Validity of risk group definition in

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1 Validity of risk group definition in differentiated thyroid carcinoma J M G\l=o'\mez,N G\l=o'\mez,M Sah\l=u'\n, A Rafecas, C Villabona and J Soler Services of Endocrinology and Surgery, Ciudad Sanitaria y Universitaria de Bellvitge. Barcelona, Spain (Requests for offprints should be addressed to J M Gómez, c/sabino de Arana 40, 3s, 2s, Barcelona, Spain) Abstract Despite the usual excellent prognosis of differentiated thyroid carcinoma, some patients die because of disease. It has been speculated that lethal disease may have a better prognosis if patients are treated with extensive surgery plus 131I ablative treatment. We have analyzed a group of 223 patients with differentiated thyroid carcinoma treated under a uniform therapeutic protocol of surgery and followed for 3 to 17.7 years, in order to differentiate patients with a high and a low risk of mortality and the influence of therapy on survival rate. The therapeutic protocol was as follows. If the diagnosis was papillary carcinoma, subtotal thyroidectomy was performed and cervical nodes were removed if they were suspicious for cancer. If the diagnosis was follicular carcinoma, a total thyroidectomy was performed. 131I was given in cases of patients who were more than 60 years old or who had extrathyroid disease or metastases in papillary carcinomas and in macroangioinvasive follicular carcinomas. In survival analysis, the event used as the end-point was death due to thyroid carcinoma and summarized by the Kaplan-Meier curve and the Mantel-Cox method. We found three independent prognostic factors which determined mortality: over 60 years of age, tumor size larger than 6 cm and metastases. On the basis of these factors we identified two risk groups: a low-risk group (A), who had no risk factors, composed of 153 patients whose survival rate at 205 months was 100% and a high-risk group (B), who had one or more risk factors, composed of 55 patients whose survival rate at 213 months was 39.6%. Seventeen patients in this second group died from thyroid carcinoma. We therefore analyzed the effect of treatment in group B. Patients who had more extensive surgery had a similar survival rate to those who had less extensive surgery and 131I administration did not modify the survival rate. These data support the idea that the identification of low-risk groups may facilitate a more rational approach to treatment of differentiated thyroid carcinoma, avoiding aggressive therapy in cases with a good prognosis. Endocrine-Related Cancer (1997)

2 Introduction Thyroid cancer is estimated to comprise approximately 1.1% of all new malignancies diagnosed annually but accounts for only 0.2% of all cancer deaths (Mazzaferri 1991). The major predictors of adverse outcome are: higher age at diagnosis, an increasing extent of spread of the disease at the time of diagnosis and an increasing size of the primary lesion (Krenning & Cady 1988, Baldet etal. 1989, Mazzaferri 1991). Therapy generally consists of surgery, often followed by radioactive iodine (I) and invariably includes thyroid hormone suppression. Several questions remain unclear when evaluating the prognosis and treatment of these cases. For example, does treatment by our approach improve prognosis? Can a more selective therapy that avoids unnecessarily aggressive treatment for tumors that are likely to follow a benign course be used? Are extensive surgery and I ablation useful only in patients who have a poor prognosis? Is it the variability and heterogeneity in clinical and biological behavior which pose some difficulty in the analysis of therapeutic efficacy (Cady et al. 1976, Mazzaferri et al. 1977, Tubiana et al. 1985, McConahey et al. 1986, Krenning & Cady 1988, Baldet et al. 1989, Brennan et al. 1991)? Is there an inherent difference in the biology of differentiated thyroid carcinoma when comparing North American with European patients? The aim of this paper was to review the outcome of treatment of differentiated thyroid carcinoma from our group of 223 cases that were managed under the same protocol and followed-up for 3 to 17.7 years. Patients and Methods From 1974 until 1994, 223 patients (174 female and 49 male, aged 40±18.1 years) with documented differentiated thyroid carcinoma were treated at our hospital. The median follow-up time was 7.5 years (range 3 to 17.7 years), and follow-up was successful in 208 patients. Fifteen patients were lost to followup. Thyroid surgery protocol was the same and was based on preoperative biopsy. If the preoperative diagnosis was papillary carcinoma without extrathyroid disease, thyroid lobectomy and subtotal lobectomy of the opposite lobe was performed. When cervical nodes suspicious for cancer were found macroscopically they were removed and total thyroidectomy was carried out. In seven cases, thyroid lobectomy was the only treatment when CO > 20% Figure 1 Kaplan-Meier predictive survival in patients with differentiated thyroid carcinoma with low risk ( ) and with high risk, papillary (Q) or follicular carcinoma (O).

3 diagnosis was made after surgery. In follicular carcinoma, total thyroidectomy was performed regardless of the presence or absence of extrathyroid disease or métastases. If the diagnosis was established after surgery the patient was reoperated only in cases of follicular carcinoma for completion of total thyroidectomy, except in those whose diagnosis was based on capsular invasion with no macroangioinvasion. As a consequence, a single thyroid lobectomy was carried out in three cases. The 131I protocol was based on a body scan with 5 mci 13II performed 1 month after surgery in patients with total thyroidectomy. In patients of more than 60 years of age with papillary carcinoma or with extrathyroid disease or métastases and in follicular macroangioinvasive tumors, 100 mci I was given for residual uptake in the thyroid bed (ablative) or 150 mci for abnormal uptake in the adjacent area. If there was uptake outside the neck area, the patient was considered to have remote métastases and received mci. All patients were treated with thyroid hormone at thyrotropin-suppressive doses. Thyroid carcinomas were histologically classified according to the WHO criteria (Hedinger 6 Solin 1978) into papillary (138 patients) and follicular carcinoma (85 patients). Patients with an anaplastic component were excluded. The patients were classified according to the TNM system (Spissel et al. 1989): T=primary tumor; T0=no primary tumor; Tl=tumor of <1 cm; T2=tumor of 1-4 cm; T3=tumor of >4 cm; T4=invasive outside thyroid; N lymph nodes; N0=no nodes; = Nla=ipsilateral nodes; Nlb=bilateral, midline, contralateral, or mediastinal nodes; M=distant métastases; M0=no distant métastases; Ml=distant métastases. Statistics The variables analyzed were sex, age at diagnosis, TNM classification, extent of surgery and 131I therapy and they were compared by Chi-square test and ANOVA (SPSS program) (Rosner 1986). In survival analysis, the event used as the end-point was death caused by thryoid cancer. Accumulative survival was summarized in a Kaplan-Meier curve (Kaplan & Meier 1958) and time-dependent variables were analyzed by the Mantel-Cox method (BMDP1L program) to describe the course of patients after treatment (Mantel 1966). Results Multivariate analysis using the Cox proportional hazards method showed that statistically significant predictors of mortality are age, tumor size and métastases. The cut-off of the risk factors in this group was one or more of the following: over 60 years old at diagnosis, tumor size larger than 6 cm or métastases. On the basis of these risk factors patients were grouped into two risk groups: a low-risk group (A) whose survival rate at 208 months was 100%. Group A was composed of 153 patients, 29 male and 124 female, 97 papillary and 56 follicular carcinoma, aged 35.5±12.7 years. A high-risk group (B) whose survival rate at 213 months was 39.6% was defined. This group was composed of 55 patients, 19 male and 36 female, aged 50.8±23.8 years. Seventeen patients died from thyroid cancer in this group, the cause of death being local recurrence in nine, lung métastases in five and bone métastases in three (Fig. 1). Relatively no more patients with progressive lethal disease were found in papillary versus follicular carcinoma (33 versus 22 patients), and the survival was no different between the two histological groups (Fig. 1). We therefore analyzed the effect of treatment. In the patients of group no difference in survival was recognized for any of the treatment groups (lobectomy only, total or near total thyroidectomy) (P=0.6 for papillary carcinoma and P=0.5 for follicular carcinoma by the Mantel-Cox method). Patients so classified were then assigned to one ^ I administration. or another subgroup according to Results again showed no survival differences between lobectomy, total or near total thyroidectomy with or without l31i administration (P=0.6 for papillary tumors and P=0.6 for follicular tumors by the Mantel-Cox method) (Table 1). Discussion Multifactorial analysis of the survival data of cancer patients enables the determination of factors that contribute significantly to a patient's survival, and the weight of each significant factor can be evaluated. These different factors are sex, age at diagnosis, tumor size, multicentricity, presence of nodes, distant métastases, associated Graves' disease and prior head and neck radiotherapy (Cady et al. 1985, Robbins er /. 1991).

4 Table 1 Survival of high-risk patients according to treatment. Survival is expressed as a percentage and maximum follow-up time is shown in parentheses. Near total Total Near total thyroidectomy Total thyroidectomy Lobectomy thyroidectomy plus 131l thyroidectomy plus 131l Differentiated thyroid carcinoma No. of patients Survival (P=0.5) 75% 30% 50% 55% 43% Papillary carcinoma (loyears) (11 years) (17years) (15years) (17years) No. of patients Survival (P=0.6) 66% 35% 100% 83% 67% (loyears) (11 years) U7years) (11 years) (16years) Follicular carcinoma No. of patients Survival (P=0.6) 100% 0% 33% 42% 30% (10 years) (6 years) (14 years) (15 years) (17 years) In the present study using a multivariate method, a group with differentiated high-risk thyroid carcinoma was identified. This group consisted of 55 patients and three risk factors predicted death from thyroid cancer: age more than 60 years at the time of diagnosis, tumors whose diameters were more than 6 cm and distant métastases. We have confirmed in our sample that the 213-month survival rate was 39.6%. Surgery is widely considered as the mainstay in the treatment of differentiated thyroid cancer. The extent of thyroid resection is, however, controversial. The controversies with regard to surgical treatment have been kept alive by the absence of conclusive data. The issue of total versus less than total never be resolved without a well- thyroidectomy may controlled prospective randomized study in the management of differentiated thyroid carcinoma. Total thyroidectomy is generally accepted as the treatment of choice in follicular carcinoma (Cady et al. 1976, Mazzaferri etal. 1977,Tubianaef al. 1985, McConahey et al. 1986, Krenning & Cady 1988, Baldet et al. 1989) but did not prove to be significantly related to outcome (DeGroot et al. 1995). The extent of thyroid surgery is in dispute for the papillary type where the mortality rate is nearly half that of follicular carcinoma and the analysis of deaths and recurrences suggests a different natural history for the disease (Cady et al. 1985, Hannequin etal. 1986, Mazzaferri 1987, DeGroot et al. 1995). Moreover, the usually indolent biological behavior hampers the collection of such data as survival of patients with thyroid cancer (Hay et al. 1987, 1993, Mazzaferri 1987, Grant & Hay 1988, Kekkonen etal. 1990, Schindler et al. 1991, Samaan etal. 1992). In our high-risk group of patients, no survival benefit was recognized for any of the commonly employed surgical operations. More aggressive surgical procedures do not significantly influence overall survival. Other groups using different classi fication scores (Cady etal. 1985, Grant & Hay 1988, Cunningham et al. 1990, Kekkonen et al. 1990, Brennan et al. 1991, Dinnen et al. 1995) reached similar conclusions without a significant effect of therapy on thyroid cancer-associated mortality. When the primary tumor is follicular carcinoma, most authors recommend I therapy postoperatively (Baldet et al. 1989, DeGroot et al. 1990, 1994, Brennan etal. 1991, Mueller-Gartner et al. 1992, Shaha etal. 1994, Solomon et al. 1996), but sharp differences of opinion continue to be expressed among the experts about the optimal use of 131I therapy (Wong et al. 1990, DeGroot et al. 1995, Noguchi et al. 1996). Some authors show that thyroidectomy followed by 131I therapy confers a distinct outcome advantage, especially in patients categorized as low risk (Coburn et al. 1994, Mazzaferri <fe Jhiang 1994, Shaha et al. 1994). This therapy reduces tumor recurrences and mortality. In our experience I ablation does not appear to be associated with a reduction in cancer mortality and we were unable to identify (after adjustment for

5 risk factors) any statistically significant difference in thyroid cancer mortality among patients who under went the various procedures (shown in Table 1). The results of different multifactorial analysis depend on the type of cancer and also on the population. Thus, in thyroid cancer, one should be cautious in applying results obtained by others when calculating a prognostic index (Hannequin et al. 1986, DeGroot et al. 1994, Gómez Arnaiz et al. 1997). We strongly believe that the creation of one's own risk group analysis and prognostic factors are extremely important in the understanding and management of differentiated thyroid cancer. The differences among low- and high-risk patients probably reflect intrinsic biological variations and not different treatment regimens. Thyroid cancer is a complex multistep process necessary for thyroid cell transformation with a progressive extension of growth signals and genes involved in cell growth (Farid et al. 1994). While the biological characterization of thyroid cancer has been determined, the identification of low- and high-risk groups on clinical grounds may facilitate a more rational approach to the treatment of differentiated thyroid carcinoma and selection of the extent of therapy. Conclusions Survival rate in differentiated thyroid carcinoma was lower in a high-risk group of patients older than 60 years at diagnosis, and with a tumor larger than 6 cm and distant métastases. In the high-risk group, neither more extensive thyroidectomy nor 131I treatment modify the prognosis but although the analysis of the effectiveness of different treatments of high-risk patients fails to show any advantage, the numbers in each group are arguably too small to show any potential difference. References Baldet L, M anderscheid J-C, Glinoer D, Jaffiol C, Coste- Seignovert efe Percheron C 1989 The management of differentiated thyroid cancer in Europe in 1988: results of an international survey. Acta Endocrinologica Brennan MD, Bergstralh EJ, van Heerden JA efe McConahey WM 1991 Follicular thyroid cancer treated at the Mayo Clinic 1976 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clinic Proceedings Cady B, Sedgwick CE, Meissner WA, Bookwalter JR, Romagosa V e& Weber J 1976 Changing clinical, pathologic, therapeutic, and survival patterns in differentiated thyroid carcinoma. Annals ofsurgery Cady B, Rossi R, Silveman M efe Wool M 1985 Further evidence of the validity of risk group definition in differentiated thyroid carcinoma. Surgery Coburn M, Teates D <fe Wanebo HJ 1994 Recurrent thyroid cancer. Role of surgery versus radioactive iodine (I). Annals of Surgery Cunningham MP, Duda RB, Recant W, Chmiel JS, Sylvester JA efe Fremgen A 1990 Survival discriminants for differentiated thyroid cancer. American Journal of Surgery DeGroot LE, Kaplan EL, McCormick M & Straus FH 1990 Natural history, treatment, and course of papillary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism DeGroot LJ, Kaplan EL, Strauss FH e& Shukla MS 1994 Does the methods of management of papillary thyroid carcinoma make a difference in outcome? World Journal ofsurgery DeGroot LJ, Kaplan EL, Shukla MS, Salti G efe Straus FH 1995 Morbidity and mortality in follicular thyroid cancer. Journal of Clinical Endocrinology and Metabolism Dinnen SF, Valimaki MJ, Bergstralh EJ, Goeller JR, Gorman CA & Hay ID 1995 Distant métastases in papillary thyroid carcinoma: 100 cases observed at one institution during 5 decades. Journal of Clinical Endocrinology and Metabolism Farid NR, Shi Y efe Zou M 1994 Molecular basis of thyroid cancer. Endocrine Reviews Gómez Arnaiz N, Gómez Sáez JM, Sahún de la Vega M, Abós R, Villabona Artero C efe Soler Ramón J 1997 Identificación y validación de factores pronósticos del cáncer diferenciado de tiroides. Medicina Clínica Grant CS efe Hay D 1988 Local recurrence of papillary thyroid carcinoma after unilateral or bilateral thyroidectomy. Weiner Klinik Wochenschrift Hannequin, Liehn JC efe Delisle MJ 1986 Multifactorial analysis of survival in thyroid cancer. Pitfalls of applying the results of published studies to another population. Cancer

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