Complete disappearance of liver metastases in a patient with iodine-refractory differentiated thyroid cancer subjected to sorafenib re-challenge

Excerpt

The tyrosine-kinase inhibitor (TKI) sorafenib is the most studied targeted agent for the treatment of radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) [1]. Its specificity for this clinical setting was suggested by the inhibition of the RAF kinases, which are strikingly involved in the development and progression of thyroid cancer [2]. Nevertheless, sorafenib has a multifunctional activity, and is also active on TK-angiogenic receptors, thus inhibiting neoangiogenesis, which is considered crucial for progression of the disease. The phase III trial DECISION has definitively proved efficacy of sorafenib in RAI-refractory DTC, leading to the approval by the Food and Drug Administration. Given that the study cohort included only TKIs naive patients, sorafenib can be fully considered the first-line systemic therapy for this clinical setting. Nevertheless, such treatment is never curative and has a temporally limited effect. To date, clear indications about the management of RAI-refractory DTC patients after the failure of first-line sorafenib are lacking [3]. The patient was a 62-year-old woman affected with metastatic papillary thyroid cancer. When admitted to our center, the first computed tomography (CT) scan demonstrated neoplastic progression, as compared with the previous morphological assessment (performed 7 months before): (a) multiple cervical lymph node metastases increased in number and size; (b) multiple pulmonary metastases increased in number and size. Hence, treatment with sorafenib was started in January 2011. The starting dose was 400 mg b.i.d. Dose reductions were gradually performed because of the development of toxicities (hand-foot syndrome and diarrhea), where 200 mg b.i.d. being the well-tolerated dosage. CT scans were performed 3 months each for assessing morphological response. Best radiological response per RECIST was partial response with a 40.7 % tumor shrinkage. In November 2012, a CT scan revealed disease progression of the pulmonary lesions. After first-line sorafenib, progression-free survival (PFS) was 22 months. Subsequently, only supportive care was performed for 8 months. In July 2013, a CT scan revealed a further neoplastic progression with enlargement of pulmonary lesions and de novo occurrence of multiple liver metastases less than 1 cm in size. Thus, sorafenib re-challenge was performed. Treatment was started with the same dose as that used at the end of the first-line sorafenib administration (200 mg b.i.d). Best radiological response per RECIST was stable disease, with a 3.5 % tumor shrinkage. Particularly, ongoing morphological progression of the pulmonary lesions was stopped (even if no significant tumor shrinkage was achieved), whereas liver metastases completely disappeared (disappearance of the liver metastasis at the VI segment has been showed in Fig. 1). In July 2014, a CT revealed disease progression with the occurrence of liver, bone (rib), and brain metastases. After sorafenib re-challenge, PFS was 12 months. In our knowledge, this is the first paper describing sorafenib re-challenge as therapeutic regimen in iodine-refractory DTC. Recently, Nozawa et al. have found that this regimen obtained disease control in six out of eight renal cancer patients experiencing disease progression with initial treatment [4]. Consistently with the rebound phenomenon that has been demonstrated following TKIs withdrawal [5], our patient experienced a strong disease progression after sorafenib interruption. The possible acceleration of neoplastic progression induced by sorafenib withdrawal should be taken into account when suspending the treatment, especially in those patients with a slow progressing disease. Sorafenib re-challange achieved disease control of target lesions and disappearance of liver metastases, thus obtaining the blockage of disease progression. This phenomenon of “resistance-reset” is likely due to intratumoral heterogeneity, which is a paradigm of carcinogenesis and has been demonstrated in thyroid cancer [6]. This heterogeneity may determine the selection of drug-resistant clones, which lose their selective advantage at sorafenib withdrawal. Thus, the therapeutic time-off may allow regain of tumor sensibility to sorafenib.

…