|Year : 2016 | Volume
| Issue : 2 | Page : 1084-1087
Off-label use of Sorafenib in patients with advanced thyroid carcinoma: Retrospective analysis of five cases
Maria Joćo Bugalho
Endocrinology Service, Portuguese Institute of Oncology Francisco Gentil EPE; NOVA Medical School/NOVA Medical School, Lisbon, Portugal
|Date of Web Publication||25-Jul-2016|
Maria Joćo Bugalho
Endocrinology Service, Portuguese Institute of Oncology Francisco Gentil EPE, Rua Professor Lima Basto, Lisboa - 1099 - 023
Source of Support: None, Conflict of Interest: None
We present results obtained in five patients with advanced thyroid cancer, derived from the follicular epithelium, treated with Sorafenib used off-label. The median age at the time Sorafenib was started was 61 years. Only one patient tolerated the standard dose of 400 mg twice daily. The most severe adverse events were:
Keywords: 131I refractory, kinase inhibitor, Sorafenib, thyroid carcinoma
|How to cite this article:|
Bugalho MJ. Off-label use of Sorafenib in patients with advanced thyroid carcinoma: Retrospective analysis of five cases. J Can Res Ther 2016;12:1084-7
| > Introduction|| |
Differentiated thyroid cancer (DTC) accounts for 90% of thyroid malignancies and includes Papillary Thyroid Carcinoma (PTC) and Follicular Thyroid Carcinoma (FTC). The vast majority of patients respond very well to standard treatment, which includes total thyroidectomy, radioactive iodine (RAI) and thyroid hormone suppression. Management of patients, with progressive disease refractory to standard approaches or with poorly differentiated thyroid carcinoma, has been challenging since, until recently, there were no effective alternatives. Conventional chemotherapeutic agents and external beam radiotherapy are ineffective and have been used but with unsatisfactory results.
PTC is driven by RET rearrangements, activating point mutations in the BRAF and activating point mutations in the RAS oncogenes (limited to PTC follicular variant).
FTC is frequently associated with Ras point mutations, rearrangements between the Pax8 transcription factor and the peroxisome proliferator-activated receptor γ (PPARγ) and mutations involving the phosphatidylinositol 3-kinase (PI3K)–Akt pathway.
A growing understanding of the molecular basis of thyroid cancer particularly the identification of key oncogenic mutations has allowed the development of targeted agents in different types of advanced thyroid carcinoma. Among the most successful agents are different kinase inhibitors (KIs).
The National Comprehensive Cancer Center Network (NCCN) Guidelines in Oncology and The American Thyroid Association Guidelines on differentiated thyroid cancer recommend including patients with advanced RAI-refractory DTC in clinical trials or considering treatment with off-label small-molecule kinase inhibitors if trials are not available.
Different collaborative placebo-controlled multicenter trials ,,,, to determine the efficacy of Sorafenib in patients with advanced DTC have documented improvement in progression-free survival. Yet no medium or long beneficial effects were found. Sorafenib side effects are not inconsequential.
The U. S. Food and Drug Administration recently (November 2013) approved Sorafenib, a multikinase inhibitor, for radioiodine-resistant metastatic DTC.
| > Case Report|| |
Off-label treatment with Sorafenib was offered to five patients with advanced thyroid cancer arising from the follicular cells; two patients had follicular variant PTC, one patient had classical PTC, another had PTC with poorly differentiated areas and one had a poorly differentiated thyroid carcinoma. Evidence of disease progression, according to Response Evaluation Criteria in Solid Tumors (RECIST), within 1 year prior to treatment was documented in all. Other inclusion criteria were WHO performance status 0/1 with preserved renal, hepatic, cardiac and bone marrow function. Further to a normal electrocardiogram, all patients had a baseline transthoracic echocardiogram documenting in all a normal left ventricular ejection fraction.
[Table 1] summarizes initial presentation and treatment prior to Sorafenib. The median age at diagnosis was 53 years (range 37–60). All patients had total thyroidectomy and RAI therapy (mean cumulative activity 489 ± 278) and four patients had external-beam radiotherapy (two for neck and bone and two for bone).
After protocol approval by the institutional review board all patients provided written informed consent.
We assessed tumor response by RECIST criteria, changes in serum tumor marker (tiroglobulin) and duration of tumor response.
Clinical benefit was defined as partial response, PR (at least a 30% decrease in the sum of diameters of target lesions) or stable disease, SD (neither sufficient increase nor decrease in the size of target lesions considered to be meaningful). Treatment was stopped following radiological evidence of progressive disease, PD (a 20% or greater increase in the sum of diameters of the target lesions) according to RECIST criteria or following severe side effects.
Patients were included between December 2009 and July 2012.
When Sorafenib was started, the median age of the patients was 61 years (range 44–69).
All patients underwent 18F-FDG PET prior to treatment and in all there were areas of positive uptake, contrasting with negative 131 I whole body scans.
The most common adverse events (grade 2/3) were anorexia/weight loss (cases 2, 3, 5) and hand-foot-skin syndrome (cases 3, 4, 5) followed by hypertension (cases 2 and 4), and maculopapular skin rash (case 1).
Median duration of therapy was 11 months (range 4–14 months). Under treatment, disease progressed in 4 patients and remained stable in one patient (case 4) who had, nonetheless, to interrupt Sorafenib because of complaints of intermittent claudication requiring surgical treatment. Base line characteristics, maximum tolerated dose and responses to Sorafenib are summarized in [Table 2].
|Table 2: Baseline characteristics, maximal tolerated dose and responses to treatment with Sorafenib|
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Shortly after interruption of Sorafenib, one patient (case 2) sought medical attention for severe complaints of cough. She was submitted to broncofibroscopy and biopsy of the right middle lobe bronchus, at a different hospital. Slides were reviewed by one of our pathologists and the pathology report was of infiltrating poorly differentiated carcinoma immunopositive for P63 thus suggesting squamous differentiation. Based on a negative immunohistochemistry for thyroglobulin and TTF1 the thyroid origin was considered unlikely.
Sequential treatment with Sunitinib was offered to one patient (case 5), unsuccessfully.
| > Discussion|| |
The vast majority of patients with DTC respond very well to standard treatment including total thyroidectomy, RAI ablation and TSH suppressive therapy. The overall prognosis of patients with DTC is good with a 10-year disease specific survival rate of 85%. The prognosis of patients with distant metastases remains favorable, when these are responsive to RAI, but the 10-year disease-specific survival rate drops to 40%. In patients with RAI-resistant disease, the long-term overall survival drops to 10%. Clinical management of these patients has been challenging, since conventional chemotherapy and radiotherapy have modest effect on advanced thyroid carcinoma.
Increased understanding of the biologic processes involved in the pathogenesis of thyroid carcinoma has led to the development of targeted therapies. Sorafenib is an orally active multi-tyrosine kinase inhibitor targeting both cell-surface tyrosine kinase receptors and downstream intracellular serine/threonine kinases in the Ras/MAPK cascade. The Food and Drug Administration (FDA) recently (November 2013) approved Sorafenib for treatment of radioiodine-resistant metastatic DTC.
The safety and efficacy of sorafenib (400 mg orally twice daily) vs placebo was evaluated in a phase III trial (DECISION) enrolling patients with locally advanced or metastatic RAI-refractory DTC. Median progression-free survival was improved by 5 months (10·8 months in the sorafenib group and 5·8 months in the placebo group).
A meta-analysis to analyze results of different clinical trials was carried out by Shen C-T et al. The results of this meta-analysis suggest a modest effect in patients with radioiodine-refractory differentiated thyroid cancer and high incidence of adverse effects likely to affect patients' quality of lives.
Data presented herein provide a longitudinal perspective of the course of disease in five patients who became refractory to 131 I and were treated with Sorafenib. Treatment was started 7.4 ± 1.5 years after diagnosis of thyroid cancer (range 5–9).
All but one patient (case 4) progressed under treatment. This patient stopped treatment because of complaints of de novo intermittent claudication caused by peripheral artery disease justifying surgical approach. An association between this event and treatment cannot be ruled out, since ischemic disease has been reported as a possible complication of kinase inhibitors. Worthy of note was the varying responses to therapy in different metastatic sites observed in one patient (case 3). In this particular patient, during the first 6 months of treatment, lung metastases did not progress however escaped control after this period. On the contrary, bone metastases increased in number and severity from the beginning of treatment.
Sorafenib was discontinued in four patients because of tumor progression and in one patient because of critical limb ischemia. Progressively, complaints of anorexia disappeared and patients recovered weight, despite disease progression. Four patients died. Median survival, after stopping Sorafenib, was 14 months (range 6–38).
Lack of response to a kinase inhibitor does not preclude absence of response to a different one. Treatment with Sunitinib was offered to patient 5, following interruption of Sorafenib but disease progressed.
Of particular concern is the development of an infiltrating poorly differentiated carcinoma of the right middle lobe bronchus observed in one patient. The immunohistochemical pattern of this carcinoma makes unlikely the thyroid origin and suggests a squamous differentiation. The development of squamous cell carcinomas of the skin has been described after treatment with Sorafenib. One case of lung squamous cell carcinoma was previously reported in association with a selective BRAF inhibitor but was considered to be a dedifferentiated thyroid cancer rather than primary lung cancer.
Results from clinical trials and reports of isolated clinical cases, including the present series, document a highly variable individual response. Until identification of clinical and/or molecular markers able to anticipating the type of response, Sorafenib should be considered for selected patients particularly those to whom tumor progression, due to anatomical or functional reasons, may be life threatening.
| > Acnowledgements|| |
The author thank Dr. Rafael Cabrera for reviewing the bronchial biopsy slides of patient 2.
| > References|| |
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[Table 1], [Table 2]