Predictors of Response and Survival to Multikinase Inhibitors in Radioiodine Resistant Differentiated Thyroid Cancer

Sorafenib and lenvatinib are the only multikinase inhibitors (MKIs) approved for the treatment of radioactive iodine refractory differentiated thyroid cancer (RR-DTC). Although they have been demonstrated to improve progression free survival and overall response rate, the risk of toxicities is very high, worsening patients’ quality of life. Therefore, predicting MKI treatment outcomes in the setting of RR-DTC is very challenging for optimizing patients’ management. The current review provides an overview of the predictive factors for the response and survival of sorafenib and lenvatinib in RR-DTC. In this setting, a systemic therapy should be considered after conducting a multidisciplinary discussion aimed at evaluating the risk-benefit ratio of the treatment and taking into account several clinical, biochemical, and molecular factors. Age, performance status, and cancer-related symptoms are the most important clinical markers to be considered prior to starting MKI treatment, together with tumor burden. Some tissue and circulating biomarkers have been investigated, those involved in the angiogenic pathways being the most promising. Finally, prospective clinical trials aimed at evaluating predictive markers for therapeutic response are needed for tailoring patient management and allowing more appropriate treatment choices.

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Health-Related Quality of Life in Asian Differentiated Thyroid Cancer Survivors

Cancer Control ◽

10.1177/10732748211029726 ◽

2021 ◽

Vol 28 ◽

pp. 107327482110297

Author(s):

Wing-Lok Chan ◽

Horace Cheuk-Wai Choi ◽

Brian Lang ◽

Kai-Pun Wong ◽

Kwok-Keung Yuen ◽

...

Keyword(s):

Quality Of Life ◽

Thyroid Cancer ◽

Cancer Survivors ◽

Differentiated Thyroid Cancer ◽

Summary Score ◽

Health Related Quality ◽

Factors Associated ◽

Related Quality ◽

Health Related

Background: Health-related quality of life (HRQoL) is important for differentiated thyroid cancer survivors, but data for Asian survivors is lacking. This study aimed to have an overview of, and identify any disease-or treatment-related factors associated with, HRQoL in Asian differentiated thyroid cancer survivors. Patients and Methods: Thyroid cancer survivors were recruited from the thyroid clinics at Queen Mary Hospital, Hong Kong from February 2016 to December 2016. All adult differentiated thyroid cancer patients with stable disease more than or equal to 1 year received a survey on HRQoL using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and Thyroid cancer specific quality of life (THYCA-QoL) questionnaire. Clinical information was collected retrospectively from the computerized clinical management system. To identify factors associated with poor HRQoL, univariable and stepwise multivariable regression analysis were performed. Results: A total of 613 survivors completed the questionnaires (response rate: 82.1%; female: 80.1%; median survivorship: 7.4 years (range: 1.0-48.2 years)). The QLQ-C30 summary score mean was 84.4 (standard deviation (SD): 12.7) while the THYCA-QoL summary score mean was 39.9 (SD: 9.7). The 2 highest symptom subscales were fatigue (mean: 26.4, SD: 20.6) and insomnia (mean: 26.2, SD: 27.6). Factors associated with worse HRQoL included serum thyrotropin (TSH) greater than 1.0 mIU/L, unemployment, and concomitant psychiatric disorders. Concomitant psychiatric illness (n = 40/613, 6.5%) also showed significant association with most of the symptom and functional subscales. Conclusions: Fatigue and insomnia were the 2 most common symptoms experienced by our differentiated thyroid cancer survivors. Long-term survivorship care with monitoring serum TSH level, supporting return-to-work and screening for concomitant psychiatric disorders should be offered.

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Cabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor–Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group Trial

Journal of Clinical Oncology ◽

10.1200/jco.2017.73.0226 ◽

2017 ◽

Vol 35 (29) ◽

pp. 3315-3321 ◽

Cited By ~ 39

Author(s):

Maria E. Cabanillas ◽

Jonas A. de Souza ◽

Susan Geyer ◽

Lori J. Wirth ◽

Michael E. Menefee ◽

...

Keyword(s):

Thyroid Cancer ◽

Targeted Therapy ◽

Phase Ii ◽

Differentiated Thyroid Cancer ◽

Kinase Inhibitor ◽

Objective Response ◽

Evaluation Criteria ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Multikinase Inhibitor

Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, there are no approved second- or third-line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer. In a phase I study of cabozantinib, five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib. Patients and Methods Patients with RAI-refractory disease with Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease and evidence of progression on prior VEGFR-targeted therapy were enrolled in this single-arm phase II study. The cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient did not experience a response. Patients underwent tumor assessment according to RECIST v1.1 every 8 weeks. In this study, if at least five of 25 response-evaluable patients had an objective response, cabozantinib would be considered a promising agent in this patient population. Results Twenty-five patients were enrolled. The median age was 64 years, and 64% of patients were men. Twenty-one patients had received only one prior VEGFR-targeted therapy (sorafenib, pazopanib, or cediranib), and four patients had received two such therapies. The most common treatment-related adverse events were fatigue, weight loss, diarrhea, palmar-plantar erythrodysesthesia, and hypertension. One drug-related death was noted. Of the 25 patients, 10 (40%) had a partial response, 13 (52%) had stable disease, and two (8%) had nonevaluable disease. The median progression-free survival and overall survival were 12.7 months and 34.7 months, respectively. Conclusion Cabozantinib demonstrated clinically significant, durable objective response activity in patients with RAI-refractory DTC who experienced disease progression while taking prior VEGFR-targeted therapy.

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Quality of Life with Well-Differentiated Thyroid Cancer: Treatment Toxicities and Their Reduction

Thyroid ◽

10.1089/105072504322880373 ◽

2004 ◽

Vol 14 (2) ◽

pp. 133-140 ◽

Cited By ~ 39

Author(s):

April Mendoza ◽

Brian Shaffer ◽

Daniel Karakla ◽

M. Elizabeth Mason ◽

David Elkins ◽

...

Keyword(s):

Quality Of Life ◽

Thyroid Cancer ◽

Cancer Treatment ◽

Differentiated Thyroid Cancer ◽

Well Differentiated

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Efficacy of Dosimetric Versus Empiric Prescribed Activity of 131I for Therapy of Differentiated Thyroid Cancer

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2011-0494 ◽

2011 ◽

Vol 96 (10) ◽

pp. 3217-3225 ◽

Cited By ~ 54

Author(s):

Joanna Klubo-Gwiezdzinska ◽

Douglas Van Nostrand ◽

Frank Atkins ◽

Kenneth Burman ◽

Jacqueline Jonklaas ◽

...

Keyword(s):

Thyroid Cancer ◽

Side Effects ◽

High Risk ◽

Confidence Interval ◽

Odds Ratio ◽

Differentiated Thyroid Cancer ◽

Progression Free Survival ◽

Response To Treatment ◽

High Risk Patients ◽

Risk Patients

Abstract Background: The optimal management of high-risk patients with differentiated thyroid cancer (DTC) consists of thyroidectomy followed by radioiodine (131I) therapy. The prescribed activity of 131I can be determined using two approaches: 1) empiric prescribed activity of 131I (E-Rx); and 2) dosimetry-based prescribed activity of 131I (D-Rx). Aim: The aim of the study was to compare the relative treatment efficacy and side effects of D-Rx vs. E-Rx. Methods: A retrospective analysis was performed of patients with distant metastases and/or locoregionally advanced radioiodine-avid DTC who were treated with either D-Rx or E-Rx. Response to treatment was based on RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria. Results: The study group consisted of 87 patients followed for 51 ± 35 months, of whom 43 were treated with D-Rx and 44 with E-Rx. Multivariate analysis, controlling for age, gender, and status of metastases revealed that the D-Rx group tended to be 70% less likely to progress (odds ratio, 0.29; 95% confidence interval, 0.087–1.02; P = 0.052) and more likely to obtain complete response (CR) compared to the E-Rx group (odds ratio, 8.2; 95% confidence interval, 1.2–53.5; P = 0.029). There was an association in the D-Rx group between the observed CR and percentage of maximum tolerable activity given as a first treatment of 131I (P = 0.030). The advantage of D-Rx was specifically apparent in the locoregionally advanced group because CR was significantly higher in D-Rx vs. E-Rx in this group of patients (35.7 vs. 3.3%; P = 0.009). The rates of partial response, stable disease, and progression-free survival, as well as the frequency of side effects, were not significantly different between the two groups. Conclusion: Higher efficacy of D-Rx with a similar safety profile compared to E-Rx supports the rationale for employing individually prescribed activity in high-risk patients with DTC.

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Prophylactic prednisolone for the prevention of early and intermediate adverse effects of radioactive iodine therapy in patients with thyroid cancer: study protocol for a single-centre, phase II/III, randomized, double-blinded, placebo-controlled clinical trial

Trials ◽

10.1186/s13063-020-04744-x ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Umesh Jayarajah ◽

Mahilal Wijekoon ◽

Sanjeewa A. Seneviratne

Keyword(s):

Quality Of Life ◽

Clinical Trial ◽

Thyroid Cancer ◽

Adverse Effects ◽

Differentiated Thyroid Cancer ◽

Radioactive Iodine ◽

Oral Prednisolone ◽

Single Centre ◽

Double Blinded

Abstract Background Radioactive iodine (RAI) therapy is the standard adjuvant treatment for differentiated thyroid cancer (i.e. papillary and follicular). RAI is associated with troublesome early, intermediate and late adverse effects. Although glucocorticoids are used for the management of these adverse effects, there is little evidence regarding the effectiveness of prophylactic glucocorticoids to prevent these complications. This trial will evaluate the efficacy of a short course of prophylactic glucocorticoids in the prevention of adverse effects of RAI treatment in patients with differentiated thyroid cancer. Methods A phase II/III, single-centre, randomized, double-blinded, placebo-controlled, parallel-arm clinical trial will be conducted. Patients with differentiated thyroid cancer who are referred to RAI therapy at the National Cancer Institute, Sri Lanka, will be randomized into two arms consisting of 200 patients each. The experimental group will receive prophylactic oral prednisolone 0.5 mg/kg and omeprazole 20 mg single dose 6 h before RAI therapy followed by oral prednisolone 0.5 mg/kg and omeprazole 20 mg daily for 3 days. The control group will receive oral placebo and omeprazole 20 mg single dose 6 h before RAI therapy followed by oral placebo and omeprazole 20 mg daily for 3 days. Clinically significant adverse effects assessed as related to RAI as well as prednisolone therapy and the quality of life parameters will be compared between the two groups. Discussion If proven beneficial, this intervention can be incorporated into the standard practice to reduce early and intermediate adverse effects of RAI for thyroid cancer with a potential improvement of quality of life. Trial registration Sri Lanka Clinical Trials Registry SLCTR/2020/009. Registered prospectively on 23 February 2020. Items of the WHO Trial Registration Data Set are provided in the supplementary file.

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Cisplatin-Based First-Line Treatment of Elderly Patients With Advanced Non–Small-Cell Lung Cancer: Joint Analysis of MILES-3 and MILES-4 Phase III Trials

Journal of Clinical Oncology ◽

10.1200/jco.2017.76.8390 ◽

2018 ◽

Vol 36 (25) ◽

pp. 2585-2592 ◽

Cited By ~ 15

Author(s):

Cesare Gridelli ◽

Alessandro Morabito ◽

Luigi Cavanna ◽

Andrea Luciani ◽

Paolo Maione ◽

...

Keyword(s):

Elderly Patients ◽

Advanced Nsclc ◽

Performance Status ◽

Progression Free Survival ◽

Phase Iii ◽

First Line ◽

Free Survival ◽

Phase Iii Trials ◽

Health Status Score

Purpose To test the efficacy of adding cisplatin to first-line treatment for elderly patients with advanced non–small-cell lung cancer (NSCLC) within a combined analysis of two parallel phase III trials, MILES-3 and MILES-4. Patients and Methods Patients with advanced NSCLC who were older than age 70 years with Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to gemcitabine or pemetrexed, without or with cisplatin. In each trial, 382 events were required to detect a hazard ratio (HR) of death of 0.75, with 80% power and two-tailed α of .05. Trials were closed prematurely because of slow accrual, but the joint database allowed us to analyze the efficacy of cisplatin on the basis of intention-to-treat and adjusted by trial, histotype, non-platinum companion drug, stage, performance status, sex, age, and size of the study center. Results From March 2011 to August 2016, 531 patients (MILES-3, 299; MILES-4, 232) were assigned to gemcitabine or pemetrexed without (n = 268) or with cisplatin (n = 263). Median age was 75 years, 79% were male, and 70% had nonsquamous histology. At a median 2-year follow-up, 384 deaths and 448 progression-free survival events were recorded. Overall survival was not significantly prolonged with cisplatin (HR, 0.86; 95% CI, 0.70 to 1.05; P = .14) and global health status score of quality of life was not improved, whereas progression-free survival (HR, 0.76; 95% CI, 0.63 to 0.92; P = .005) and objective response rate (15.5% v 8.5%; P = .02) were significantly better. Significantly more severe hematologic toxicity, fatigue, and anorexia were found with cisplatin. Conclusion The addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival, and it does not improve global health status score of quality of life in elderly patients with advanced NSCLC.

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Preoperative Serum Thyroglobulin and Its Correlation with the Burden and Extent of Differentiated Thyroid Cancer

Cancers ◽

10.3390/cancers12030625 ◽

2020 ◽

Vol 12 (3) ◽

pp. 625

Author(s):

Hosu Kim ◽

So Young Park ◽

Jun-Ho Choe ◽

Jee Soo Kim ◽

Soo Yeon Hahn ◽

...

Keyword(s):

Thyroid Cancer ◽

Primary Tumor ◽

Differentiated Thyroid Cancer ◽

Medical Center ◽

Distant Metastases ◽

Predictive Biomarker ◽

Tumor Burden ◽

Serum Thyroglobulin ◽

Preoperative Serum ◽

Clinical Records

Lymph node metastasis (LNM) in differentiated thyroid cancer (DTC) is usually detected with preoperative ultrasonography; however, this has limited sensitivity for small metastases, and there is currently no predictive biomarker that can help to inform the extent of surgery required. We evaluated whether preoperative serum thyroglobulin levels can predict tumor burden and extent. We retrospectively reviewed the clinical records of 4029 DTC cases diagnosed and treated at a Samsung Medical Center between 1994 and 2016. We reviewed primary tumor size, number and location of LNM, and presence of distant metastases to reveal relationships between tumor burden and extent and preoperative serum thyroglobulin levels. We found a linear association between increasing preoperative thyroglobulin levels, the size of the primary tumor, and the number of LNM (r = 0.34, p < 0.001, r = 0.20, p < 0.001, respectively). Tumor extent also increased with each decile of increasing preoperative thyroglobulin level (r = 0.18, p < 0.001). Preoperative thyroglobulin levels of 13.15 ng/mL, 30.05 ng/mL, and 62.9 ng/mL were associated with the presence of ipsilateral lateral LNM, contralateral lateral LNM, and distant metastasis, respectively. Our results suggest that preoperative measurement of serum thyroglobulin may help to predict LNM and help to tailor surgery.

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A phase I study determining the safety and tolerability of combination therapy with pazopanib, a VEGFR/PDGFR/raf inhibitor, and GSK1120212, a MEK inhibitor, in advanced solid tumors enriched with patients with advanced differentiated thyroid cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.tps3117 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. TPS3117-TPS3117 ◽

Cited By ~ 2

Author(s):

Shabina Roohi Ahmed ◽

Nilofer Saba Azad ◽

Douglas Wilmot Ball ◽

Michelle A. Rudek ◽

Barry Nelkin ◽

...

Keyword(s):

Thyroid Cancer ◽

Phase I ◽

Differentiated Thyroid Cancer ◽

Kinase Inhibitor ◽

Performance Status ◽

Critical Role ◽

Growth Factor Receptor ◽

Primary Objective ◽

Open Label ◽

Expansion Cohort

TPS3117 Background: Mutations of the RAS/RAF/MEK/ERK signaling pathway, especially RAS, BRAF and IGF-I/II receptor genes play a critical role in the development of many different types of cancers, including breast, colorectal, melanoma, NSCLC, and thyroid. Differentiated thyroid cancer (DTC) is the most common endocrine malignancy, but there is currently no approved therapy for advanced radioiodine-resistant disease. In DTC xenograft models, vertical inhibition of this pathway, achieved by targeting the vascular endothelial growth factor receptor (VEGFR) and MEK, has shown greater clinical efficacy than with either agent alone. Pazopanib (P) is a small molecule tyrosine kinase inhibitor that selectively inhibits VEGFR1-3, PDGFR-α, PDGFR-b, c-kit, and FGFR 1-3. Phase II data in advanced DTC from Bible, et al, indicate a 49% response rate with a PFS of 11.7 months in a patients with PD within 6 months. GSK1120212 (G) is a potent, highly selective, allosteric inhibitor of MEK1/2. In a phase I/II study, Infante et al. reported an ORR of 81% in BRAF mutant melanoma patients when G was combined with a RAF inhibitor. Methods: A phase I, open label, dose escalation trial with P+G is currently accruing pts with advanced malignancies. The study is a standard 3+3 design with an expansion cohort of 25 pts with advanced DTC for correlative endpoints and PK studies. Pts will be treated with P at 400 mg QD, 600 mg QD and 800 mg QD, with G held constant at 1 mg QD; G will then be escalated to 1.5 mg QD and 2 mg QD. Eligibility includes advanced solid tumor, good end organ function and performance status, and PD within 6 months in the expansion cohort. The primary objective is to determine the safety and tolerability of the combination and determine the MTD. Secondary objectives include assessing preliminary efficacy as defined by RECIST criteria and PFS, and exploration of PK/PD endpoints. Serial tumor biopsies will be evaluated for changes in signaling through p-ERK. RAS and RAF mutation sites will be sequenced in order to correlate with PD endpoints and disease response. Currently, DL1 has accrued with no DLTs.

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