Phase 3 Trial of Adjuvant External Beam Radiotherapy for Locally Invasive Differentiated Thyroid Carcinoma
MSDS was designed as a comprehensive cohort trial with randomization and observation arms.
Patients are enrolled at the time of the first ablative radioiodine therapy (RIT). Inclusion
criteria are papillary or follicular DTC pT4 pN0/1/x M0/x, age between 18 (incl.) and 70
years (excl.) at the time of initial surgery, completion of primary surgical therapy with R0
(no tumor residues) or R1 (microscopic residues) resection, Karnofsky index of at least 70
%, freedom from distant metastases at the time of initial radioiodine therapy (RIT), and
informed patient consent. Criteria for exclusion are secondary malignancy except basalioma,
pregnancy, serious general disease, serious psychiatric disorder, inability to give informed
consent, previous RTx and recurrence of previous DTC. From 2003, the first inclusion
criterion was changed into DTC pT3/4 pN0/1/x M0/x to reflect the 2002 revision of the TNM
The treatment protocol is in accordance with current guidelines in Germany and includes
total thyroidectomy (TT) with central lymphadenectomy (LNA), RIT to ablate the thyroid
remnant, and TSH-suppressive therapy with L-thyroxine (TSH < 0.1 mU/l). RIT is administered
under endogenous TSH-stimulation after 4 weeks’ cessation of L-thyroxine using standard
activities of 1–4, and 1–2, GBq I-131 in patients with a 24-h-I-131 uptake below 10 % and
10–20 %, resp., or individual dosimetry aiming for at least 300 Gy in the thyroid remnant.
If scintigraphic I-131 uptake by the thyroid remnant persists at whole-body scintigraphy (at
least 200 MBq; at least 48 h) 3 months after RIT, a second fraction of RIT is given with
Patients who consented to randomization at centers actively taking part in randomization
were randomized to treatment arms A (additional adjuvant RTx) and B (no RTx) 3 months after
initial RIT after confirmation of the histological diagnosis by the reference pathologist
and when distant metastases had been excluded by means of serum thyroglobulin (Tg), WBS (s.
a.) and a native thoracic computed tomogram (CCT). Randomization was stratified according to
histological type (papillary v. follicular), nodal status (pN0/1/x), and participating
center, and performed by an operator-independent randomization routine embedded in the
database. The remaining patients were assigned to arms A and B by the participating centers.
RTx is begun after documented elimination of cervical I-131 uptake in a I-131 WBS 3 months
after the last fraction of ablative RIT. RT includes the thyroid bed (in unilateral tumors
only the affected side) with a dose of 59.4 Gy and 66.6 Gy after R0 and R1 resection, resp.,
and the regional lymph nodes of the neck and upper mediastinum including the posterior
cervical chain from the mandible and mastoid process to the tracheal bifurcation with a dose
of 50.4 Gy and 54.0 Gy in pN0 and pN1/x disease, resp. Fractionation is conventional (1.8
Gy/d 5 days a week). 3-D planning according to IRCU 50 is mandatory.
Patient follow-up includes, as a minimum, out-patient appointments with cervical ultrasound
and measurement of serum TSH, hTG, anti-Tg antibodies and a blood count 2 and 8 months after
each RIT or WBS, and a WBS (with at least 200 MBq over at least 48 h) under endogenous
TSH-stimulation 3 and 12 months after ablative RIT and then at 24-month intervals. FDG-PET
and other imaging modalities can be performed if needed. At each follow-up appointment, RTx
toxicity is recorded according to RTOG criteria and quality of life by the QLQ-C30
questionnaire (v. 3.0 German) of the EORTC.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
time to local or distant failure
Otmar Schober, Prof MD PhD
Department of Nuclear Medicine, Münster University Hospital, Münster, Germany
Germany: Ethics Commission