OVERVIEW OF MANAGEMENT OF WELL-DIFFERENTIATED PANCREATIC NEUROENDOCRINE TUMOURS - (PanNETs) Current State-of-the-Art and Future Steps
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OVERVIEW OF MANAGEMENT OF WELL-DIFFERENTIATED PANCREATIC NEUROENDOCRINE TUMOURS (PanNETs) Current State-of-the-Art and Future Steps Angela Lamarca The Christie NHS Foundation Trust; University of Manchester Manchester, United Kingdom
INTRODUCTION TO PANCREATIC NETs Epidemiology Clinical presentation Grading Staging
EPIDEMIOLOGY
NETs are rare malignancies but incidence is increasing
Among Stage Groups. incidence Among Grade Groups, incidence
increased in the most in localized NETs increased the most in G1 NETs
Incidence of NETs is increasing
▪ Most dramatic rise in incidence in
Incidence per 100,000 persons
patients 65 years or older (8-fold rise to p
EPIDEMIOLOGY
PanNETs are rare (low incidence)
Current incidence of NETs by site
Increase in incidence of NETs (SEER 18 [2000–2012])
Incidence per 100,000 persons
from 1973 to 2012 across all
sites, stages, and grades
▪ 15-fold increase in the stomach
▪ 2-fold increase in the cecum
PanNETs represent
EPIDEMIOLOGY
Most PanNETs are sporadic
Most PanNETs are sporadic (non-hereditary); risk factors could include diabetes, smoking, chronic pancreatitis
Hereditary syndromes include:
◆ MEN1 (multiple endocrine neoplasia 1)
◆ VHL (von Hippel Lindau disease)
◆ NF1 (von Recklinghausen’s syndrome; neurofibromatosis 1)
◆ TS (tuberous sclerosis)
Patients who develop PanNETs in the context of an hereditary syndrome are expected to be associated with
a more indolent course; consider separately for management / prognosis
Halfdanarson TR, et al. Pancreas 2014;43(8):1219–22; Capurso G, et al. Am J Gastroenterol 2009;104:2175–81; Falconi M, et al. Neuroendocrinology 2016;103(2):153–71
CLINICAL PRESENTATION
Functioning vs. Non-Functioning
Most frequent functioning PanNETs
Biologically Most (60–90%) of PanNETs are
active Associated
peptide(s)
Incidence
Malignant, with
non-functioning
(new cases/106
Name secreted population/year) Tumour location % MEN1, % Main symptoms/signs ◆ 10–40% are expected to be
The most common F-P-NET syndromes functioning
Insulinoma Insulin 1–32 Pancreas (>99%) 100 cases)
VIPoma (Verner- Vasoactive 0.05–0.2 Pancreas (90%, 40–70 6 Diarrhoea (90–100%)
Morrison intestinal adult) Hypokalaemia (80–100%)
syndrome, peptide Other (10%, Dehydration (83%)
pancreatic neural, adrenal,
cholera, WDHA) periganglionic)
Glucagonoma Glucagon 0.01–0.1 Pancreas (100%) 50–80 1–20 Rash (67–90%)
Glucose intolerance (38–87%)
Weight loss (66–96%)
Falconi M, et al. Neuroendocrinology 2016;103(2):153–71 CgA: Chromogranin A; WDHA, watery diarrhoea, hypokalaemia, achlorhydria
CLINICAL PRESENTATION
Functioning vs. Non-Functioning
Less frequent functioning PanNETs
Incidence
Biologically active (new cases/106 Associated with
Name peptide(s) secreted population/year) Tumour location Malignant, % MEN1, % Main symptoms/signs
Among functioning SSoma Somatostatin Rare Pancreas (55%)
Duodenum/jejunum (44%)
>70 45 Diabetes mellitus (63–90%)
Cholelithiases (65–90%)
PanNETs, hormone Diarrhoea (35–90%)
GRHoma Growth hormone- Unknown Pancreas (30%) >60 16 Acromegaly (100%)
secretion may releasing hormone Lung (54%)
Jejunum (7%)
drive treatment Other (13%)
strategy and needs ACTHoma ACTH Rare Pancreas (4–16% all
ectopic Cushing’s
>95 Rare Cushing’s syndrome (100%)
to be taken into syndrome)
P-NET causing carcinoid Serotonin Rare (43 cases) Pancreas (
GRADING
WHO classification update 2017: G3-NET
Classification relies on grade (Ki-67 / mitotic index) and tumour morphology
◆ NEN: neuroendocrine neoplasms (NET + NEC; regardless of morphology / grade)
◆ NET: neuroendocrine tumours (well-differentiated morphology)
◆ NEC: neuroendocrine carcinoma (poorly-differentiated morphology)
Classification / grade Ki-67 proliferation index (%) Mitotic index
Well-differentiated PanNENs
PanNET G1 20
Poorly-differentiated PanNENs
PanNEC G3 >20 >20
Lloyd RV, et al. WHO Classification of Tumours of Neuroendocrine Organs 4th Ed 2017
GRADING
G3-NET vs. G3-NEC
Differential immunolabeling and molecular alterations of pancreatic NET and NECs
Coriat R, et al. The Oncologist 2016;21(19):1191–9;
The Oncologist by Society for Translational Oncology. Reproduced with permission of JOHN WILEY & SONS - JOURNALS in the format Use in an e-coursepack via Copyright Clearance Center
GRADING: G3-NEC, A SEPARATE ENTITY
Principles of management: chemotherapy is the cornerstone of treatment for G3-NEC
◆ Affects approximately 7% of patients with PanNENs
◆ Presents with locally advanced (20%) or metastatic (65%) disease
◆ Nordic NEC study:
◆ Patients with Ki67 ≥55% had greater response rate (42% vs. 15%, pSTAGING
ENETS TNM (2010) AJCC 8th Edition (2017)
T Stage
AJCC vs. ENETS T1 Confined for pancreas 4cm, or invasion of Tumour limited to pancreas, more than 4 cm in greatest
duodenum or bile duct dimension or tumour invading duodenum or bile duct
T4 Invasion of adjacent organs or major vessels Tumour perforates visceral peritoneum (serosa) or invades
other organs or adjacent structures
N Stage
Current classifications NX Regional lymph nodes cannot be assessed Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis No regional lymph node metastasis
Very similar: except N1 Regional lymph node metastasis Regional lymph node metastasis
M Stage
T4, M1 status M0 No distant metastasis No distant metastasis
M1 Distant metastasis Distant metastasis
M1a / M1b / M1c n/a Hepatic only / Extrahepatic only / Both
TNM Stage groups
Stage I T1, N0, M0 T1, N0, MO
Stage IIa T2, N0, M0 T2, N0, M0
Stage IIb T3, N0, MO T3, N0, MO
Stage IIIa T4, N0, MO T4, N0, MO
Stage IIIb Any T, N1, M0 Any T, N1, M0
Stage IV Any T, Any N, M1 Any T, Any N, M1
ENETS: European Neuroendocrine Tumour Society; AJCC: American Joint Committee on Cancer .
Klöppel G, et al. Virchows Arch 2010;456(6):595–7; Rindi G, et al. J Natl Cancer Inst 2012;104(10):764–77;
Amin M., Edge S., Greene F., Byrd D. R., Brookland R. K., Washington M. K., et al. 2017. AJCC cancer staging manual, 8th ed. Springer, New York, NY.STAGING
AJCC vs. ENETS classification
ENETS 2010 AJCC v.7 (2010)
Multiple versions of the AJCC
TNM classification
Retrospective analysis:
◆ 1072 PanNEN patients
◆ ENETS vs. AJCCv.7 (2010)
◆ ENETS classification seemed
superior?
Klöppel G, et al. Virchows Arch 2010;456(6):595–7; Teo RYA, et al. Surgery 2019;165(4):672–85
Rindi G, et al. TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study, J Natl Cancer Inst. 2012;104(10):764–77, by permission of Oxford University Press.STAGING
AJCC vs. ENETS classification
Cross-sectional imaging +/- Somatostatin receptor scintigraphy (SRS; OctreoScan®)
Recently, it has become possible to use somatostatin receptor PET/CT (i.e. 68Ga-PET)
instead, which might improve diagnostic quality:
◆ Systematic review and metanalysis (22 studies)
◆ DTA of 68Ga-PET in NETs: Se 93%, Sp 90%
Exception: insulinomas (Se 25%)
◆ Glucagon-Like Peptide-1 Receptor and 68Ga-NOTA-Exendin-4 PET/CT may have a role
(currently on development)
68Ga-PET is the method of choice to fully stage disease in patients
with PanNETs; expected change of management (surgical,
medical, staging) in 20–55% of patients
Reprinted by permission from Springer Nature: Geijer Eur J Nucl Med Mol Imaging, Somatostatin receptor PET/CT in neuroendocrine tumours: update on systematic review and meta-analysis, Geijer H, et al. Copyright 2013;
Falconi M, et al. Neuroendocrinology 2016;103(2):153–71; Sharma P, et al. Q J Nucl Med Mol Imaging 2016;60(1):69–76LOCALISED STAGE: MANAGEMENT Surgical management Adjuvant treatment Risk stratification Post-surgical follow-up
SURGICAL MANAGEMENT
Localised disease; 2 cm size cut-off
Algorithm for treating NF-P-NETs
Clinical evaluation Treatment Follow-up
In selected patients with and diagnostics Tumour 2 cm – surgery
Option 2. Surgery
◆
EUS (+/- EUS-guided Resectable G2, symptoms, patient wishes
Rationale: small risk of size
◆
biopsy) No distant metastases
increase or spread; 14% of ◆ Somatostatin receptor Tumour >2 cm
imaging Surgeryb
patients expected to require Limited resection only if conditions Surveillance depending on final
Somatostatin receptor pathology
subsequent surgery favourable to preserve organ
◆
scinigraphy Unresectable
function (otherwise oncological
(eg, Octreoscan©) or (or resectable resection)
68Gallium PET/CT
distant metastases
See section on treatment for
advanced disease
aIf low Ki-67 value and stability after the initial 6 monthly evaluations; bspecific additional tests may be required to accurately stage the tumour (eg, intraoperative US, interoperative frozen section
Falconi M, et al. Neuroendocrinology 2016; 103(2):153–71; NCCN v3.2018 guidelines; Choi SB, et al. Pancreatology 2017;17(3):342–9; Partelli S, et al. Br J Surg 2017;104(1):34–41ADJUVANT TREATMENT
There is NO evidence to support adjuvant treatment
Clinical trials not performed in this setting, mainly due to lack of definition of “population at risk of relapse”
◆ Overall, relapse rate is low in the completely resected population
◆ Predicting clinical behaviour in PanNETs has been difficult due to lack of data
Stratification for risk of relapse is crucial for the development of adjuvant strategies
Falconi M, et al. Neuroendocrinology 2016;103(2):153–71RISK STRATIFICATION
Risk factors for relapse (PanNETs)
Relapse Rate Risk factors Site of recurrence
Relapse rate 129/505 (25.5%).
Gao 2018 T3, T4, N1, Ki67 >2%, functional Not reported
Median disease-free survival of 19 months (range 6–96 months)
Relapse rate 23/140 (16.3%).
All recurrences were distant
Sho 2018 5- and 10-year relapse-free survival were 84.6% and 67.1%, Size >5 cm, N1, Ki67 >20%
(liver, peritoneal and bone)
respectively
Relapse rate 35/211 (17%).
Pancreatic remnant (69%),
The 5- and 10-year disease-specific/overall survival was 98%/91%
Genç 2018 Grade 2, N1, perineural invasion distant (14%), 1 patient had
and 84%/68%, respectively.
lymph node metastasis
Median timeto recurrence was 43 months (IQR 23–62)
Relapse rate 19/137 (13.9%). Tumour size >2 cm, N1, Ki67>5%
Ausania 2019 Not reported
Median DFS was 55 months or mitotic index >2
Recurrence rate 12.3%. Liver (11.1%), local recurrence
>21 mm size, G3, N1,
Marchegiani 2018 Recurrence occurred either during the first year of follow-up (n=9), (2.3%), lymph node (2.1%),
vascular infiltration
or after ten years (n=4) other organs (1.6%)
Gao H, et al. Cancer Lett. 2018;412:188–93; Sho S, et al. J Gastroint Surg 2018 Oct 23 [Epub ahead of print]; Genç CG, et al. Ann Surg 2018;267(6):1148–54; Ausania F, Pancreatology 2019;19(2):367–71; Marchegiani G, et
al. Neuroendocrinology 2018 Nov 27 [Epub ahead of print]Lesson 1: Relapse rate 12–25%
RISK STRATIFICATION
Risk factors for relapse (PanNETs)
Relapse Rate Risk factors Site of recurrence
Relapse rate 129/505 (25.5%).
Gao 2018 T3, T4, N1, Ki67 >2%, functional Not reported
Median disease-free survival of 19 months (range 6–96 months)
Relapse rate 23/140 (16.3%).
All recurrences were distant
Sho 2018 5- and 10-year Relapse-free survival were 84.6% and 67.1%, Size >5 cm, N1, Ki67 >20%
(liver, peritoneal and bone)
respectively
Relapse rate 35/211 (17%).
Pancreatic remnant (69%),
The 5- and 10-year disease-specific/overall survival was 98%/91%
Genç 2018 Grade 2, N1, perineural invasion distant (14%), 1 patients had
and 84%/68%, respectively.
lymph node metastasis
Median time to recurrence was 43 months (IQR 23–62)
Relapse rate 19/137 (13.9%). Tumour size >2 cm, N1, Ki67>5%
Ausania 2019 Not reported
Median DFS was 55 months or mitotic index >2
Relapse rate (12.3%). Liver (11.1%), local recurrence
>21 mm size, G3, N1,
Marchegiani 2018 Recurrence occurred either during the first year of follow-up (n=9), (2.3%), lymph node (2.1%),
vascular infiltration
or after ten years (n= 4) other organs (1.6%)
Gao H, et al. Cancer Lett. 2018;412:188–93; Sho S, et al. J Gastroint Surg 2018 Oct 23 [Epub ahead of print]; Genç CG, et al. Ann Surg 2018;267(6):1148–54; Ausania F, Pancreatology 2019;19(2):367–71; Marchegiani G, et
al. Neuroendocrinology 2018 Nov 27 [Epub ahead of print]Lesson 1: Relapse rate 12–25%
Lesson 2: Late relapses DO exist (>5/10 years)
RISK STRATIFICATION
Risk factors for relapse (PanNETs)
Relapse Rate Risk factors Site of recurrence
Relapse rate 129/505 (25.5%).
Gao 2018 T3, T4, N1, Ki67 >2%, functional Not reported
Median disease-free survival of 19 months (range 6–96 months)
Relapse rate 23/140 (16.3%).
All recurrence were distant
Sho 2018 5- and 10-year Relapse-free survival were 84.6% and 67.1%, Size >5 cm, N1, Ki67 >20%
(liver, peritoneal and bone)
respectively
Relapse rate 35/211 (17%).
Pancreatic remnant (69%),
The 5- and 10-year disease-specific/overall survival was 98%/91%
Genç 2018 Grade 2, N1, perineural invasion distant (14%), 1 patients had
and 84%/68%, respectively.
lymph node metastasis
Median time to recurrence was 43 months (IQR 23–62)
Relapse rate 19/137 (13.9%). Tumour size >2 cm, N1, Ki67>5%
Ausania 2019 Not reported
Median DFS was 55 months or mitotic index >2
Recurrence rate 12.3%. Liver (11.1%), local recurrence
>21 mm size, G3, N1,
Marchegiani 2018 Recurrence occurred either during the first year of follow-up (n=9), (2.3%), lymph node (2.1%),
vascular infiltration
or after ten years (n=4) other organs (1.6%)
Gao H, et al. Cancer Lett. 2018;412:188–93; Sho S, et al. J Gastroint Surg 2018 Oct 23 [Epub ahead of print]; Genç CG, et al. Ann Surg 2018;267(6):1148–54; Ausania F, Pancreatology 2019;19(2):367–71; Marchegiani G, et
al. Neuroendocrinology 2018 Nov 27 [Epub ahead of print]Lesson 1: Relapse rate 12–25%
Lesson 2: Late relapses DO exist (>5/10 years)
RISK STRATIFICATION Lesson 3: Size/T, N, Ki67/grade are repetitive prognostic factors
Risk factors for relapse (PanNETs)
Relapse Rate Risk factors Site of recurrence
Relapse rate 129/505 (25.5%).
Gao 2018 T3, T4, N1, Ki67 >2%, functional Not reported
Median disease-free survival of 19 months (range 6–96 months).
Relapse rate 23/140 (16.3%).
All recurrences were distant
Sho 2018 5- and 10-year Relapse-free survival were 84.6% and 67.1%, Size >5 cm, N1, Ki67 >20%
(liver, peritoneal and bone)
respectively
Relapse rate 35/211 (17%).
Pancreatic remnant (69%),
The 5- and 10-year disease-specific/overall survival was 98%/91%
Genç 2018 Grade 2, N1, perineural invasion distant (14%), 1 patients had
and 84%/68%, respectively.
lymph node metastasis
Median time to recurrence was 43 months (IQR 23 – 62)
Relapse rate 19/137 (13.9%). Tumour size >2 cm, N1,
Ausania 2019 Not reported
Median DFS was 55 months Ki67>5% or mitotic index >2
Recurrence rate 12.3%. Liver (11.1%), local recurrence
>21 mm size, G3, N1,
Marchegiani 2018 Recurrence occurred either during the first year of follow-up (n= 9), (2.3%), lymph node (2.1%),
vascular infiltration
or after ten years (n= 4) other organs (1.6%)
Gao H, et al. Cancer Lett. 2018;412:188–93; Sho S, et al. J Gastroint Surg 2018 Oct 23 [Epub ahead of print]; Genç CG, et al. Ann Surg 2018;267(6):1148–54; Ausania F, Pancreatology 2019;19(2):367–71; Marchegiani G, et
al. Neuroendocrinology 2018 Nov 27 [Epub ahead of print]Lesson 1: Relapse rate 12–25%
Lesson 2: Late relapses DO exist (>5/10 years)
RISK STRATIFICATION Lesson 3: Size/T, N, Ki67/grade are repetitive prognostic factors
Lesson 4: Other factors may require further confirmation
Risk factors for relapse (PanNETs)
Relapse Rate Risk factors Site of recurrence
Relapse rate 129/505 (25.5%).
Gao 2018 T3, T4, N1, Ki67 >2%, functional Not reported
Median disease-free survival of 19 months (range 6–96 months)
Relapse rate 23/140 (16.3%).
All recurrences were distant
Sho 2018 5- and 10-year Relapse-free survival were 84.6% and 67.1%, Size >5 cm, N1, Ki67 >20%
(liver, peritoneal and bone)
respectively
Relapse rate 35/211 (17%).
Pancreatic remnant (69%),
The 5- and 10-year disease-specific/overall survival was 98%/91% Grade 2, N1, perineural
Genç 2018 distant (14%), 1 patients had
and 84%/68%, respectively. invasion
lymph node metastasis
Median time to recurrence was 43 months (IQR 23–62)
Relapse rate 19/137 (13.9%). Tumour size >2 cm, N1, Ki67>5%
Ausania 2019 Not reported
Median DFS was 55 months or mitotic index >2
Recurrence rate 12.3%. Liver (11.1%), local recurrence
>21 mm size, G3, N1,
Marchegiani 2018 Recurrence occurred either during the first year of follow-up (n=9), (2.3%), lymph node (2.1%),
vascular infiltration
or after ten years (n=4) other organs (1.6%)
Gao H, et al. Cancer Lett. 2018;412:188–93; Sho S, et al. J Gastroint Surg 2018 Oct 23 [Epub ahead of print]; Genç CG, et al. Ann Surg 2018;267(6):1148–54; Ausania F, Pancreatology 2019;19(2):367–71; Marchegiani G, et
al. Neuroendocrinology 2018 Nov 27 [Epub ahead of print]Lesson 1: Relapse rate 12–25%
Lesson 2: Late relapses DO exist (>5/10 years)
RISK STRATIFICATION Lesson 3: Size/T, N, Ki67/grade are repetitive prognostic factors
Lesson 4: Other factors may require further confirmation
Risk factors for relapse (PanNETs) Lesson 5: Site of recurrence distal (liver) > local
Relapse Rate Risk factors Site of recurrence
Relapse rate 129/505 (25.5%).
Gao 2018 T3, T4, N1, Ki67 >2%, functional Not reported
Median disease-free survival of 19 months (range 6–96 months)
Relapse rate 23/140 (16.3%).
All recurrences were distant
Sho 2018 5- and 10-year Relapse-free survival were 84.6% and 67.1%, Size >5 cm, N1, Ki67 >20%
(liver, peritoneal and bone)
respectively
Relapse rate 35/211 (17%).
Pancreatic remnant (69%),
The 5- and 10-year disease-specific/overall survival was 98%/91%
Genç 2018 Grade 2, N1, perineural invasion distant (14%), 1 patients had
and 84%/68%, respectively. Median time
lymph node metastasis
to recurrence was 43 months (IQR 23–62)
Relapse rate 19/137 (13.9%). Tumour size >2 cm, N1, Ki67>5%
Ausania 2019 Not reported
Median DFS was 55 months. or mitotic index >2
Recurrence rate 12.3%. Liver (11.1%), local recurrence
>21 mm size, G3, N1,
Marchegiani 2018 Recurrence occurred either during the first year of follow-up (n=9), (2.3%), lymph node (2.1%),
vascular infiltration
or after ten years (n=4) other organs (1.6%)
Gao H, et al. Cancer Lett. 2018;412:188–93; Sho S, et al. J Gastroint Surg 2018 Oct 23 [Epub ahead of print]; Genç CG, et al. Ann Surg 2018;267(6):1148–54; Ausania F, Pancreatology 2019;19(2):367–71; Marchegiani G, et
al. Neuroendocrinology 2018 Nov 27 [Epub ahead of print]RISK STRATIFICATION Towards development of adjuvant strategies for selected resected PanNETs Clinical trials not performed in this setting, mainly due to lack of definition of “population at risk of relapse” ◆ Overall, relapse rate is
POST-SURGICAL FOLLOW-UP
Recommendations
3–12 months post-resection:
◆ Patient history and physical examination
◆ Biochemistry follow-up as clinically required based on previous findings (CgA vs. GUT hormones)
◆ Cross-sectional imaging (CT/MRI)
◆ OctreoScan®/68Ga-Pet (if not previously performed)
After 1st year and until 10 years post-resection
6–12 monthly: history/physical examination; biochemistry; radiological follow-up (cross-sectional imaging)
Frequency of review / radiology investigations should be adjusted to presence of risk factors of relapse
T1N0, G1 and N0 insulinomas may require a less intensive follow-up
NCCN v3.2018 guidelinesPOST-SURGICAL FOLLOW-UP
Current practice is variable between centres
Data from a US/Canada survey:
Follow-up for Resected Gastroenteropancreatic
◆ Clinicians aware of guidelines but there was Neuroendocrine Tumours: A Practice Survey of the
still very significant variability between sites Commonwealth Neuroendocrine Tumour Collaboration
(CommNETS) and the North American Neuroendocrine
The current guidelines are not widely adopted, Tumour Society (NANETS)
potentially due to a lack of high-quality evidence to
inform follow-up for this heterogeneous disease
We should work towards improved
standardisation of follow-up
Chan DL, et al. Neuroendocrinology 2017;107(1):32–41ADVANCED STAGE: MANAGEMENT How to select the most adequate treatment Liver-directed therapies Somatostatin analogues Targeted therapies Chemotherapy PRRT
HOW TO SELECT THE MOST ADEQUATE TREATMENT
ENETS guidelines
Morphological and functional
Resection of primary imaging
◆ Surgery can have a role in
metastatic disease (a) Simple pattern of LMs (b) Complex pattern of LMs (c) Diffuse LMs
G1/G2 (unilobar or limited) G1/G2 (bilobar) G1/G2
◆ Liver-directed therapy plays a role
in selected patients Or surgery Selected
contraindicated cases (HOW TO SELECT THE MOST ADEQUATE TREATMENT
ENETS guidelines
Morphological and functional
Resection of primary imaging
◆ Surgery can have a role in
metastatic disease (a) Simple pattern of LMs (b) Complex pattern of LMs (c) Diffuse LMs
G1/G2 (unilobar or limited) G1/G2 (bilobar) G1/G2
◆ Liver-directed therapy plays a role
in selected patients Or surgery Selected
contraindicated cases (LIVER-DIRECTED THERAPIES Resection of liver metastases from PanNETs A very significant proportion of patients diagnosed with Resection of liver metastases (if resectable) seems to PanNET will have liver metastases improve survival (no prospective randomised data available) Reprinted from The Lancet Oncol 2014, 15(1), Frilling A, et al. Recommendations for management of patients with neuroendocrine liver metastases, e8-e21, Copyright (2014), with permission from Elsevier.
HOW TO SELECT THE MOST ADEQUATE TREATMENT
ENETS guidelines
Morphological and functional
Resection of primary imaging
◆ Surgery can have a role in
metastatic disease (a) Simple pattern of LMs (b) Complex pattern of LMs (c) Diffuse LMs
G1/G2 (unilobar or limited) G1/G2 (bilobar) G1/G2
◆ Liver-directed therapy plays a role
in selected patients Or surgery Selected
contraindicated cases (LIVER-DIRECTED THERAPIES Liver embolisation (TAE, TACE) in PanNETs Overall survival worse than after resection (likely to reflect unresectable (more extensive disease) Main role in patients with functioning tumours and with liver-predominant disease Data for NETs (no specific data in PanNETs): • symptomatic response 53–100% • morphological response 35–74% • progression-free survival 18 months • 5-year survival of 40–83% Reprinted from The Lancet Oncol 2014, 15(1), Frilling A, et al. Recommendations for management of patients with neuroendocrine liver metastases , e8-e21, Copyright (2014), with permission from Elsevier.
HOW TO SELECT THE MOST ADEQUATE TREATMENT
ENETS guidelines
Morphological and functional
Resection of primary imaging
◆ Surgery can have a role in
metastatic disease (a) Simple pattern of LMs (b) Complex pattern of LMs (c) Diffuse LMs
G1/G2 (unilobar or limited) G1/G2 (bilobar) G1/G2
◆ Liver-directed therapy plays a role
in selected patients Or surgery Selected
contraindicated cases (HOW TO SELECT THE MOST ADEQUATE (SYSTEMIC) TREATMENT
Understanding the effect of different systemic treatments
Chemotherapy (20–50%)
PRRT (18%)
May be higher in Targeted (5-10%)
PanNETs (58%)
SSA (0%)
SSA: somatostatin analogue; PRRT: Peptide Receptor Radionuclide Therapy
Adapted from Lamarca A, et al. J Oncopathol 2014;2(1):15–25;
Caplin ME, et al. N Engl Med 2014;371: 224–33; Strosberg J, et al. N Engl J Med 2017;376:125–35; Ramage J, et al. Semin Oncol. 2018;45(4):236–48HOW TO SELECT THE MOST ADEQUATE (SYSTEMIC) TREATMENT
Decision based on tumour burden, Ki-67 and rate of progression (tumour kinetics)
Principles for treatment selection:
1. Targeted therapies are effective in treatment-naïve as well as or PRRT
chemotherapy pre-treated patients
2. Chemotherapy is associated with a higher response rate
3. Treatment decision is based on the aims of therapy (disease
response versus time to progression)
4. Decision may depend on expected toxicities
5. Concept of ''mitotically-active'' disease
6. Patients usually live long enough to receive multiple therapies
or SSA
7. Need to identify sub-groups of patients (through research) who
benefit most from each therapy
8. One-size does not fit all (importance of MDTs)
Adapted from Lamarca A, et al. J Oncopathol 2014;2(1):15–25HOW TO SELECT THE MOST ADEQUATE (SYSTEMIC) TREATMENT
Tailoring systemic treatment to patient/tumour characteristics
Therapeutic options and conditions for preferential use as first-line therapy in advanced NEN
Drug Functionality Grading Primary site SSTR status Special considerations
Octreotide +/- G1 Midgut + Low tumour burden
Lanreotide +/- G1/G2 (-10%) Midgut, pancreas + Low and high (>25%) liver tumor burden
IFN-α 2b +/- G1/G2 Midgut If SSTR negative
STZ/5-FU +/- G1/G2 Pancreas Progressive in short-term* or high tumour burden or
symptomatic
TEM/CAP +/- G2 Pancreas Progressive in short-term* or high tumour burden or
symptomatic; if STZ is contraindicated or not available
Everolimus +/- G1/G2 Lung Atypical carcinoid and/or SSTR negative
Pancreas Insulinoma or contraindication for CTX
Midgut If SSTR negative
Sunitinib +/- G1/G2 Pancreas Contraindication for CTX
PRRT +/- G1/G2 Midgut + (required) Extended disease; extrahepatic disease, e.g. bone
metastasis
Cisplatin†/etoposide +/- G3 Any All poorly differentiated NEC
CAP, Capecitabine; TEM, temozolomide. *≤6-12 months. †Cisplatin can be replaced by carboplatin.
Pavel M, et al. Neuroendocrinology 2016;103(2):172–85.SOMATOSTATIN ANALOGUES
Octreotide (PROMID study)
Octreotide LAR 30 mg
◆ G1 metastatic or locally advanced well diff, 4-weekly
functioning* or non-functioning midgut NETs
(no PanNETs included) R
◆ Randomisation 1:1 (n=85 patients) Placebo
Primary endpoint: Progression free survival
*Only patients tolerating flushing without intervention or responding to treatment with loperamide or cholestyramine in case of
diarrhoea were included
Rinke A, et al. J Clin Oncol 2009;27(28):4656–63SOMATOSTATIN ANALOGUES
Lanreotide (CLARINET study)
◆ G1 or G2 (Ki-67SOMATOSTATIN ANALOGUES
Octreotide vs. Lanreotide (role beyond anti-hormone function)
Octreotide LAR Lanreotide Autogel
30 mg, im 4-weekly 120 mg; deep sc, 4-weekly
(PROMID study; vs. placebo) (CLARINET study; vs. placebo)
Advanced, functional or non-functional midgut Advanced, non-functioning, somatostatin
Population of patients primary tumour or tumour of unknown. receptor-positive, grade 1 or 2 (Ki-67TARGETED THERAPIES
Potential pathways to target
Molecular biology in pNETs
Two main pathways to target:
◆ mTOR (everolimus)
◆ Angiogenesis (sunitinib)
Adapted from Lamarca A, et al. J Oncopathol 2014;2(1):15–25TARGETED THERAPIES
Sunitinib
G1 or G2 metastatic or locally advanced well
Sunitinib 37.5 mg PO OD
◆
diff, functioning or non-functioning PanNETs
◆ Progressed within previous 12 m R
Randomisation 1:1 (n=171 patients
Placebo
◆
randomised*)
Primary endpoint: Progression-free survival
*Enrolment completed in the first interim analysis (therefor recruitment not fully completed)
Raymond E, et al. N Engl J Med 2011;364:501–13TARGETED THERAPIES
Everolimus
◆ G1 or G2 metastatic or locally advanced well Everolimus 10 mg PO OD
diff, functioning or non-functioning PanNETs
R
◆ Progressed within previous 12 m
◆ Randomisation 1:1 (n=410 patients) Placebo
Primary endpoint: Progression-free survival
Yao JC, et al. N Engl J Med 2011; 364:514-523TARGETED THERAPIES
Sunitinib and Everolimus
Sunitinib Everolimus
37.5 mg once daily 10 mg once daily
(Phase 3 vs. placebo) (Phase 3 vs. placebo)
Unresectable or metastatic, well- or moderately- Unresectable or metastatic, well- or moderately-
Population of patients
differentiated PanNETs differentiated PanNETs
Documented disease
Yes Yes
progression at study entry
Objective response rate 9.3% vs. 0% 5% vs. 2%
Median PFS (experiment vs. 11.4 vs. 5.5 11.0 vs. 4.6
placebo) (months) HR 0.42 (95% CI 0.26, 0.66); pTARGETED THERAPIES
Sunitinib and Everolimus: Toxicity profile
Sunitinib Everolimus
Yao JC, et al. N Engl J Med 2011;364:514–23; Raymond E, et al. N Engl J Med 2011;364:501–13; Lombard-Bohas C, et al. Pancreas 2015;44(2):181–9.TARGETED THERAPIES
Sunitinib and Everolimus: Toxicity profile
Sunitinib Everolimus
Selection between Sunitinib or Everolimus usually relies on comorbidities due to different toxicity profile
Yao JC, et al. N Engl J Med 2011;364:514–23; Raymond E, et al. N Engl J Med 2011;364:501–13; Lombard-Bohas C, et al. Pancreas 2015;44(2):181–9.CHEMOTHERAPY
Benefit from chemotherapy in PanNETs: Objective response
Systematic review and meta-analysis: Among well-differentiated NETs, PanNETs seem to benefit more from
chemotherapy (increased response rate) than other NETs (i.e. small intestinal NETs)
Non-PanNETs
Response Rate
9.5%
Vs.
PanNETs
Response Rate
26.3%
Reprinted from Cancer Treat Rev 2014, 44(16), Lamarca A, et al. Chemotherapy for advanced non-pancreatic well-differentiated neuroendocrine tumours of the gastrointestinal tract, a systematic review and meta-analysis: A
lost cause?, 26-41, Copyright 2014, with permission from Elsevier.CHEMOTHERAPY OPTIONS OF CHEMOTHERAPY
Chemotherapy and Targeted Therapy Studies for Well-differentiated Pancreatic NETs
Treatment Type of Trial Patients’ Number of pNET Response rate (%) Disease Median PFS Median overall Year of publication
characteristics patients control (months) survival (months) (References)
rate (%)
Chemotherapy
Chlorozotocin vs. Phase III Previous chemo 33 30 No data 17 18 1992 (12)
Streptozocin and allowed (no data) 33 45 14 16.8
fluorouracil vs. Doxorubicin 36 69 18 26.4
and streptozocin
Multiple different chemotherapy Doxorubicin and Retrospective 24% previous 45 36 60 16 2-year survival rate: 2004 (13)
streptozocin analysis chemotherapy 50.2%
combinations have been tested
Streptozocin, doxorubicin Retrospective 5% second line 84 39 89 18 37 2004 (14)
over the years, most of them and fluorouracil analysis
in retrospective series of small 5-fluororuracil, cisplatin and Retrospective Chemo naïve 82 (49 pNETs) 38 86 9.1 31.4 2010 (15)
streptozocin analysis patients
prospective studies
Capecitabine and Randomised Previous chemo 86 (48% pNETs) 14/8 78/82 9.7/10.2 34.7 2012 (16)
streptozocin +/-cisplatin Phase II allowed (no data)
Decarbazine Phase II 44% second line 50 34 No data No data 19.3 2001 (18)
Temozolomide and Phase II 45% second line 29 (38% 45 93 No data 2-year survival rate 2006 (19)
thalidomine pancreatic) 61%
Temozolomide and Retrospective Chemo naïve 30 70 97 18 2-year survival rate 2011 (21)
capecitabine analysis patients 92%
Temozolomide and Phase II 44% second line 35 (44% 33.3 87 14.3 41.7 2012 (20)
bevacizumab pancreatic)
Temozolomide, everolimus Phase I/II 33% second line 43 40 93 15.4 No data 2013 (37)
Capecitabine and Retrospective Second line 27 well- 27 well- 30 78 20 40 2007 (23)
oxaliplatin analysis differentiated NETs differentiated NETs
included (unknown number
of pNETs)
5-fluorouracil, oxaliplatin Phase II No 6 of 13 patients 20 100 No data No data 2008 (24)
and bevacizumab included
Adapted from Lamarca A, et al. Capecitabine, oxaliplatin Phase II No data 20 30 94 13.7 No data 2011 (25)
J Oncopathol 2014;2(1):15–25 and bevacizumabCHEMOTHERAPY
Temozolomide + Capecitabine
◆ Capecitabine (750 mg/m2 twice
daily day 1–14) + temozolomide
(200 mg/m2 once daily day
10–14); 28-day cycle
% change
◆ Median PFS 18 months
◆ Radiological response rate:
70%
◆ Toxicity: myelosuppression
Best radiographic response | 70% of patients achieved PR (RECIST)
Strosberg JR, et al. Cancer 2011;117(2); 268–75. Courtesy of John Wiley and Sons. Copyright © 2010 American Cancer SocietyCHEMOTHERAPY
Temozolomide Capecitabine vs. Capecitabine: E2211 clinical trial
Randomised phase II study in progressive PanNETS
Primary endpoint:
n=72 Arm A:
PFS (local review)
Temozolomide 200 mg/m2 po QD days 1–5
Progressive, Secondary endpoint:
G1 / G2, metastatic R RR, OS, toxicity
pancreatic NETs Arm B: Correlative endpoints:
1:1 n=72 Capecitabine 750 mg/m2 po BID days 1–14 MGMT by IHC, MGMT by
Temozolomide 200 mg/m2 po QD days 10–14 promoter methylation
Stratified by:
◆ Prior everolimus Cycle length = 28 days; max 13 cycles.
◆ Prior sunitinib Imaging performed every 12 weeks (RECIST 1.1)
◆ Concurrent octreotide
Kunz P, et al. J Clin Oncol 36, 2018 (suppl; abstr 4004). By permission of Dr Pamela KunzCHEMOTHERAPY
Temozolomide Capecitabine vs. Temozolomide: E2211 clinical trial
Randomised Phase 2 study in progressive PanNETS
Tem TemCap Comments
Grade 1 45.1% 68.1%
Grade 2 54.9% 31.9%
HR 0.58 (95% CI 0.36, 0.93); p=0.023
PFS (median) (months) 14.4 22.7 If adjusted for grade results are
unchanged (HR 0.61 p=0.042)
HR 0.41 (95% CI 0.21, 0.82); p=0.012
OS (median) (months) 38.0 Not reached If adjusted for grade results are
unchanged (HR 0.46 p=0.033)
Complete Response 2.8% 0%
Partial Response 25.0% 33.3%
Response duration (months) 9.7 12.1
Kunz P, et al. J Clin Oncol 36, 2018 (suppl; abstr 4004) 2018. By permission of Dr Pamela Kunz.PEPTIDE RECEPTOR RADIONUCLIDE THERAPY (PRRT)
NETTER-1 clinical trial: PRRT vs. Octreotide 60 mg
◆ Radiolabelled octreotide: selection of patients based on somatostatin receptor positive imaging
◆ Metastatic midgut neuroendocrine tumours (excluding PanNETs) with progressive disease to SSA
◆ Benefit in terms of survival (PFS: HR 0.21 [95%CI 0.13, 0.33]) → approved for its use in GEP-NETs
(including PanNETs)
From The New England Journal of Medicine, Strosberg J, et al.,
Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine
Tumors, 376(2), 125–35. Copyright © 2017 Massachusetts
Medical Society. Reprinted with permission from
Massachusetts Medical SocietyPEPTIDE RECEPTOR RADIONUCLIDE THERAPY (PRRT)
Experience of PRRT in PanNETs
◆ Review of the literature; multiple retrospective studies
◆ Among these studies, the median disease control rate was 83% (range 50%–94%) and the median
objective response rate was 58% (range 13%–73%)
◆ Reported median progression-free survival for the overall PanNET population ranged from 25 to 34 months;
the median overall survival ranged from 42 to 71 months
“The effect may be at least as great as in midgut NET”
Ramage J, et al. Semin Oncol 2018;45(4):236–48THE FUTURE OF MANAGEMENT OF PANCREATIC NETS New targeted therapies Challenges for treatment sequencing Immunotherapy
NEW TARGETED THERAPIES
Role of Lenvatinib: TALENT study
◆ Cohort A: Lenvatinib in PanNETs (pre-treated); n=55
◆ Objective response rate (RECIST): 40.4%
◆ Median PFS: 14.2 months (95% CI 11.4, not reached)
◆ Dose reduction required: 88%
◆ AEs: G3 8.6%; G4 0.5%; G5 0.1%
◆ Good response rate in PanNETs. Confirmatory trials
awaited
Cabozantinib, Sulfatinib
◆ Phase 3 trials ongoing in view of promising Phase 2 results
Capdevila J, et al. Ann Oncol 2018;29(Suppl 8): Abstract 1307O (presented at ESMO 2018); By permission of Dr Jaume Capdevila.
Chan ASCO-GI 2017; Xu ENETS 2017CHALLENGES FOR TREATMENT SEQUENCING
Targeted or PRRT: COMPETE study (n=300)
◆ G1 or G2 metastatic or locally advanced well 177Lu-DOTA-TOC 7.5 Gbq
diff, functioning or non-functioning GEP-NETs (4 cycles; 1 dose/12 wks)
◆ SSTR +ve R
◆ PD as per RECIST 1.1
Everolimus 10 mg PO OD
◆ Randomisation 2:1
Primary endpoint: Progression free survival at 2 years
Primary completion date: Dec 2020CHALLENGES FOR TREATMENT SEQUENCING
Targeted or Chemotherapy: SEQTOR study (n=180)
Everolimus 10 mg PO OD
◆ G1 or G2 metastatic or locally advanced well
diff, functioning or non-functioning Pan-NETs R
◆ Randomisation 1:1 Streptozocin + 5-FU
3/6-weekly
Primary endpoint: Progression free survival
Accrual completed: October 2018
Expected results: 2020IMMUNOTHERAPY
Current data in PanNETS
Pembrolizumab (KEYNOTE-028 study; anti-PD-1)
◆ 16 PanNETs (PD-L1 positive )
◆ 6% objective responses
Spartalizumab (PRD001; anti PD-1) in NETs
◆ Cohort of patients with PanNETS (n=30)
◆ Partial response rate: 3%
◆ Disease-control rate: 58%
Further studies are required in PanNETS to assess the role of immunotherapy
Mehnert ESMO 2017; Yao J, et al. Ann Oncol 2018;29 (suppl_8): viii467-viii478. Presented at ESMO 2018. By permission of Dr J. Yao.TAKE HOME MESSAGES
TAKE HOME MESSAGES
◆ PanNETs are rare types of neoplasms whose incidence and prevalence are increasing
◆ Proliferation index and morphology are the cornerstone of tumour classification, which impacts both treatment
and prognosis
◆ Surgery is the only curative treatment for localised disease
◆ Surgery for metastatic disease (if resectable) does have a role
◆ Liver directed therapies are of use for patients with unresectable liver disease if liver predominant or functional
symptoms are present
◆ Systemic treatment includes somatostatin analogues, targeted therapies (everolimus, sunintinib), chemotherapy
(TemCap) and PRRT
◆ Most adequate treatment sequencing is unknown and is a current challenge
◆ Discussion of patients in expert MDTs is recommended for adequate treatment planning at time of presentation
◆ Selection of systemic treatment relies on tumour proliferation rate, Ki-67 and disease burdenTHANK YOU!
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