Viveque Egsgaard Nielsen

Time to reconsider nonsurgical therapy of benign non-toxic multinodular goitre: focus on recombinant human TSH augmented radioiodine therapy

The treatment of benign multinodular goitre (MNG) is controversial, but surgery is recommended in large compressive goitres. While some patients decline surgery others may have contraindications due to comorbidity, since MNG is prevalent in the elderly. Therefore, non-surgical treatment alternatives are needed. Until recently, levothyroxine therapy was the preferred non-surgical alternative, but due to low efficacy and potential side-effects, it is not recommended for routine use in recent international guidelines. Conventional radioiodine ((131)I) therapy has been used for two decades as an effective and safe alternative to surgery in the treatment of symptomatic non-toxic MNG. Since much higher activities of (131)I are employed when treating non-toxic rather than toxic MNG, there has been reluctance in many countries to use this treatment modality. Frequently, the (131)I -uptake in a non-toxic MNG is low, which makes (131)I therapy less feasible. Another challenge is the negative correlation between the initial goitre size and goitre volume reduction (GVR). With its ability to more than double the thyroid (131)I-uptake, recombinant human TSH (rhTSH) increases the absorbed radiation dose and thus enhances the GVR by 35-56% at the expense of up to fivefold higher rate of permanent hypothyroidism. An alternative strategy is to reduce the administered (131)I-activity with a factor corresponding to the rhTSH induced increase in (131)I-uptake. Hereby, the extrathyroidal irradiation can be reduced without compromising efficacy. Thus, although in its infancy, and still experimental, rhTSH-augmented (131)I therapy may profoundly alter the non-surgical treatment of benign non-toxic MNG.

Recombinant Human Thyrotropin-Stimulated Radioiodine Therapy of Large Nodular Goiters Facilitates Tracheal Decompression and Improves Inspiration

INTRODUCTION The impact on tracheal anatomy and respiratory function of recombinant human (rh)TSH-stimulated (131)I therapy in patients with goiter is not clarified. METHODS In a double-blinded design, patients (age 37-87 yr) with a large multinodular goiter (range, 99-440 ml) were randomized to placebo (n = 15) or 0.3 mg rhTSH (n = 14) 24 h before (131)I therapy. The smallest cross-sectional area of the trachea (SCAT; assessed by magnetic resonance imaging) and the pulmonary function were determined before, 1 wk, and 12 months after therapy. RESULTS Data on goiter reduction have been reported previously. In the placebo group, no significant changes in the lung function or SCAT were found throughout the study. In the rhTSH group, a slight decrease was observed in the forced vital capacity 1 wk after therapy, whereas the mean individual change in SCAT was significantly increased by 10.5% (95% confidence interval = 0.9-20.0%). A further increase in SCAT to 117 +/- 36 mm(2) (P = 0.005 compared with 92 +/- 38 mm(2) at baseline) was seen at 12 months, corresponding to a mean of 31.4% (95% confidence interval = 16.0-46.8%). The expiratory parameters did not change significantly, whereas forced inspiratory flow at 50% of the vital capacity (FIF50%) increased from initially 3.34 +/- 1.33 liters/sec to ultimately 4.23 +/- 1.88 liters/sec (P = 0.015) in the rhTSH group, corresponding to a median increase of 24.6%. By 12 months, the relative improvements in FIF50% and in SCAT were inversely correlated to the respective baseline values (FIF50%: r = -0.47, P = 0.012; SCAT: r = -0.57, P = 0.001). CONCLUSION On average, neither compression of the trachea nor deterioration of the pulmonary function was observed in the acute phase after rhTSH-augmented (131)I therapy. In the long term, tracheal compression is diminished, and the inspiratory capacity improved, compared with (131)I therapy alone.

Recombinant Human Thyrotropin-Stimulated Radioiodine Therapy of Nodular Goiter Allows Major Reduction of the Radiation Burden with Retained Efficacy

CONTEXT AND OBJECTIVE Stimulation with recombinant human TSH (rhTSH) before radioiodine (131I) therapy augments goiter volume reduction (GVR). Observations indicate that rhTSH has a preconditioning effect beyond increasing thyroid (131)I uptake. We test the hypothesis that an equivalent GVR might be obtained by an absorbed thyroid dose well below what has been used previously. PATIENTS AND DESIGN In a double-blinded setup, 90 patients (78 women; median age, 52 yr; range, 22-83) with a nontoxic nodular goiter (median size, 63 ml; range, 25-379 ml) were randomized to either 0.1 mg rhTSH (n=60) followed by a thyroid dose of 50 Gy or placebo followed by 100 Gy (n=30). RESULTS At 12 months, the mean relative GVR in the placebo and the rhTSH group was identical (35+/-3%; P=0.81). The median administered 131I-activity was 170 MBq (45-1269) in the rhTSH group and 559 MBq (245-3530) in the placebo group (70% reduction, P<0.0001). According to the official radiation regulation, hospitalization was required in 14 patients in the placebo group vs. one patient in the rhTSH group (P<0.0001). In both groups, goiter-related symptoms were effectively relieved in the majority of patients. The prevalence of myxedema (10%) did not differ among groups. CONCLUSIONS This is the first study to demonstrate that rhTSH not only increases the thyroid 131I uptake, but per se potentiates the effect of 131I-therapy, allowing a major reduction of the 131I-activity without compromising efficacy. This approach is attractive in terms of minimizing posttherapeutic restrictions and in reducing the potential risk of radiation-induced malignancy.

Optimizing 131I Uptake After rhTSH Stimulation in Patients with Nontoxic Multinodular Goiter: Evidence from a Prospective, Randomized, Double-Blind Study

Prestimulation with recombinant human thyroid-stimulating hormone (rhTSH) augments radioiodine 131I therapy for benign nontoxic multinodular goiter. The purpose of this study was to determine the optimal time interval between rhTSH and 131I administration to enhance thyroid radioactive iodine uptake (RAIU). Methods: Patients were randomized, in a 2-factorial design, to receive either a 0.1-mg dose of rhTSH (n = 60) or placebo (n = 30) and to a time interval of 24, 48, or 72 h before 131I administration. The rhTSH- or placebo-stimulated RAIU study was performed at 4 wk after a baseline RAIU assessment in a tertiary referral center at a university hospital. A total of 90 patients (78 women; median age, 52 y; range, 22–83 y) referred to 131I therapy for symptomatic nontoxic goiter (median goiter volume, 63 mL; range, 25–464 mL) were included in the study. Change in thyroid RAIU was determined at 24 and 96 h after 131I tracer administration. Results: In the placebo subgroups, RAIU did not change significantly from baseline. The mean (±SE) 24-h RAIU increased from 33.8% ± 2.3% to 66.0% ± 1.8% (111.2% increase) with a 24-h interval, from 36.8% ± 2.1% to 64.6% ± 2.7% (83.3% increase) with a 48-h interval, and from 33.0% ± 2.7% to 49.6% ± 2.5% (62.4% increase) with a 72-h interval. All within-group changes were highly significant (P < 0.001). The effect was negatively correlated with initial RAIU (r = −0.703, P < 0.001). The increase in 24- and 96-h RAIU was significantly higher in the rhTSH/24-h group than it was in the rhTSH/72-h group (P = 0.023 and 0.012, respectively) and insignificantly higher than in the rhTSH/48-h group (P = 0.37 and 0.26, respectively). Conclusion: The effect of rhTSH on thyroid RAIU is most pronounced when administered 24 h before 131I administration and declines with longer time intervals. Whether there is a similar time dependency for goiter reduction after rhTSH-stimulated 131I-therapy remains to be clarified.

Prestimulation with Recombinant Human Thyrotropin (rhTSH) Improves the Long-Term Outcome of Radioiodine Therapy for Multinodular Nontoxic Goiter

OBJECTIVE The objective of the study was to evaluate the long-term outcome of recombinant human TSH (rhTSH)-augmented radioiodine ((131)I) therapy for benign multinodular nontoxic goiter. PATIENTS AND METHODS Between 2002 and 2005, 86 patients with a multinodular nontoxic goiter were treated with (131)I in two randomized, double-blind, placebo-controlled trials. (131)I-therapy was preceded by 0.3 mg rhTSH (n = 42) or placebo (n = 44). In 2009, 80 patients completed a follow-up (FU) visit, including determination of thyroid volume, thyroid function, and patient satisfaction by a visual analog scale. RESULTS In both groups, thyroid volume was further reduced from 1 yr to final FU (71 months). The mean goiter volume reductions obtained at 1 yr and final FU [59.2 ± 2.4% (sem) and 69.7 ± 3.1%, respectively] in the rhTSH group were significantly greater than those obtained in the (131)I-alone group (43.2 ± 3.7 and 56.2 ± 3.6%, respectively, P = 0.001 and P = 0.006), corresponding to a gain of 24% at final FU. At last FU the mean reduction in compression visual analog scale score was significantly greater in patients receiving rhTSH (P = 0.049). Additional therapy (thyroid surgery or (131)I) was required more often in the placebo group (nine of 44) compared with the rhTSH group (two of 42) (P = 0.05). The prevalence of hypothyroidism at 1 yr [9 and 43% in the placebo and rhTSH groups, respectively (P < 0.0001)] increased to 16 and 52%, respectively, at final FU (P = 0.001). CONCLUSION Enhanced goiter volume reduction with rhTSH-augmented (131)I therapy improves the long-term reduction in goiter-related symptoms and reduces the need for additional therapy compared with plain (131)I therapy. Overall patient satisfaction is benefited, despite a higher rate of permanent hypothyroidism.

Dose-dependent acute effects of recombinant human TSH (rhTSH) on thyroid size and function: comparison of 0.1, 0.3 and 0.9 mg of rhTSH.

Context  Recombinant human TSH (rhTSH) is used to augment the effect of radioiodine therapy for nontoxic multinodular goitre. Reports of acute thyroid swelling and hyperthyroidism warrant safety studies evaluating whether these side‐effects are dose dependent.

Radioiodine therapy in non-toxic multinodular goitre. The possibility of effect-amplification with recombinant human TSH (rhTSH)

There is no consensus regarding the optimum treatment of benign non-toxic goitre. L-thyroxine suppressive therapy is widely used, but there is poor evidence of its efficacy, and it may have serious adverse effects on health. Surgery is first choice in large goitres or if malignancy is suspected. 131I therapy results in a one-year goitre reduction of around 40% in multinodular goitres, usually with a high degree of patient satisfaction and improvement of the inspiratory capacity. The effect is attenuated with increasing goitre size. The risk of hypothyroidism is 22–58% within 5–8 years. A sufficient thyroid 131I uptake is mandatory for 131I therapy to be feasible and pre-stimulation with recombinant human TSH (rhTSH) increases this considerably. This leads to an increased absorbed thyroid dose by approx.75%, mainly in those patients with the lowest thyroid 131I uptake, and a more homogeneous intrathyroidal isotope distribution. Pre-stimulation with even a small dose of rhTSH seems to allow a reduction of the 131I activity while still achieving a mean goitre reduction of approximately 40% within a year. A significantly lower extrathyroidal radiation is achieved by this approach. With an unchanged 131I activity, rhTSH pre-stimulation improves the goitre reduction by 30–50%. However, this is at the expense of a higher rate of hypothyroidism, cervical pain and transient thyrotoxicosis. Of particular concern is the observation made in healthy persons, that rhTSH results in a transient average thyroid volume increase of 35%. A similar goitre swelling may cause problems in susceptible patients during rhTSH-augmented 131I therapy. Thus, this concept still needs a closer evaluation before routine use.

Serum thyroxine and age — rather than thyroid volume and serum TSH — are determinants of the thyroid radioiodine uptake in patients with nodular goiter

Background: Radioiodine (131|) therapy is widely used for treatment of non-toxic goiters. A limitation for this treatment is a low thyroid radioiodine uptake (RAIU), often encountered in these patients. Aim: To estimate the impact of various factors on the thyroid RAIU. Methods: We examined prospectively 170 patients (146 females; age range: 22–87 yrs) with nodular goiter (median 64 ml, range: 20–464 ml) selected for 131| therapy. Serum TSH was sub-normal in 42.4%. None were treated with anti-thyroid drugs. The thyroid RAIU was determined at 24h and 96h. The goiter volume was measured by ultrasound (no.=127), or by magnetic resonance imaging (no.=43). Results: The 24h and the 96h RAIU were 34.2±9.8(SD)% (range: 11.4–66.0%) and 34.0±10.0% (range: 10.5–60.9%), respectively. Sixty-one patients had a 24h RAIU <30% and these individuals were older than patients with a 24h RAIU ≥30% (median 58 vs 51 yrs, p=0.02). These two subgroups did not differ significantly in other variables. Overall, the 24h RAIU was positively correlated to the serum (s) free T4-index (r=0.20, p=0.01), and negatively to age (r=−0.18, p=0.02), but not significantly related to serum TSH or thyroid volume. Age correlated positively with thyroid volume (r=0.31, p<0.001). In a regression analysis, s-free T4-index and age remained as the only determinants of the 24h and the 96h RAIU. Conclusions: In patients with a symptomatic nodular goiter, serum T4 and age are the major determinants of the thyroid RAIU. A sub-normal serum TSH is not a marker of a compromised thyroid RAIU but reflects that the iodine is confined to a few ‘hot spots’.

Response evaluation of the neck in oropharyngeal cancer: Value of magnetic resonance imaging and influence of p16 in selecting patients for post-radiotherapy neck dissection

ABSTRACT Background. Residual neck disease after radiotherapy in advanced oropharyngeal squamous cell carcinoma (OPSCC) is associated with increased mortality, and some patients may benefit from post-radiotherapy neck dissection (PRND). The aim of the present study was to assess the value of magnetic resonance imaging (MRI) and other clinical characteristics in selecting patients for PRND. Materials and methods. Retrospective cohort study. Consecutive patients with N+ OPSCC were included. Medical records, pathology reports and imaging reports were reviewed. Pre- and post-therapeutic imaging was re-evaluated. Results. A total of 100 consecutive patients from a three-year period were included. Neck response was evaluated with MRI two months after treatment. Sixty patients were suspicious for residual neck disease, and were offered surgery; seven of these patients had histologic evidence of carcinoma. Cumulative neck failure after three years was 14% (8.4–24%), and did not differ significantly among patients with positive compared to negative MRI (radiologists initial description; p = 0.47, log-rank test). Applying neck failure as gold standard, sensitivity and specificity of MRI was 69% and 41%, respectively; positive and negative predictive value was 15% and 90%. Patients with p16 + disease had significantly larger lymph nodes after treatment, and imaging based on lymph node size resulted in many false positives. Analysis of receiver operating characteristic curves in 191 individual lymph nodes showed that a short axis ≥ 10 mm should be classified as suspicious. Furthermore, T-stage and p16-status were associated with increased risk of neck recurrence. Salvage was successful in four patients with early detected nodal recurrence. Conclusion. These results suggest that lymph node size, T-stage and p16 status could be used in selecting patients for PRND in OPSCC. Yet, early anatomical imaging may be inappropriate for evaluating neck response in patients with p16 + disease as enlarged lymph nodes often do not indicate residual neck disease.

Is the reproducibility of shear wave elastography of thyroid nodules high enough for clinical use? A methodological study

To systematically assess the reproducibility of thyroid ultrasonographic shear wave elastography (SWE).