Differentiated thyroid cancer patients more than 60 years old paradoxically show an increased life expectancy.

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Journal of Nuclear Medicine, published on January 22, 2015 as doi:10.2967/jnumed.114.150284

Differentiated thyroid cancer patients > 60 years of age paradoxically show an increased life expectancy. Tobias Markus Maier1, Otmar Schober1, Joachim Gerß2, Dennis Görlich2, Christian Wenning1, Burkhard Riemann1 and Alexis Vrachimis1 1: Department of Nuclear Medicine, University Hospital Münster, Germany; 2: Institute of Biostatistics and Clinical Research, University Hospital Münster, Germany

BR and AV contributed equally to this work Correspondence to: Alexis Vrachimis, M.D. Department of Nuclear Medicine, University Hospital Münster Albert-Schweitzer-Campus 1, Building A1, 48149 Münster, Germany Tel. +49/2 51/ 83 47 853 Fax +49/2 51/ 83 47 383 Email: [email protected] Word count: 5154 Words; 1 Figure, 3 Tables (6 Figures and 1 Table as suppl. material) Disclosure statement: The authors have nothing to disclose. Abbreviated title: Survival of DTC patients


Abstract The aim of this study was to compare the overall survival of a large single center cohort of patients with differentiated thyroid cancer (DTC) to that of a matched general population.

Methods: We have analyzed 2428 consecutive patients with DTC, who underwent treatment from 1965 to 2013 at the Department of Nuclear Medicine of the University Hospital of Münster (Germany) according to international standards. Patients were classified using the current 7th edition of the AJCC/UICC classification system. Additionally, a subgroup analysis with regard to age at diagnosis was performed. The overall survival of the patients was compared to the expected survival of the general population based on age and sex as provided by the Federal Statistical Office of Germany.

Results: Compared to the expected survival, stage I patients paradoxically have a significantly better overall survival (p < 0.001). In the subgroup analysis, a significantly lower mortality rate was observed in elderly patients (≥ 60 years old) with stage I disease. On the other hand, patients between 20-45 years of age with distant metastasis at diagnosis show a significantly increased standardized mortality rate. This is in contrast with other stage II patients >45 years of age, who show a normal mortality rate. Furthermore the mortality rate was significantly increased in all stage IVc patients.

Conclusion: Older patients with a more limited disease paradoxically show a better survival than would be expected based on age and gender, whereas young adults as well as patients >45 years with distant metastases show an increased mortality. All other DTC patients, regardless of age or TNM stage, show no significant survival difference. 1


Key words: differentiated thyroid cancer, overall survival, expected survival Malignant tumors of the thyroid are the most common malignant endocrine neoplasms, comprising of approximately 1 % of all malignant tumors (1). In the last years, there has been a clear rise in the incidence of malignant thyroid carcinomas (2), especially in small papillary carcinomas, which is most probably due to the recent enhancement of diagnostic methods such as ultrasound and needle aspiration cytology. There is a big difference between the survival rates of the various thyroid carcinomas, with medullary carcinomas originating from the parafollicular Ccells and the rare undifferentiated anaplastic carcinomas having a worse survival rate than DTCs. It has been well documented in the last 70 years that DTCs, with the capacity to store iodine have a very good outcome compared to other cancers (1, 3-5) with an average survival rate of over 90 %.This fact is largely due to the possible administration of radioactive

131

I as a radioiodine

therapy with the aim of a complete remission, even in more advanced stages. Even high-risk patients have a favorable life-expectancy, which has been improved through the implementation and analysis of high quality clinical studies (6).Indeed, it has been shown that up to stage III there is no survival difference in DTC patients when compared to the general population. It remains controversial whether stage IVa patients experience a shorter life span due to their disease (7, 8).Nevertheless there is no doubt that patients ≥ 45 years diagnosed with distant metastases (stage IVc) show a worse survival rate than the general population. The presence of lateral lymph node metastasis on recurrence of the disease after initial standardized treatment and the worse survival of such patients is still subject to debate (7-11). For staging these carcinomas, the tumor node metastasis (TNM) classification of the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) is most commonly and widely accepted. The T categories are based both on tumor size and on 2


extra-thyroidal extension. In the current 7th edition lymph node metastasis is classified into two categories: patients having metastasis only in the central compartment are graded as N1a and those having metastasis in the lateral or mediastinal compartments are graded as N1b (12). In a previous study of life expectancy in our population, several interesting trends could be observed which however failed to reach statistical significance (7). Since then, we were able to widen our database with a considerable number of patients and follow-up years. The aim of the present study was therefore to re-examine life expectancy in our DTC population in order to identify DTC patient subgroups with significantly altered life expectancy.

MATERIALS AND METHODS

A total of 2476 patients presented themselves between 12/31/1965 and 04/23/2013 at the Department of Nuclear Medicine of the University Hospital of Münster (Germany) with a diagnosed DTC. The University Hospital of Münster represents a tertiary referral center serving around 5-10 % of immigrants which is also the average percentage of immigrants in the general population in Germany. Forty-eight patients had to be censored, resulting in 2428 individuals analyzed (further information are provided below).There were 1823 patients with papillary thyroid carcinoma (PTC) and 570 with follicular thyroid carcinoma (FTC). The remaining 35 patients were diagnosed with poor differentiated thyroid carcinoma (PDTC). Approximately three quarters of the patient collective were females (26.2% males). The median age at time of diagnosis was 47 years with a median follow-up time of 6.6 years. The study categorization in the TNM classification was made according to the 7thAJCC/UICC classification after successful ablation of thyroid remnants with radioiodine if applicable. Both the post-therapeutic and the first diagnostic radioiodine scintigraphy (6-9 months after 3


radioiodine remnant ablation) in combination with the surgery and histology reports, as well as other existing imaging (e.g. MRI, CT, ultrasound, PET/CT) were used for the classification. Treatment was made according to current international standards (13-16). Follow-up data were obtained from the patient records of our clinic and from the patient’s family doctors. Overall survival analysis was performed computing the time at risk from the date of diagnosis of thyroid cancer to the date of death or the date of last contact, whichever occurred first (observed overall survival). Observed overall survival rates were compared to expected survival. Expected survival was computed using data of the general population of former Western Germany excluding (Western) Berlin published by the Federal Statistical Office (Wiesbaden, Germany), controlling for gender, age and calendar year periods. The Federal Statistical Office of Germany did not provide information on the expected survival of persons > 90 years of age. Therefore, the followup of DTC patients > 90 was censored at the age of 90. Accordingly, the deaths which occurred > 90 (n=13) were excluded from statistical comparison of expected and observed overall survival rates. One patient was omitted because she was > 90 at diagnosis. Other reasons for the exclusion from analysis were: no specific death cause (n=7), lack of analytical histological report for exact classification (n=9), lack of information on gender (n=1) and follow-up = 0 (n=30). Matching of life expectancy for the control group was made individually for every year in the database up to 2008. The calculation for the patients from 2008-2013 was made using life expectancy tables from 2008.Histological classification was taken from the corresponding pathological report. If a patient had ≥ 2 different entities of DTC, he/she was then classified using the DTC with the worse outcome (PDTC < FTC < PTC). Similarly, in the presence of multifocal disease the biggest diameter was chosen.

4


The institutional review board of the Medical Association of Westphalia-Lippe and the Faculty of Medicine, University of Münster, approved this retrospective study and the requirement to obtain informed consent was waived.

Surgical Treatment and Radioiodine Therapy

Most of our patients underwent total (90.4%) or subtotal (8.0%) thyroidectomy. Only a small part received more limited surgery (hemithyroidectomy (1.5%), microdissection (< 0.1%)). Neck dissection was applied in 39.9% of the cases. In 5.3% of the cases, histopathological examination reported an R1 and in 1.4% an R2 situation after initial operation. In the following, the vast majority (91.1%) obtained a radioiodine remnant ablation with a median cumulative activity of around

4

GBqI131 and

a

median

tumor

diameter

of

1.5

cm.

A

levothyroxin

substitution/suppression therapy was administered according to international guidelines (13, 14). There were 234 patients with distant metastases (n=270 in total). Recurrences (n=27) occurred in 21 patients. More detailed information is provided in TABLE 1.Follow-up included ultrasonography, measurement of the tumor marker thyroglobulin (Tg) under TSH suppression/stimulation and diagnostic neck and whole-body scans with radioiodine according to international standards. Complex cases were presented and discussed interdisciplinary. Decisions on treatment were then often based on supplementary examinations, such as 18F-FDG-PET (/CT) or needle aspiration biopsy. If locoregional recurrence was encountered, decisions were made individually, with a major consideration for compartment orientated lymphadenectomy as the primary therapeutic option (17) as well as a second radioiodine therapy for residual lesions with 5


the capacity to store iodine.

Statistics

Survival analytic methods were applied to compare expected and observed overall survival, i.e. Kaplan-Meier estimation and the one sample log-rank test, conditioning on patients’ observed follow-up (18).Overall survival (OS) was calculated from time of diagnosis until death, or last contact. Event-free survival (EFS) was calculated from time of diagnosis until relapse, death, or last contact. The observed survival of DTC patients was compared to the expected survival of a matched general population as proposed by Finkelstein (19). Matching criteria were age at diagnosis, sex and calendar year. For each DTC patient, individual mortality rates of a matched person in the general population were derived in each follow-up year after inclusion. Based on individual mortality rates the expected survival distribution was obtained as well as the expected number of deaths. The null hypothesis that mortality rates in our patient cohort were not different from the expected mortality rates was tested using the one sample log-rank test (20). We also calculated the standardized mortality ratio (SMR), defined as the ratio of the number of observed deaths in our patients group to the number of expected deaths in the matched general population in the analyzed time span. We calculated a 95% confidence interval of the SMR, using the method introduced by Finkelstein et al. (19). Additional to the comparison to the reference population, subgroups were compared to identify potential risk factors for survival. Kaplan-Meier estimates and two-sided log-rank testes were used to test for differences in survival. Coxproportional hazard models were used to estimate respective hazard ratios (HR) and 95% confidence intervals (CI).Inferential statistics are exploratory (hypothesis-generating), not confirmatory and are interpreted accordingly. P-values are considered statistically significant if p 6


≤ 0.05. No adjustment for multiple testing was performed. Statistical analyses were performed using TIBCO Spotfire S+ (Version 8.1 for Windows, TIBCO Software Inc.) and SPSS (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0).

RESULTS

The completeness index, defined as the quotient of the observed number of person-years to the expected number of person-years, at the last date of follow-up on 04/23/2013 was 0.8290 for the entire collective. Furthermore, the indexes did not differ between the different stages (stage I: 0.8323; II: 0.8442; III: 0.7992; IVa: 0.7612 and IVc: 0.8508). Patients in stage I (n=1577) have a significantly better outcome than the general population (SMR: 0.61). Patients in stage II (n=306) show no significant difference between the two cohorts. Also patients in stage III (n=300) did not show a significant survival difference. Stage IVa (T13N1bM0 or T4aN0-1M0, ≥ 45 years, n=95) patients have no significant survival difference compared to the control group, while stage IVc (M1, ≥ 45 years, n=150) patients clearly show a worse survival rate (SMR: 2.45). The SMR with the running 95 % confidence intervals and pvalues for different follow-up periods are provided in TABLE 2. It is noteworthy that there were no stage IVb patients in our cohort, as this stage reflects a large extra-thyroidal growth, which is rare in countries with a highly developed medical system such as Germany. Considering that there is a considerable difference in biological behavior between patients of different ages and taking advantage of the large number of patients in this population, the influence of age was analyzed further by subdividing into different age categories as follows: a) Juvenile (0-19 years), b) early adulthood (20-44 years), c) middle adulthood (45-59 years) and d) late adulthood (60+ years) (see Supplemental Figures 1-6 and Supplemental Table 1). In 7


summary, the most important findings are that patients between 20-45 years of age with distant metastasis at diagnosis (Stage II) show a significantly and considerably increased standardized mortality rate. This is in contrast with other stage II patients >45 years of age, who show a normal mortality rate. Furthermore, as we already found previously (7), the mortality rate was significantly increased in stage IVc patients in both those ages 45-60 and >60. On the other hand, a significantly lower mortality rate was observed in elderly patients (≥ 60 years old) with stage I disease, i.e. patients with small primary tumors (≤ 2cm) with no lymph node or distant metastasis. Further statistical analysis of risk parameters for overall survival (OS) and event-free survival (EFS) reveal differences (p ≤ 0.05) in sex, age, distant metastases and histology. As shown before women have a favorable outcome as compared to men and the presence of metastasis is the major predictive factor for survival. Furthermore, patients ≥ 45 years at time of diagnosis show worse EFS as compared to younger patients. With regards to histology PDTCs patients have the worst and PTC the most favorable outcome. The presence of macroscopic residuals (R2) is indicative for a worse outcome as compared to R0 and R1. With regards to the lymph nodal status, only the comparison between N0 and N1b shows a significant difference in OS and EFS in favor of N0 Analytical information of the SMR, their 95 % confidence intervals and p-values for OS and EFS are provided in TABLE 3.

DISCUSSION

In recent years thyroid cancer has shown ever increasing incidence rates throughout the world. This is mainly due the earlier diagnosis by improved diagnostic procedures, including ultrasound and fine-needle aspiration cytology as well as thin-section histopathological examinations of thyroid surgically originally removed for non-cancerous disease. The enhanced incidence is 8


reflected in a marked increase in the number of patients which were included in the Münster Thyroid Cancer Registry in recent years. There are numerous studies on the treatment of DTC. Surprisingly, there are very few that address the difference in survival between the patients and the general population (7, 8, 21). As Eustatia-Rutten et al. quote, only 2 of 28 reviewed articles on DTC outcome had an initial and continued standardized treatment through the follow-up (22). Furthermore, studies on survival in DTCs have often failed to classify their patients in the UICC-classification, which appears to be the most powerful method in clinical treatment and risk-stratification (23-25). Updating the former published Münster Thyroid Cancer Registry (7) has created one of the largest cohorts of a uniformly treated collective of DTC patients known so far. Accordingly, the patient number has been raised from 1497 patients to 2428 patients between 2008 and 2013 and the number of available follow-up years was increased by 78%. In contrast to the previous study a small but significant improvement in survival (SMR from 0.77 to 0.61) has been documented in stage I patients with thyroid cancer as compared to that of the general population. This may in part be due to a selection bias since particularly those people who undergo regular preventive medical checkups may have the opportunity of earlier thyroid cancer diagnosis. In addition, the increased follow-up time -in particular by adding patients diagnosed since 1966- might accentuate the benefits of the life-long medical surveillance of patients included in the clinical study. Thereby, a healthier life style is promoted in this patient group by continuous monitoring and patient reflection of health parameters such as body weight, physical training, blood pressure and heart rate. In addition, earlier medical clarification of other diseases is initiated leading to a long-term prognostic advantage in these patients. Another fact that supporting this hypothesis, is that a significantly better outcome as expected is shown only in the elderly group of stage I patients. Another fact supporting this hypothesis is that a significantly better outcome as expected 9


is shown only in the elderly group of stage I patients. In particular, this group being at higher risk for health hazards will benefit the most of an intense medical surveillance within the first years of initial diagnosis. Thereby further diseases can be revealed in premature stages/on time, contributing to improvement of the survival. Furthermore, the introduction of dedicated SPECT/CT and PET/CT systems may have facilitated timely detection of tumor recurrence and metastasis. It would be conceivable that that deaths in stage I were missed more often than in other stage groups because the good prognosis would lead to patients no longer being followed after a long recurrence free period, especially when more serious diseases would make it difficult to attend regular visits in our outpatient clinic. However, this is highly unlikely considering that the completeness index for this group was as good as for patients in higher stages. Furthermore, a “healthy patient phenomenon” has been reported before in a population in which the effect of pregnancy on overall survival after the diagnosis of early-stage breast cancer (26) was compared. The investigators observed a better outcome in the patients who became pregnant after diagnosis of early-stage breast cancer as compared to non-pregnant matched patients and interpreted the result as a “healthy mother” effect. In the discussion the authors stated that this may merely represent a “healthy patient” bias, in that women with less subclinical tumor load, and therefore a superior prognosis, may be more likely to attempt or to achieve subsequent pregnancy. Another study shows a superior survival in patients undergoing in vitro fertilization as compared to the general population (27). Also these authors suggest a “healthy patient effect” due to the fact that the unhealthiest women in the community may be deterred from planning a pregnancy or accessing IVF services, i.e. the women who are planning a pregnancy may be healthier than other women of the same age. One of the most frequently debated points in publications on survival of DTC patients has recently been the outcome and recurrence difference of patients with lateral lymph node 10


metastasis, compared to other patients. While Bhattacharyya asserted that cervical lymph node metastasis does not influence the survival in DTC patients (11), Podnos et al. report the opposite result (10).Also, two of the most recent studies pertaining to this question in Germany come up with different answers. While Verburg et al. underline the worse survival of patients with lateral lymph node metastasis (8), Vrachimis et al. show that there is no reduced survival in patients with a stage IVa disease (7).In the present study we could confirm our previous results showing no worsening of the outcome for the IVa patients, enhancing the opinion expressed by Verburg who assumes that this might be due to an earlier compartment-orientated surgical intervention instead of watchful waiting and subsequent additional radioiodine therapy (28).Whilst having good outcomes in stage I-IVa, the present study as well as others (7- 8, 21) show that stage IVc patients still have a clearly poorer outcome than the general population. Accordingly, especially in this stage it is important to conduct further research on definitive individual treatment with modern, promising therapies such as tyrosine-kinase inhibitors, radioimmuno- and -receptor therapies, use of bisphosphonates in metastasis in the bones or stereotactic radiation of brain metastases (29). In another important finding, the present study clearly indicates that the conventionally held belief that young adults with distant metastases have a very good prognosis with likely unimpaired life expectancy may not conform to reality, as the present study is the first one to show that young adults (20-45 years age) with distant metastasis at the time of diagnosis have a significantly increased standardized mortality rate. This finding is in contrast with those reported by Verburg et al. (8), who did not find a lower life relative survival for this patients group. Our study did have some limitations. One of the most challenging parts of the comparison of our patients to the German general population was the formation of a valid cohort. Nonetheless we concede that, having achieved this goal for Germany, the present study is not necessarily representative for other countries with a different population and geographic background, the 11


reason being that the incidence of DTC differs very much (30-32) with potential differences in genetics, which can influence the prognosis and outcome (2). This potential bias is also represented by the fact that we did not have any stage IVb patients with large extra-thyroidal growth as they do not occur frequently in highly industrialized countries like Germany. Patients were censored at the age of 90 until the year 2000 because the Federal Statistic Office did not provide any further information beyond this age. As a consequence 13 patients had to be censored, which could lead to minor biases represented in wrong descending the survival rates. The median follow-up was 6.6 years, which is comparable to other similar studies, with a very long surveillance period of up to 47 years. Nevertheless, due to the very good prognosis of most of the tumors, the time is relatively short to make statements pertaining to long- term recurrence rates among our patients, which could be part of a further analysis in the future. However, this limitation is partially compensated by the adequate patient-years assessed in our study.

CONCLUSION

Older (aged >60) patients with a more limited disease (stage I) paradoxically show a better survival than would be expected based on age and gender, whereas young adults (aged 20-45) as well as any patient >45 years with distant metastases show an increased mortality. All other DTC patients, regardless of age or TNM stage, show no significant survival difference.

Author Disclosure Statement

All authors have nothing to declare in terms of competing interests related to this study.

12


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standard population. J Natl Cancer Inst. 2003; 95:1434–1439. 20. Woolson R. Rank tests and a one-sample Logrank test for comparing observed survival data to a standard population. Biometrics.1981; 37:687–696. 21. Links TP, van Tol KM, Jager PL, et al. Life expectancy in differentiated thyroid cancer: a novel approach to survival analysis. Endocr Relat Cancer.2005; 12:273–280. 22.Eustatia-Rutten CF, Corssmit EP, Biermasz NR, et al. Survival and death causes in differentiated thyroid carcinoma. J Clin Endocrinol Metab.2006; 91:313–319. 23. Brierley JD, Panzarella T, Tsang RW, Gospodarowicz MK, O’Sullivan B.A comparison of different staging systems predictability of patient outcome. Thyroid carcinoma as an example.Cancer.1997; 79:2414–2423. 24. Passler C, Prager G, Scheuba C, Kaserer K, Zettinig G, Niederle B. Application of staging systems for differentiated thyroid carcinoma in an endemic goiter region with iodine substitution. Ann Surg. 2003; 237:227–234. 25. Verburg FA, Mäder U, Kruitwagen CL, Luster M, Reiners C. A comparison of prognostic classification systems for differentiated thyroid carcinoma. Clin Endocrinol (Oxf). 2010; 72:830– 838. 26. Gelber S, Coates AS, Goldhirsch A, et al. International Breast Cancer Study Group. Effect of pregnancy on overall survival after the diagnosis of early-stage breast cancer. J Clin Oncol. 2001; 19:1671-5. 27. Venn A, Hemminki E, Watson L, Bruinsma F, Healy D. Mortality in a cohort of IVF patients.Hum Reprod. 2001; 16:2691-6. 28. Verburg F, Weber T, Luster M.¹³¹I sodium-iodide versus ⁵⁶Fe surgical steel. Which is better for lateral lymph node metastases in differentiated thyroid cancer patients? Nuklearmedizin. 2013;52:113-114. 15


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16


FIGURE 1: Overall survival rates according to the 7th edition of the UICC/TNM stages with running 95% confidence intervals in a patient population treated for differentiated thyroid cancer at the University Hospital of Münster, Germany, compared to survival rates of a matched population. 17


TABLE 1: Cohort characteristics Patient characteristics

Number of patients

Gender

Man

637

Woman

1791

< 45 years ≥ 45 PTC FTC PDTC Stage I Stage II Stage III Stage IVa Stage IVc Thyroidectomy

1059 1369 1823 570 35 1577 306 300 95 150 2196

Subtotal thyroidectomy

194

Hemithyroidectomy

36

Microdissection

2

Neck dissection

969

All

2213

PTC

1613

FTC PDTC R0 R1 R2

566 34 2265 128 35 234 (270 sites) 162 68 19 14 6 1 21 (27 sites) 9 13 5

Age at diagnosis Histology

UICC 7th edition

Surgery

131

I

therapy

R- Status

Distant metastasis

Lung Bones Brain Mediastinal lymph nodes Liver Kidney

Recurrence Thyroid Local lymph nodes Distant metastasis

Table 1 Abbreviations: PTC=Papillary thyroid carcinoma; FTC= Follicular thyroid carcinoma; PDTC= Poor differentiated thyroid carcinoma; UICC= Union for International Cancer Control; R= Residual status after surgery; R1= Microscopic residual; R2= Macroscopic residual.

18


TABLE 2: Observed versus expected number of deaths in each UICC/TNM 2009 stage for different follow-up periods. Stage

I

II

III

IVa

IVc

Number of patients

1577

306

300

95

150

DTC, O

13

11

19

6

38

E

27.0

11.5

13.7

5.4

14.0

SMR O/E (95% CI) p value

0.48 (0.26-0.89) 0.007

0.96 (0.49-1.86) 0.887

1.39 (0.84-2.31) 0.149

1.11 (0.46-2.69) 0.801

2.72 (1.90-3.91)

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