TUMORES NEUROENDOCRINOS

Miguel Navarro. Salamanca

Introduction to Neuroendocrine Tumours (NETs)

• NETs are relatively RARE

• At least 40 different entities are described arising in different organs.

• Different terminologies

have also caused confusion.

Most NETs 70% are non functional

Diagnostic challenges in NET

Wide variety of clinical presentations – Late presentation

• Over 60% of NETs are advanced at the time of diagnosis

• The median survival for patients with advanced NET is 33 months

Incidence Trends of NETs

Dasari A et al. JAMA Oncol. April 2017

NETs Are Second Most Prevalent Gastrointestinal Tumor

Median survival • Localized 203 months • Regional 114 months • Distant 39 months

Confusion Caused by the Term “Carcinoid”

• Oberndorfer coined the term “karzinoide” in 1907 .

• This term implies that these tumours are benign; this is an unfortunate misnomer for the majority of NET.

• NET have malignant potential and metastasize, generally to the liver.

Histologic classification

Treatment challenges in NET

One Treatment Does Not Fit All

Treatment challenges in NET

Somatostatin Analogues AAS

Telotristat. A Tryptophan Hydroxylase (TPH) Inhibitor

to treat carcinoid syndrome diarrhea

Indicated for carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy

Telotristat

Patients who received telotristat etiprate also experienced a lower frequency of flushing episodes and less intense abdominal pain compared to placebo, though these differences did not reach statistical significance.

Where does telotristat fit in?

• Active in controlling diarrhea from carcinoid syndrome.

• Does it have QOL benefits beyond diarrhea control? Flushing? Abdominal pain?

• Is there a role in prevention of carcinoid heart disease?

New options in NETs

Treatment challenges in NET

WATCHFUL WAITING

“cancers in slow motion”

Somatostatin Analogues AAS

PROMID Trial

CLARINET Trial

Somatostatin Analogues AAS

• Previous restrictions on the

use of AAS in non functioning tumors are no longer justified.

• Favorable side effects profile.

• Appropriate 1st line agents in most well-differenciated NETs.

• Early antitumor therapy

Indications for cytotoxic chemotherapy

QT en NETS

Newer chemotherapy regimens have demonstrated acceptable toxicity in advanced NET

Cap/Tem Example of response Baseline Maximal response

Targeting NETs

Targeting NETs

Targeting NETs

• AAS

Targeting NETS

There are several biological agents being evaluated.

• Pazopanib (Votrient)

• Cabozantinib (Cabometyx) • Axitinib (Inlyta)

• Lenvatinib (Lenvima)

Targeting NETS

Radionuclide Therapy

Theranostics-Diagnosis and Therapy

n engl j med 376;2 nejm.org January 12, 2017

Number of deaths: LU-Dotate: 14 Control: 26 Estimated risk of death 60% lower

n engl j med 376;2 nejm.org January 12, 2017

Case Report 58 yo m. Large cell Neuroendocrine carcinoma.

Surgery. Stage Ib Cisplatin-Vp16 (Ady)

2009-2015 Liver- Bone Mtx Carboplatin-Vp16, Lanreotide, Everolimus,Pazopanib,TMZ-Cap Topotecan ECOG -2. Oxycontin 60 mg/12 h plus oxinorm

2016-2017 ECOG-0, weight gain 20 KG, no opioids

PRRT

Case Report 2

• 2018 Progression

• If patient had responded to the first few rounds of Lutathera and then the tumors start to grow again, it can be given safely for a second time?

• 5 round of Lutathera May/18

Where does PRRT fit in?

• Phase 3 randomized data only in midgut NETs. – Early phase data suggesting higher response rates in non-midgut NETs

– COMPETE trial.

• Somatostatin-receptor (SSTR) expression is strong predictive marker.

• Consider as 2nd line therapy in patients with strong SSTR expression.

• Advantages: Limited treatment course (4x), exceptionally long-PFS, low toxicity

• Are there long-term risks to consider?

Inmunotherapy

• NETs do not have many mutations.

• Merkel cell carcinoma (MCC).

– Rare and aggressive neuroendocrine tumor of the skin.

– MCC incidence is higher in immunocompromised populations.

– Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway.

CarboVp16 –Rt - Avelumab

Ongoing clinical trials

Take Home Messages

Nets are not rare.

Consider patient and tumor characteristic.

Increasing number of treatment options

Octeotride / Lanreotide

Telotristat

Sunitinib / Everolimus

Temozolomide.

PPRT

Exciting Decade in Neuroendocrine Tumor Treatment

lmnavarro@saludcastillayleon.es

Muchas gracias