TNE

1. TUMOR NEUROENDOCRINO
METASTASICO - MANEJO
MR YESENIA MILAGROS HUERTA COLLADO
ONCOLOGIA MÉDICA- HNERM
26 DE SETIEMBRE DEL 2018

3. Classification of NET by Site

4. Grading

5.  Metastatic disease from NEN(neuroendocrine neoplasms):
 very prevalentintestinal and pancreatic NEN
 At initial diagnosis,40–50% of NEN patients present with distant
metastases.
 Metastases are predominantly found in the liver and/or lymph nodes. In
contrast, bone metastases are reported in <15% of cases

6. GEP NEN patients survival is associated with
tumor grade

7. Bases for treatment

8. Carcinoid syndrome
• In 20-30% of METASTATIC small bowel
NENs & (in 5% of bronchial and 1% of
pancreatic NENs)
b. “Carcinoid crisis”
Severe symptoms of carcinoid syndrome + hypotension during
procedures that involve GA, as well as in TAE, and when the
patient is on inotropes
a. “ Carcinoid syndrome”
lushing, diarrhoea,
bronchospasm, Carcinoid heart disease
20 – 30 % of patients with liver metastases
5% of patients with carcinoid syndrome do not have liver
metastases

9. Pancreatic NET – Functional vs. Non-Functional

10. BIOMARCADORES

11. BIOMARCADORES

16. Therapeutic Options
In grade 1 (G1) and G2 NET.
• surgery with curative intent always has to be considered, even if liver and/
or lymph node metastases are present
In non-resectable disease
• Considered to control symptoms secondary to a functional syndrome
• AND/OR tumor growth control.

17. Locoregional therapies
Bland embolization
Chemoembolization
Radioembolization
Radiofrequency ablation
Microwave destruction
Functionally active NET :
Locoregional therapies should be exploited early,
following SSA therapy, to prevent carcinoid crisis
Non-functional tumors :
they may be an alternative option to systemic
therapies (If the disease is limited to the liver).
May be considered repetitively during the course
of the disease.

18. Debulking Surgery
• Could be considered in patients with uncontrolled functional tumors.
• May be considered in patients with non-functional tumors if the disease
is not progressive over a 6-month period .
• Patients with symptoms related to tumor burden.
• Some retrospective studies indicate that surgery for liver metastasis is
associated with improved survival.

19. Liver Transplantation
 An option in highly selected patients with
 Carcinoid syndrome or other functional NET and extended liver disease
 Early refractory to multiple systemic treatments including SSA, interferon
(IFN)-alpha, locoregional therapies and petide receptor-targeted radiotherapy
(PRRT)p

21. Systemic Therapy: SSA and Novel Compounds for
Syndrome Control
• SSA are first-line therapy in functionally active NEN (carcinoid syndrome and
functionally active endocrine pancreatic NET such as vipoma and glucagonoma).
• Octreotide and lanreotide are considered equally effective for symptom control
• Long-acting formulations (octreotide LAR 10–30 mg i.m. per month; lanreotide
autogel 60–120 mg deeply s.c. per month) are used.
• There is consensus that dose escalation can be recommended in refractory
carcinoid syndrome for improvement of symptoms.

23. Systemic Therapy: SSA and Novel Compounds for
Syndrome Control
• SSA are first-line therapy in functionally active NEN.
Octreotide lanreotide
Dose escalation can be recommended in refractory carcinoid syndrome for
improvement of symptoms.
= effective for symptom control
LAR 10–30 mg i.m. per month autogel 60–120 mg deeply s.c. per
month

24. SSA
• First & best choice medications
• Reduce flushing > 70%
• Reduce diarrhoea > 60%
• Biochemical response ~ 50

25. Gastrointestinal neuroendocrine tumors treated with
high dose octreotide-LAR: A systematic literature review

26. Systemic Therapy: SSA and Novel Compounds
for Syndrome Control
Pasireotide
Telotristat etiprate
 Might be considered in individual highly selected patients when other treatments
failed or are not feasible depending on accessibility (locoregional therapies,
debulking surgery, IFN-alpha and novel drugs in clinical trials )
 An oral serotonin synthesis inhibitor, is a potential novel option in refractory
carcinoid syndrome.
 In a phase III placebo controlled trial (TELESTAR), telotristat etiprate significantly
reduced diarrea in patients with refractory carcinoid syndrome while on SSA.

27. Phase III study of pasireotide LAR vs octreotide
LAR in patients with metastatic midgut NET
Trial was terminated early based on interim analysis demonstrating futility for primary
endpoint (symptom response at month 6)

30. Systemic Therapy: SSA for Tumor Growth Control
• SSA can be recommended for the prevention or inhibition of tumor growth in
both intestinal and pancreatic NET.
• Octreotide LAR and lanreotide autogel, are recommended as first-line systemic
therapy in midgut NET to control tumor growth.
• Based on the CLARINET study, the use of SSA in GEP NET is recommended up to a
Ki-67 of 10%
• For the overall group of NEN, there was no consensus among experts on a clear
cut-off value for the recommendation of SSA for antiproliferative purposes.

31. • Patients with higher hepatic tumor burden (>25% liver involvement) as
supported by a subgroup analysis from the CLARINET study.
• if SSA should be started at initial diagnosis or after the observation of
spontaneous tumor growth and be initiated in case that disease
progression occurs.
• SSA may also be used in NET of other sites (e.g. rectal or bronchial NET),
when the SSTR status is positive (on somatostatin imaging or histology), if
the tumor is slowly growing, G1 or G2 and preferably with Ki-67 <10%.
Systemic Therapy: SSA for Tumor Growth Control
HEPATIC TUMOR BURDEN
CONTROVERSIAL
OTHER

34. Compara la SLP( objetivo primario ) entre el uso
de lanreotide 120 mg sc vs placebo
en pacientes con TNE
enteropancreaticos, bien o
moderadamente diferenciados ,no
funcionales ( ki67 menor de 10%)
Objetivos secundarios : Seguridad y
sobrevida media
96% estaba en enfermedad estable
antes de la randomizacion

37. • La mediana de supervivencia libre de progresión (SLP) fue
de 18,0 meses
• Los pacientes tratados con placebo, la mediana de
supervivencia libre de progresión (SLP) estimada a los 24
meses del 33 % vs 65% con Lanreotide 120 mg (p
<0,001)
• El riesgo de progresión de la enfermedad o de muerte
disminuyó en un 53 % con el uso de lanreotide , con un
hazard ratio de 0,47 (IC del 95 %: 0,30-0,730)
• Seguridad :Bien tolerado , el efecto adverso mas
frecuene fueron diarreas ( 26% lanreotide vs 9 %
placebo)
.

39. Conclusiones del estudio
• Lanreotida se asoció con prolongada supervivencia libre de progresión entre pacientes con NET enteropancreaticos
avanzado , grado 1 o 2 (Ki-67 <10%) con receptor de somatostatina positivo y enfermedad estable previa ,
independientemente del volumen del tumor hepático

40. KEY FEACTURES OF PROMAID VS CLARINET

41. SINTOMAS
ANTIPROLIFE
RATIVO

42. Interferon-Alpha
 IFN-alpha is an established and approved therapy for
syndrome control
 Primarily used as second-line (add-on) therapy in refractory
carcinoid syndrome or functional pancreatic NET.
 IFN is an option for inhibiting tumor growth and, due to
limited therapy options in midgut NET, it may be considered
an antiproliferative option (less so in pancreatic NET).

43. Novel Targeted Drugs (everolimus and
sunitinib)
• Everolimus or Sunitinib is recommended in progressive G1/G2
pancreatic NET, irrespective of Ki-67 and tumor burden.
• In pancreatic NET may be used as first- or second-line options with
respect to chemotherapy or subsequent to SSA therapy.
• The median PFS is around 11 months with either of the drugs
• While tumor remission occurs in 5% and <10% of the patients with
everolimus and sunitinib, respectively.
• Dose for everolimus is 10 mg/day and for sunitinib 37.5 mg/day as
continuous treatment.

44. • Everolimus can be recommended in advanced NET of non-pancreatic
origin in case of disease progression (e.g. NET of intestinal or lung
origin).
• It can be used in midgut NET as second- or third-line therapy after
failure of SSA and/or IFN-alpha or PRRT.
• based on the results of the RADIANT-4 trial

45. (0.77, 95% CI, 0.59
1.00).

49. • End Point : Supervivencia libre de progresión
• Objetivos secundarios : La sobrevida global , seguridad
• Estratificado :
• Tratamiento previo con ASS (si o no)
• Oriigen de tumor ( Grupo A (mejor pronostico) : apendice , ciego , yeyuno , ileon , duodeno y desconocido Grupo B ( peor
pronostico) : pulmon , estomago , recto y colon
• ECOG 0 -1
Placebo ( n=97)
Everolimus 10mg/d (
n=205)
302 pacientes con TNE
Gastrointestinal o pulmonar
bien diferenciado.
Ausencia de sindrome
carcinoide
R
2:1
• Tratados hasta Progresión de
enfermedad , intolerancia al
medicamento o no
consentimiento.
• Tiempo de evaluación : cada 12
semanas

50.  La tasa de control de la enfermedad fue más alta para los
pacientes que recibieron el Everolimus (82 frente al 65%)
 64% de Pacientes lograron la reducción del tumor con
Everolimus vs 26% de pacientes lograron reducción con placebo
 Enfermedad progresiva Everolimus 9% versus un 27%. Placebo
 Everolimus redujo el riesgo de mortalidad en un 36%, pero el
resultado no alcanzó significación estadística

53. • A comparative trial on progressive pancreatic NET (COOPERATE-2)
with everolimus versus everolimus and pasireotide, a novel SSA with a
broader binding affinity to SSTR compared to first-generation SSA,
failed to demonstrate superiority of the combination therapy with
respect to PFS
• There is not sufficient data to support the use of other targeted drugs
including bevacizumab, sorafenib, pazopanib or axitinib in either
pancreatic or non-pancreatic NEN

55. Systemic Chemotherapy
• Systemic chemotherapy is indicated in progressive or bulky pancreatic
NET and in G3 NEN.
• Chemotherapy may be considered in NET of other sites (lung, thymus,
stomach, colon or rectum) under certain conditions [e.g. when Ki-67
is at a high level (upper G2 range), in rapidly progressive disease
and/or after failure of other therapies, or if SSTR imaging is negative].
• Systemic chemotherapy may be considered without prior progression
in patients with high tumor burden.
• There is no established Ki-67 cut-off value for the recommendation of
chemotherapy

56. • Temozolomide +/– capecitabine may be considered as an alternative
regimen depending on the availability of STZ/5-FU.
• Reported objective response rates from small prospective and
retrospective studies achieved with temozolomide either combined
with antiangiogenic drugs or capecitabine range between 15 and
70%.
• After failure of STZ-based chemotherapy in pancreatic NET, the
following are alternative chemotherapeutic options:
• temozolomide +/– capecitabine and
• oxaliplatin based chemotherapy + 5-FU or capecitabine.
Systemic Chemotherapy

57. • Metronomic chemotherapy may be an option using temozolomide
and/or capecitabine +/– SSA in G2 NET or in SSTR-negative NET, or
capecitabine + bevacizumab after failure of other treatments (such as
locoregional therapies, IFN-alpha or everolimus).
Systemic Chemotherapy

58. • In G3 NEC, cisplatin-based chemotherapy (e.g. cisplatin/etoposide) is
standard therapy and recommended as a first-line therapy.
• Although objective remission rates are high (40–67%), the median
PFS is limited with 4–6 months.
• Second-line systemic therapy options include FOLFOX and FOLFIRI.
• Temozolomide- based chemotherapy should be preferably used in
pancreatic G3 NET or in gastrointestinal NEC with Ki-67 <55%
Systemic Chemotherapy

61. Peptide Receptor Radionuclide Therapy
• PRRT is a therapeutic option in progressive SSTR-positive NET with homogenous
SSTR expression.
• Radionuclide therapy with either 90 Y and/or 177 Lu-labeled SSA is most
frequently used in NET
• 177 Lu-labelled SSA is increasingly used due to lower kidney toxicity
NETTER-1
• PRRT may be recommended in midgut NET as a second-line therapy after failure
of SSA if the general requirements for applying PRRT are fulfilled or as a third-line
therapy after failure of everolimus.
• Lack of a prospective trial with PRRT in pancreatic NET, PRRT (if available) is in
general recommended in G1/G2 NET after failure of medical therapy including
SSA, chemotherapy or novel targeted drugs.

65. Therapeutic algorithm for the management of intestinal (midgut) NEN with
advanced locoregional disease and/or distant metastases.

66. Therapeutic algorithm for the management of pancreatic
NEN with advanced locoregional disease and/or distant metastases

69. Management of liver Metastases

72. gracias