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Pitoia F, Jerkovich F, Trimboli P, Smulever A. New approaches for patients with advanced radioiodine-refractory thyroid cancer. World J Clin Oncol 2022; 13:9-27. [PMID: 35116229 PMCID: PMC8790300 DOI: 10.5306/wjco.v13.i1.9] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 08/31/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma (DTC) has exponentially increased. Approximately 10% of patients with DTC exhibit recurrent or metastatic disease, and about two-thirds of the latter will be defined as refractory to radioactive iodine (RAIR) treatment. Since this condition implies 10-year survival rates less than 10% after detection, using available treatments, such as systemic and targeted therapies, have become increasingly relevant. The initiation of these treatments aims to reach stabilization, tumor volume reduction, and/or symptom improvement and it should be decided by highly specialized endocrinologists/oncologists on the basis of patient's features. Considering that despite enlarged progression-free survival was proven, multikinase inhibitors remain non-curative, their benefits last for a limited time and the side effects potentially cause harm and quality of life reduction. In this context, molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy, progression free survival, overall survival and adverse events profile. This review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC, including approved target therapies as well as those for off-label use, RAI resensitization agents, and immunotherapy.
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Affiliation(s)
- Fabián Pitoia
- Division of Endocrinology, Hospital de Clínicas José de San Martin, University of Buenos Aires, Buenos Aires 1120, Argentina
| | - Fernando Jerkovich
- Division of Endocrinology, Hospital de Clínicas José de San Martin, University of Buenos Aires, Buenos Aires 1120, Argentina
| | - Pierpaolo Trimboli
- Clinic for Endocrinology and Diabetology, Lugano Regional Hospital, Ente Ospedaliero Cantonale, Lugano 1111, Switzerland
- Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano 1111, Switzerland
| | - Anabella Smulever
- Division of Endocrinology, Hospital de Clínicas José de San Martin, University of Buenos Aires, Buenos Aires 1120, Argentina
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Fierro-Maya LF, González GG, Rojas Melo LJ, Cuéllar Cuéllar AA, Carreño A, Córdoba C. Safety and efficacy of sorafenib in patients with advanced thyroid carcinoma: a phase II study (NCT02084732). ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2021; 65:404-410. [PMID: 39421700 PMCID: PMC10522190 DOI: 10.20945/2359-3997000000373] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 01/10/2021] [Indexed: 10/19/2024]
Abstract
Objective Sorafenib significantly prolonged progression-free survival in patients with iodine-refractory advanced thyroid cancer. The present study was initiated before sorafenib was approved in Colombia and therefore represents an effort by an oncology institution to evaluate its efficacy and safety in this population. Subjects and methods This phase II clinical trial had a single treatment arm. We included adult patients with progressive metastatic iodine-refractory thyroid cancer who received treatment with sorafenib 800 mg/day (400 mg every 12 hours) up to a maximum of 24 months or until the occurrence of limiting related toxicity, the progression of the disease, or voluntary withdrawal. Results Nineteen patients received the treatment and were included in the safety analysis. However, for the efficacy analysis, 6 patients were excluded because they received only one month of therapy. Thirteen (68%) patients were women, and the mean age at diagnosis was 61.8 years. No complete responses were observed; 5 patients had a partial response (35.7%), 6 patients had stable disease, and 3 showed progression. Mean progression-free survival was calculated at 18 months (95% CI 10.7-20.3). Overall survival was estimated at 21.3 months (95% CI 17.8-24.8). Conclusion For the first time in Colombia, the efficacy of sorafenib was evaluated in patients with advanced and progressive thyroid carcinoma refractory to radioactive iodine, with an efficacy and a safety profile similar to those previously reported.
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Affiliation(s)
- Luis Felipe Fierro-Maya
- Instituto Nacional de CancerologíaUnidad de Endocrinología OncológicaBogotáColombiaUnidad de Endocrinología Oncológica, Instituto Nacional de Cancerología, Bogotá, Colombia.
| | - Gloria Garavito González
- Instituto Nacional de CancerologíaUnidad de Endocrinología OncológicaBogotáColombiaUnidad de Endocrinología Oncológica, Instituto Nacional de Cancerología, Bogotá, Colombia.
- Instituto Nacional de CancerologíaBogotáColombiaInstituto Nacional de Cancerología, Endocrinóloga en Colsanitas, Bogotá, Colombia.
| | - Leonardo Javier Rojas Melo
- Instituto Nacional de CancerologíaUnidad de Endocrinología OncológicaBogotáColombiaUnidad de Endocrinología Oncológica, Instituto Nacional de Cancerología, Bogotá, Colombia.
- Hospital Universitario San IgnacioBogotáColombiaServicio de Endocrinología, Hospital Universitario San Ignacio, Bogotá, Colombia.
| | - Andrés Arturo Cuéllar Cuéllar
- Instituto Nacional de CancerologíaUnidad de Endocrinología OncológicaBogotáColombiaUnidad de Endocrinología Oncológica, Instituto Nacional de Cancerología, Bogotá, Colombia.
| | - Alexander Carreño
- Instituto Nacional de CancerologíaUnidad de InvestigacionesBogotáColombiaUnidad de Investigaciones, Instituto Nacional de Cancerología, Bogotá, Colombia.
| | - Claudia Córdoba
- Instituto Nacional de CancerologíaUnidad de Imágenes DiagnósticasBogotáColombiaUnidad de Imágenes Diagnósticas, Instituto Nacional de Cancerología, Bogotá, Colombia.
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Verburg FA, Amthauer H, Binse I, Brink I, Buck A, Darr A, Dierks C, Koch C, König U, Kreissl MC, Luster M, Reuter C, Scheidhauer K, Willenberg HS, Zielke A, Schott M. Questions and Controversies in the Clinical Application of Tyrosine Kinase Inhibitors to Treat Patients with Radioiodine-Refractory Differentiated Thyroid Carcinoma: Expert Perspectives. Horm Metab Res 2021; 53:149-160. [PMID: 33652491 PMCID: PMC7932822 DOI: 10.1055/a-1380-4154] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Notwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue.
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Affiliation(s)
- Frederik A. Verburg
- Department of Nuclear Medicine, University Hospital Marburg, Marburg,
Germany
- Erasmus Medical Center, Department of Radiology and Nuclear Medicine,
Rotterdam, The Netherlands
- Correspondence Frederik A. Verburg M.D., PhD. Department of Radiology and Nuclear MedicineErasmus Medical CenterDoctor Molewaterplein 403015 GD RotterdamThe Netherlands+31 10 704 0 704
| | - Holger Amthauer
- Charité - Universitätsmedizin Berlin, Freie
Universität Berlin, Humboldt-Universität zu Berlin, and Berlin
Institute of Health, Department of Nuclear Medicine, Berlin,
Germany
| | - Ina Binse
- Department of Nuclear Medicine, University Clinic Essen, Essen,
Germany
| | - Ingo Brink
- Department of Medical Diagnostics and Therapy, Ernst von Bergmann
Hospital Potsdam, Potsdam, Germany
| | - Andreas Buck
- Department of Nuclear Medicine, University Hospital Würzburg,
Würzburg, Germany
| | - Andreas Darr
- Department of Nuclear Medicine, University Hospital Jena, Jena,
Germany
| | - Christine Dierks
- Department of Medical Oncology, University Hospital Freiburg, Freiburg,
Germany
| | - Christine Koch
- Department of Gastroenterology, Hepatology, and Endocrinology,
University Clinic Frankfurt, Frankfurt Am Main, Germany
| | - Ute König
- Department of Gastroenterology and Endocrinology, University of
Göttingen, Göttingen, Germany
| | - Michael C. Kreissl
- Division of Nuclear Medicine, Department of Radiology and Nuclear
Medicine, Otto von Guericke University Magdeburg, Magdeburg,
Germany
| | - Markus Luster
- Department of Nuclear Medicine, University Hospital Marburg, Marburg,
Germany
| | - Christoph Reuter
- Department of Palliative Care, Hannover Medical School, Hannover,
Germany
| | - Klemens Scheidhauer
- Interdisclipinary Endocrine Center, Technical University of Munich,
Munich, Germany
| | - Holger Sven Willenberg
- Division of Endocrinology and Metabolism, Medical University of
Rostock, Rostock, Germany
| | - Andreas Zielke
- Department of Endocrine Surgery, Diakonie Klinikum Stuttgart,
Stuttgart, Germany
| | - Matthias Schott
- Division of Endocrinology, University Hospital Düsseldorf,
Düsseldorf, Germany
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Feng G, Luo Y, Zhang Q, Zeng F, Xu J, Zhu J. Sorafenib and radioiodine-refractory differentiated thyroid cancer (RR-DTC): a systematic review and meta-analysis. Endocrine 2020; 68:56-63. [PMID: 31955344 DOI: 10.1007/s12020-019-02167-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 12/18/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Except conventional treatments, research on medical approach for radioiodine-refractory differentiated thyroid cancer (RR-DTC) was considered particularly challenging. Sorafenib, a novel biological agent, has been widely studied in the treatment of RR-DTC for years. We performed a systematic review and meta-analysis to explore the efficiency and safety of treating RR-DTC patients with sorafenib. METHODS An electronic search on PubMed/Medline and Embase was carried out to search associated articles. Fixed-effects or random-effects models were chose according to the heterogeneity. RESULTS A total of 15 eligible studies (636 patients) were included. As shown by the only randomised clinical trial-DECISION, sorafenib significantly improved progression-free survival (PFS) compared with placebo in patients with progressive RR-DTC. The pooled analysis indicated that there were 26% patients (95% CI: 0.19-0.34) achieved partial response (PR), and 44% patients (98% CI: 0.39-0.48) achieved stable disease (SD). The most frequent adverse effects (AEs) observed included hand-foot syndrome (HFS), diarrhoea, fatigue, alopecia, weight loss (WS) and rash, the incidence of all grades AEs for which were 71%, 60%, 59%, 55%, 51% and 50%, respectively. There were 68% patients (252/368), who had a dose reduction because of the drug toxicities and AEs. CONCLUSIONS Sorafenib could improve PFS in patients with progressive RR-DTC, comparing with placebo. Due to the resistance to conventional treatments, sorafenib is considered as a promising treatment for RR-DTC by most physicians specialised in this field. However, the use of sorafenib should be cautious due to a high incidence of AEs caused by the agent. More effective agents with less toxicities are warranted.
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Affiliation(s)
- Guoli Feng
- Department of Thyroid & Parathyroid Surgery Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Luo
- Department of Thyroid & Breast Surgery, Affiliated Hospital Of Zunyi Medical University, Zunyi, China
| | - Qi Zhang
- Department of Thyroid & Breast Surgery, Affiliated Hospital Of Zunyi Medical University, Zunyi, China
| | - Feng Zeng
- Department of Thyroid & Breast Surgery, The Second Affiliated Hospital Of Zunyi Medical University, Zunyi, China
| | - Jie Xu
- School of Public Health, Zunyi Medical University, Zunyi, China
| | - Jingqiang Zhu
- Department of Thyroid & Parathyroid Surgery Center, West China Hospital, Sichuan University, Chengdu, China.
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Cheng L, Fu H, Jin Y, Sa R, Chen L. Clinicopathological Features Predict Outcomes in Patients with Radioiodine-Refractory Differentiated Thyroid Cancer Treated with Sorafenib: A Real-World Study. Oncologist 2020; 25:e668-e678. [PMID: 31957916 DOI: 10.1634/theoncologist.2019-0633] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 12/12/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Because beneficial response and progression-free survival (PFS) were achieved by well-designed clinical trials with tyrosine kinase inhibitors (TKIs) in patients with progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC), the overall survival (OS) and improvement of therapeutic outcomes in the real world have been anticipated. SUBJECTS, MATERIALS, AND METHODS This prospective, single-center, real-world study assessed the predictive significance of clinicopathological features on disease control rate (DCR), objective response rate (ORR), PFS, and OS in a cohort of 72 patients with progressive RR-DTC treated with sorafenib at an initial dose of 200 mg twice daily. RESULTS Disease control, objective response, and biochemical effectiveness were achieved in 73.3%, 21.7%, and 77.9% of patients, respectively. The median PFS and OS were 17.6 and 28.9 months, respectively. Multivariate analyses showed that hand-foot syndrome (HFS) was an independent predictor for better DCR and ORR, and 131 I-avidity for higher ORR. In univariate analyses, longer PFS and OS were observed in patients with Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, pathologically well DTC, lung-only metastasis, absence of bone metastasis, biochemically nonineffective response, HFS, or radiological disease control. In multivariate analyses, only well DTC and ECOG PS ≤2 remained as independent prognostic factors for more favorable PFS and OS, respectively, whereas the absence of bone metastasis and biochemically nonineffective response independently predicted superior PFS and OS. CONCLUSION This study demonstrated that clinicopathological features might play a vital role in predicting therapeutic outcomes in patients with progressive RR-DTC treated with sorafenib, warranting further optimization of candidates for TKIs. IMPLICATIONS FOR PRACTICE This prospective, single-center, real-world study was designed to investigate the significance of clinicopathological features in predicting response, progression-free survival, and overall survival in patients with progressive radioiodine-refractory differentiated thyroid cancer (DTC) treated with sorafenib. Multivariate analyses showed that hand-foot syndrome was an independent predictor for better response. Meanwhile, well DTC, Eastern Cooperative Oncology Group performance status ≤2, biochemically nonineffective response, and the absence of bone metastasis were independent prognostic factors for more favorable survival. This study demonstrated that clinicopathological features might play a vital role in predicting outcomes in sorafenib-treated patients with radioiodine-refractory DTC, warranting optimization of indications.
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Affiliation(s)
- Lin Cheng
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
| | - Hao Fu
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
| | - Yuchen Jin
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
| | - Ri Sa
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
| | - Libo Chen
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
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Fleeman N, Houten R, Bagust A, Richardson M, Beale S, Boland A, Dundar Y, Greenhalgh J, Hounsome J, Duarte R, Shenoy A. Lenvatinib and sorafenib for differentiated thyroid cancer after radioactive iodine: a systematic review and economic evaluation. Health Technol Assess 2020; 24:1-180. [PMID: 31931920 PMCID: PMC6983913 DOI: 10.3310/hta24020] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Thyroid cancer is a rare cancer, accounting for only 1% of all malignancies in England and Wales. Differentiated thyroid cancer (DTC) accounts for ≈94% of all thyroid cancers. Patients with DTC often require treatment with radioactive iodine. Treatment for DTC that is refractory to radioactive iodine [radioactive iodine-refractory DTC (RR-DTC)] is often limited to best supportive care (BSC). OBJECTIVES We aimed to assess the clinical effectiveness and cost-effectiveness of lenvatinib (Lenvima®; Eisai Ltd, Hertfordshire, UK) and sorafenib (Nexar®; Bayer HealthCare, Leverkusen, Germany) for the treatment of patients with RR-DTC. DATA SOURCES EMBASE, MEDLINE, PubMed, The Cochrane Library and EconLit were searched (date range 1999 to 10 January 2017; searched on 10 January 2017). The bibliographies of retrieved citations were also examined. REVIEW METHODS We searched for randomised controlled trials (RCTs), systematic reviews, prospective observational studies and economic evaluations of lenvatinib or sorafenib. In the absence of relevant economic evaluations, we constructed a de novo economic model to compare the cost-effectiveness of lenvatinib and sorafenib with that of BSC. RESULTS Two RCTs were identified: SELECT (Study of [E7080] LEnvatinib in 131I-refractory differentiated Cancer of the Thyroid) and DECISION (StuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine-refractory thyrOid caNcer). Lenvatinib and sorafenib were both reported to improve median progression-free survival (PFS) compared with placebo: 18.3 months (lenvatinib) vs. 3.6 months (placebo) and 10.8 months (sorafenib) vs. 5.8 months (placebo). Patient crossover was high (≥ 75%) in both trials, confounding estimates of overall survival (OS). Using OS data adjusted for crossover, trial authors reported a statistically significant improvement in OS for patients treated with lenvatinib compared with those given placebo (SELECT) but not for patients treated with sorafenib compared with those given placebo (DECISION). Both lenvatinib and sorafenib increased the incidence of adverse events (AEs), and dose reductions were required (for > 60% of patients). The results from nine prospective observational studies and 13 systematic reviews of lenvatinib or sorafenib were broadly comparable to those from the RCTs. Health-related quality-of-life (HRQoL) data were collected only in DECISION. We considered the feasibility of comparing lenvatinib with sorafenib via an indirect comparison but concluded that this would not be appropriate because of differences in trial and participant characteristics, risk profiles of the participants in the placebo arms and because the proportional hazard assumption was violated for five of the six survival outcomes available from the trials. In the base-case economic analysis, using list prices only, the cost-effectiveness comparison of lenvatinib versus BSC yields an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £65,872, and the comparison of sorafenib versus BSC yields an ICER of £85,644 per QALY gained. The deterministic sensitivity analyses show that none of the variations lowered the base-case ICERs to < £50,000 per QALY gained. LIMITATIONS We consider that it is not possible to compare the clinical effectiveness or cost-effectiveness of lenvatinib and sorafenib. CONCLUSIONS Compared with placebo/BSC, treatment with lenvatinib or sorafenib results in an improvement in PFS, objective tumour response rate and possibly OS, but dose modifications were required to treat AEs. Both treatments exhibit estimated ICERs of > £50,000 per QALY gained. Further research should include examination of the effects of lenvatinib, sorafenib and BSC (including HRQoL) for both symptomatic and asymptomatic patients, and the positioning of treatments in the treatment pathway. STUDY REGISTRATION This study is registered as PROSPERO CRD42017055516. FUNDING The National Institute for Health Research Health Technology Assessment programme.
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Affiliation(s)
- Nigel Fleeman
- Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK
| | - Rachel Houten
- Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK
| | - Adrian Bagust
- Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK
| | - Marty Richardson
- Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK
| | - Sophie Beale
- Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK
| | - Angela Boland
- Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK
| | - Yenal Dundar
- Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK
| | - Janette Greenhalgh
- Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK
| | - Juliet Hounsome
- Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK
| | - Rui Duarte
- Liverpool Reviews and Implementation Group, University of Liverpool, Liverpool, UK
| | - Aditya Shenoy
- The Clatterbridge Cancer Centre NHS Foundation Trust, Birkenhead, UK
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Schuller Y, Gispen-de Wied C, Hollak CEM, Leufkens HGM, Stoyanova-Beninska V. Dose-Finding Studies Among Orphan Drugs Approved in the EU: A Retrospective Analysis. J Clin Pharmacol 2018; 59:229-244. [PMID: 30192386 PMCID: PMC6585723 DOI: 10.1002/jcph.1304] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 07/22/2018] [Indexed: 11/21/2022]
Abstract
In the development process for new drugs, dose‐finding studies are of major importance. Absence of these studies may lead to failed phase 3 trials and delayed marketing authorization. In our study we investigated to what extent dose‐finding studies are performed in the case of orphan drugs for metabolic and oncologic indications. We identified all orphan drugs that were authorized until August 1, 2017. European Public Assessment Reports were used to extract the final dose used in the summary of product characteristics, involvement of healthy volunteers, study type, end points used, number of patients, number of doses, studies in special populations, and dose used for phase 3 studies. Each drug was checked for major objections and dose changes postmarketing. We included 49 orphan drugs, of which 28 were indicated for metabolic disorders and 21 for oncologic indications. Dose‐finding studies were performed in 32 orphan drugs, and studies in healthy volunteers in 26. The absence of dose‐finding studies was mostly due to the rarity of the disease. In this case the dose was determined based on factors such as animal studies or clinical experience. Dose‐related major objections were raised for 9 orphan drugs. Postmarketing dose‐finding studies were conducted in 18 orphan drugs, but dose changes were applied in only 2 drugs. In conclusion, dose‐finding studies in the case of metabolic and oncologic orphan drugs were conducted in the development programs of two thirds of orphan drugs. Dose‐finding studies performed postmarketing suggest that registered doses are not always optimal. It is thus important to perform more robust dose‐finding studies both pre‐ and postmarketing.
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Affiliation(s)
- Yvonne Schuller
- Department of Endocrinology and Metabolism, Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands
| | - Christine Gispen-de Wied
- College ter Beoordeling Geneesmiddelen/Medicines Evaluation Board, Graadt van Roggenweg, Utrecht, The Netherlands
| | - Carla E M Hollak
- Department of Endocrinology and Metabolism, Academic Medical Center, Meibergdreef, Amsterdam, The Netherlands
| | - Hubertus G M Leufkens
- Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg, Utrecht, The Netherlands
| | - Violeta Stoyanova-Beninska
- College ter Beoordeling Geneesmiddelen/Medicines Evaluation Board, Graadt van Roggenweg, Utrecht, The Netherlands
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Tasoulas J, Tsourouflis G, Theocharis S. Neovascularization: an attractive but tricky target in thyroid cancer. Expert Opin Ther Targets 2018; 22:799-810. [DOI: 10.1080/14728222.2018.1513494] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Jason Tasoulas
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Gerasimos Tsourouflis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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9
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Priya SR, Dravid CS, Digumarti R, Dandekar M. Targeted Therapy for Medullary Thyroid Cancer: A Review. Front Oncol 2017; 7:238. [PMID: 29057215 PMCID: PMC5635342 DOI: 10.3389/fonc.2017.00238] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Accepted: 09/19/2017] [Indexed: 12/16/2022] Open
Abstract
Medullary thyroid cancers (MTCs) constitute between 2 and 5% of all thyroid cancers. The 10-year overall survival (OS) rate of patients with localized disease is around 95% while that of patients with regional stage disease is about 75%. Only 20% of patients with distant metastases at diagnosis survive 10 years which is significantly lower than for differentiated thyroid cancers. Cases with regional metastases at presentation have high recurrence rates. Adjuvant external radiation confers local control but not improved OS. The management of residual, recurrent, or metastatic disease till a few years ago was re-surgery with local measures such as radiation. Chemotherapy was used with marginal benefit. The development of targeted therapy has brought in a major advantage in management of such patients. Two drugs—vandetanib and cabozantinib—have been approved for use in progressive or metastatic MTC. In addition, several drugs acting on other steps of the molecular pathway are being investigated with promising results. Targeted radionuclide therapy also provides an effective treatment option with good quality of life. This review covers the rationale of targeted therapy for MTC, present treatment options, drugs and methods under investigation, as well as an outline of the adverse effects and their management.
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Affiliation(s)
- S R Priya
- Head Neck Surgery, Homi Bhabha Cancer Hospital and Research Centre, Visakhapatnam, India.,Tata Memorial Centre, Mumbai, India
| | - Chandra Shekhar Dravid
- Head Neck Surgery, Homi Bhabha Cancer Hospital and Research Centre, Visakhapatnam, India.,Tata Memorial Centre, Mumbai, India
| | - Raghunadharao Digumarti
- Tata Memorial Centre, Mumbai, India.,Medical Oncology, Homi Bhabha Cancer Hospital and Research Centre, Visakhapatnam, India
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Lirov R, Worden FP, Cohen MS. The Treatment of Advanced Thyroid Cancer in the Age of Novel Targeted Therapies. Drugs 2017; 77:733-745. [PMID: 28361210 PMCID: PMC5683961 DOI: 10.1007/s40265-017-0733-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Until recently, patients with advanced thyroid cancers had limited options for systemic treatment. With the introduction of tyrosine kinase inhibitors (TKIs) as a promising new class of targeted therapies for thyroid cancer, suddenly patients with advanced disease were given new options to extend survival. Guidelines worldwide have been updated to include general indications for these newer agents, but questions remain regarding which agent(s) to select, when to begin treatment, and how long therapy should continue. Additionally, the true impact of TKIs on overall survival and quality-of-life in thyroid cancer patients needs further clarification. As familiarity with approved agents and longer-term data become available, better strategies for implementation of these targeted drugs will evolve to optimize benefit for patients living with metastatic disease.
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Affiliation(s)
- Roy Lirov
- Division of Endocrine Surgery, University of Michigan, Ann Arbor, MI, USA
- Department of Surgery, University of Michigan Hospital and Health Systems, 2920K Taubman Center, SPC 5331, 1500 East Medical Center Drive, Ann Arbor, MI, 48109-5331, USA
| | - Francis P Worden
- Division of Medical Oncology, University of Michigan, Ann Arbor, MI, USA
| | - Mark S Cohen
- Division of Endocrine Surgery, University of Michigan, Ann Arbor, MI, USA.
- Department of Surgery, University of Michigan Hospital and Health Systems, 2920K Taubman Center, SPC 5331, 1500 East Medical Center Drive, Ann Arbor, MI, 48109-5331, USA.
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11
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Mattina J, Carlisle B, Hachem Y, Fergusson D, Kimmelman J. Inefficiencies and Patient Burdens in the Development of the Targeted Cancer Drug Sorafenib: A Systematic Review. PLoS Biol 2017; 15:e2000487. [PMID: 28158308 PMCID: PMC5291369 DOI: 10.1371/journal.pbio.2000487] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 01/06/2017] [Indexed: 02/06/2023] Open
Abstract
Failure in cancer drug development exacts heavy burdens on patients and research systems. To investigate inefficiencies and burdens in targeted drug development in cancer, we conducted a systematic review of all prelicensure trials for the anticancer drug, sorafenib (Bayer/Onyx Pharmaceuticals). We searched Embase and MEDLINE databases on October 14, 2014, for prelicensure clinical trials testing sorafenib against cancers. We measured risk by serious adverse event rates, benefit by objective response rates and survival, and trial success by prespecified primary endpoint attainment with acceptable toxicity. The first two clinically useful applications of sorafenib were discovered in the first 2 efficacy trials, after five drug-related deaths (4.6% of 108 total) and 93 total patient-years of involvement (2.4% of 3,928 total). Thereafter, sorafenib was tested in 26 indications and 67 drug combinations, leading to one additional licensure. Drug developers tested 5 indications in over 5 trials each, comprising 56 drug-related deaths (51.8% of 108 total) and 1,155 patient-years (29.4% of 3,928 total) of burden in unsuccessful attempts to discover utility against these malignancies. Overall, 32 Phase II trials (26% of Phase II activity) were duplicative, lacked appropriate follow-up, or were uninformative because of accrual failure, constituting 1,773 patients (15.6% of 11,355 total) participating in prelicensure sorafenib trials. The clinical utility of sorafenib was established early in development, with low burden on patients and resources. However, these early successes were followed by rapid and exhaustive testing against various malignancies and combination regimens, leading to excess patient burden. Our evaluation of sorafenib development suggests many opportunities for reducing costs and unnecessary patient burden in cancer drug development.
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Affiliation(s)
- James Mattina
- Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, Quebec, Canada
| | - Benjamin Carlisle
- Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, Quebec, Canada
| | - Yasmina Hachem
- Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, Quebec, Canada
| | - Dean Fergusson
- Department of Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Jonathan Kimmelman
- Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, Quebec, Canada
- * E-mail:
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12
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Neoadjuvant Therapy in Differentiated Thyroid Cancer. Int J Surg Oncol 2016; 2016:3743420. [PMID: 27747102 PMCID: PMC5055971 DOI: 10.1155/2016/3743420] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Revised: 08/10/2016] [Accepted: 08/29/2016] [Indexed: 12/01/2022] Open
Abstract
Objectives. Invasion of differentiated thyroid cancer (DTC) into surrounding structures can lead to morbid procedures such as laryngectomy and tracheal resection. In these patients, there is a potential role for neoadjuvant therapy. Methods. We identified three studies involving the treatment of DTC with neoadjuvant chemotherapy: two from Slovenia and one from Japan. Results. These studies demonstrate that in selected situations, neoadjuvant chemotherapy can have a good response and allow for a more complete surgical resection, the treatment of DTC. Additionally, the SELECT trial shows that the targeted therapy lenvatinib is effective in the treatment of DTC and could be useful as neoadjuvant therapy for this disease due to its short time to response. Pazopanib has also demonstrated promise in phase II data. Conclusions. Thus, chemotherapy in the neoadjuvant setting could possibly be useful for managing advanced DTC. Additionally, some of the new tyrosine kinase inhibitors (TKIs) hold promise for use in the neoadjuvant setting in DTC.
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Bikas A, Vachhani S, Jensen K, Vasko V, Burman KD. Targeted therapies in thyroid cancer: an extensive review of the literature. Expert Rev Clin Pharmacol 2016; 9:1299-1313. [PMID: 27367142 DOI: 10.1080/17512433.2016.1204230] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Patients with progressive, metastatic, RAI-refractory differentiated thyroid cancer (DTC), as well as patients with advanced medullary (MTC) and anaplastic thyroid cancer represent a cohort for which therapeutic options are limited. The recent discoveries in the molecular mechanisms implicated in TC have provided insight of the pathogenesis and progression of disease. In that respect, targeted therapies have emerged as a promising alternative for the treatment of those patients. Areas covered: Tyrosine Kinase Inhibitors (TKIs) have been studied extensively in TC: sorafenib and lenvatinib have been approved by the FDA for the treatment of metastatic, RAI-refractory DTC, while vandetanib and cabozantinib are FDA approved for use in advanced MTC. Moreover, several additional TKIs, multi-targeted or specific, are currently under investigation in TC. The current manuscript provides an extensive review of the literature regarding targeted therapies in TC including the rationale behind their use, the clinical trials and an expert opinion on their use. Literature in English appearing at PubMed was thoroughly reviewed, especially manuscripts of the last 5 years. Expert commentary: Patients with advanced, progressive, metastatic TC should be evaluated for enrollment in a clinical trial or should be placed on treatment with one of the FDA- and EMA- approved agents.
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Affiliation(s)
- Athanasios Bikas
- a Division of Endocrinology, Department of Medicine , MedStar Washington Hospital Center , Washington , DC , USA
| | - Shivangi Vachhani
- a Division of Endocrinology, Department of Medicine , MedStar Washington Hospital Center , Washington , DC , USA
| | - Kirk Jensen
- b Department of Pediatrics , Uniformed Services University of the Health Sciences , Bethesda , MD , USA
| | - Vasyl Vasko
- b Department of Pediatrics , Uniformed Services University of the Health Sciences , Bethesda , MD , USA
| | - Kenneth D Burman
- a Division of Endocrinology, Department of Medicine , MedStar Washington Hospital Center , Washington , DC , USA
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14
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Herrick CJ, Moley JF. New systemic therapies for locally advanced and metastatic thyroid cancer. INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2016. [DOI: 10.2217/ije-2015-0002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Thyroid cancer affects one in 100 people over their lifetime. Differentiated and medullary thyroid cancer, refractory to traditional therapy, respond poorly to chemotherapeutic agents. However, tyrosine kinase inhibitors provide new hope for stabilizing disease in patients with advanced progressive disease. There are multiple tyrosine kinase inhibitors under study for thyroid cancer and currently four drugs that are US FDA approved. Nonetheless, use of these drugs should be selective given a significant adverse event profile and diseases with a typically indolent course. This review will cover molecular mechanisms in thyroid cancer as they are relevant to targeted therapies and review available evidence for the safety and efficacy of therapies currently approved and under study for thyroid cancer.
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Affiliation(s)
- Cynthia J Herrick
- Division of Endocrinology, Metabolism & Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Jeffrey F Moley
- Section of Endocrine & Oncologic Surgery, Department of Surgery, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA
- Department of Surgery, St. Louis Veterans Affairs Medical Center, St. Louis, MO, USA
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Abstract
Sorafenib is a multiple kinase inhibitor (MKI) approved for the treatment of primary advanced renal cell carcinoma and advanced primary liver cancer. It was recently approved by several health agencies around the world as the first available MKI treatment for radioactive iodine-refractory advanced and progressive differentiated thyroid cancer. Sorafenib targets C-RAF, B-RAF, VEGF receptor-1, -2, -3, PDGF receptor-β, RET, c-kit, and Flt-3. As a multifunctional inhibitor, sorafenib has the potential of inhibiting tumor growth, progression, metastasis, and angiogenesis and downregulating mechanisms that protect tumors from apoptosis and has shown to increase the progression-free survival in several Phase II trials. This led to the Phase III trial (DECISION) which showed that there was an improvement in progression-free survival of 5 months for patients on sorafenib when compared to those on placebo. Adverse events with this drug are common but usually manageable. The development of resistance after 1 or 2 years is almost a rule in most patients who showed partial response or stabilization of the disease while on sorafenib, which makes it necessary to think of a plan for subsequent therapies. These may include the use of another MKI, such as lenvatinib, the second approved MKI for advanced differentiated thyroid cancer, or include patients in clinical trials or the off-label use of other MKIs. Given sorafenib's earlier approval, most centers now have access to its prescription. The goal of this review was to improve the care of these patients by describing key aspects that all prescribers will need to master in order to optimize outcomes.
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Affiliation(s)
- Fabián Pitoia
- Division of Endocrinology, Hospital de Clinicas – University of Buenos Aires, Buenos Aires, Argentina
| | - Fernando Jerkovich
- Division of Endocrinology, Hospital de Clinicas – University of Buenos Aires, Buenos Aires, Argentina
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Chrisoulidou A, Mandanas S, Margaritidou E, Mathiopoulou L, Boudina M, Georgopoulos K, Pazaitou-Panayiotou K. Treatment compliance and severe adverse events limit the use of tyrosine kinase inhibitors in refractory thyroid cancer. Onco Targets Ther 2015; 8:2435-42. [PMID: 26366098 PMCID: PMC4562763 DOI: 10.2147/ott.s86322] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Objective The aim of the present study was to assess patient compliance with tyrosine kinase inhibitor (TKI) treatment used for refractory and progressive thyroid cancer, in addition to the efficacy and serious adverse events associated with these agents. Methods We retrospectively analyzed data from adult patients with metastatic differentiated or medullary thyroid cancer unresponsive to conventional treatment and treated with TKIs. Patients received treatment until disease progression or onset of serious adverse events, or until they expressed an intention to stop treatment. Results Twenty-four patients received TKIs. The median duration of treatment was four (range: 1–19) cycles. The most frequent adverse events were fatigue, nausea, diarrhea, hypertension, and stomatitis, and the most severe were nasal bleeding, diarrhea, heart failure, rhabdomyolysis, renal failure, QT prolongation, neutropenia, and severe fatigue. Dose reduction was required in eight patients, while five decided to terminate TKI therapy because adverse events impaired their everyday activities. During therapy, two patients showed a partial response and three showed stable disease. The lungs were the metastatic sites favoring a response to treatment. Conclusion Patient selection and meticulous pretreatment education are necessary in order to ensure adherence with TKI therapy. If adverse events appear, dose reduction or temporary treatment interruption may be offered because some adverse events resolve with continuation of treatment. In the event of serious adverse events, treatment discontinuation is necessary.
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Affiliation(s)
| | - Stylianos Mandanas
- Department of Endocrinology, Theagenio Cancer Hospital, Thessaloniki, Greece
| | | | | | - Maria Boudina
- Department of Endocrinology, Theagenio Cancer Hospital, Thessaloniki, Greece
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Gallo M, Michelon F, Castiglione A, Felicetti F, Viansone AA, Nervo A, Zichi C, Ciccone G, Piovesan A, Arvat E. Sorafenib treatment of radioiodine-refractory advanced thyroid cancer in daily clinical practice: a cohort study from a single center. Endocrine 2015; 49:726-34. [PMID: 25414068 DOI: 10.1007/s12020-014-0481-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 11/12/2014] [Indexed: 12/13/2022]
Abstract
Treatment options for recurrent or metastatic differentiated thyroid cancer (DTC) refractory to radioactive iodine (RAI) are inadequate. Multitargeted kinase inhibitors have recently shown promising results in phase 2-3 studies. This retrospective study aimed to document our clinical experience on the effects of sorafenib in the setting of daily clinical practice. Retrospective study evaluating the efficacy and safety of sorafenib in a cohort of patients consecutively treated with sorafenib at a single center. Twenty patients with advanced RAI-refractory thyroid carcinoma were enrolled (March 2011-March 2014). Patients generally started with 400 mg of sorafenib twice daily, tapering the dose in case of side effects. Radiological response and toxicity were measured during follow-up, together with safety parameters. CT scans were performed by a single experienced radiologist every 3-4 months. Five patients stopped sorafenib within 90 days due to severe toxicities. Median progression-free survival was 248 days. Five patients had a partial response (PR), achieved in all cases within 3 months, whereas 5 had stable disease (SD) at 12 months. Durable response rate (PR plus SD) for at least 6 months was 50 %, among those who received sorafenib for at least 3 months. Commonest adverse events included skin toxicity, gastrointestinal and constitutional symptoms. In our cohort of patients with advanced RAI-refractory thyroid carcinoma, sorafenib confirmed antitumor activity leading to SD or PR in the majority of cases, at the expense of clinically relevant side effects. More effective and tolerable agents are still needed in the treatment of RAI-refractory DTC.
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Affiliation(s)
- Marco Gallo
- Oncological Endocrinology Unit, Department of Medical Sciences, AOU Città della Salute e della Scienza di Torino, University of Turin, Via Genova 3, 10126, Turin, Italy,
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Ruan M, Liu M, Dong Q, Chen L. Iodide- and glucose-handling gene expression regulated by sorafenib or cabozantinib in papillary thyroid cancer. J Clin Endocrinol Metab 2015; 100:1771-9. [PMID: 25768669 DOI: 10.1210/jc.2014-3023] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT The aberrant silencing of iodide-handling genes accompanied by up-regulation of glucose metabolism presents a major challenge for radioiodine treatment of papillary thyroid cancer (PTC). OBJECTIVE This study aimed to evaluate the effect of tyrosine kinase inhibitors on iodide-handling and glucose-handling gene expression in BHP 2-7 cells harboring RET/PTC1 rearrangement. MAIN OUTCOME MEASURES In this in vitro study, the effects of sorafenib or cabozantinib on cell growth, cycles, and apoptosis were investigated by cell proliferation assay, cell cycle analysis, and Annexin V-FITC apoptosis assay, respectively. The effect of both agents on signal transduction pathways was evaluated using the Western blot. Quantitative real-time PCR, Western blot, immunofluorescence, and radioisotope uptake assays were used to assess iodide-handling and glucose-handling gene expression. RESULTS Both compounds inhibited cell proliferation in a time-dependent and dose-dependent manner and caused cell cycle arrest in the G0/G1 phase. Sorafenib blocked RET, AKT, and ERK1/2 phosphorylation, whereas cabozantinib blocked RET and AKT phosphorylation. The restoration of iodide-handling gene expression and inhibition of glucose transporter 1 and 3 expression could be induced by either drug. The robust expression of sodium/iodide symporter induced by either agent was confirmed, and (125)I uptake was correspondingly enhanced. (18)F-fluorodeoxyglucose accumulation was significantly decreased after treatment by either sorafenib or cabozantinib. CONCLUSIONS Sorafenib and cabozantinib had marked effects on cell proliferation, cell cycle arrest, and signal transduction pathways in PTC cells harboring RET/PTC1 rearrangement. Both agents could be potentially used to enhance the expression of iodide-handling genes and inhibit the expression of glucose transporter genes.
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Affiliation(s)
- Maomei Ruan
- Department of Nuclear Medicine (M.R., M.L., L.C.), Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; and Section of Cancer Stem Cells (Q.D.), Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200032, China
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Gruber JJ, Colevas AD. Differentiated thyroid cancer: focus on emerging treatments for radioactive iodine-refractory patients. Oncologist 2015; 20:113-26. [PMID: 25616432 PMCID: PMC4319630 DOI: 10.1634/theoncologist.2014-0313] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Accepted: 12/01/2014] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND 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. MATERIALS AND METHODS 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. RESULTS 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. CONCLUSION 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.
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Affiliation(s)
- Joshua J Gruber
- Stanford Cancer Center, Stanford University Medical Center, Stanford, California, USA
| | - A Dimitrios Colevas
- Stanford Cancer Center, Stanford University Medical Center, Stanford, California, USA
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Krajewska J, Handkiewicz-Junak D, Jarzab B. Sorafenib for the treatment of thyroid cancer: an updated review. Expert Opin Pharmacother 2015; 16:573-83. [PMID: 25605317 DOI: 10.1517/14656566.2015.1005601] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Sorafenib (Nexavar) is an oral multi-kinase inhibitor targeting B-type Raf kinase (BRAF) (both wild type and BRAF(V600E)), VEGFR1, VEGFR2, VEGFR3, PDGFRβ and RET (also RET/PTC) influencing both differentiated thyroid cancer (DTC) cell proliferation and angiogenesis. AREAS COVERED Encouraging results achieved in numerous Phase II trials were confirmed in a Phase III study conducted in radioiodine-refractory DTC. Sorafenib compared to placebo significantly prolongs progression-free survival, 10.8 versus 5.8 months, respectively. However, its administration resulted mainly in disease stabilization. No complete remission was obtained in any study. Beneficial effects were also demonstrated for medullary and anaplastic thyroid cancer; however further studies fulfilling evidence based medicine criteria are necessary. Its toxicity profile is convergent with other VEGFR inhibitors. The most common treatment-related side-effects involve skin toxicity (predominantly hand-foot skin reaction, different rashes and alopecia), gastrointestinal disturbances (diarrhea, abdominal pain), constitutional adverse reactions (anorexia, weight loss, fatigue) and hypertension. Although most adverse reactions are manageable, > 50% of patients required dose reduction. EXPERT OPINION Sorafenib constitutes the first line treatment option in advanced, radioiodine-refractory DTC. However, there are still no data on its efficacy in patients progressed after another tyrosine kinase inhibitor. Other applications of the drug, such as use as adjuvant therapy to 131-I treatment, requires further studies.
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Affiliation(s)
- Jolanta Krajewska
- Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Nuclear Medicine and Endocrine Oncology Department, Gliwice Branch , Gliwice , Poland + 48 32 2789301 ; +48 32 2789310 ;
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Abstract
Thyroid cancer is the most common endocrine malignancy, and its incidence is increasing. Standard therapy for most patients with localized differentiated thyroid cancer (DTC) includes surgery, radioactive iodine, and thyroid hormone replacement. A minority of thyroid cancer patients requires systemic therapy for metastatic disease. Patients with metastatic DTC do not usually benefit from traditional cytotoxic chemotherapy. In this review, we describe newly developed small-molecule tyrosine kinase inhibitors (TKIs) that are being actively tested and used in the management of advanced thyroid cancer. The use of TKIs as a form of molecular targeted therapy is evolving based on understanding of the pathways involved in DTC. Disrupting tumor vascular supply by targeting vascular endothelial growth factor receptor signaling is the most commonly used approach to treat advanced/metastatic DTC. Other mechanisms include targeting BRAF, MAPK/ERK kinase, or mammalian target of rapamycin signaling. Although TKIs appear to have superior efficacy compared to cytotoxic chemotherapy, they can cause substantial adverse effects; symptomatic management of adverse effects, dose adjustment, or cessation of therapy may be required.
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Affiliation(s)
- Sina Jasim
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, USA
| | - Levent Ozsari
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mouhammed Amir Habra
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Lindner C, Dierneder J, Pall G, Pirich C, Hoffmann M, Raderer M, Becherer A, Niederle B, Lipp R, Lind P, Gallowitsch H, Romeder F, Virgolini I. [Treatment of patients with radioiodine refractory, differentiated thyroid carcinoma. A Consensus Statement]. Nuklearmedizin 2014; 54:125-30. [PMID: 25421138 DOI: 10.3413/nukmed-0688-14-07] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 11/11/2014] [Indexed: 02/01/2023]
Abstract
There is no clear standard therapy for patients with radioactive iodine (131I)-refractory locally advanced or metastatic differentiated thyroid cancer. The therapeutic options for this indication have expanded with the recently approved multiple kinase inhibitor sorafenib. Recommendations for the definition and the management of iodine refractory patients were worked up by an interdisciplinary expert panel, consisting of endocrine surgeons, medical oncologists and nuclear medicine specialists.
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Affiliation(s)
- Christina Lindner
- Christina Lindner, MSc, Department Life Sciences, Medizinische und Pharmazeutische Biotechnologie, IMC FH Krems, E-Mail:
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McFarland DC, Misiukiewicz KJ. Sorafenib in radioactive iodine-refractory well-differentiated metastatic thyroid cancer. Onco Targets Ther 2014; 7:1291-9. [PMID: 25053887 PMCID: PMC4105272 DOI: 10.2147/ott.s49430] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Recent Phase III data presented at the American Society of Clinical Oncology (ASCO) 2013 annual conference by Brose et al led to the US Food and Drug Administration (FDA) approval of sorafenib for the treatment of well-differentiated radioactive iodine-resistant metastatic thyroid cancer. This is the second drug in 40 years to be FDA approved for this indication. Recent reviews and a meta-analysis reveal a modest ability to induce a partial remission but substantial ability to halt disease progression. Given the significant activating mutations present in thyroid cancer, many of which are inhibited by sorafenib, the next logical approach may be to combine targeted rational therapies if permitted by collective toxicity profiles. This systematic review aims to summarize the recent Phase II/III data leading to the FDA approval of sorafenib for radioactive iodine therapy differentiated thyroid cancer and highlights recent novel combination therapy trials.
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Affiliation(s)
- Daniel C McFarland
- Division of Hematology and Medical Oncology, Mount Sinai Medical Center, New York, NY, USA
| | - Krzysztof J Misiukiewicz
- Division of Hematology and Medical Oncology, New York, NY, USA
- Department of Otolaryngology, Mount Sinai Medical Center, Ruttenberg Treatment Center, New York, NY, USA
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Liu M, Shen Y, Ruan M, Li M, Chen L. Notable decrease of malignant pleural effusion after treatment with sorafenib in radioiodine-refractory follicular thyroid carcinoma. Thyroid 2014; 24:1179-83. [PMID: 24684401 DOI: 10.1089/thy.2013.0703] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Malignant pleural effusion (MPE) caused by metastatic differentiated thyroid carcinoma (DTC) is usually associated with a rapid fatal outcome and should be recognized as a grim prognostic indicator. A standard therapeutic strategy has not been established for this situation. Here, we report a radioiodine-refractory follicular thyroid carcinoma (FTC) patient in whom a notable decrease of MPE was achieved after treatment with sorafenib. PATIENT FINDINGS A 50-year-old patient underwent a total thyroidectomy and resection of recurrence for poorly differentiated FTC followed by radioiodine therapy with a negative whole body scan. One year later, dissection of the inferior lobe of the left lung was performed because two fluorodeoxyglucose-avid nodules were identified; pathological examination revealed a metastatic poorly differentiated FTC. Half a year later, he was referred to our clinic because of cough, thoracic pain, nausea, and loss of appetite. Chest computed tomography showed right lung multiple nodules, left pleural effusion, and left lung collapse with left-sided pleural thickening. We treated him with sorafenib. Clinical and radiographic assessments were performed periodically. SUMMARY Symptoms and signs improved dramatically and continuously after initiation of sorafenib treatment. A duration of more than 12 weeks of apparent reduction of pleural effusion was achieved, which was confirmed by consecutive computed tomography examinations. Despite grade 1 alopecia, no other obvious treatment-related adverse events occurred. CONCLUSIONS As a grim prognostic indicator for patients with DTC, no standard treatment recommendation for pleural effusion exists. Targeted therapy using sorafenib may be an effective therapeutic strategy in the treatment of MPE caused by FTC.
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Affiliation(s)
- Min Liu
- 1 Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai, China
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Benvenga S, Koch CA. Molecular pathways associated with aggressiveness of papillary thyroid cancer. Curr Genomics 2014; 15:162-70. [PMID: 24955023 PMCID: PMC4064555 DOI: 10.2174/1389202915999140404100958] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 02/26/2014] [Accepted: 03/03/2014] [Indexed: 02/07/2023] Open
Abstract
The most common thyroid malignancy is papillary thyroid cancer (PTC). Mortality rates from PTC mainly depend on its aggressiveness. Geno- and phenotyping of aggressive PTC has advanced our understanding of treatment failures and of potential future therapies. Unraveling molecular signaling pathways of PTC including its aggressive forms will hopefully pave the road to reduce mortality but also morbidity from this cancer. The mitogen-activated protein kinase and the phosphatidylinositol 3-kinase signaling pathway as well as the family of RAS oncogenes and BRAF as a member of the RAF protein family and the aberrant expression of microRNAs miR-221, miR-222, and miR-146b all play major roles in tumor initiation and progression of aggressive PTC. Small molecule tyrosine kinase inhibitors targeting BRAF-mediated events, vascular endothelial growth factor receptors, RET/PTC rearrangements, and other molecular targets, show promising results to improve treatment of radioiodine resistant, recurrent, and aggressive PTC.
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Affiliation(s)
- Salvatore Benvenga
- Department of Clinical & Experimental Medicine, Section of Endocrinology, University of Messina, Messina, Italy
| | - Christian A Koch
- Division of Endocrinology, University of Mississippi Medical Center, Jackson, MS, USA ; GV (Sonny) Montgomery VA Medical Center, Jackson, MS, USA
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Update on the molecular diagnosis and targeted therapy of thyroid cancer. Med Oncol 2014; 31:973. [PMID: 24788398 DOI: 10.1007/s12032-014-0973-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 04/18/2014] [Indexed: 02/07/2023]
Abstract
Thyroid cancer (TC) is the most common endocrine malignancy with steadily increasing incidence over the past few decades. Although standard strategies for the management of TC offer optimal outcomes in TC patients with favorable histological types at early stage, challenges arising from diagnosis and therapy still exist during clinical practice. A number of genetic alterations have been described in thyroid cancer, which provides an unprecedented opportunity for the identification of novel diagnostic and prognostic molecular markers as well as novel therapeutic targets. Molecular-targeted therapies, which have been investigated recently with increasing success, may prove to be a breakthrough in patients with advanced, radioiodine-refractory thyroid cancers. This review summarizes the latest progression in molecular diagnosis and targeted therapy of TC.
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Dadu R, Waguespack SG, Sherman SI, Hu MI, Busaidy NL, Jimenez C, Habra MA, Ying AK, Bassett RL, Cabanillas ME. Efficacy and tolerability of different starting doses of sorafenib in patients with differentiated thyroid cancer. Oncologist 2014; 19:477-82. [PMID: 24733667 PMCID: PMC4012968 DOI: 10.1634/theoncologist.2013-0409] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 01/28/2014] [Indexed: 12/13/2022] Open
Abstract
Sorafenib has proven efficacy in advanced differentiated thyroid cancer (DTC), but many patients must reduce the dose or discontinue treatment because of toxicity. The tolerability and efficacy of lower starting doses of sorafenib for DTC remain largely unstudied. Methods. We retrospectively examined overall survival, time to treatment failure, time to progression, discontinuation rates, and dose-reduction and interruption rates in patients with metastatic DTC treated with first-line sorafenib outside of a clinical trial. Two patient groups were compared; group 1 received the standard starting dose of 800 mg/day, and group 2 received any dose lower than 800 mg/day. Results. We included 75 adult patients, with 51 in group 1 and 24 in group 2. Mean age at diagnosis was 54 years, and 56% were male. The most common histologies included 43% papillary thyroid cancer of the conventional type, 15% papillary thyroid cancer of the follicular variant, and 15% Hürthle cell carcinoma. Time to treatment failure was 10 months (95% confidence interval [CI]: 5.6-14.3) in group 1 and 8 months (95% CI: 3.4-12.5) in group 2 (p = .56). Median overall survival was 56 months (95% CI: 30.6-81.3) in group 1 and 30 months (95% CI: 16.1-43.8) in group 2 (p = .08). Rates of discontinuation due to disease progression were 79% in group 1 and 91% in group 2, and 21% in group 1 and 9% in group 2 (p = .304) stopped treatment because of toxicity. Dose-reduction rates were 59% and 43% (p = .29), and interruption rates were 65% and 67% (p = .908) in group 1 and group 2, respectively. Conclusion. Efficacy and tolerability of sorafenib in treatment-naïve DTC patients does not appear to be negatively influenced by lower starting daily doses.
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Shen CT, Qiu ZL, Luo QY. Sorafenib in the treatment of radioiodine-refractory differentiated thyroid cancer: a meta-analysis. Endocr Relat Cancer 2014; 21:253-61. [PMID: 24302666 DOI: 10.1530/erc-13-0438] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The advent of biologically targeted agents and increased understanding of thyroid carcinogenesis have generated much interest in the development of biologically targeted therapeutic agents for thyroid cancer. Among them, sorafenib is the most commonly studied drug. The current meta-analysis was carried out to estimate the efficacy and safety of sorafenib administered in radioiodine-refractory differentiated thyroid cancer patients. An electronic search was conducted using PubMed/MEDLINE and EMBASE. Statistical analyses were carried out using either random-effects or fixed-effects models according to heterogeneity. All the statistical analyses were carried out using the Stata version 12.0 software. Seven eligible studies were identified. The final results indicated that 22% of the patients (95% CI: 15-28) achieved a partial response. Hand-foot syndrome, diarrhea, fatigue, rash, weight loss, and hypertension were the most frequently observed adverse effects (AEs) associated with sorafenib use and the incidence of these AEs (all grades) was 80% (95% CI: 68-91), 68% (95% CI: 59-77), 67% (95% CI: 57-78), 66% (95% CI: 50-82), 52%(95% CI: 33-72), and 31% (95% CI: 21-42) respectively. Sixty-two percent (95% CI: 36-89) patients required dose reductions due to toxicity of sorafenib. As far as PR and AEs are concerned, the results of this meta-analysis indicate that sorafenib has a modest effect in patients with radioiodine-refractory differentiated thyroid cancer and the high incidence of AEs associated with this agent may affect the quality of patients' lives. Though the use of sorafenib in the treatment of radioiodine-refractory differentiated thyroid cancer is considered promising by most physicians working in this field, more effective agents with less toxicity and cost are still needed.
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Affiliation(s)
- Chen-Tian Shen
- Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, People's Republic of China
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Thomas L, Lai SY, Dong W, Feng L, Dadu R, Regone RM, Cabanillas ME. Sorafenib in metastatic thyroid cancer: a systematic review. Oncologist 2014; 19:251-8. [PMID: 24563075 PMCID: PMC3958462 DOI: 10.1634/theoncologist.2013-0362] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2013] [Accepted: 11/27/2013] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Sorafenib was recently approved by the U.S. Food and Drug Administration for radioiodine-resistant metastatic differentiated thyroid cancer (DTC). In addition, two drugs (vandetanib and cabozantinib) have received U.S. Food and Drug Administration approval for use in medullary thyroid cancer (MTC). Several published phase II trials have investigated the efficacy of sorafenib in thyroid cancers, but to date, results from those studies have not been compared. METHODS A systematic review of the literature was performed to assess response rate, median progression-free survival, and adverse events associated with sorafenib therapy for metastatic thyroid cancers. RESULTS This review included seven trials involving 219 patients: 159 with DTC (papillary, follicular, and poorly differentiated), 52 with MTC, and 8 with anaplastic thyroid cancer. No study reported complete responses to treatment. Overall partial response, stable disease, and progressive disease rates were 21%, 60%, and 20%, respectively. The median progression-free survival was 18 months for patients with all subtypes of thyroid cancer. Drug was discontinued in 16% of patients because of toxicities or intolerance, and the dose was reduced in a further 56%. Side effects with an incidence ≥ 50% were hand-foot syndrome (74%), diarrhea (70%), skin rash (67%), fatigue (61%), and weight loss (57%). Deaths not related to progressive disease occurred in nearly 4% of patients. CONCLUSION Treatment with sorafenib in patients with progressive DTC and MTC is a promising strategy, but the adverse event rate is high, leading to a high rate of dose reduction or discontinuation. Consequently, sorafenib use in patients with metastatic thyroid cancer requires careful selection of patients and careful management of side effects.
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Ruan M, Shen Y, Chen L, Li M. RECIST 1.1 and serum thyroglobulin measurements in the evaluation of responses to sorafenib in patients with radioactive iodine-refractory differentiated thyroid carcinoma. Oncol Lett 2013; 6:480-486. [PMID: 24137351 PMCID: PMC3789091 DOI: 10.3892/ol.2013.1424] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Accepted: 06/02/2013] [Indexed: 12/15/2022] Open
Abstract
The present study was designed to investigate the association between response evaluation criteria in solid tumors (RECIST) 1.1 and 1.0, and to explore the utility of thyroglobulin (Tg) measurements in assessing tumor responses to sorafenib in patients with radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC). In total, 23 patients with RAI-refractory DTC were enrolled. A comparison of RECIST 1.1 and 1.0 was performed in all patients with measurable disease. Following the exclusion of patients who were positive for anti-Tg antibody, the correlation between RECIST 1.1 and Tg was investigated in patients with measurable disease, and the concordance of the change in Tg between these patients and the patients with non-measurable disease only was analyzed over time. Tumor responses, assessed by RECIST 1.1 and 1.0, were concordant in 96% of the 23 records. However, the number of target lesions, according to RECIST 1.1, was significantly lower than when using RECIST 1.0. Progressive disease (PD) was identified in one of the five patients who underwent fluorodeoxyglucose-positron emission tomography (FDG-PET)/computed tomography (CT) scanning. A correlation between the Tg levels and the sum of the diameters of the target lesions was verified, with the percentage decrease in Tg levels significantly greater than that in the radiograph, demonstrating shrinkage. Furthermore, the percentage change in Tg levels was consistent between the patients with measurable disease and the subjects with non-measurable disease only. In conclusion, in patients with RAI-refractory DTC, RECIST 1.1 is highly concordant with RECIST 1.0 in the assessment of responses to sorafenib treatment, with the advantage of simplified procedures and the complementary use of FDG-PET. Tg measurements, in concordance with RECIST 1.1, are valuable in the evaluation of tumor responses.
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Affiliation(s)
- Maomei Ruan
- Department of Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233
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Savvides P, Nagaiah G, Lavertu P, Fu P, Wright JJ, Chapman R, Wasman J, Dowlati A, Remick SC. Phase II trial of sorafenib in patients with advanced anaplastic carcinoma of the thyroid. Thyroid 2013; 23:600-4. [PMID: 23113752 PMCID: PMC3643255 DOI: 10.1089/thy.2012.0103] [Citation(s) in RCA: 160] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy with a median survival of 3-5 months. The BRAF oncogene is mutated to its active form in up to 24% of ATC cases. Sorafenib is a tyrosine kinase inhibitor that acts on the RAF-1 serine/threonine kinase. In preclinical mouse models, sorafenib inhibits the growth of ATC xenografts and improves survival. No study of sorafenib in ATC has been conducted. We conducted a multi-institutional phase II trial of sorafenib in patients with ATC who had failed up to two previous therapies. METHODS The primary endpoint of the trial was the Response Evaluation Criteria In Solid Tumors (RECIST)-defined imaging response rate. Twenty patients with ATC were treated with sorafenib 400 mg twice daily. RESULTS Two of the 20 patients had a partial response (10%) and an additional 5 of 20 (25%) had stable disease. The duration of response in the two responders was 10 and 27 months, respectively. For the patients with stable disease, the median duration was 4 months (range 3-11 months). The overall median progression-free survival was 1.9 months with a median and a 1-year survival of 3.9 months and 20%, respectively. Toxicity was manageable and as previously described for sorafenib, including hypertension and skin rash. CONCLUSION Sorafenib has activity in ATC, but at a low frequency and similar to our previous experience with fosbretabulin. One patient with a response had previously progressed on fosbretabulin. Toxicities were both predictable and manageable.
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Affiliation(s)
- Panayiotis Savvides
- Division of Hematology/Oncology, Seidman Cancer Center, University Hospitals, Cleveland, Ohio
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
| | - Govardhanan Nagaiah
- Division of Hematology/Oncology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia
| | - Pierre Lavertu
- Division of Hematology/Oncology, Seidman Cancer Center, University Hospitals, Cleveland, Ohio
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
| | - Pingfu Fu
- Division of Hematology/Oncology, Seidman Cancer Center, University Hospitals, Cleveland, Ohio
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
| | - John J. Wright
- Cancer Therapy and Evaluation Program, National Cancer Institute, Bethesda, Maryland
| | - Robert Chapman
- Division of Hematology/Oncology, Henry Ford Hospital Health System, Detroit, Michigan
| | - Jay Wasman
- Division of Hematology/Oncology, Seidman Cancer Center, University Hospitals, Cleveland, Ohio
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
| | - Afshin Dowlati
- Division of Hematology/Oncology, Seidman Cancer Center, University Hospitals, Cleveland, Ohio
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
| | - Scot C. Remick
- Division of Hematology/Oncology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia
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Anderson RT, Linnehan JE, Tongbram V, Keating K, Wirth LJ. Clinical, safety, and economic evidence in radioactive iodine-refractory differentiated thyroid cancer: a systematic literature review. Thyroid 2013; 23:392-407. [PMID: 23294230 DOI: 10.1089/thy.2012.0520] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND Thyroid cancer is the most common endocrine malignancy, with differentiated thyroid cancer (DTC) comprising ~93% of all thyroid cancers. While most cases of DTC are curable with the use of surgery and radioactive iodine (RAI) ablation of the remaining thyroid remnant, prognosis is dire and treatment options limited when DTC becomes RAI-refractory (RAI-R). Standard cytotoxic chemotherapy has limited efficacy, making enrollment in clinical trials of novel targeted therapies the preferred treatment approach. Thus, we conducted a comprehensive systematic review of the clinical trial scientific literature with a focus on efficacy, safety, and economics to identify all potential treatment options that have been or are currently being evaluated for the treatment of RAI-R DTC. METHODS Embase.com (including Medline), Medline In-Process and other nonindexed citations, the Cochrane Libraries, ClinicalTrials.gov, and relevant recent conference proceedings were searched using predefined search criteria. Important inclusion criteria included English language, randomized controlled studies or interventional single-arm studies only, and studies of drug therapies only. Search results were screened utilizing the discretion of multiple researchers, and key data were abstracted. RESULTS Forty-five unique trials (16 full-text, 4 conference abstracts, and 25 ClinicalTrials.gov entries) were included in the clinical review. No studies that met criteria for inclusion in the economic review were identified. Among 20 trials with results available, all were Phase II and only one was randomized. The most commonly studied drugs were tyrosine kinase inhibitors (TKIs); other drugs included celecoxib, doxorubicin with interferon alpha-2b, rosiglitazone, selumetinib (AZD6244), thalidomide, VEGF trap, and vorinostat. Overall, efficacy and safety profiles were specific to treatment regimen, with objective response rates (ORR) ranging from 0% on gefitinib, rosiglitazone, VEGF trap, and vorinostat to 50% on lenvatinib, a TKI. CONCLUSIONS Limited clinical research and no economic research has been conducted in RAI-R DTC. Certain treatments, notably TKIs, have shown promise in Phase II trials, and two Phase III randomized placebo-controlled trials are ongoing. New research on the economic and humanistic burden of RAI-R DTC must be paired with the clinical evidence currently in development to examine the existing burden and future promise in treating patients with RAI-R DTC.
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Affiliation(s)
- Roger T Anderson
- Department of Public Health Sciences, Penn State College of Medicine, Pennsylvania State University, Hershey, Pennsylvania, USA
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Zygulska AL, Krzemieniecki K, Sowa-Staszczak A. The Use of Sorafenib in the Thyroid Cancer. EUROPEAN ENDOCRINOLOGY 2013; 9:28-31. [PMID: 30349607 DOI: 10.17925/ee.2013.09.01.28] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Accepted: 01/27/2013] [Indexed: 12/18/2022]
Abstract
There are not effective therapies for metastatic unresectable, non-RAI-avid thyroid carcinomas. Fortunately, thyroid carcinomas represent a promising paradigm for targeted therapy due to the presence of activing mutations of genes coding the kinase tyrosines which are involved in all functions of cancer cells (such as: growth or invasion). In this paper an efficacy and toxicity of sorafenib, one of the multi-kinase inhibitors in thyroid carcinomas treatment is presented.
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Affiliation(s)
- Aneta L Zygulska
- Senior Lecturer, Endocrinological Department, University Hospital, Cracow, Poland
| | | | - Anna Sowa-Staszczak
- Associate Professor, Endocrinological Department, University Hospital, Cracow, Poland
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35
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New molecular targeted therapy and redifferentiation therapy for radioiodine-refractory advanced papillary thyroid carcinoma: literature review. J Thyroid Res 2012; 2012:818204. [PMID: 23320248 PMCID: PMC3540819 DOI: 10.1155/2012/818204] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Accepted: 12/03/2012] [Indexed: 01/26/2023] Open
Abstract
Although the majority of papillary thyroid carcinoma could be successfully managed by complete surgical resection alone or resection followed by radioiodine ablation, a small proportion of patients may develop radioiodine-refractory progressive disease which is not amenable to surgery, local ablative treatment or other treatment modalities. The use of FDG-PET/CT scan for persistent/recurrent disease has improved the accuracy of restaging as well as cancer prognostication. Given that patients with RAI-refractory disease tend to do significantly worse than those with radioiodine-avid or non-progressive disease, an increasing number of phase I and II studies have been conducted to evaluate the efficacy of new molecular targeted drugs such as the tyrosine kinase inhibitors and redifferentiation drugs. The overall response rate of these drugs ranged between 0–53%, depending on whether the patients had been previously treated with these drugs, performance status and extent of disease. However, drug toxicity remains a major concern in administration of target therapies. Nevertheless, there are also ongoing phase III studies evaluating the efficacy of these new drugs. The aim of the review was to summarize and discuss the results of these targeted drugs and redifferentiation agents for patients with progressive, radioiodine-refractory papillary thyroid carcinoma.
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Shen Y, Ruan M, Luo Q, Yu Y, Lu H, Zhu R, Chen L. Brain metastasis from follicular thyroid carcinoma: treatment with sorafenib. Thyroid 2012; 22:856-60. [PMID: 22793259 DOI: 10.1089/thy.2011.0419] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Sorafenib has shown promise in the treatment of patients with advanced or metastatic thyroid carcinoma. However, its therapeutic effect has not been assessed in patients with brain metastases from follicular thyroid carcinoma (FTC). Here, we report a patient in whom this treatment was employed with a relatively favorable response. PATIENT AND METHODS A 56-year-old woman had a thyroidectomy 8 years previously for FTC. She subsequently developed lung metastases, for which she received seven courses of radioiodine ((131)I) therapy. She developed right hemiplegia and other symptoms and was found to have a ≈ 5-cm lesion in the left parietal lobe. Radiosurgery with a total dose of 28 Gy (7 Gy/day, for 4 days) to treat her brain metastatic lesion was ineffective, and she was referred to us. We treated her with sorafenib, 200 mg orally, on a twice-daily basis. The effect of this intervention was assessed clinically and radiographically using Response Evaluation Criteria in Solid Tumors (RECIST). SUMMARY Symptoms and signs improved dramatically and continuously after initiation of sorafenib treatment. Partial response (PR) in the brain metastasis and stable disease (SD) in lung metastatic lesions were verified by consecutive imaging findings for more than one year. Despite alopecia, other treatment-related adverse events did not occur. CONCLUSIONS Targeted therapy such as with sorafenib could be an effective alternative therapeutic strategy in the treatment of progressive brain metastasis from differentiated thyroid carcinoma (DTC) when surgery, external beam radiation, and (131)I are not suitable or give poor outcomes. A paradigm of sustained low dose of sorafenib (200 mg,twice a day) may be well-tolerated without compromising maintenance of the therapeutic effect.
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Affiliation(s)
- Yan Shen
- Department of Radiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
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Aziz K, Nowsheen S, Pantelias G, Iliakis G, Gorgoulis VG, Georgakilas AG. Targeting DNA damage and repair: embracing the pharmacological era for successful cancer therapy. Pharmacol Ther 2011; 133:334-50. [PMID: 22197993 DOI: 10.1016/j.pharmthera.2011.11.010] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Accepted: 11/30/2011] [Indexed: 12/19/2022]
Abstract
DNA is under constant assault from genotoxic agents which creates different kinds of DNA damage. The precise replication of the genome and the continuous surveillance of its integrity are critical for survival and the avoidance of carcinogenesis. Cells have evolved an arsenal of repair pathways and cell cycle checkpoints to detect and repair DNA damage. When repair fails, typically cell cycle progression is halted and apoptosis is initiated. Here, we review the different sources and types of DNA damage including DNA replication stress and oxidative stress, the repair pathways that cells utilize to repair damaged DNA, and discuss their biological significance, especially with reference to cancer induction and cancer therapy. We also describe the main methodologies currently used for the detection of DNA damage with their strengths and limitations. We conclude with an outline as to how this information can be used to identify novel pharmacological targets for DNA repair pathways or enhancers of DNA damage to develop improved treatment strategies that will benefit cancer patients.
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Affiliation(s)
- K Aziz
- Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA
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Paeng JC, Kang KW, Park DJ, Oh SW, Chung JK. Alternative medical treatment for radioiodine-refractory thyroid cancers. Nucl Med Mol Imaging 2011; 45:241-7. [PMID: 24900013 DOI: 10.1007/s13139-011-0107-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2011] [Revised: 08/22/2011] [Accepted: 08/23/2011] [Indexed: 11/26/2022] Open
Abstract
Thyroid cancer is one of the most rapidly increasing cancers in many countries. Although most thyroid cancers are differentiated cancers and easily treated with radioiodine (RI), a portion of differentiated and undifferentiated cancers is refractory not only to RI therapy, but also to radiotherapy and chemotherapy. Thus, various alternative therapies have been tested in RI-refractory thyroid cancers. These alternative therapies include two major categories: redifferentiation therapy and recent molecular target therapy. Several clinical trials have investigated these therapies. They demonstrated potential effects of the therapies, although the results have been somewhat limited so far. Thus, the future strategy for undifferentiated thyroid cancers will involve individualized, lesion-specific, and combined therapy. In this review, the basic mechanism of each redifferentiation and molecular target therapy is discussed, and results of recent clinical trials using these therapeutic agents are summarized.
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Affiliation(s)
- Jin Chul Paeng
- Department of Nuclear Medicine, Seoul National University College of Medicine, 101 Daehak-ro 101, Jongno-gu Seoul, 110-744 Korea ; Thyroid Center, Seoul National University Cancer Hospital, Seoul, Korea
| | - Keon Wook Kang
- Department of Nuclear Medicine, Seoul National University College of Medicine, 101 Daehak-ro 101, Jongno-gu Seoul, 110-744 Korea ; Thyroid Center, Seoul National University Cancer Hospital, Seoul, Korea
| | - Do Joon Park
- Thyroid Center, Seoul National University Cancer Hospital, Seoul, Korea ; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - So Won Oh
- Department of Nuclear Medicine, Seoul National University College of Medicine, 101 Daehak-ro 101, Jongno-gu Seoul, 110-744 Korea ; Department of Nuclear Medicine, Seoul National University Boramae Medical Center, Seoul, Korea
| | - June-Key Chung
- Department of Nuclear Medicine, Seoul National University College of Medicine, 101 Daehak-ro 101, Jongno-gu Seoul, 110-744 Korea ; Thyroid Center, Seoul National University Cancer Hospital, Seoul, Korea
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Walsh S, Prichard R, Hill ADK. Emerging therapies for thyroid carcinoma. Surgeon 2011; 10:53-8. [PMID: 22233555 DOI: 10.1016/j.surge.2011.08.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2011] [Revised: 08/01/2011] [Accepted: 08/17/2011] [Indexed: 11/29/2022]
Abstract
Thyroid carcinoma is the most commonly diagnosed endocrine malignancy. Its incidence is currently rising worldwide. The discovery of genetic mutations associated with the development of thyroid cancer, such as BRAF and RET, has lead to the development of new drugs which target the pathways which they influence. Despite recent advances, the prognosis of anaplastic thyroid carcinoma is still unfavourable. In this review we look at emerging novel therapies for the treatment of well-differentiated and medullary thyroid carcinoma, and advances and future directions in the management of anaplastic thyroid carcinoma.
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Affiliation(s)
- S Walsh
- Department of Surgery, RCSI Smurfitt Building, Beaumont Hospital, Dublin 9, Ireland.
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