The standard treatment for differentiated thyroid cancer (DTC) consists of thyroidectomy followed by radio ablation therapy (RAT) [
Here we present long-term follow-up data of a randomized clinical trial comparing the efficacy of RAT after preconditioning by rhTSH with hypothyroidism. In addition, we have measured and compared the impact of both competing strategies of preconditioning by rhTSH or hypothyroidism on quality-of-life and job performance.
Forty-four patients with a diagnosis of DTC (Table
Clinical data of all patients | rhTSH | Hypothyroidism |
|
---|---|---|---|
Gender (M/F) | 6/18 | 5/15 | n.s. |
Age [yrs.] (mean, median, range) | 47, 50, 17–66 | 56, 58, 30–73 | n.s. |
Tumor histology (PTC/FTC) | 22/2 | 19/1 | n.s. |
Tumor size [mm] (mean, median, range) | 20.4, 20.0, 1–60 | 10.3, 8.5, 1.5–30 | <0.01 |
pT | |||
1a | 5 | 10 | n.s. |
1b | 8 | 7 | |
2 | 5 | 1 | |
3 | 6 | 2 | |
pN | |||
X | 4 | 0 | n.s. |
0 | 10 | 11 | |
1 | 10 | 9 | |
pM | |||
X | 23 | 20 | n.s. |
1 | 1 | 0 | |
UICC 2002 staging | |||
X | 4 | 0 | n.s. |
I | 13 | 13 | |
II | 0 | 0 | |
III | 5 | 5 | |
IVA | 1 | 2 | |
IVB | 0 | 0 | |
IVC | 1 | 0 | |
Risk category | |||
High | 12 | 11 | n.s. |
Low | 4 | 4 | |
Very low | 5 | 5 | |
Sick leave* from surgery to first RAT (mean, median, range) | |||
(Days) | 4, 0, 0–23 | 41, 28, 4–150 | <0.001 |
All patients had to complete a questionnaire at five weeks after surgery. The questionnaire’s main targets were clinical symptoms such as fatigue/lethargy, lack of concentration, disturbance of sleep/insomnia, intolerance to cold, cold skin, rough skin, slowed down movements, periorbital edema, and peripheral edema. Possible answers were
RhTSH (Thyrogen, Genzyme, Cambridge, Mass.) with a biological potency of 10 U/mg of protein was used according to the manufacturer’s instructions. Each vial containing 0.9 mg of rhTSH-alpha was dissolved in 1.2 mL of water for injection and administered by the i.m. route to the gluteal region 48 h and 24 h before RAT.
After iodine uptake was confirmed by neck scan with 100 Milli-Becquerel (MBq) 131I, the ablative activity of 3700 MBq 131I was administered orally.
Serum levels of thyroxin (T4), 3,5,3′-triiodothyronine (T3), TSH, thyroglobulin (Tg), urinary iodine excretion, and urinary creatinine were measured on examination days.
Whole body scans and scans of the neck region were conducted before RAT, at the time of RAT, and at three and twelve months after surgery in both groups with and without rhTSH. Additional scans were performed depending on the results of US examinations and Tg readings (Table
Follow-up data of all patients.
Pat. | # | UICC 2002 | Risk | Follow-up I | Follow-up II | Follow-up III | Follow-up IV | Follow-up V | Follow-up VI | Follow-up VI | ||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Month | Reccur. | Therapy | Month | Reccur. | Therapy | Month | Reccur. | Therapy | Month | Reccur. | Therapy | Month | Reccur. | Therapy | Month | Reccur. | Therapy | Month | Reccur. | Therapy | ||||
rhTSH | 11 | I | X | 4 | No | 12 | No | 19 | No | 32 | No | 44 | No | 55 | No | |||||||||
23 | X | X | 3 | No | 10 | No | f | |||||||||||||||||
24 | X | X | 3 | No | 5 | No | 13 | No | 20 | No | f | |||||||||||||
3 | I | Very low | 3 | No | 12 | No | p | p | p | p | 64 | No | ||||||||||||
4 | I | Very low | 4 | No | 13 | No | p | p | p | p | 63 | No | ||||||||||||
13 | I | Very low | 3 | No | 13 | No | 20 | No | 29 | No | 37 | No | 47 | No | 61 | No | ||||||||
15 | I | Very low | 2 | No | 13 | No | 24 | No | 38 | No | f | |||||||||||||
18 | I | Very low | 4 | No | 12 | No | 18 | No | 30 | No | P | 54 | No | f | ||||||||||
5 | I | Low | 4 | No | 12 | No | p | p | p | p | 66 | No | ||||||||||||
8 | I | Low | 3 | No | p | p | p | p | p | 64 | No | |||||||||||||
14 | X | Low | 4 | No | 13 | No | p | p | p | 44 | No | f | ||||||||||||
17 | I | Low | SAE | No | ||||||||||||||||||||
1 | I | High | 4 | No | 12 | No | 26 | No | 38 | No | 50 | No | 59 | No | 85 | No | ||||||||
2 | III | High | 3 | No | 13 | No | 18 | No | 32 | No | 38 | No | 44 | No | 82 | No | ||||||||
6 | III | High | 4 | No | 12 | No | 28 | No | 37 | No | f | |||||||||||||
7 | III | High | 3 | sus | RAT | 10 | No | 28 | LN | Surg | 36 | TB | Surg | 36 | oss | Surg | 56 | oss | Surg | 59 | oss | |||
9 | I | High | 4 | No | 12 | No | 19 | No | 36 | No | 39 | No | 50 | No | 69 | No | ||||||||
10 | IVA | High | 4 | sus | RAT | 8 | No | 17 | No | 25 | No | 38 | No | 57 | No | 72 | No | |||||||
12 | I | High | 4 | sus | RAT | 9 | No | 20 | No | 33 | No | 40 | No | 52 | No | 61 | No | |||||||
16 | I | High | 4 | No | 11 | No | p | p | p | 43 | No | f | ||||||||||||
19 | X | High | AE | No | ||||||||||||||||||||
20 | IVC | High | AE | No | ||||||||||||||||||||
21 | III | High | 3 | No | 12 | No | 16 | No | 24 | No | 30 | No | 42 | No | f | |||||||||
22 | III | High | 3 | No | 11 | No | 24 | No | f | |||||||||||||||
| ||||||||||||||||||||||||
Hypothyroidism | 1 | I | Very low | 4 | No | 7 | No | 11 | No | 20 | No | 29 | No | 41 | No | f | ||||||||
3 | I | Very low | 4 | No | 12 | No | p | p | p | 53 | No | f | ||||||||||||
9 | I | Very low | 3 | No | 10 | No | 21 | No | 28 | No | 36 | No | 40 | No | 66 | No | ||||||||
10 | I | Very low | 4 | sus | RAT | 9 | No | 21 | No | 24 | No | f | ||||||||||||
15 | I | Very low | AE | |||||||||||||||||||||
4 | I | Low | 3 | No | 14 | No | 27 | No | df | |||||||||||||||
12 | I | Low | 4 | No | 12 | No | 30 | No | f | p | 67 | No | ||||||||||||
13 | I | Low | 3 | No | 12 | No | 19 | No | 32 | No | 45 | No | 56 | No | f | |||||||||
17 | I | Low | 3 | No | 12 | No | 18 | No | f | 45 | No | f | ||||||||||||
2 | I | High | 3 | No | 13 | No | 25 | No | 32 | No | 44 | No | 57 | No | f | |||||||||
5 | III | High | 4 | sus | RAT | 8 | No | 16 | No | 40 | No | f | ||||||||||||
6 | IVA | High | 4 | No | 8 | No | 13 | No | 21 | No | 46 | No | 59 | No | 62 | No | ||||||||
7 | IVA | High | 4 | sus | RAT | 12 | sus | RAT | 18 | No | 25 | No | 32 | No | p | 63 | No | |||||||
8 | I | High | 4 | No | 9 | No | 28 | No | 37 | No | 43 | No | 53 | No | 66 | No | ||||||||
11 | III | High | 4 | sus | RAT | 8 | No | 24 | No | 30 | No | 36 | No | 50 | No | 62 | No | |||||||
14 | I | High | 4 | sus | RAT | 9 | No | 18 | No | 24 | No | 37 | No | 43 | No | 63 | No | |||||||
16 | III | High | df | |||||||||||||||||||||
18 | I | High | 3 | No | 12 | No | 20 | No | 27 | No | f | |||||||||||||
19 | III | High | 4 | No | 12 | No | 16 | No | 23 | No | 37 | No | 43 | No | 55 | No | ||||||||
20 | III | High | 4 | No | 12 | No | 18 | No | 32 | No | 38 | No | f |
RAT: additional radio ablation therapy, Surg: surgery, sus: suspicion for tumor recurrence, LN: lymph node, oss: bone, TB: thyroid bed, AE: adverse event (e.g., protocol violation), SAE: serious adverse event (surgical complication), df: discontinued follow-up, f: follow-up in progress, p: patient did not show up for follow-up, Recurr.: tumor recurrence.
Clinical symptoms | rhTSH | Hypothyroidism | ||
---|---|---|---|---|
Points per symptom | Avrg. points per symptom and patient | Points per symptom | Avrg. points per symptom and patient | |
Gain in weight | 6 | 0.27 | 14 | 0.74 |
Fatigue/lethargy | 9 | 0.41 | 33 | 1.65 |
Laps of concentration | 5 | 0.23 | 20 | 1.00 |
Disorder of sleep/insomnia | 10 | 0.45 | 14 | 0.70 |
Intolerance to cold | 9 | 0.41 | 16 | 0.80 |
Constipation | 5 | 0.23 | 15 | 0.75 |
Cold skin | 1 | 0.05 | 10 | 0.53 |
Rough skin | 5 | 0.25 | 17 | 0.94 |
Slowed movements | 6 | 0.30 | 13 | 0.68 |
Periorbital edema | 2 | 0.10 | 13 | 0.68 |
Peripheral edema | 0 | 0.00 | 4 | 0.22 |
| ||||
Avrg. points per symptom, patient, and study arm |
|
|
||
| ||||
Mann-Whitney's statistic | 113.0 | |||
|
— | |||
2-tailed |
|
Impairment of job performance | rhTSH | Hypothyroidism |
---|---|---|
No questionnaire | 1 | 0 |
Pensioner | 5 | 5 |
| ||
No |
|
|
Light |
|
0 |
Medium |
|
|
Strong | 0 |
|
Very strong | 0 |
|
| ||
Pearson's |
17.58 | |
DF | 4 | |
|
|
Ultrasound (US) of the neck region was carried out at the time of RAT, at three- and twelve-month intervals after surgery, and subsequently at each follow-up examination. If the US revealed suspiciously enlarged lymph nodes or a suspicious mass paratracheal, an additional follow-up scintigraphy was planned and carried out shortly thereafter.
Statistical analysis was performed using
Patients were followed up for an average period of 52 months (median = 56 months; SE ± 2.8) (see also Table
In the group of rhTSH receivers, 13 (62%) patients were employees, 4 (19%) were housewives, and 4 (19%) pensioners. In the L-T4 abstinence group 9 (50%) patients were employees, 5 (28%) were housewives, and 4 (22%) patients were pensioners.
The mean tumor size for rhTSH receivers was 20.4 mm (SD ± 14.4 mm), with one measurement for tumor size missing. The mean tumor size in patients preconditioned by L-T4 abstinence was 10.3 mm (SD ± 7.1 mm). Twenty-two rhTSH receivers had a histology of papillary differentiated carcinoma (PTC) and two had a follicular differentiation (FTC). In the hypothyroidism group eighteen patients had a PTC and two patients had a FTC. The rhTSH group and the hypothyroidism group had an equal distribution of high-risk, low-risk, very low-risk, and nonspecifiable-risk (X) tumors (Table
DTC recurrence was suspected in three rhTSH receivers and four patients after hypothyroidism (Figures
DTC-recurrence and patient survival.
The average time interval from surgery to primary ablation was 7.3 days for rhTSH receivers (SD ± 2.5; median = 7) and 31.4 days for patients preconditioned by hypothyroidism (SD ± 6.6; median = 31) (
The average sick-leave time for rhTSH receivers was 4.8 days (SD ± 7.2; median = 0) and 40.7 days (SD ± 44.5; median = 28) for patients in the hypothyroidism group (
Patients preconditioned by rhTSH experienced significantly fewer clinical symptoms in comparison to patients preconditioned by hypothyroidism (Table
Symptoms of hypothyroidism. Comparison of clinical symptoms for rhTSH receivers versus hypothyroidism patients by comparison of average points per category and patient. RhTSH patients had significantly fewer symptoms in comparison to standard protocol patients (
About one third of hypothyroidism patients experienced
While
In contrast to the patients of the rhTSH group, who reported that their treatment for thyroid cancer had no or only little impact on their job performance up to 5 weeks after surgery, nearly all patients of the hypothyroidism group—except three patients—reported a significant negative impact on their ability to maintain regular job performance (Table
Today’s standard in treatment of differentiated thyroid cancer (DTC) is a combination of thyroidectomy followed by radio-ablation therapy (RAT) [
In our clinic it was a common procedure that patients with a diagnose of DTC would receive their first RAT after a postoperative L-T4-abstinence period. This strategy was maintained until we had tested a shortened treatment protocol that utilizes rhTSH and merges surgery and radio-ablation therapy into one hospitalization period. When preconditioned by rhTSH, the consecutive primary RAT can be initiated within one week after thyroidectomy. This procedure was then compared to the common procedure of preconditioning by 4–6 weeks of L-T4-abstinence. In the initial study [
Now, seven years after study initiation we report our long-term follow-up data of all 44 patients with the diagnosis of DTC (including
We conclude that RAT after rhTSH preconditioning and in quick succession after thyroidectomy should be the standard procedure in the initial treatment of DTC—regardless of the DTC risk category.
All authors declare that there is no conflict of interests that could be perceived as prejudicing the impartiality of the research reported.
Thyrogen medication was provided by Genzyme Corp. Other than Thyrogen medication there was no financial support or other support whatsoever by internal, external, government or industry.
We acknowledge support by Deutsche Forschungs-Gemeinschaft (DFG).