Oncology: Radioiodine-refractory DTC New Developments in Giuseppe COSTANTE, MD, Head, Endocrinology Clinic Institut Jules Bordet Université Libre de Bruxelles (U.L.B.) Targeted Therapies Targeted Treatments
Rate per 100,000 Thyroid Cancer Incidence Thyroid (1975-2008) http://seer.cancer.gov/cgi-bin/csr/1975_2008 All cancer sites (1988-2008) Years of Diagnosis G. Costante
Thyroid Cancer Incidence Screening Ahn, 2014 G. Costante
Epidemiology Stage specific trend (1975-2008) Enewold, 2009 G. Costante
Thyroid Cancer Incidence Ahn, 2014 Screening G. Costante
Treatement Total Thyroidectomy 131 I Ablation Suppressive Therapy
Epidemiology Stage at Diagnosis SEER summary stage 2000-2007 Intrathyroidal Regional metastases Distant metastases Unknown 5% High Risk Patients G. Costante
Long Term Outcome High Risk Patients Jonklaas, 2006 G. Costante
N. Cases Differentiated Thyroid Cancer Long Term Outcome High Risk Patients 25 Disease free Persistence 20 15 10 Durante, 2013 5 0 Diagnosis End follow up G. Costante
Distant Metastases Long Term survival Jonklaas, 2006 G. Costante
Survival Differentiated Thyroid Cancer Distant Metastases 131 I-Treatment 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 1 168 pts 3 2 149 pts 127 pts 0.0 0 5 10 15 20 25 30 35 40 Years after metastasis discovery G. Costante Survival & 131 I avidity Group 1: 131 I-avid lesions remission Group 2: no/low 131 I uptake persistent disease Group 3: 131 I-avid lesions persistent disease Durante, 2006
RAI refractory disease Index lesion that did not take up 131 I on a RAI scan RAI-avid index lesion that do not respond to RAI treatment within 6-12 months issue of lesion dosimetry Cumulative treatment > 600 mci G. Costante
N. Cases Differentiated Thyroid Cancer Response to Chemotherapy 40 Complete Response Progression No Response 30 20 10 0 Shimaoka, 1985 Doxo Doxo+CisPl
Thyroid Cancer Tumorigenesis Intracellular Signalling Pathways PTC RET/PTC C-MET FTC EGFR VEGF-A 165 Endothelial cell VEGFR-2 Ras Ras B-Raf PI3K Raf PI3K MEK AKT MEK AKT ERK mtor ERK mtor S6K S6K Growth Survival Proliferation HIF1a Inhibition of apoptosis Migration Growth Survival Proliferation Migration Angiogenesis Keefe et al. Clin Cancer Res 2010;16:778.
Thyroid Cancer Tumorigenesis Molecular Events Giordano, 2014 G. Costante
Thyroid Cancer Tumorigenesis Targeting Cell Signalling Pathways Tumor Cell Endothelial Cell Axitinib Motesanib Sorafenib Sunitinib Vandetanib XL184 Pazopanib Lenvatinib RET/PTC Sorafenib Selumetinib Ras B-Raf MEK ERK Growth Survival Proliferation PI3K AKT mtor S6K EGFR Vandetanib Sorafenib Selumetinib Everolimus Sirolimus Pasireotide HIF1a Inhibition of apoptosis Migration Raf MEK ERK Ras Growth Survival Proliferation VEGFR-2 PI3K AKT mtor S6K Migration Angiogenesis Axitinib Motesanib Sorafenib Sunitinib Vandetanib XL184 Pazopanib Lenvatinib Everolimus Sirolimus Pasireotide Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:778-83.
Targeted Therapies Approved Drugs for clinical use Sorafenib Lenvatinib FDA 2013 FDA 2015 EMA 2014 EMA 2015
Targeted Therapies Outline Efficacy Safety Eligible patients
Sorafenib Decision Study Brose, 2014
Lenvatinib Schlumberger, 2015
Targeted Therapies Outline Efficacy Safety Eligible patients
Sorafenib Adverse events Worden, 2015
Lenvatinib Adverse events Schlumberger, 2015
Targeted Therapies Adverse events Accurate patient selection Close monitoring
Targeted Therapies Outline Efficacy Safety Eligible patients
RAI refractory disease Differentiated Thyroid Cancer Index lesion that did not take up 131 I on a RAI scan RAI-avid index lesion that do not respond to RAI treatment within 6-12 months issue of lesion dosimetry Cumulative treatment > 600 mci Others? G. Costante
18 FDG-PET scan vs survival Wang, 2000
18-FDG-PET scan vs RAI response Survival at 60 months RAI + FDG - 95% RAI + FDG + 45% RAI - FDG + 45% RAI: radioactive iodine FDG: [ 18 F]fluoro-2-deoxy-D-glucose Robbins, 2006
RAI refractory disease Differentiated Thyroid Cancer Index lesion that did not take up 131 I on a RAI scan RAI-avid index lesion that do not respond to RAI treatment within 6-12 months issue of lesion dosimetry Cumulative treatment > 600 mci Avid Others? 18 FDG lesions G. Costante
131 I-Refractory Management Strategy Close monitoring of disease extension Consider focal treatment modalities for tumor foci at high risk for complications» Cementoplasty» Stereotactic RT» Thermal ablation General strategy planned as early as possible
Male, 46 yrs Insular Thyroid Carcinoma April 2013 December 2013 Thyroidectomy 131 131 I dose 222 mci I dose 219 mci pt3n1m1 August 2014 131 I dose 217.3 mci Stimulated Tg=1049 Stimulated Tg=436 Stimulated Tg=1058 Denosumab G. Costante
Male, 46 yrs Insular Thyroid Carcinoma March 2015 June 2015 pt3n1m1 131 I 218.4 mci 131 I cumulative dose 877.7 mci Stimulated Tg=1423 1200 1000 800 600 400 131 I 131 I 131 I 131 I 200 0 0 200 400 600 800 Basal Thyroglobulin G. Costante
Eligible Patients for New Drugs American Thyroid Association guidelines, Thyroid 2015 Recommendation 96 Kinase inhibitor therapy should be considered in RAI-refractory DTC patients with metastatic, rapidly progressive, symptomatic and/or imminently threatening disease not otherwise amenable to local control using other approaches.the impact of these agents on overall survival and quality of life remains to be defined. (Weak recommendation, Moderate-quality evidence) G. Costante
Targeted Therapies Initiation of systemic treatment Tumor burden Progression (RECIST) Small (no Target RECIST) Large >1-2 cm > 12-14 months No? High SUV < 12-14 months No YES Schlumberger, 2014
Male, 46 yrs Insular Thyroid Carcinoma March 2015 131 I 218.4 mci June 2015 131 I cumulative dose 877.7 mci pt3n1m1 June 2015 1200 1000 131 I 800 Stimulated Tg=1423 600 400 200 131 I 131 I 131 I 0 0 200 400 600 800 Basal Thyroglobulin G. Costante
Male, 46 yrs Insular Thyroid Carcinoma 25000 20000 15000 10000 5000 July 2015 December 2015 0 0 500 1000 Basal Thyroglobulin G. Costante
Basal Thyroglobulin Male, 46 yrs Insular Thyroid Carcinoma Start Sorafenib 50000 40000 30000 20000 10000 0 0 2 4 6 8 Months G. Costante
Treatment with MKIs When to withdraw? At structural progression after the nadir (RECIST +20%)? More pronounced progression? No general consensus G. Costante
G. Costante
Withdrawal of MKIs What to do next? Second line treatment» Lenvatinib
Male, 46 yrs Insular Thyroid Carcinoma Sorafenib Start Lenvatinib 50000 40000 30000 20000 10000 0 0 5 10 15 20 Basal Thyroglobulin G. Costante
Withdrawal of MKIs What to do next? Clinical protocols» New drugs Nintedanib Immunotherapy» Sequential treatment» Association of drugs UPCC 19309»Redifferentiation
Retinoic Acid Redifferentiation Prof. Pierre Bourgeois Schmultzer 2000 G. Costante
Selumetinib Redifferentiation DTC refractory N=20 124-I / rhtsh Selumetinib 4 weeks 124-I / rhtsh 131- I Ho, 2013
Ho, 2013 Differentiated Thyroid Cancer Redifferentiation