The Incidence of Hypothyroidism in Patients with Advanced Squamous Cell Carcinoma of the Head and Neck Treated with Radical Radiotherapy and Cetuximab
Corresponding author: Dr. Martin Borg, Adelaide Radiotherapy Centre, 352 South Terrace, Adelaide, SA 5000, South Australia, Australia, Fax: 61+ 8 82321243; Tel: 61+ 8 82286700; Email: firstname.lastname@example.org
Most patients with squamous cell carcinoma present with locally advanced stage disease.1 In Adelaide, standard therapy for advanced squamous cell carcinoma of the head and neck involves primary surgery followed by chemoradiotherapy (CRT) or primary CRT alone, chemotherapy involving concurrent single agent Cisplatin. Treatment is associated with improvement in locoregional control and overall survival but also with marked acute and long-term toxicity [1-4].
Primary hypothyroidism is a well-known and irreversible side-effect of radical radiotherapy to the neck the reported incidence after whole thyroid irradiation in the absence of thyroid surgery being 30% after 35-45 Gy (overt and subclinical) [5,6]. This is in contrast to a population-based prevalence of 5%, which increases with age in particular in women [5-7]. This radiation-induced effect is believed to be secondary to damage to the endothelial cells of the thyroid capillary network . It may be associated with thyroid enlargement, nodularity and malignancy . There is limited data on a radiation dose-response for hypothyroidism which is mainly derived from patients treated for Hodgkin’s disease and Head and Neck Cancer [6,10,11].The risk at 20 years in this cohort of patients is reportedly 20% after doses less than 35 Gy, 35% following 35-45 Gy and 50 % following doses higher than 45 Gy to the thyroid gland [6,10]. Hypothyroidism may manifest itself initially subclincally with elevated thyroid stimulating hormone (TSH) levels in the absence of symptoms and in the presence of normal free thyroxine (T4) readings (subclinical hypothyroidism) . Subsequently patients often become symptomatic (overt hypothyroidism), symptoms including fatigue, lethargy, weight gain, poor appetite, cold intolerance, hoarseness, constipation, myalgia, dry skin, hair loss, arthralgia, paraesthesia and congestive heart failure, amongst others . The onset is often insidious whilst a number of these symptoms are also commonly experienced by head and neck cancer patients after chemoradiotherapy. The time course of this late radiation effect is variable but one study reported onset of hypothyroidism in the first 3-5 years, whilst the incidence of benign or malignant nodules increased 10 years or more from diagnosis . Others have reported a median time for the development of hypothyroidism of between 1.4- 1.8 years [7, 9, 10-19] Such patients will require long-term monitoring and life-long hormone replacement therapy when clinically symptomatic [7-12].
Cetuximab (Erbitux, Merck Serono Pty Ltd), an immunoglobulin monoclonal antibody which specifically targets the epidermal growth factor. It has been shown to significantly improve locoregional and overall survival in patients with advanced head and neck squamous cell carcinoma when combined with radiotherapy alone, without adversely affecting quality of life [2, 20]. In our oncology community, it is increasingly prescribed in patients unsuitable for Cisplatin therapy. The incidence of hypothyroidism in patients treated with Cetuximab is unknown. The aim of this non-randomised case-controlled study was therefore to determine whether Cetuximab when compared to Cisplatin in combination with radical radiotherapy is associated with a lower incidence of hypothyroidism in patients with histologically confirmed advanced squamous cell carcinoma of the head and neck.
Material and Methods
The incidence of hypothyroidism was compared in two cohorts of patients treated for head and neck carcinoma, treated between 2008 and 2010. In one cohort, 13 patients were treated with radical radiotherapy and concurrent Cetuximab, and in the second cohort, 13 patients were treated with concurrent radical radiotherapy and Cisplatin.
All cases received a radical dose of radiotherapy of 60-70 Gy in 30-35 fractions at 2 Gy per fraction prescribed to the isocentre for a squamous cell carcinoma of the head and neck. This was delivered using a linear accelerator, 6 megavoltage photons and initially a 2- or 3-dimensional conformal technique, and more recently intensity modulated radiation therapy. The Cetuximab and Cisplatin regimens were identical in their respective cohorts. Patients treated with Cetuximab received a loading dose of 400mg/m2 starting 1 week before the commencement of radiotherapy and then 250 mg/m2 weekly. Those treated with Cisplatin received a daily intravenous dose of 6 mg/m2 starting on the first day of radiotherapy. Both drugs ceased once radiotherapy was completed. Radical surgery involved local excision of the primary tumour in a standard fashion or by means of laser resection, and unilateral or bilateral modified neck dissection. Patients with a family history of thyroid disease, or who underwent total or subtotal thyroidectomy or suffered from thyroid pathology at diagnosis were excluded. Patient cohorts were of similar age (although Cetuximab was more commonly offered to patients deemed medically unsuitable for Cisplatin), stage and follow-up, and all received a minimum of 35 Gy to the whole thyroid gland as determined from dose volume histograms (Figure 1). The group of patients receiving radiotherapy and Cetuximab were followed up for a median of 19 months (range 8-34 months), whilst that receiving radiotherapy and Cisplatin were followed up for a median of 17 months (range 5-33 months) (Tables 1, 2). Overt hypothyroidism, in contrast to subclinical hypothyroidism described above, was defined as a serum free thyroxine (T4) level below the normal range (11-26 pmol/L) and an associated rise above the normal range (0.5-4.0 mIU/L) of serum thyroid stimulating hormone (TSH) . Serum levels were measured before commencing CRT, 3-4 months after completion of treatment and thereafter 4 monthly for the first 2 years and 6 monthly thereafter, and/or if clinically symptomatic. According to our protocol patients were commenced on thyroxine replacement therapy if symptomatic
and/or developed overt hypothyroidism biochemically.TG, thyroid gland
Figure 1. CT scan generated IMRT planning image illustrating the dose distribution across the thyroid gland (TG) in case no 13, Table 1.
Proportions and exact confidence limits were calculated. The incidence of hypothyroidism in the two cohorts were compared using Fishers exact test. All statistical analyses were conducted using Stata v13.0 (Statacorp, Texas, USA) with a significance level of p<0.05 .
Ten males and 3 females of median age 70 years (range 61 to 91 years) received radiotherapy and Cetuximab (Table 1) . Eleven patients had stage IV disease and two stage III disease. All achieved complete remission at completion of treatment. Twelve patients completed the planned course of Cetuximab. Only 4 patients were treated with primary chemoradiotherapy alone. Four patients received intensity modulated radiotherapy (IMRT), 1 three-dimensional conformal radiotherapy (3- DCRT) and 8 two-dimensional radiotherapy (2-DRT) (Table 1).
OT, oral tongue; BOT, base of tongue; SG, Supraglottic larynx; RMT, retromolar trigone; BRCA 1, germline genetic defect; HPV, human papilloma virus; P, primary; LN, lymph nodes; RT tech, radiotherapy technique; 2D, 2-dimensional, IMRT, intensity modulated radiation therapy; 3DCRT, 3-dimensional conformal radiotherapy; F/U, follow-up; CR/PR, complete/partial response; PD, progressive disease; DEC, deceased; T4, free thyroxine; TSH, thyroid stimulating hormone.
Table 1. Summary of patient cases receiving Cetuximab with radiotherapy
OT, oral tong ue; BM, buccal mucosa; PS, pyriform sinus; UK 1’, unknown primary; P, primary; LN, lymph nodes; RT tech, radiotherapy technique; 2D, 2-dimensional, IMRT, intensity modulated radiation therapy; 3DCRT, 3-dimensional conformal radiotherapy; F/U, follow-up; CR/PR, complete/ partial response; PD, progressive disease; DEC, deceased; T4, free thyroxine; TSH, thyroid stimulating hormone.
Table 2. Summary of patient cases receiving Cisplatin with radiotherapy
RT, radiotherapy; F /U, follow-up; T4, free thyroxine; TSH, thyroid stimulating hormone;
HT, hypothyroidism; subcl, subclinical.
Table 3. Comparism of patients receiving radical radiotherapy and either Cetuximab or Cisplatin (data gleaned from Tables 1 and 2, respectively).
Eight patients underwent an ipsilateral neck dissection whilst 5 did not undergo any neck surgery. None underwent bilateral neck dissection (Table 3). Five patients had relapsed, 3 dying from disease at 21 and 25 months, respectively. Two patients (male) (15%) developed overt hypothyroidism after completion of radiotherapy (Table 3).
In the comparative group, 7 females and 6 males of median age 63 years (range 38 to 74 years) received radical radiotherapy and concurrent Cisplatin (Table 2) . Eleven patients had stage IV disease and two stage III disease. All patients underwent radical surgery (at least to the primary site) and postoperative chemoradiotherapy. Four patients underwent IMRT, three 3-DCRT and six 2-DRT (Table 2). As in the comparative group, 8 patients underwent an ipsilateral neck dissection. In contrast to the group of patients receiving Cetuximab, 3 patients underwent a bilateral neck dissection and 2 patients did not undergo any neck surgery (Table 3). Only 1 patient had relapsed. Eleven patients completed the planned course of Cisplatin. Five 2 males and 3 females) developed overt hypothyroidism and 2 other (one female and one male) patients’ TSH reading was elevated in the presence of a normal serum T4 reading, the time of onset being a median of 7 months, ranging from 4 to 30 months (Table 3). None of the patients were lost to follow-up. Only 1 patient did not complete the prescribed radiation dose, receiving 68 Gy of a planned 70 Gy.
The incidence and exact confidence intervals for the Cetuximab group are 23.1% (3.4 – 49.6%) and for the Cisplatin group are 53.8% (22.5 – 85.2%). The proportions were compared using Fishers exact test; the p-value for the comparison was not statistically significant (p=0.226) . The power to detect a statistically significant difference with the sample size used for this study is small but the absolute difference is hypothesis generating.
This study only identified 2 patients (15%) receiving radical radiotherapy and Cetuximab who developed overt hypothyroidism. The incidence of overt hypothyroidism in a similar cohort of patients treated with radical radiotherapy and Cisplatin was 5 patients (38%). Although only 13 patients were included in each of the 2 cohorts this incidence compares favourably with that reported in the literature of 30% [5,6]. In a recent review of radiation-induced hypothyroidism, the incidence was reported to be 23-53%.23 This incidence however may range from 10-80%, depending on the duration of patient follow-up [10,14]. The risk increases within 3-5 years, although this was reported in children and adolescents treated for Hodgkin’s disease and is very variable . In our study, the median follow-up was 73 and 76 months, respectively. Monitoring complications in patients receiving radical radiotherapy o the head and head neck over a prolonged period of time is essential: the incidence of side-effects is not insignificant, including that of hypothyroidism. The latter complication may be followed up relatively simply with blood tests (thyroid function tests) and clinical examination [10,12,16]. Treatment is also reasonably safe and successful and involves varying doses of thyroxine tailored to the individual patient .
Other factors may also influence the incidence of radiation-induced hypothyroidism. For instance, the risk in patients undergoing laryngectomy and radiotherapy is reportedly 60- 70%, commonly within the first year of treatment [15,17]. The risk also increases in patients undergoing bilateral neck irradiation (suggestive of a volume effect), surgery to the thyroid gland and in patients treated with concurrent Cisplatin [6,10,13,14]. A number of recent studies have suggested that cisplatin chemotherapy for head and neck cancer is not a risk factor for radiation-induced hypothyroidism [24-28]. Conversely, a number of authors have identified chemotherapy (commonly Cisplatin), as well as higher radiation doses (60-70
Gy), young age, women and pre-elevated TSH levels as significant risk factors for the development of hypothyroidism after irradiation to the neck [6,10,11, 17-19, 23, 29]. However, Boomsma et al in a systemic review could not define a clear threshold radiation dose for the thyroid gland . All our patients received similar radiation doses, were euthyroid prior to initiating treatment and did not undergo thyroid surgery. All patient’s whole thyroid gland received a minimum of 35 Gy to the whole gland irrespective of the technique utilised (IMRT, 3-D CRT or 2-D) (Tables 1, 2). IMRT has been shown to increase the incidence of hypothyroidism as a result of the delivery of a higher dose to the thyroid gland when compared to 3-D CRT . However, an equal number of our patients in both cohorts where treated with IMRT (4 in each; Tables 1, 2). Boomsma et all identified only 1 well designed study on radiation-induced hypothyroidism (Diaz et al); this study did not identify any significant relationship between thyroid dose distribution and the incidence of hypothyroidism [23,30].Because of small numbers, 14 (54%) of whom were treated with 2-DRT, we did not report on the dose distribution across the thyroid gland.
The main clinically important differences between the 2 cohorts related to a higher number of females included within the group of patients receiving Cisplatin (4 of whom became hypothyroid) and to the 3 patients in this group who underwent bilateral neck dissection (Table 3). 2 of these 3 latter patients developed hypothyroidism. And, all 3 patients receiving Cetuximab who became hypothyroid were male. The group of patients who received Cisplatin were slightly younger as one would expect: the less tolerant and older patients received Cetuximab. The difference in age range was minimal (7 years, Table 3). However, allowing for the small number of patients, the age range of the cisplatin-treated patients who developed hypothyroidism was different from the overall cohort in which they were treated – these patients were respectively 38, 51, 56, 57, 63, 69 and 73 years old (median 63 years, range 34- 74 years), suggesting as previously published, that younger patients may be at a higher risk of hypothyroidism following radiotherapy[6,10,11, 17-19, 23, 29]. However, this did not apply to the 3 patients in the Cetuximab group who were 60, 74 and 89 years old, respectively (median 70 years, range 61-91 years).
Though the difference in incidence of hypothyroidism between the 2 groups is not statistically significant,  it is noteworthy. Allowing for the small cohort of patients and the above differences noted between the 2 cohorts, at a median follow-up of 73 months the reduction in incidence of hypothyroidism in the cohort who received Cetuximab could reasonably be attributed to the favourable toxicity of Cetuximab and absence of theradiosensitising effect of Cisplatin . Cetuximab, after all, is not known to potentiate the effect of radiation on normaltissues. [1,2,20] This difference may also overcome the influence of age and gender in this increasingly younger group ofpatients .To our knowledge this has not been reported before. Two major ongoing trials, that being the TROG 12.01 andRTOG 1016 trials, may provide further data regarding the radiation- related thyroid toxicity of Cetuximab vs cisplatin therapy when treating head & neck cancer with chemoradiation.
In spite of the small number of patients, results suggest that patients treated with Cetuximab and radiotherapy are at a lower risk of developing hypothyroidism. We regard this as a hypothesis worth further investigation and clarification.
2.Curran D, Giralt J, Harari PM et al. Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with Cetuximab. J Clin Oncol. 2007, 25(16): 2191-2197.
13.Machtay M, Moughan J, Trotti A et al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: An RTOG analysis. Journal of Clinical Oncology. 2008. 26(21): 3582-3589.
24.Akgun Z, Atasoy BM, Ozen Z, Yavuz D, Gulluoglu B et al. V30 as a predictor for radiation-induced hypothyroidism: a dosimetric analysis in patients who received radiotherapy to the neck. Radiat Oncol. 2014, 9: 104.
25.Fujiwara M, Kamikonya N, Odawara S, Suzuki H, Niwa Y et al. The threshold of hypothyroidism after radiation therapy for head and neck cancer: a retrospective analysis of 116 cases. J Radiat Res. 2015, 56(3): 577-582.
30.Diaz R, Jaboin JJ, Morales-Paliza M et al. Hypothyroidism as a consequence of intensity-modulated radiotherapy with concurrent taxane-based chemotherapy for locally advanced head-andneck cancer. Int J Radiat Oncol Biol Phys. 2010, 77(2): 468-476.
31. Bartelink H, Kallman RF, Rapacchietta D et al. Therapeutic enhancement in mice by clinically relevant dose and fractionation schedules of cis-diamminedichloroplatinum (II) and irradiation. Radiother Oncol 1986, 6(1): 61-74.