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The treatment of advanced differentiated thyroid cancer (DTC) remains challenging. In spite of our best efforts, about 15% of patients with high-risk DTC have a significantly reduced life expectancy as many do not respond sufficiently to I therapy to prevent recurrence and progression of DTC, or even death [1]. Furthermore, it has been firmly established that the more advanced the DTC, the worse will be the prognosis [1]. Therefore, there is an ongoing quest to optimize I therapy in patients with locally advanced or metastatic disease. Although at the other end of the disease spectrum, the discussion on optimization of I therapy in advanced DTC essentially comes down to the same point as is currently debated extensively in low-risk and intermediate-risk DTC: what I activity is Bbest^ or Bbetter^ [2–4]? However, in contrast to the discussion in patients at the lower end of the risk spectrum, in patients with advanced DTC, the scientific debate is not about a Blow ,̂ a Blower^ or Bno^ I activity, but instead about a Bhigh^ or a Bhigher^ I activity [5, 6]. For advancedDTC several I activity selection strategies are available [7–11]. The most commonly used approach is empirical activity selection, in which the physician chooses an activity based on convention, experience and patient-related parameters. With this strategy patients with advanced DTC are most commonly given activities of 3,700, 5,550 or 7,400 MBq [12], with some physicians going as high as 11,100 MBq. However, it has been demonstrated clearly, not just for I therapy but for essentially all therapy procedures with radiopharmaceuticals, that absorbed doses delivered to lesions per unit of administered activity can range widely [13, 14]. It is therefore quite feasible that, while for a given patient a specific administered activity may deliver a high lesion absorbed dose, a second patient may receive a much lower lesion absorbed dose from the same or even higher activity. The second available strategy is to perform lesion dosimetry. In this case, the activity to be administered is determined after a pretherapeutic dosimetric assessment (either with I or I) to calculate the minimal activity required to achieve an effective absorbed dose [13–15]. This strategy primarily aims to deliver effective I therapy with an activity as low as reasonably achievable (ALARA). The third strategy is to determine the therapeutic activity needed to deliver a blood/bone marrow absorbed dose of 2Gy based on blood andwhole-bodymeasurements [5, 6, 16–19]. This 2 Gy limit is a commonly accepted value based on the findings of Benua et al. [18] and is used with the aim of minimizing haematological complications after I therapy. The primary aim of this strategy is to give an activity which is as high as safely achievable (AHASA). The underlying rationale for an AHASA approach is based on the hypotheses that higher administered activities result in higher absorbed doses delivered to lesions and that treatment outcome is related to the level of absorbed dose delivered. The AHASA approach has been endorsed by the European Association of Nuclear Medicine in its procedural guidelines [17]. * Frederik A. Verburg verburg@med.uni-marburg.de

The “reset button” revisited: why high activity 131I therapy of advanced differentiated thyroid cancer after dosimetry is advantageous for patients