Objetivos e avaliação das terapêuticas dos NET G1 e G2: Combinações e sequências terapêuticas

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Objetivos e

o das terape

̂uticas dos NET G1 e G2

es e seque

̂ncias terapêuticas

Ana Ferreira Castro, MD

Oncologia Médica Centro Hospitalar do Porto Instituto de Ciências Biomédicas de Abel Salazar

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Classification of neuroendocrine tumors

Neuroendocrine

tumors

Pancreas

Small Intestine

(3)

Pancreas Neuroendocrine tumors

Pancreas

_{R0/R1 ressection}Ressectable:

_Recurrence

Non-resectable/meta

stases

Non-functioning: Endocrine symptoms Functioning: Endocrine symptoms

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Pancreas Neuroendocrine tumors

Functioning: Endocrine symptoms Non-functioning: Endocrine symptoms Cytoreductive surgery Symptomatic treatment PPI: gastrinomas Everolimus? SS-analogs: all functional EPT 177_Lu-DOTATATE 90_Y-DOTATOC Ki67 <30% Carboplatin+Etop oside Ki67: >20% Everolimus Sunitinib Ki 67:2-20% Streptozotocin+5FU /Doxorrubicin Ki 67:2-20% Temozolamide Ki67: >10% G2 G1/G2 G2/G3 G3

(5)

Pancreas Neuroendocrine tumors

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L. Dahan, et al. Chemotherapy in advanced carcinoid tumors

5FU+STZ vs Interferon

Dat e Regimen Number of patients Respons e (%) Survival (months) P value 198 4 5FU/STZ 80 22 15 0.25 DOX 81 21 11 200 5 5FU/Dox 85 16 16 0.027 5FU/STZ 78 16 24

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Pancreas Neuroendocrine tumors

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Everolimus

Everolimus vs Placebo Metastatic or unressectable disease with or without prior

chemotherapy

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Sunitinib

Eric Raymond, et al; Sunitinib Malate for the treatment of Pancreatic Neuroendocrine Tumors, N Engl J Med 2011;364:501-13.

Sunitinib vs Placebo

Metastatic disease with or without prior chemotherapy

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Pancreas Neuroendocrine tumors

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Temozolamide

Temozolamide+Capecitabine First-line Chemotherapy in metastatic

pancreatic neuroendocrine tumors

(12)

Small intestine endocrine tumors

Small Intestine

(carcinoid)

Ressectable: R0/R1 ressection

Recurrence

Non-resectable/meta

stases

No Endocrine symptoms Endocrine symptoms Cytoreductive surgery Somatostatin analog

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Small intestine endocrine tumors

Small Intestine

(carcinoid)

Ressectable: R0/R1 ressection

Recurrence

Non-resectable/meta

stases

No Endocrine symptoms Endocrine symptoms Cytoreductive surgery Somatostatin analog

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Octreotide LAR 30 mg significantly prolongs time to

tumour progression compared with placebo

Octreotide LAR 30 mg: 42 patients / 26 events Median TTP = 14.3 months [95% CI: 11.0–28.8]

Placebo: 43 patients / 40 events

Median TTP = 6.0 months [95% CI: 3.7–9.4]

Time (months) Pr o p o rt ion w it h o u t p ro gr essio n 0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 66 72 78

Based on the conservative ITT analysis

66% reduction in the risk of tumour progression HR=0.34; 95% CI: 0.20–0.59; P=0.000072

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Octreotide LAR 30 mg extends TTP in patients with functioning

or non-functioning tumours

0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90

Based on the per protocol analysis

P=0.0008; HR=0.25 [95% CI: 0.10–0.59] Pr op or tion withou t pr ogr ession P=0.0007; HR=0.23 [95% CI: 0.09–0.57] Pr op or tion withou t pr ogr ession

Patients with non-functioning tumours Patients with functioning tumours

Time (months) Time (months)

Octreotide LAR: 17 patients / 11 events Median TTP 14.26 months

Placebo: 16 patients / 14 events Median TTP 5.45 months

Octreotide LAR: 25 patients / 9 events

Median TTP 28.8 months

Arnold R. Abst # 4508 presented at ASCO 2009, Orlando FL Rinke A et al. J Clin Oncol 2009

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Octreotid LAR 30 mg vs placebo: hepatic tumour load

Stratified log-rank test

P<0.0001; HR=0.26 [95% CI: 0.14–0.50]

Placebo: 32 patients / 31 events Median TTP 7.21 months 0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Pr op or tion withou t pr ogr ession Time (months)

Stratified log-rank test

P=0.345; HR=0.64 [95% CI: 0.25–1.63] 0 0.25 0.5 0.75 1 0 6 12 18 24 30 36 42 48 54 60 Pr op or tion withou t pr ogr ession Time (months)

Patients with tumour load ≤10% Patients with tumour load >10%

Based on the ITT analysis Arnold R. Presented at ASCO-GI 2009

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Lanreotide

Stable disease

Progressive disease

Palazzo et al. Eur J Gastroenterol Hepatol 2013;25(2):232-238

Liver involvement

All 3 factors Ki-67

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PROMID

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Small Intestine (Carcinoid) Neuroendocrine tumors

No Endocrine symptoms 177_Lu-DOTATATE 90_Y-DOTATOC Ki67 <30% Carboplatin+Etop oside Ki67: >20% Interferon-alpha Ki 67:<10% Somatostatin analog Ki67: <2-10% Everolimus Ki67: 10-20% G1/G2 G3 G1/G2 G1/G2 Liver Transplantation

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Interferon-alpha

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Small Intestine (Carcinoid) Neuroendocrine tumors

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Combined therapy with Everolimus+Octreotide

RADIANT 2

Median PFS: 16.4 vs 11.3 months ORR = 2% in both arms

PFS (Central review)

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Small Intestine (Carcinoid) Neuroendocrine tumors

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PRRT

Overview of Results of Peptide Receptor Radionuclide Therapy with 3 Radiolabeled Somatostatin Analogs - J Nucl Med. 2005;46:62S-66S.

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PRRT

177Lu-octreotate treatment for GEP tumors - J Clin Oncol 26:2124-2130.

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Small Intestine (Carcinoid) Neuroendocrine tumors

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Liver transplantation

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Liver transplantation

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Liver transplantation

LeTreut et al. – Annals of Surgery r Volume 257, Number 5, May 2013

Overall survival of 106 patients according to the number of adverse prognostic factors: hepatomegaly, resec- tion in addition to LT, and age more than 45 years. Top: 5- year survival rates: 77%, 79%, 39%, and 33% for 0, 1, 2, or 3 factors, respectively. Bottom: after gathering in 2 groups. 0–1 factors (n = 58) and 2–3 factors (n = 48). P < 0.0001.