4.37 > 1,400 28.78 ± 5.34 2.34 1.29–4.25 0.005
*P < 0.05, BRT, biochemical persistent/recurrent time; Ctn, calcitonin; LNR, lymph node metastasis ratio; SD, standard deviation; HR, hazard ratio; CI, confidence interval
Time-dependent curve on CN of 190 MTC patients according to gender and LNR cutoff were presented in Fig. 4. Time-dependent curves on BP of 190 MTC patients according to LNR and preoperative serum Ctn cutoff were presented in Fig. 5.
Graph: Fig. 4 Time-dependent curve on CN of 190 MTC patients according to LNR cutoff and gender. Differences in CNT between groups were significant (P<0.05, log-rank test)
Graph: Fig. 5 Time-dependent curve on BP of 190 MTC patients according to LNR cutoff (a) and preoperative serum Ctn cutoff (b). Differences in BPT between groups were significant (P<0.05, log-rank test)
To compare the clinical and pathological characteristics of patients with different CNT and BPT, the 120 patients who achieved CN were divided into CNT ≤ 1 month (n = 103) and > 1 month (n = 17) group, and the 76 patients who developed BP were divided into BPT ≤ 3 month (n = 32) and > 3 month (n = 44) group, respectively. As demonstrated in Table 5, low N stage was related to CNT ≤ 1 month, primary tumor size ≤ 2 cm and preoperative serum Ctn ≤ 1,400 (ng/L) was related to BPT > 3 month (all P < 0.05), in subgroup analysis. Sixty-nine (93.2%) patients of N0 and 68 (93.2%) patients of I/II had shorter CNT (≤ 1 month). Table 5 demonstrated the clinical and pathological characteristics of MTC patients related to CNT ≤ 1 month or > 1 month, and BPT ≤ 3 month or > 3 month.
Table 5 Comparison of clinical and pathological characteristics of MTC patients with different calcitonin normalization time (CNT) and biochemical persistent/recurrent time (BRT).
Characteristic CNT BRT ≤ 1 month ( > 1 month ( x2/t/Z ≤ 3 month ( > 3 month ( x2/t/Z Gender 0.14 0.711 1.32 0.250 Female 68 (85.0) 12 (15.0) 9 (33.3) 18 (66.7) Male 35 (87.5) 5 (12.5) 23 (46.9) 26 (53.1) Age (year) 0.92 0.337 3.04 0.081 ≤ 50 67 (88.2) 9 (11.8) 25 (40.9) 26 (51.0) > 50 36 (81.8) 8 (18.2) 7 (28.0) 18 (72.0) Multifocality 0.57# 0.735 1.57 0.210 Solitary 83 (84.7) 15 (15.3) 15 (35.7) 27 (64.3) Multiple 20 (90.9) 2 (9.1) 17 (50.0) 17 (50.0) Extrathyroid invasion 0.88# 0.470 0.35 0.556 No 88 (87.1) 13 (12.9) 16 (39.0) 25 (61.0) Yes 15 (78.9) 4 (21.1) 16 (45.7) 19 (54.3) Primary tumor size (cm) 0.00# 1.000 5.40 0.020 ≤ 2 78 (85.7) 13 (14.3) 11 (28.9) 27 (71.1) > 2 25 (86.2) 4 (13.8) 21 (55.3) 17 (44.7) T stage 0.32# 0.699 3.29 0.070 T1/T2 90 (86.5) 14 (13.5) 16 (34.0) 31 (66.0) T3/T4 13 (81.3) 3 (18.8) 16 (55.2) 13 (44.8) N stage 6.87# 0.032 3.46# 0.160 0 67 (90.5) 7 (9.5) 2 (20.0) 8 (80.0) N1a 17 (89.5) 2 (10.5) 3 (30.0) 7 (70.0) N1b 19 (70.4) 8 (29.6) 27 (48.2) 29 (51.8) Clinical stage 3.21 0.073 4.02# 0.071 I/II 66 (90.4) 7 (9.6) 1 (11.1) 8 (88.9) III/IV 37 (78.7) 10 (21.3) 31 (46.3) 36 (53.7) LNR 0.54# 0.532 3.75 0.053 ≤ 0.23 81 (87.1) 12 (12.9) 3 (20.0) 12 (80.0) > 0.23 22 (81.5) 5 (18.5) 29 (47.5) 32 (52.5) Preoperative serum Ctn(ng/L) 2.63# 0.117 15.90 < 0.01 ≤ 1,400 86 (88.7) 11 (11.3) 7 (18.9) 30 (81.1) > 1,400 11 (73.3) 4 (26.7) 25 (64.1) 14 (35.9)
#Fisher exact test; *P < 0.05, CNT, calcitonin normalization time; BRT, biochemical persistent/recurrent time; Ctn, calcitonin; LNR, lymph node metastasis ratio
Male gender, multifocality, extrathyroid invasion, primary tumor size > 2 cm, T3/T4, N1a/N1b, III/IV stage, LNR > 0.23, preoperative serum Ctn level > 1,400 ng/L as well as CNT > 1 month and BPT ≤ 3 month were negative predictors of DFS. In multivariate analysis, primary tumor size > 2 cm (HR, 5.81; 95% CI,2.20-15.38; P < 0.01), CNT > 1 month (HR, 5.69; 95% CI, 1.17–27.61; P = 0.031).
and multifocality (HR, 3.1;0 95% CI, 1.45–6.65; P = 0.004) were independent predictor of DFS. The results were demonstrated in Table 6. The cumulative survival curves with primary tumor size, CNT and multifocality for 190 MTC patients were presented in Fig. 6. The cumulative survival curve of 190 MTC patients was presented in Fig. 7.
Table 6 Univariate Kaplan-Meier analysis and multivariate COX analysis for the predictors of disease-free survival (DFS).
Characteristic Univariate Kaplan-Meier analysis Multivariate COX analysis ¯x ± SD x2 HR HR 95.0% CI Gender 4.46 0.035 Female 111.11 ± 3.71 Male 99.86 ± 5.15 1.10 0.50–2.39 0.816 Age (year) 0.01 0.922 ≤ 50 105.79 ± 3.83 > 50 106.65 ± 5.30 Multifocality 17.23 < 0.01 Solitary 114.07 ± 2.99 Multiple 81.94 ± 6.31 3.10 1.45–6.65 0.004 Extrathyroid invasion 9.50 0.02 No 112.25 ± 3.30 Yes 87.84 ± 6.12 1.24 0.46–3.32 0.672 Primary tumor size (cm) 30.71 < 0.01 ≤ 2 118.07 ± 2.70 > 2 83.94 ± 6.49 5.81 2.20-15.38 < 0.01 T stage 40.74 < 0.01 T1/T2 112.71 ± 3.13 T3/T4 86.13 ± 7.69 0.76 0.25–2.30 0.621 N stage 27.84 < 0.01 0 123.88 ± 1.76 0.677 N1a 98.90 ± 4.91 0.44 0.05–4.17 0.476 N1b 89.72 ± 5.18 0.39 0.05–3.21 0.384 Clinical stage 25.93 < 0.01 I/II 125.08 ± 1.31 III/IV 93.03 ± 4.72 6.31 0.37-107.63 0.203 LNR 37.54 < 0.01 ≤ 0.23 123.82 ± 1.80 > 0.23 82.53 ± 4.89 2.95 0.64–13.51 0.164 Preoperative serum Ctn(ng/L) 27.96 < 0.01 ≤ 1,400 114.52 ± 3.07 > 1,400 76.76 ± 6.58 0.95 0.39–2.27 0.900 CNT 37.02 < 0.01 ≤ 1 month 122.91 ± 1.46 > 1 month 87.62 ± 5.29 5.69 1.17–27.61 0.031 BRT 39.35 < 0.01 ≤ 3 month 66.92 ± 8.85 > 3 month 114.39 ± 2.77 0.76 0.37–1.58 0.459
*P < 0.05, CNT, calcitonin normalization time; BRT, biochemical persistent/recurrent time; Ctn, calcitonin; DFS, disease-free survival; LNR, lymph node metastasis ratio
Graph: Fig. 6 Kaplan–Meier survival curves of MTC patients with primary tumor size (a), calcitonin normalization time (b) and multifocality (c) for DFS. Differences in DFS between groups were significant (P<0.05, log-rank test)
Graph: Fig. 7 Cumulative survival curve of 190 MTC patients
Neither effective of radioactive iodine nor the standard chemotherapy or radiotherapy, surgery is recommended treatment for patients with MTC. Despite curative resection of primary tumor, up to 50% of patients do not achieve biochemical cure, as evidenced by persistent elevated Ctn, and 10–25% of patients progressed to structural recurrence ultimately [[
Most studies chiefly focused on the prognostic role of postoperative Ctn levels for MTC [[
The prognostic roles of CNT and BPT were studied. CTN and BPT were both related to DFS. CNT > 1 month independently correlated with shorter DFS, but BPT was not, which was firstly reported. Similar to previous report, serum Ctn nadirs to undetectable levels within 1 month of curative surgery in MTC suggested low risk of structural disease [[
Moreover, risk factors attributing to the turning point of Ctn dynamic changes remains elusive. A previous study reported that the length of time to Ctn normalization was dependent on both nodal disease burden and preoperative Ctn levels [[
We further compared clinical and pathological factors related to shorter CNT and longer BPT in subgroup analysis. Advanced N stage was related to CNT ≤ 1 month, larger primary tumor size and higher preoperative serum Ctn was related to BPT > 3 month (all P < 0.05). Secreted by C cells, preoperative Ctn correlates with tumor burden, including tumor size [[
As a retrospective study, limitations can't be neglected. Firstly, other biomarkers, such as CEA, were not taken into consideration since few patients data was available and no dynamic follow up. Secondly, Ctn was tested routinely at 1month intervals post-operation resulting that the exact time of CN and BP can't be identified. Finally, the patients in our study underwent preoperative vocal cord motility through laryngoscopy, whereas transcutaneous laryngeal ultrasonography was reported as a reliable, non-invasive and inexpensive preoperative method in the evaluation of vocal cords motility [[
We conducted a thorough analysis based on a large cohort to evaluate the time kinetics and prognosis roles of CN or BP after Surgery for MTC. In conclusion, early changes of Ctn after surgery can predict the risk of long-term biochemical cure and survival. The tumor burden and Ctn level at the time of initial treatment are important for biochemical prognosis. LNR plays a crucial role in CN and BP, and has been identified as an independent predictor of CNT and BPT. Longer CNT and lager tumor burden indicate shortened DFS. We suggest that early time kinetic of postoperative Ctn can be a useful tool to plan intensity of follow-up.
We thank Pengfei Gu for data analysis support and Xianhui Ruan for essential help in establishing the clinical cohort.
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by FLG, GMF and FXL. The first draft of the manuscript was written by FLG and all authors commented on previous versions of the manuscript. JZZ and MG critically revised the manuscript. All authors read and approved the final manuscript.
This work was funded by the National Natural Science Foundation of China (grant numbers: 82372753, 82172821, 82103386, 82303871); Tianjin Municipal Science and Technology Project (grant numbers: 19JCYBJC27400, 21JCZDJC00360); The Science &Technology Development Fund of Tianjin Education Commission for Higher Education (2021ZD033), Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-058B, TJYXZDXK-009 A) and Tianjin Health Research Project (TJWJ2022XK024). The Medical and Health Science and Technology Project of Shandong Province (202304011426). There are no conflicts of interest and no competing financial interest exists for any of the authors.
No datasets were generated or analysed during the current study.
The following information was supplied relating to ethical approvals (i.e., approving body and any reference numbers): The present study was approved by the Institutional Review Board of Tianjin Medical University Cancer Institute and Hospital (EK2022260).
Written informed consent was obtained from all patients for publication of this manuscript.
The authors declare no competing interests.
• MTC
- medullary thyroid cancer
• Ctn
- calcitonin
• CN
- calcitonin normalization
• BP
- biochemical recurrence
• LNR
- lymph node metastasis ratio
• CNT
- calcitonin normalization time
• BPT
- biochemical persistent/recurrent time
• DFS
- disease-free survival
• OS
- overall survival
• SD
- standard deviation
• HR
- hazard ratio
• OR
- Odd ratio
• CI
- confidence interval
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By Fengli Guo; Guiming Fu; Fangxuan Li; Yitong Hua; Zhongyu Wang; Xiangqian Zheng; Jingzhu Zhao and Ming Gao
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