Thyroglobulin fluctuations in patients with iodine-refractory differentiated thyroid carcinoma on lenvatinib treatment - initial experience.
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ABSTRACT:
SUBMITTER: Werner RA
PROVIDER: S-EPMC4910099 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Standard therapy for radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) is multi-targeted kinase inhibitors (m-TKIs), represented by sorafenib and lenvatinib. One of the main target molecules of m-TKIs is vascular endothelial growth factor receptor (VEGF-R). m-TKIs are known to cause adverse reactions such as hypertension and proteinuria as a class effect. In particular, proteinuria is thought to result from vascular endothelial damage and podocytopathy in glomeruli, and the development of thrombotic microangiopathy (TMA) has been reported for VEGF inhibitors. We encountered a patient with RAI-refractory (RR) papillary thyroid carcinoma (PTC) who developed proteinuria and renal dysfunction due to lenvatinib. Renal biopsy demonstrated that these changes were caused by TMA. To our knowledge, this is the first reported case of TMA due to lenvatinib in a Japanese patient with RR-PTC. A 70-year-old woman developed proteinuria, renal impairment and hypertension while receiving lenvatinib for RR-PTC. Her proteinuria and renal damage continued to worsen despite dose reductions and dose interruptions. Renal biopsy was consistent with the chronic type of TMA. These findings indicate that TMA is a possible cause of proteinuria due to lenvatinib, as has been reported for the VEGF inhibitors.
| S-EPMC6276762 | biostudies-other
Project description:Introduction: Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Methods: Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining partial response [PR]), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided α = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. Results: From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6-50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: -86.8%; interquartile range [IQR]: -90.7% to -70.9%) compared with the 28 who did not (median: -69.0%; IQR: -78.1% to -27.7%, Wilcoxon rank-sum test: p = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (-23.5% [CI: -55.3 to 8.3]; Fisher's exact test p-value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. Conclusions: This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.
| S-EPMC7482116 | biostudies-literature
Project description:Until recently, no truly effective treatment options have existed for patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC), a serious disease with poor prognosis. In November 2013, the targeted multikinase inhibitor, sorafenib, was approved for use in these patients based on substantially improved progression-free survival compared with placebo. A number of other targeted agents, including lenvatinib, are being investigated in phase II and phase III trials. With the advent of these new treatment options, practitioners are faced with making important decisions in determining which patients are candidates for systemic treatment and the optimal timing for treatment initiation. Since patients may remain asymptomatic for a protracted period of time, tumor size and growth rate are the primary considerations for making these choices. Proactive management of side effects is also critical in optimizing the effectiveness of treatment. Here we review targeted systemic agents that are either in use or are under investigation for RAI-refractory DTC and provide recommendations on the rationale for initiating systemic treatment and on managing adverse events. Four illustrative case studies are provided.
| S-EPMC4206652 | biostudies-literature
Project description:BackgroundThe objective of the study was to reveal through pragmatic MCDA (EVIDEM) the contribution of a broad range of criteria to the value of the orphan drug lenvatinib for radioiodine refractory differentiated thyroid cancer (RR-DTC) in country-specific contexts.MethodsThe study was designed to enable comprehensive appraisal (12 quantitative, 7 qualitative criteria) in the current disease context (watchful waiting, sorafenib) of France, Italy and Spain. Data on the value of lenvatinib was collected from diverse stakeholders during country-specific panels and included: criteria weights (individual and social values); performance scores (judgments on evidence-collected through MCDA systematic review); qualitative impacts of contextual criteria; and verbal and written insights structured by criteria. The value contribution of each criterion was calculated and uncertainty explored.ResultsComparative effectiveness, Quality of evidence (Spain and Italy) and Disease severity (France) received the greatest weights. Four criteria contributed most to the value of lenvatinib, reflecting its superior Comparative effectiveness (16-22% of value), the severity of RR-DTC (16-22%), significant unmet needs (14-21%) and robust evidence (14-20%). Contributions varied by comparator, country and individuals, highlighting the importance of context and consultation. Results were reproducible at the group level. Impacts of contextual criteria varied across countries reflecting different health systems and cultural backgrounds. The MCDA process promoted sharing stakeholders' knowledge on lenvatinib and insights on context.ConclusionsThe value of lenvatinib was consistently positive across diverse therapeutic contexts. MCDA identified the aspects contributing most to value, revealed rich contextual insights, and helped participants express and explicitly tackle ethical trade-offs inherent to balanced appraisal and decisionmaking.
| S-EPMC5393009 | biostudies-literature
Project description:ObjectiveCurrent diagnosis of radioactive iodine (RAI)-refractory (RAIR) differentiated thyroid cancer (DTC) is based on the imaging technique, which is of a high cost. Serum thyroglobulin (Tg) is a sensitive and easily obtained biomarker. Hence, we aimed to assess the predicting value of quantitative response of Tg in earlier identifying the RAIR-DTC with pulmonary metastasis.Patients and methodsPulmonary metastatic DTC patients who underwent total or near-total thyroidectomy and at least two times of RAI therapy were included in this study. The pre-ablative stimulated Tg at the first and second RAI therapy were defined as pstim-Tg1 and pstim-Tg2, while the suppressed Tg before and after the second RAI therapy were designated sup-Tg1 and sup-Tg2. The predicted value of pstim-Tg2/Tg1 and sup-Tg2/Tg1 ratio were detected using the receiver operating characteristic (ROC) curve and logistic regression analyses.ResultsTotally 115 patients were involved in this study. ROC curves showed a cut-off value of 0.544 for pstim-Tg2/ pstim-Tg1 in detecting RAIR, with a sensitivity of 0.9 and specificity of 0.477, and an area under the curve (AUC) of 0.744. Similarly, the cut-off of sup-Tg2/ sup-Tg1 was 0.972, with a sensitivity of 0.733 and specificity of 0.935, and AUC of 0.898. Univariate analysis illustrated that age, tumor size, pstim-Tg2/Tg1, sup-Tg2/ sup-Tg1 and BRAFV600E mutation were eligible to predict RAIR. While from multivariate analysis, only age, pstim-Tg2/Tg1, sup-Tg2/ sup-Tg1 and BRAFV600E mutation were verified to be the independent predictive factors.ConclusionThe quantitative Tg response was encouraging in identifying RAIR-DTC with pulmonary metastasis. Age, BRAFV600E mutation and Tg response were independent predictors in predicting RAIR-DTC.
| S-EPMC5509138 | biostudies-literature
Project description:The treatment of differentiated thyroid cancer refractory to radioactive iodine (RAI) had been hampered by few effective therapies. Recently, tyrosine kinase inhibitors (TKIs) have shown activity in this disease. Clinical guidance on the use of these agents in RAI-refractory thyroid cancer is warranted.Molecular mutations found in RAI-refractory thyroid cancer are summarized. Recent phase II and III clinical trial data for TKIs axitinib, lenvatinib, motesanib, pazopanib, sorafenib, sunitinib, and vandetinib are reviewed including efficacy and side effect profiles. Molecular targets and potencies of these agents are compared. Inhibitors of BRAF, mammalian target of rapamycin, and MEK are considered.Routine testing for molecular alterations prior to therapy is not yet recommended. TKIs produce progression-free survival of approximately 1 year (range: 7.7-19.6 months) and partial response rates of up to 50% by Response Evaluation Criteria in Solid Tumors. Pazopanib and lenvatinib are the most active agents. The majority of patients experienced tumor shrinkage with TKIs. Common adverse toxicities affect dermatologic, gastrointestinal, and cardiovascular systems.Multiple TKIs have activity in RAI-refractory differentiated thyroid cancer. Selection of a targeted agent should depend on disease trajectory, side effect profile, and goals of therapy.
| S-EPMC4319630 | biostudies-literature
Project description:Patients with radioactive iodine refractory differentiated thyroid cancer (RAIR-DTC) are resistant to radioactive iodine-131(131I) treatment, and the clinical treatment for these patients is complex. The implantation of iodine-125 (125I) seeds in the lesion has been successfully applied to treat malignant tumors, but there are few reports on using 125I particles in the treatment of RAIR-DTC. This retrospective study collected data of 92 patients with RAIR-DTC. Patients treated with sorafenib were included in a control group (50 cases with 72 lesions) and patients treated with 125I implantation were included in an observation group (42 cases with 68 lesions). The results showed that compared with those in the control group, the lesion volume was lower and the VVR was higher in the observation group (P<0.05). The Tg and Tg-Ab levels 6 months after treatment were lower than those before treatment in both groups, and the post-treatment Tg and Tg-Ab levels of the observation group were lower than those of the control group (P<0.05). The efficacy, disease control rate, and objective remission rate were not significantly different between the observation group and the control group (P>0.05). Overall survival of patients in the observation group was longer than that in the control group, χ2 = 4.430, P = 0.035. The incidence of total adverse reactions in the observation group was lower than that in the control group (P<0.05). In conclusion, 125I seed implantation is effective in RAIR-DTC treatment as it can prolong the overall survival of patients while maintaining a safe profile.
| S-EPMC10636672 | biostudies-literature
Project description:The incidence of differentiated thyroid cancer (DTC) has increased over the last few decades, though it remains to be a rare disease. The prognosis of DTC is excellent; its treatment includes surgery (near-/total thyroidectomy), which is usually followed by remnant thyroid bed ablation using radio-iodine, as well as a risk-stratified follow-ups, including hormone replacement. Treatment of patients who are non-responsive to radioactive iodine (RAI) remains a challenge. Targeted therapies for RAI refractory DTC act primarily through inhibition of cell proliferation, survival and angiogenesis. Tyrosine kinase inhibitors (TKI) have achieved prolonged responses and improved progression-free survival, thereby representing a shift in the treatment of advanced thyroid cancer. There will be number of targeted treatment options for this patient population in the near future. Evidence regarding which drug should be used first and whether there is crossover drug resistance between these drugs is still lacking. Clinicians should be able to choose precisely which patients should be treated with novel targeted therapies after taking into account the following facts: i) TKIs have still not demonstrated a survival benefit. ii) The adverse effects of long-lasting treatment with TKIs could worsen quality of life, which is mostly excellent in these patients before starting treatment with these agents.
| S-EPMC7788563 | biostudies-literature
Project description:The role of postoperative external beam radiotherapy (EBRT) in patients with residual iodine refractory-differentiated thyroid cancer (IR-DTC) is still inconclusive. The aim of this retrospective study was to evaluate locoregional control (LRC) and overall survival (OS), and potential side effects after postoperative EBRT for both microscopic and macroscopic non-radically resected, locally advanced IR-DTC. Between 1990 and 2016, 49 patients with locally advanced IR-DTC received EBRT for microscopic (R1; n = 28) or macroscopic (R2; n = 21) locoregional residual disease. For more insight into the added effect of EBRT, we performed an intrapatient sub-analysis in 32 patients who had undergone more than 1 surgical intervention, comparing LRC after primary, curative-intended surgery with LRC after repeated surgery plus EBRT. To estimate LRC and OS, we used Kaplan-Meier curves. From 2007 onward, we prospectively recorded toxicity data in our head and neck cancer database (n = 10). LRC rates 5 years after EBRT were higher for R1 (84.3%) than for R2 (44.9%) residual disease (P = 0.016). The 5-year OS rate after EBRT was 72.1% for R1 and 33.1% for R2 disease (P = 0.003). In the intrapatient analysis (n = 32), LRC rates were 6.3% 5 years after only initial surgery and 77.9% after repeated surgery with EBRT (P < 0.001). Acute toxicity was limited to grade I and II xerostomia, mucositis, and hoarseness; only one patient developed late grade III dysphagia. Postoperative EBRT is associated with long-lasting LRC and OS with acceptable toxicity in patients with locally advanced IR-DTC, especially in microscopic residual disease.
| S-EPMC9142801 | biostudies-literature
Project description:While there is a clear consensus for defining radioiodine-refractory differentiated thyroid cancer (RR-DTC), it is unknown whether these criteria are equally valid for determining when radioiodine (RAI) therapy is no longer beneficial and systemic treatment should be considered. Lenvatinib, a multikinase inhibitor, significantly prolonged progression-free survival (PFS) compared to placebo in a Phase 3 trial in RR-DTC (SELECT; hazard ratio [HR]: 0.21 [99% confidence interval (CI) 0.14-0.31]; p?<?0.001). This sub-analysis compared clinical outcomes of lenvatinib-treated patients in SELECT stratified by RR-DTC inclusion criteria.In SELECT, patients with measurable RR-DTC and radiologic evidence of disease progression ?13 months prior to study entry were randomized 2:1 to lenvatinib (24?mg/day; 28-day cycle) or placebo. In this analysis, patients were stratified based on the following RR-DTC inclusion criteria: no RAI uptake, disease progression within 12 months of RAI therapy despite RAI avidity at the time of treatment, and extensive (>600?mCi) cumulative RAI exposure. All had disease progression as an inclusion criterion for SELECT.Of 392 patients (261 lenvatinib; 131 placebo) enrolled, 275, 235, and 73 patients met the inclusion criteria for no RAI uptake, disease progression despite RAI avidity, and extensive RAI exposure, respectively. There was significant overlap between the patient groups, with 167 (42.6%) patients meeting more than one inclusion criterion. Lenvatinib improved median PFS compared to placebo in all groups ("no RAI uptake": lenvatinib not quantifiable [NQ; CI 14.8-NQ] vs. placebo, 3.7 months [CI 2.5-5.3]; "disease progression despite RAI avidity": lenvatinib 16.5 months [CI 12.8-NQ] vs. placebo, 3.7 months [CI 1.9-5.4]; "extensive RAI exposure": lenvatinib 18.7 months [CI 10.7-NQ] vs. placebo, 3.6 months [CI 1.9-5.5]). Objective response rates were 71.8%, 60.0%, and 56.0% for patients with no RAI uptake, disease progression despite RAI avidity, and extensive RAI exposure, respectively. Lenvatinib-related adverse events were similar across groups.Comparable efficacy and safety profiles were observed in lenvatinib-treated patients regardless of RR-DTC criteria, possibly because of a large overlap among patients fulfilling each criterion. However, differing definitions for RR-DTC may be equally valid because both lenvatinib and placebo arms exhibited similar PFS outcomes across groups.
| S-EPMC5646742 | biostudies-literature