In some people with thyroid cancer, the tumour stops responding to treatment with radioactive iodine and treatment options are limited. In this study, sorafenib tablets were compared with a placebo (dummy pill). The median time until the disease got worse was about 10.8 months with sorafenib and about 5.8 months with placebo. Sorafenib caused side effects such as a skin reaction on the hands and feet, diarrhoea and hair loss, which were mostly mild to moderate. The decision to take this drug should be made with the treating doctor, taking each patient's situation into account.
Locally advanced or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer
| Drug | Dose | Route | Schedule |
|---|---|---|---|
| Sorafenib | 400 mg | Oral, on an empty stomach (1 hour before or 2 hours after a meal) | Twice daily, continuously |
Source: FDA label. Dose reduction levels in thyroid cancer: 600 mg per day (400 mg and 200 mg, 12 hours apart), then 200 mg twice daily, then 200 mg once daily. Pivotal trial: DECISION.
Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.
Sorafenib orally 400 mg twice daily (800 mg per day), 12 hours apart and fasting (at least 1 hour before or 2 hours after food), continuously until disease progression, unacceptable toxicity, non-compliance or withdrawal (207 patients). To manage adverse events, dose interruption or stepwise dose reduction was allowed: 600 mg per day (400 mg and 200 mg in two doses), then 400 mg per day (200 mg twice daily), then 200 mg per day, with re-escalation allowed per protocol criteria (the same levels appear in the FDA label for DTC). Mean daily dose received was 651 mg and median treatment duration 10.6 months. After progression, continuing or starting open-label sorafenib was allowed until loss of benefit in the investigator's judgement. The authors recommended frequent TSH monitoring and levothyroxine dose adjustment to maintain TSH suppression.
Matching placebo twice daily, taken the same way (210 patients). On protocol-defined disease progression, treatment was unblinded and patients could receive open-label sorafenib; 150 patients (71%) in the placebo group crossed over to sorafenib.
Source of the regimen details: Author manuscript of the full text in PMC (PMC4366116): dose, administration, dose-reduction levels and dose received; FDA label for sorafenib (NEXAVAR, DailyMed) for the DTC dose-reduction table.
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Adults (18 years or older) with locally advanced or metastatic radioactive iodine (131I)-refractory differentiated thyroid cancer (papillary, follicular including Hürthle cell, and poorly differentiated) that had progressed by RECIST within the previous 14 months, from 77 centres in 18 countries. Inclusion criteria: at least one measurable lesion on CT or MRI; ECOG performance status 0 to 2 (per the abstract; the author manuscript in PMC states "0 to 1"); adequate bone marrow, liver and kidney function; and serum TSH below 0.5 mIU/L. Definition of iodine refractoriness: (1) at least one target lesion without iodine uptake; or (2) in iodine-avid tumours: progression within 16 months of one iodine treatment, progression after two iodine treatments within 16 months of each other (the last more than 16 months earlier), or cumulative iodine activity of 22.3 GBq (600 mCi) or more. Prior targeted therapy, thalidomide or chemotherapy for thyroid cancer was an exclusion criterion (low-dose chemotherapy for radiosensitisation was allowed).
Primary endpoint: progression-free survival (PFS), assessed every 8 weeks by independent central review (modified RECIST). Analysis was by intention to treat. Secondary endpoints: overall survival, time to progression, objective response rate, disease control rate and duration of response. Archival tumour tissue was tested for BRAF and RAS mutations, and serum thyroglobulin was measured at baseline and at each visit.
Adverse events occurred in 204 of 207 patients (98.6%) in the sorafenib group and 183 of 209 patients (87.6%) in the placebo group; mostly grade 1 or 2 and early in treatment. Grade 3 events in the sorafenib group: hand-foot skin reaction 20.3% (any grade 76.3%), diarrhoea 5.3% (any grade 68.6%), fatigue 5.3% and rash/desquamation 4.8%; grade 3 hypocalcaemia in 5.8% and grade 4 in 3.4% (any grade 18.8%). Alopecia 67.1% and TSH increase above 0.5 mIU/L in 33.3%. Dose interruption, dose reduction and permanent discontinuation due to adverse events: 66.2%, 64.3% and 18.8% with sorafenib versus 25.8%, 9.1% and 3.8% with placebo (hand-foot skin reaction the most common reason). Serious adverse events: 37.2% versus 26.3%; second malignancies in 9 sorafenib patients (4.3%; including 7 cutaneous squamous cell carcinomas). According to the FDA label, cardiac ischaemia/infarction was 1.9% versus 0% and haemorrhage 17.4% versus 9.6% (grade 3: 1% versus 1.4%). One death in each group was attributed to study drug.
According to the abstract, sorafenib significantly improved progression-free survival in progressive radioactive iodine-refractory differentiated thyroid cancer, and the authors consider it a new treatment option for these patients. The benefit was seen in all subgroups examined, regardless of BRAF and RAS mutation status. The abstract gives no information on overall survival, drug approvals or the place of this treatment in clinical guidelines, and these should be checked separately.
The abstract does not report overall survival or the rate of grade 3 or higher adverse events. Placebo patients could cross over to sorafenib after disease progression. The high frequency of adverse events in the sorafenib group (98.6%) should be considered in patient selection and treatment monitoring. For other limitations see the full text.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.
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