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Table of Contents
EDITORIAL
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 118-120

Treatment-induced hypothyroidism in head-and-neck cancer – Is it a crystal ball?


Department of Medicine, Eli Lilly and Company, Gurgaon, Haryana, India

Date of Web Publication17-May-2019

Correspondence Address:
Tarun Puri
Eli Lilly and Company, Plot No. 92, Sector 32, Gurgaon - 122 001, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_15_19

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How to cite this article:
Puri T. Treatment-induced hypothyroidism in head-and-neck cancer – Is it a crystal ball?. Cancer Res Stat Treat 2018;1:118-20

How to cite this URL:
Puri T. Treatment-induced hypothyroidism in head-and-neck cancer – Is it a crystal ball?. Cancer Res Stat Treat [serial online] 2018 [cited 2019 Jun 19];1:118-20. Available from: http://www.crstonline.com/text.asp?2018/1/2/118/258532



Thyroid hormones including triiodothyronine (T3) and thyroxine (T4) are known to play an important role in the growth and development of normal body cells. There is also a hypothesis that thyroid hormones may positively modulate tumor cells. The mechanism of action of thyroid hormones and their receptors may be responsible for this effect, which is mediated through phosphatidylinositol-3-kinase and mitogen-activated protein kinases and involves stimulation of angiogenesis.[1] The removal of this tumorigenic stimulus may result in antitumor effects.

From a clinical perspective, the above hypothesis raises important questions regarding thyroid hormones and cancer, including the possible influence of thyroid hormones on tumor incidence, progression and metastases, and the success of treatment.

Population-based retrospective studies have shown that there may be an increased risk for ovarian and pancreatic cancer, with higher thyroid hormone levels. Ness et al. and Ko et al. showed an odds ratio of 1.9 and 2.1, respectively, for the occurrence of ovarian and pancreatic cancers in women with hyperthyroidism, after adjusting for other known etiologic factors.[2],[3] Lehrer et al. reported a possible relationship between thyroid hormones and prostate cancer, wherein patients with prostate cancer and benign prostatic hyperplasia had higher T3 levels than controls.[4] A prospective study of 2696 women with breast cancer showed a significantly higher risk of breast cancer in women with higher T3 levels at baseline.[5]

Animal studies such as those reported by Shoemaker et al. have shown a connection between survival and induced hypothyroidism in mice after implantation of murine mammary adenocarcinoma cells.[6] Mice who were rendered hypothyroid with propylthiouracil (PTU) showed reduction in tumor size compared to the control group.


  Hypothyroidism and the Success of Anticancer Treatment Top


With the knowledge that thyroid function may be correlated to tumor incidence, as well as with animal models showing possible correlation between thyroid hormones and tumor growth, metastasis, and survival; it seems possible that thyroid function could influence the outcome of antitumor therapy. This has been found to be true in some tumors including renal cell carcinoma (RCC) and glioma.

Riesenbeck et al. reported a study of the antiangiogenic agents, sorafenib or sunitinib, as the first- or second-line therapy for metastatic RCC and showed that the development of hypothyroidism was indicative of better prognosis in both univariate and multivariate analysis.[7] Patients who developed hypothyroidism had longer progression-free survival (PFS) compared to those who remained euthyroid (16 months vs. 6 months, P = 0.032). Patients with overt hypothyroidism were treated with T4; however, the association of hypothyroidism with PFS was not diminished by thyroid hormone replacement. In a prospective study of patients with recurrent glioma who were rendered hypothyroid with PTU, biochemical hypothyroidism was associated with significantly longer overall survival (OS) of 10.1 months vs. 3.1 months, P = 0.03.[8]


  Head-and-neck Cancer Top


A study published by Nelson et al. reported a retrospective analysis of association between thyroid function and treatment outcome in head-and-neck squamous cell cancer.[9] A total of 155 patients were treated with radiotherapy alone or in combination with chemotherapy and/or surgery. Fifty-nine patients developed hypothyroidism during the course of treatment and follow-up, which was likely a consequence of radiation. Sixteen of these patients had a recurrence (ten before or with diagnosis of hypothyroidism and six after). Recurrence was detected in 41 of 96 euthyroid patients. The risk of death or recurrence was significantly lower in hypothyroid patients (HR: 0.37, P < 0.001) [Table 1]. Landmark analysis performed at 3-month intervals in the first 2 years after treatment showed better survival outcomes for patients who developed hypothyroidism. In contrast to the intended induction of hypothyroidism in the glioma patients, the hypothyroid head-and-neck cancer patients were started on T4 supplementation, but efficacy of supplementation was not known.
Table 1: Studies showing the association of hypothyroidism with treatment outcome in head-and-neck cancer

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Noronha et al. published a study of weekly or 3-weekly cisplatin and concurrent radiation in locally advanced head-and-neck cancer patients.[11] After completion of treatment, patients underwent thyroid function tests at 3-monthly intervals for the first 2 years and thereafter at 6-monthly intervals. The authors reported the impact of hypothyroidism on locoregional failure rate (LRFR), PFS, and OS [Table 1].[10] They also studied the impact of the duration of hypothyroidism and the level of thyroid-stimulating hormone (TSH) on the efficacy parameters. In patients who developed hypothyroidism, there was a favorable impact of longer duration of hypothyroidism and hypothyroidism with TSH levels up to 40 uIU/ml (versus values above 40 uIU/ml) on LRFR, PFS, and OS.

In this issue of Cancer Res Stat Treat, Patil et al. report the detailed analysis of hypothyroidism on outcomes in head-and-neck cancer, of their previously published study of chemoradiation in head-and-neck cancer.[10],[11],[12] They evaluated factors that may predict the development of hypothyroidism, including age, gender, site of primary, nodal stage, T stage, cumulative radiotherapy dose, and cumulative cisplatin dose. They also analyzed the relation between duration of hypothyroidism and outcomes including LRFR, PFS, and OS as well as the relation between TSH level (as a time-varying repeated measure) and outcome. The authors report that young patients (P = 0.007), patients with primary in larynx or hypopharynx (P = 0.004), and a lower T stage (P = 0.004) had a higher incidence of hypothyroidism. At a median follow-up of 22 months (range: 3–51 months), the 2-year LRFR was 36.61% in the euthyroid cohort as against 12.37% in the hypothyroid patient cohort (HR: 0.345; 95% CI: 0.122–0.972; P = 0.044, favoring the hypothyroid cohort). Hypothyroid patients had superior efficacy outcomes including PFS (not reached vs. 28.4 months; HR: 0.571; 95% CI: 0.324–1.006; P = 0.053) and OS (not reached vs. 36.07 months; HR: 0.321; 95% CI: 0.167–0.614; P = 0.001) compared to euthyroid patients. Longer duration of time spent in hypothyroid state had a favorable impact on locoregional failure (HR: 0.990; 95% CI: 0.979–1.001; P = 0.062), PFS (HR: 0.996; 95% CI: 0.994–0.999; P = 0.007), and OS (HR: 0.995; 95% CI: 0.991–0.999; P = 0.016). Higher TSH levels also correlated with improvement in outcome.

Based on the studies published thus far, the occurrence of hypothyroidism may be associated with improved outcomes with chemoradiation in patients with head-and-neck cancer.[9] However, a number of questions still remain unanswered, particularly in the context of head-and-neck cancer.

Could hypothyroidism be only a surrogate marker for the delivery of the therapeutic agent as seen with sunitinib in RCC? In head-and-neck cancer, evidence thus far is not clear on whether hypothyroidism following radiation is an index of the delivery of radiation. The impact of duration of hypothyroidism and of thyroid hormone supplementation on treatment outcome is also not completely well known. Linked to the latter point is the lack of consensus on when one should treat secondary hypothyroidism, and the importance of striking the right balance between the impact of symptomatic hypothyroidism on quality of life and the possible impact on outcome that this treatment may have. The option of rendering patients hypothyroid with agents like PTU may also be considered in case the association of hypothyroidism and treatment outcomes is replicated in a prospective study in head and neck cancer, specifically designed with that objective.[9] Finally, chemotherapeutic agents are also known to have a causal association with hypothyroidism and the interaction between chemotherapy and radiation, and hypothyroidism, at a biologic level, is as yet not clear.

Pending answers to the above questions, the association between hypothyroidism and treatment outcomes in head-and-neck cancer is an interesting observation, for which the final word remains as yet unwritten.



 
  References Top

1.
Moeller LC, Führer D. Thyroid hormone, thyroid hormone receptors, and cancer: A clinical perspective. Endocr Relat Cancer 2013;20:R19-29.  Back to cited text no. 1
    
2.
Ness RB, Grisso JA, Cottreau C, Klapper J, Vergona R, Wheeler JE, et al. Factors related to inflammation of the ovarian epithelium and risk of ovarian cancer. Epidemiology 2000;11:111-7.  Back to cited text no. 2
    
3.
Ko AH, Wang F, Holly EA. Pancreatic cancer and medical history in a population-based case-control study in the San Francisco Bay Area, California. Cancer Causes Control 2007;18:809-19.  Back to cited text no. 3
    
4.
Lehrer S, Diamond EJ, Stone NN, Droller MJ, Stock RG. Serum triiodothyronine is increased in men with prostate cancer and benign prostatic hyperplasia. J Urol 2002;168:2431-3.  Back to cited text no. 4
    
5.
Tosovic A, Bondeson AG, Bondeson L, Ericsson UB, Malm J, Manjer J, et al. Prospectively measured triiodothyronine levels are positively associated with breast cancer risk in postmenopausal women. Breast Cancer Res 2010;12:R33.  Back to cited text no. 5
    
6.
Shoemaker JP, Bradley RL, Hoffman RV. Increased survival and inhibition of mammary tumors in hypothyroid mice. J Surg Res 1976;21:151-4.  Back to cited text no. 6
    
7.
Riesenbeck LM, Bierer S, Hoffmeister I, Köpke T, Papavassilis P, Hertle L, et al. Hypothyroidism correlates with a better prognosis in metastatic renal cancer patients treated with sorafenib or sunitinib. World J Urol 2011;29:807-13.  Back to cited text no. 7
    
8.
Hercbergs AA, Goyal LK, Suh JH, Lee S, Reddy CA, Cohen BH, et al. Propylthiouracil-induced chemical hypothyroidism with high-dose tamoxifen prolongs survival in recurrent high grade glioma: A phase I/II study. Anticancer Res 2003;23:617-26.  Back to cited text no. 8
    
9.
Nelson M, Hercbergs A, Rybicki L, Strome M. Association between development of hypothyroidism and improved survival in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 2006;132:1041-6.  Back to cited text no. 9
    
10.
Patil VM, Noronha V, Joshi A, Bhattacharjee A, Goel A, Talreja V, et al. Influence of hypothyroidism after chemoradiation on outcomes in head and neck cancer. Clin Oncol (R Coll Radiol) 2018;30:675.  Back to cited text no. 10
    
11.
Noronha V, Joshi A, Patil VM, Agarwal J, Ghosh-Laskar S, Budrukkar A, et al. Once-a-week versus once-every-3-weeks cisplatin chemoradiation for locally advanced head and neck cancer: A phase III randomized noninferiority trial. J Clin Oncol 2018;36:1064-72.  Back to cited text no. 11
    
12.
Patil VM, Noronha V, Joshi A, Mandal TK, Bhattacharjee A, Goel A, et al. Hypothyroidism postchemoradiation on outcomes in head-and-neck cancer. Cancer Res Stat Treat 2018;2:84-91.  Back to cited text no. 12
    



 
 
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