tumores de la glándula tiroides - … · tumores de la glándula tiroides dr. julio lambea...

Tumores de la glándula tiroides

Dr. Julio Lambea Sorrosal

Servicio de Oncología Médica

Hospital Clínico Lozano Blesa de Zaragoza

Profesor Asociado de la Universidad de Zaragoza

Thyroid Cancer: Clinical Pathology

American Cancer Society.

www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_is_thyroid_cancer_43.asp. Carling

T and Uldesman R. Cancer of the Endocrine System.: Section 2: Thyroid Cancer. Principles

of Clinical Oncology. 7th edition. Lippincott Williams and Wilkins. 2005.

Parafollicular cells

Follicular cells Differentiated

Anaplastic

Medullary

Papillary

Follicular

Hurtle Cell

Sporadic

Familial

Thyroid Cancer: Risk Factors

Female sex

– 3 times more common in women than in men

Diet low in iodine

– Higher incidence of follicular thyroid cancer

Exposure to radiation

Hereditary

– About 20% of medullary thyroid cancers due to either familial medullary thryoid carcinoma (FMTC) or multiple endocrine neoplasia type 2 (MEN2)

– Inherited genetic conditions such as Gardner syndrome, Cowden disease, and familial adenomatous polyposis

American Cancer Society Web site.

www.cancer.org/docroot/CRI/content/CRI_2_4_2X_What_are_the_risk_factors_for_thyroid_cancer_43.asp

Radiación

• Chernobyl 26 abril 1986

• Niños <1 año 10 veces más riesgo

• Tumores más agresivos • Mutaciones RET-PTC

• Aumento de 74 veces la incidencia • 1990 100 casos/año

• 2000 1800 casos

Williams E. J Surg Oncol 2006; 94-670-677

Robbins J. Rev Endocr Metabol Dis 2000; 1: 197-203

Initial Disease Stage Predicts Overall Survival

Jonklaas J et al. Thyroid. 2006;16:1229-1242. Presented at ASCO Annual Meeting; May 29-June 2, 2009; Orlando, FL.

Years

Su

rviv

al

(%)

0 2 4 6

0

40

60

80

100

8 10 12 14

20

P<.001

Stage I

Stage II

Stage III

Stage IV

75%

of all tumors

25%

of all tumors

Thyroid Cancer: Treatment Strategy

High Risk: (Age >45, male, metastasis, extrathyroidal

extension, >4cm)

– Total Thyroidectomy and lymphadenectomy.

– RAI (131I) Ablation

– TSH Suppression Therapy with Thyroid Hormone

– Follow Serial Thyroglobulin Levels (Tg)

– XRT for recurrent local disease/positive margins

– Surveillance: NeckUS, Tg, Neck MRI, Chest CT, RAI Whole body scan, FDG-PET

TSH Suppression Improves Survival for metastasic DTC

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18

Su

rviv

al, %

Years

All > 45 yr

TSH suppressed 15 yr 10 yr

TSH unsuppressed 11 yr 6 yr

p < 0.01 p < 0.005

Median n = 450

Jonklaas et al. Thyroid. 2006;16:1299-1242.

Su

rviv

al (%

)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Years after the discovery of metastases

0 5 10 15 20 25 30 35 40

1

2

3

127 patients

4 cancer related

deaths

168 patients

149 patients

Survival and Response to Treatment with I131

Group 1: initial 131I uptake

and CR

– Age < 40 years

– Well-differentiated cancer

– Small size of metastases

Group 2: initial 131I uptake

and persistent disease

Group 3: no initial 131I uptake

Durante et al. J Clin Endocrinol Metab. 2006;91:2892-2899.

DOXORRUBICINA

Radioactive-iodine (RAI)-refractory

differentiated thyroid cancer (DTC)

It is estimated that in the USA in 2013 there will be:

– >60 000 new cases of thyroid cancer, and

– 1850 deaths due to thyroid cancer

In approximately 5–15% of patients with thyroid cancer, the disease

becomes refractory to RAI2,3

Median survival for patients with RAI-refractory DTC and distant

metastases is estimated to be 2.5–3.5 years.

Patients often suffer multiple complications associated with disease

progression

There is no standard therapy for patients with RAI-refractory DTC

1. Howlader N et al. SEER Cancer Statistics Review; http://seer.cancer.gov/statfacts/html/thyro.html; 2. Xing M et al. Lancet 2013; 381:1058–69; 3. Pacini F et al. Expert Rev Endocrinol Metab 2012;7:541–54; 4. Durante C et al. J Clin Endocrinol Metab 2006;91:2892–99. 5. Robbins RJ et al. J Clin Endocrinol Metab 2006;91:498–505.

BIOLOGÍA MOLECULAR DEL

CÁNCER DE TIROIDES

DIFERENCIADO

Papel de la vía RAS-RAF-MEK

• Las alteraciones genéticas de esta vía son la anomalía

genético / molecular más frecuente en los pacientes con

cáncer diferenciado de tiroides.

• BRAF es un regulador de la diferenciación tiroidea y de la

capacidad proliferativa in vitro de los modelos celulares

tiroideos benignos.

• BRAF pertenece a la familia RAF de serina/treonina kinasas

intracelulares. La mutación activadora en el codón V600E del

gen que codifica BRAF se ha observado en hasta el 70% de

los cánceres papilares de tiroides.

• La mutación en RAF favorece la resistencia al Iodo radiactivo

por lo que conlleva peor pronóstico. (menor avidez por él).

Nucleus

Ras

Célula endotelial o pericito Célula tumoral

KIT/Flt-3/RET

Raf

VEGFR/PDGFR

Ras

MEK

ERK

Raf

Nucleus

ERK

MEK

Sorafenib

PLC PI3K

Papel de la vía RAS-RAF-MEK

• Mutaciones puntuales en el gen que codifica para la

oncoproteína RAS son menos frecuentes en CDTs; un

15%

• Son más frecuentes en las histologías menos

diferenciadas.

• Conllevan una activación anómala de la proteina cinasa

activada mitogénica (MAPK) y de la ruta paralela

alternativa de PI3K/AKT/mTOR.

El gen RET

• RET, un receptor tirosina kinasa , está activado en

cáncer papilar de tiroides y activa la vía RAS-RAF-MEK

y otras cascadas de señalización.

• El reordenamiento cromosómico anómalo de los

protooncogenes RET (rearranged during transfection) y

PTC (carcinoma papilar de tiroides) origina el oncogén

de fusión RET/PTC: papel hasta en el 30% de CDT. (es

un 95% de los reordenamientos de RET).

• Alteración muy frecuente en tumor tiroideo en edad

infantil y en tumores tiroideos radioinducidos.

El gen RET

Otros reordenamientos genéticos.

• Existen otros reordenamientos: gen del factor de

transcripción de la paired-box 8 (PAX8) y gen del

receptor-γ-activado por el proliferador del peroxisoma

(PPARγ), formando el reordenamiento PAX8/PPARγ

que se da hasta en un 35% de cánceres foliculares de

tiroides.

Otras alteraciones moleculares

• La activación y regulación de la cascada de

señalización intracelular de PI3K/AKT/mTOR mediante

la pérdida de expresión de la fosfatasa supresora de

tumores PTEN.

• Mutaciones del gen PI3CA que codifica para la proteina

PI3K (cinasa del fosfatidil-inositol-tri-fosfato) que es un

gatillo iniciador de esta vía.

• Amplificación del gen c-MET hasta en 80% de ca.

papilares (factor de crecimiento hepatocitario). Este

receptor coopera con el VGFR.

ANGIOGÉNESIS

• VEGFR 1,2,3.

• FGFR

• PDGFR.

• Su sobreexpresión se correlaciona con mayor número

de metástasis, de recurrencia y SLP más corta.

• Además se asocian a mutaciones BRAF.

RESUMEN

• Mutaciones en BRAF,RAS y reordenamientos de RET

están implicados en más del 70% de los CDT.

• PAPILAR: RAF 45%

RAS 15%

RET/PTC 20%

C-MET 80%

• FOLICULAR: RAS 45%

PAX8/PPARγ 20%

PI3K/Akt 80%

DIANAS TERAPEUTICAS

Active drugs in thyroid cancer

Sorafenib

Advanced Refractory Thyroid

Cancer Phase II Clinical Trials

ENSAYOS FASE II SORAFENIB

ESTUDIO N

TIPOS HISTOLÓGICOS

N (%)

RESPUESTA

(%)

PFS (m)

DIF INDIF MED

RP

SD

PD

Gupta –

Abramson

2008

30 27 2 1 23 53 24 20m

Kloos

2009 56 52 4 0 15 56 29 15m CPT

Ahmed 34 ND ND ND 20 48 32 12 m

Hoftizjer 31 ND ND ND 24 34 42 14 m

Gupta-Abramson V. et al. J Clin Oncol; 26:4714-4719 2008

Kloos RT et al.. J Clin Oncol, 27, No 10 , 2009: 1675-1684.

Ahmed M., et al. Eur J Endocriol. 2011165:315-22

Hoftizjer H, et al. Eur J Endocriol. 209: 161:923-31

Capdevila et al ASCO 2010 #5590

Capdevila 24 16 ND ND 19 50 31 13.5 m

Sorafenib in Advanced Thyroid Cancer: UPCC 03305

Primary endpoints: RECIST, PFS, RR

* Leukocyte count ≥3.090/L, absolute neutrophil count ≥1.509/L, platelets more than 100,000/L, hemoglobin ≥9

g/dL, serum creatinine ≤1.5 upper limit of normal (ULN) or 24-hour creatinine clearance ≥75 mL/min, serum

bilirubin ≤1.5 ULN, serum AST ≤2.5 ULN, alkaline phosphatase ≤2.5 ULN, and prothrombin time-international

normalized ratio/partial thromboplastin time ≤1.5 ULN.

Gupta-Abramson et al. J Clin Oncol. 2008 (epub ahead of print).

Adapted from Brose M et al. Presented at ASCO Annual Meeting; May 29-June 2, 2009; Orlando, FL.

Sorafenib

400 mg bid

N=55

Eligibility Criteria

• Metastatic, iodine refractory

thyroid cancer

• Life expectancy >3 months

• Evidence of progressive disease

within 6 months of study entry

• ECOG 0-2

• Good organ and bone marrow

function*

UPCC 03305: Trial Design

Design

– Phase II, single arm, single institution trial

– Opened February 2006

– Primary endpoint overall response rate

– Two stage design:

• Stage I: 30 patients (complete October 2007)

• Total accrual of 55 patients (complete May 2009)

Treatment

– Sorafenib 400 mg PO BID (starting dose)

– CT assessment at months 2, 4 and Q3 months thereafter


UPCC 03305: Patient Demographics


Attribute No. (%)

Male/Female 28/27 51

Histology

Papillary thyroid cancer 26 47

Follicular/Hürthle cell variant 19 35

Medullary 3 5

Poorly differentiated/Anaplastic 3/4 5/7

PET completed/FDG uptake positive 46/48 96

Age range: 30-86

Update UPCC 03305: May 2009

Results:

– Response for all 50 evaluable patients

• PR: 36% (18 patients)

• SD: 46% (23 patients)

• Clinical benefit: 82% (41 patients)

– PFS is 63 weeks for all patients, and 84 weeks in patients with differentiated thyroid cancer


UPCC 03305: Best Response 46 Evaluable Patients


Evaluable Patients (n=46)

Ch

an

ge

in

Su

m o

f Ta

rge

t L

es

ion

by R

EC

IST

Co

mp

are

d t

o B

as

eli

ne

(%

)

-10

10

30

20

0

-20

-30

-40

-50

-60

-70

-80

-90

-100

PD SD PR

Papillary

Medullary

Follicular/Hürthle Cell

Poorly Differentiated/Anaplastic

UPCC 03305: Update on First 30 Patients Median Overall Survival Is 140 Weeks

Compares favorably to doxorubicin OS of 40 weeks Adapted from Brose M et al. Presented at ASCO Annual Meeting; May 29-June 2, 2009; Orlando, FL.

0

0.25

0.50

0.75

1.00

0 50 100 150 200

PFS

OS

PFS 63 Weeks

OS 140 Weeks

Time (weeks)

Other Multikinases in

Advanced Refractory Thyroid

Cancer Phase II Clinical Trials

Vandetanib 11 8,3 vs 5,5% 11 vs 5,8

11 Leboulleaux et al. Lancet Oncol 2012:9, 897-905.

SD 16 weeks

Median PFS 18.1 months (95% CI, 12.1 to not estimable).

Median Time of treatment 4.8 months.

At median follow up of 16.6 months

OS had not been reached .

DECISION Trial Schema-Phase III

Locally advanced or metastatic

RAI refractory differentiated

thyroid cancer

Progression w/in 14 mo

ECOG 0-2

Child Pugh A

No prior systemic Tx w/in 4

weeks

No prior TKIs

Nexavar 400 mg bid

Placebo Ra

nd

om

ize

Primary Endpoint:

PFS (RECIST) Independent review

Secondary Endpoints: OS, TTP, RR, DCR, PRO, PK

Safety

Exploratory Biomarkers

Cro

ss o

ver

Nexavar 400 mg bid

FPFV: 10/2009

LPFV: 01/2011

Data available: Q2 2012

Launch:

Q1 2013 US

Q2 2013 EU

Q1 2014 Japan

1:1

N=190

N=190

Key inclusion and exclusion criteria (1)

Inclusion

Locally advanced or metastatic DTC (papillary, follicular

including Hürthle cell or poorly differentiated)

RAI-refractory DTC

– At least one target lesion without iodine uptake, or

– Progression following treatment dose of RAI, or

– Cumulative RAI treatment ≥600 mCi

Progressive disease within the last 14 months

(RECIST)

Adequate TSH suppression (<0.5 mU/l)

Presented by: Marcia S. Brose MD PhD

Key inclusion and exclusion criteria (2)

Inclusion (cont.)

Not a candidate for surgery or radiotherapy with

curative intent

Adequate bone marrow, liver and renal function

Eastern Cooperative Oncology Group (ECOG)

performance status (PS) 0–2

Exclusion

Prior anti-cancer treatment with targeted therapy or

chemotherapy


Patient demographics

Sorafenib (n=207)

Placebo (n=210)

Gender, % Male Female

50.2 49.8

45.2 54.8

Age Median (range) ≥60 years, %

63 (24–82) 61.4

63 (30–87) 61.4

Region, %

Europe North America Asia

59.9 17.4 22.7

59.5 17.1 23.3

ECOG PS, %

0 1 2

62.8 33.3 3.4

61.4 35.2 2.9


Baseline disease characteristics Sorafenib (n=207)

Placebo (n=210)

Histology, investigator assessed, %

Papillary Follicular Hürthle cell Missing

66.2 21.3 11.6 1.0

67.1 26.2 6.7 0

Metastases

Locally advanced Distant

3.4 96.6

3.8 96.2

Most common target/non-target lesion sites, %

Lung Lymph nodes (any) Bone Pleura Head and neck Liver

86.0 54.6 27.5 19.3 15.9 13.5

86.2 48.1 26.7 11.4 16.2 14.3

Prior thyroidectomy, % 100 99.0

Locoregional therapy or EBRT, % 40.1 43.3

Median cumulative RAI activity 400 mCi 376 mCi

EBRT, external beam radiation therapy

n Median PFS,

days (months)

Sorafenib 207 329 (10.8)

Placebo 210 175 (5.8)

Progression-free survival (by independent central review)

PF

S p

robabili

ty (

%)

Days from randomization

0 100 200 300 400 500 600 700 800 0

10

20

40

60

80

100

30

50

70

90

HR: 0.587; 95% CI: 0.454–0.758;

p<0.0001

Full analysis set.

CI, confidence interval; HR, hazard ratio; PFS, progression-free survival

Variable n HR (95% CI)

Region Europe 249

North America 72

Asia 96

Age group <60 years 161

≥60 years 256

Histology (central review) Papillary 235

Hürthle cell 74

Follicular 31

Poorly differentiated 38

Lung metastases only No 347

Yes 70

Bone metastases No 304

Yes 113

FDG uptake Negative 29

Positive 320

No. target or non-target lesions <Median 163

≥Median 254

Target lesion size <Median 208

≥Median 209

Gender Male 199

Female 218

Cumulative RAI ≥600 mCi No 264

Yes 133

PFS in predefined subgroups

Favors sorafenib Favors placebo

0.0 0.5 1.0 1.5 2.0

FDG, fluorodeoxyglucose

Overall survival S

urv

ival pro

bab

ility

(%

)

Days from randomization

0

10

20

40

60

80

100

30

50

70

90

0 100 200 300 400 500 600 700 800 900 1000

At progression:

• 150 patients on placebo (71%) received open-label sorafenib

• 55 patients on sorafenib (27%) received open-label sorafenib

Median OS

Sorafenib Not reached

Placebo Not reached

HR: 0.802; 95% CI: 0.539–1.194

p=0.138, one-sided


Other secondary efficacy endpoints

Sorafenib

n (%)

Placebo

n (%) p value

Total evaluable patients 196 201

Response rate 24 (12.2) 1 (0.5) <0.0001

Complete response 0 0 –

Partial response 24 (12.2) 1 (0.5) –

Stable disease for ≥6 months 82 (41.8) 67 (33.2) –

Disease control rate (CR + PR +

SD ≥6 months) 106 (54.1) 68 (33.8) <0.0001

Median duration of response (PRs)

months (range) 10.2 (7.4–16.6) NA –

CR, complete response; PR, partial response;

SD, stable disease; NA, not assessed

Maximum reduction in target lesion size (by independent central review)

Maximum reduction is defined as the difference in the sum of the longest diameter of target lesions

from baseline. Negative values refer to maximal reduction and positive values to the minimal

increase.

Maxim

um

reduction in targ

et

lesio

n s

ize (

%)

–70

–50

–40

–20

0

20

60

–30

–10

10

30

50

40

–60

Sorafenib Placebo

27% of patients 73% of patients

Treatment and dose modifications (double-blind period)

Sorafenib

(n=207)

Placebo

(n=209)

Mean dose 651 mg 793 mg

Median (range) treatment duration 46.1 weeks

(0.3−135.3)

28.3 weeks

(1.7−132.1)

Dose modification due to AEs, %

Dose reduction

Dose interruption

77.8

64.3

66.2

30.1

9.1

25.8

Permanent discontinuation due to

AEs, % 18.8 3.8

AE, adverse event


Most common treatment-emergent AEs (double-blind period)

AE*, % Sorafenib (n=207) Placebo (n=209)

Any grade Grade 3/4 Any grade Grade 3/4

Hand–foot skin reaction 76.3 20.3 9.6 0

Diarrhea 68.6 5.8 15.3 1.0

Alopecia 67.1 0 7.7 0

Rash/desquamation 50.2 4.8 11.5 0

Fatigue 49.8 5.8 25.4 1.4

Weight loss 46.9 5.8 13.9 1.0

Hypertension 40.6 9.7 12.4 2.4

Metabolic – lab (other) 35.7 0 16.7 0

Anorexia 31.9 2.4 4.8 0

Oral mucositis 23.2 1.0 3.3 0

Pruritus 21.3 1.0 10.5 0

Nausea 20.8 0 11.5 0

Hypocalcemia 18.8 9.2 4.8 1.4

*National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0


Serious adverse events and deaths (double-blind period)

Sorafenib

n=207

Placebo

n=209

Serious AEs, n (%) 77 (37.2) 55 (26.3)

Most frequent serious AEs*, n (%)

Secondary malignancy

• Squamous cell carcinoma of the skin

Dyspnea

Pleural effusion

9 (4.3)

7 (3.4)

7 (3.4)

6 (2.9)

4 (1.9)

0

6 (2.9)

4 (1.9)

Grade 5 events (deaths), n (%)

Drug-related**

14 (6.8)

1 (0.5)

6 (2.9)

1 (0.5)

* Occurring in ≥2.0% of sorafenib-treated patients

** Myocardial infarction (sorafenib); subdural hematoma (placebo)

Summary

DECISION is the first Phase 3 study of a targeted

agent in

RAI-refractory DTC, a rare condition with poor

prognosis and no effective standard treatment

Sorafenib significantly improved PFS and extended

median PFS by 5 months vs placebo

– 10.8 vs 5.8 months (HR: 0.587; 95% CI: 0.454–0.758; p<0.0001)

Safety results are consistent with the known safety

profile of sorafenib

– The most frequent AEs were hand–foot skin reaction, diarrhea, alopecia, rash/desquamation, fatigue and hypertension


Conclusion

Sorafenib is a potential new treatment option for

patients with locally advanced or metastatic

RAI-refractory DTC


WHICH DO YOU DECIDE?

WHICH DO YOU SELECT?

GUIAS NCCN 2013

CARCINOMA MEDULAR

CARCINOMA MEDULAR DE TIROIDES

Vandetanib

In the ZETA trial, VANDETANIB improved PFS from 19.3 months

for the placebo arm to 30.5 months.

Vandetanib

Baseline patient characteristics

Prior systemic therapy was administered in 37% of enrolled patients on

the cabozantinib arm (20% of whom had received a TKI, and 46%

were positive for RET mutation)

42% of patients on the placebo arm (of whom 22% had received a TKI,

and 52% were positive for RET mutation).

FUTURO


CONCLUSIONES


CONCLUSIONES

Sorafenib es el primer fármaco multikinasa que demuestra su efectividad en un ensayo fase III randomizado en pacientes con CDT iodo-refractario.

Lenvatiinb demuestra su eficacia e otro ensayo fase III con resultados muy prometedores.

¿Cuando es un paciente iodorefractario?:

La investigación y avances en biología molecular han cambiado el pronóstico de los pacientes iodorefractarios.

El Abordaje multidisciplinar es fundamental en esta patología.

GRACIAS

tumores de la glándula tiroides - … · tumores de la glándula tiroides dr. julio lambea...

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