Radioiodine-refractory DTC

Transcription

1 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

2 Rate per 100,000 Thyroid Cancer Incidence Thyroid ( ) All cancer sites ( ) Years of Diagnosis G. Costante

3 Thyroid Cancer Incidence Screening Ahn, 2014 G. Costante

4 Epidemiology Stage specific trend ( ) Enewold, 2009 G. Costante

5 Thyroid Cancer Incidence Ahn, 2014 Screening G. Costante

6 Treatement Total Thyroidectomy 131 I Ablation Suppressive Therapy

7 Epidemiology Stage at Diagnosis SEER summary stage Intrathyroidal Regional metastases Distant metastases Unknown 5% High Risk Patients G. Costante

8 Long Term Outcome High Risk Patients Jonklaas, 2006 G. Costante

9 N. Cases Differentiated Thyroid Cancer Long Term Outcome High Risk Patients 25 Disease free Persistence Durante, Diagnosis End follow up G. Costante

10 Distant Metastases Long Term survival Jonklaas, 2006 G. Costante

11 Survival Differentiated Thyroid Cancer Distant Metastases 131 I-Treatment pts pts 127 pts 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

12 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

13 N. Cases Differentiated Thyroid Cancer Response to Chemotherapy 40 Complete Response Progression No Response Shimaoka, 1985 Doxo Doxo+CisPl

14 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.

15 Thyroid Cancer Tumorigenesis Molecular Events Giordano, 2014 G. Costante

16 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:

17 Targeted Therapies Approved Drugs for clinical use Sorafenib Lenvatinib FDA 2013 FDA 2015 EMA 2014 EMA 2015

18 Targeted Therapies Outline Efficacy Safety Eligible patients

19 Sorafenib Decision Study Brose, 2014

20 Lenvatinib Schlumberger, 2015

21 Targeted Therapies Outline Efficacy Safety Eligible patients

22 Sorafenib Adverse events Worden, 2015

23 Lenvatinib Adverse events Schlumberger, 2015

24 Targeted Therapies Adverse events Accurate patient selection Close monitoring

25 Targeted Therapies Outline Efficacy Safety Eligible patients

26 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

27 18 FDG-PET scan vs survival Wang, 2000

28 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

29 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

30 131 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

31 Male, 46 yrs Insular Thyroid Carcinoma April 2013 December 2013 Thyroidectomy I dose 222 mci I dose 219 mci pt3n1m1 August I dose mci Stimulated Tg=1049 Stimulated Tg=436 Stimulated Tg=1058 Denosumab G. Costante

32 Male, 46 yrs Insular Thyroid Carcinoma March 2015 June 2015 pt3n1m1 131 I mci 131 I cumulative dose mci Stimulated Tg= I 131 I 131 I 131 I Basal Thyroglobulin G. Costante

33 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

34 Targeted Therapies Initiation of systemic treatment Tumor burden Progression (RECIST) Small (no Target RECIST) Large >1-2 cm > months No? High SUV < months No YES Schlumberger, 2014

35 Male, 46 yrs Insular Thyroid Carcinoma March I mci June I cumulative dose mci pt3n1m1 June I 800 Stimulated Tg= I 131 I 131 I Basal Thyroglobulin G. Costante

36 Male, 46 yrs Insular Thyroid Carcinoma July 2015 December Basal Thyroglobulin G. Costante

37 Basal Thyroglobulin Male, 46 yrs Insular Thyroid Carcinoma Start Sorafenib Months G. Costante

38 Treatment with MKIs When to withdraw? At structural progression after the nadir (RECIST +20%)? More pronounced progression? No general consensus G. Costante

39 G. Costante

40 Withdrawal of MKIs What to do next? Second line treatment» Lenvatinib

41 Male, 46 yrs Insular Thyroid Carcinoma Sorafenib Start Lenvatinib Basal Thyroglobulin G. Costante

42 Withdrawal of MKIs What to do next? Clinical protocols» New drugs Nintedanib Immunotherapy» Sequential treatment» Association of drugs UPCC 19309»Redifferentiation

43 Retinoic Acid Redifferentiation Prof. Pierre Bourgeois Schmultzer 2000 G. Costante

44 Selumetinib Redifferentiation DTC refractory N= I / rhtsh Selumetinib 4 weeks 124-I / rhtsh 131- I Ho, 2013

45 Ho, 2013 Differentiated Thyroid Cancer Redifferentiation