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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 TOPANCREATIC NETsEpidemiology

Clinical presentation

Grading

Staging

EPIDEMIOLOGY

NETs are rare malignancies but incidence is increasing

Incidence of NETs is increasing

▪ Most dramatic rise in incidence in

patients 65 years or older (8-fold rise to

25.3 per 100,000 persons)

Diagnosis of localised stages and

grade 1 tumours is increasing:

better diagnosis?

Dasari A, et al. JAMA Oncol 2017;3(10):1335–42.

p

EPIDEMIOLOGY

PanNETs are rare (low incidence)

Increase in incidence of NETs

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)

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

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

CLINICAL PRESENTATION

Functioning vs. Non-Functioning

Most (60–90%) of PanNETs are

non-functioning

◆ 10–40% are expected to be

functioning

◆ Specific GUT hormones may be

assessed at diagnosis if clinical

suspicion of specific syndrome

(+CgA)

Falconi M, et al. Neuroendocrinology 2016;103(2):153–71 CgA: Chromogranin A; WDHA, watery diarrhoea, hypokalaemia, achlorhydria

Most frequent functioning PanNETs

Name

Biologically

active

peptide(s)

secreted

Incidence (new cases/106

population/year) Tumour location

Malignant,

%

Associated

with

MEN1, % Main symptoms/signs

The most common F-P-NET syndromes

Insulinoma Insulin 1–32 Pancreas (>99%) 100 cases)

VIPoma (Verner-

Morrison

syndrome,

pancreatic

cholera, WDHA)

Vasoactive

intestinal

peptide

0.05–0.2 Pancreas (90%,

adult)

Other (10%,

neural, adrenal,

periganglionic)

40–70 6 Diarrhoea (90–100%)

Hypokalaemia (80–100%)

Dehydration (83%)

Glucagonoma Glucagon 0.01–0.1 Pancreas (100%) 50–80 1–20 Rash (67–90%)

Glucose intolerance (38–87%)

Weight loss (66–96%)

CLINICAL PRESENTATION

Functioning vs. Non-Functioning

Falconi M, et al. Neuroendocrinology 2016;

103(2):153–71

Less frequent functioning PanNETs

Among functioning

PanNETs, hormone

secretion may

drive treatment

strategy and needs

to be taken into

account

Name

Biologically active

peptide(s) secreted

Incidence(new cases/106

population/year) Tumour location Malignant, %

Associated with

MEN1, % Main symptoms/signs

SSoma Somatostatin Rare Pancreas (55%)

Duodenum/jejunum (44%)

>70 45 Diabetes mellitus (63–90%)

Cholelithiases (65–90%)

Diarrhoea (35–90%)

GRHoma Growth hormone-

releasing hormone

Unknown Pancreas (30%)

Lung (54%)

Jejunum (7%)

Other (13%)

>60 16 Acromegaly (100%)

ACTHoma ACTH Rare Pancreas (4–16% all

ectopic Cushing’s

syndrome)

>95 Rare Cushing’s syndrome (100%)

P-NET causing carcinoid

syndrome

Serotonin

? Tachykinins

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)

Lloyd RV, et al. WHO Classification of Tumours of Neuroendocrine Organs 4th Ed 2017

Classification / grade Ki-67 proliferation index (%) Mitotic index

Well-differentiated PanNENs

PanNET G1 20

Poorly-differentiated PanNENs

PanNEC G3 >20 >20

GRADING

G3-NET vs. G3-NEC

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

Differential immunolabeling and molecular alterations of pancreatic NET and NECs

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%, p

STAGING

AJCC vs. ENETS

classification

Current classifications

Very similar: except

T4, M1 status

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.

ENETS TNM (2010) AJCC 8th Edition (2017)

T Stage

T1 Confined for pancreas 4cm, or invasion of

duodenum or bile duct

Tumour limited to pancreas, more than 4 cm in greatest

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

NX Regional lymph nodes cannot be assessed Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis No regional lymph node metastasis

N1 Regional lymph node metastasis Regional lymph node metastasis

M Stage

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 .

STAGING

AJCC vs. ENETS classification

Multiple versions of the AJCC

TNM classification

Klöppel G, et al. Virchows Arch 2010;456(6):595–7; Teo RYA, et al. Surgery 2019;165(4):672–85

ENETS 2010 AJCC v.7 (2010)

Retrospective analysis:

◆ 1072 PanNEN patients

◆ ENETS vs. AJCCv.7 (2010)

◆ ENETS classification seemed

superior?

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)

Falconi M, et al. Neuroendocrinology 2016;103(2):153–71; Sharma P, et al. Q J Nucl Med Mol Imaging 2016;60(1):69–76

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;

LOCALISED STAGE: MANAGEMENTSurgical management

Adjuvant treatment

Risk stratification

Post-surgical follow-up

SURGICAL MANAGEMENT

Localised disease; 2 cm size cut-off

In selected patients with

tumours 2 cm – surgery

Surveillance depending on final

pathology

Tumour >2 cm

Surgeryb

Limited resection only if conditions

favourable to preserve organ

function (otherwise oncological

resection)

See section on treatment for

advanced disease

ADJUVANT 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):153–71

RISK STRATIFICATION

Risk factors for relapse (PanNETs)

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]

Relapse Rate Risk factors Site of recurrence

Gao 2018Relapse rate 129/505 (25.5%).

Median disease-free survival of 19 months (range 6–96 months) T3, T4, N1, Ki67 >2%, functional Not reported

Sho 2018

Relapse rate 23/140 (16.3%).

5- and 10-year relapse-free survival were 84.6% and 67.1%,

respectively

Size >5 cm, N1, Ki67 >20%All recurrences were distant

(liver, peritoneal and bone)

Genç 2018

Relapse rate 35/211 (17%).

The 5- and 10-year disease-specific/overall survival was 98%/91%

and 84%/68%, respectively.

Median timeto recurrence was 43 months (IQR 23–62)

Grade 2, N1, perineural invasion

Pancreatic remnant (69%),

distant (14%), 1 patient had

lymph node metastasis

Ausania 2019Relapse rate 19/137 (13.9%).

Median DFS was 55 months

Tumour size >2 cm, N1, Ki67>5%

or mitotic index >2Not reported

Marchegiani 2018

Recurrence rate 12.3%.

Recurrence occurred either during the first year of follow-up (n=9),

or after ten years (n=4)

>21 mm size, G3, N1,

vascular infiltration

Liver (11.1%), local recurrence

(2.3%), lymph node (2.1%),

other organs (1.6%)

RISK STRATIFICATION





Gao 2018Relapse rate 129/505 (25.5%).

Median disease-free survival of 19 months (range 6–96 months)T3, T4, N1, Ki67 >2%, functional Not reported

Sho 2018

Relapse rate 23/140 (16.3%).

5- and 10-year Relapse-free survival were 84.6% and 67.1%,

respectively



Genç 2018




Median time to recurrence was 43 months (IQR 23–62)



distant (14%), 1 patients had





or mitotic index >2Not reported

Marchegiani 2018

Relapse rate (12.3%).


or after ten years (n= 4)




(2.3%), lymph node (2.1%),

other organs (1.6%)

Lesson 1: Relapse rate 12–25%

RISK STRATIFICATION





Gao 2018Relapse rate 129/505 (25.5%).


Sho 2018

Relapse rate 23/140 (16.3%).


respectively

Size >5 cm, N1, Ki67 >20%All recurrence were distant


Genç 2018












or mitotic index >2 Not reported

Marchegiani 2018







(2.3%), lymph node (2.1%),

other organs (1.6%)


Lesson 2: Late relapses DO exist (>5/10 years)

RISK STRATIFICATION





Gao 2018Relapse rate 129/505 (25.5%).

Median disease-free survival of 19 months (range 6–96 months). T3, T4, N1, Ki67 >2%, functional Not reported

Sho 2018

Relapse rate 23/140 (16.3%).


respectively



Genç 2018




Median time to recurrence was 43 months (IQR 23 – 62)







Tumour size >2 cm, N1,

Ki67>5% or mitotic index >2 Not reported

Marchegiani 2018


Recurrence occurred either during the first year of follow-up (n= 9),

or after ten years (n= 4)




(2.3%), lymph node (2.1%),

other organs (1.6%)



Lesson 3: Size/T, N, Ki67/grade are repetitive prognostic factors

RISK STRATIFICATION





Gao 2018Relapse rate 129/505 (25.5%).

Median disease-free survival of 19 months (range 6–96 months)T3, T4, N1, Ki67 >2%, functional Not reported

Sho 2018

Relapse rate 23/140 (16.3%).


respectively



Genç 2018





Grade 2, N1, perineural

invasion








Marchegiani 2018







(2.3%), lymph node (2.1%),

other organs (1.6%)




Lesson 4: Other factors may require further confirmation

RISK STRATIFICATION





Gao 2018Relapse rate 129/505 (25.5%).


Sho 2018

Relapse rate 23/140 (16.3%).


respectively



Genç 2018



and 84%/68%, respectively. Median time

to recurrence was 43 months (IQR 23–62)






Median DFS was 55 months.



Marchegiani 2018







(2.3%), lymph node (2.1%),

other organs (1.6%)




Lesson 4: Other factors may require further confirmation

Lesson 5: Site of recurrence distal (liver) > local

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

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 guidelines

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)

POST-SURGICAL FOLLOW-UP

Current practice is variable between centres

Data from a US/Canada survey:

◆ Clinicians aware of guidelines but there was

still very significant variability between sites

Chan DL, et al. Neuroendocrinology 2017;107(1):32–41

The current guidelines are not widely adopted,

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

Follow-up for Resected Gastroenteropancreatic

Neuroendocrine Tumours: A Practice Survey of the

Commonwealth Neuroendocrine Tumour Collaboration

(CommNETS) and the North American Neuroendocrine

Tumour Society (NANETS)

ADVANCED STAGE: MANAGEMENTHow to select the most adequate treatment

Liver-directed therapies

Somatostatin analogues

Targeted therapies

Chemotherapy

PRRT

HOW TO SELECT THE MOST ADEQUATE TREATMENT

ENETS guidelines

◆ Surgery can have a role in

metastatic disease

◆ Liver-directed therapy plays a role

in selected patients

◆ Multiple systemic therapy options

Importance of individualised

treatment and planification of a

treatment strategy by an

experienced MDT

Pavel M, et al. Neuroendocrinology 2016;103(2):172–85

Resection of primary

Two-step surgery

1.Minor resection

± RFA, RPVE,

RPVL

2.Sequential

major liver

resection

Resection (minor

or anatomical)

Surgery

contraindicated

Selected

cases (


ENETS guidelines


metastatic disease



◆ Multiple systemic therapy options




experienced MDT


Two-step surgery

1.Minor resection

± RFA, RPVE,

RPVL

2.Sequential

major liver

resection

Resection (minor

or anatomical)

Surgery

contraindicated

Selected

cases (

LIVER-DIRECTED THERAPIES

A very significant proportion of patients diagnosed with

PanNET will have liver metastases

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.

Resection of liver metastases from PanNETs

Resection of liver metastases (if resectable) seems to

improve survival (no prospective randomised data available)


ENETS guidelines


metastatic disease



◆ Multiple options of systemic therapy




experienced MDT


Two-step surgery

1.Minor resection

± RFA, RPVE,

RPVL

2.Sequential

major liver

resection

Resection (minor

or anatomical)

Surgery

contraindicated

Selected

cases (

LIVER-DIRECTED THERAPIES

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.

Liver embolisation (TAE, TACE) in PanNETs


ENETS guidelines


metastatic disease



◆ Multiple options of systemic

therapy




experienced MDT


Two-step surgery

1.Minor resection

± RFA, RPVE,

RPVL

2.Sequential

major liver

resection

Resection (minor

or anatomical)

Surgery

contraindicated

Selected

cases (

HOW TO SELECT THE MOST ADEQUATE (SYSTEMIC) TREATMENT

Understanding the effect of different systemic treatments

Chemotherapy (20–50%)

Targeted (5-10%)

SSA (0%)

PRRT (18%)May be higher in

PanNETs (58%)

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):236–48

Principles for treatment selection:

1. Targeted therapies are effective in treatment-naïve as well as

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

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):15–25

Decision based on tumour burden, Ki-67 and rate of progression (tumour kinetics)


or SSA

or PRRT

CAP, Capecitabine; TEM, temozolomide. *≤6-12 months. †Cisplatin can be replaced by carboplatin.Pavel M, et al. Neuroendocrinology 2016;103(2):172–85.

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

Pancreas

Midgut

Atypical carcinoid and/or SSTR negative

Insulinoma or contraindication for CTX

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

SOMATOSTATIN ANALOGUES

Rinke A, et al. J Clin Oncol 2009;27(28):4656–63

Octreotide (PROMID study)

◆ G1 metastatic or locally advanced well diff,

functioning* or non-functioning midgut NETs

(no PanNETs included)

◆ Randomisation 1:1 (n=85 patients)

R

Octreotide LAR 30 mg

4-weekly

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


Caplin ME, et al. N Engl J Med 2014;371: 224–33

Lanreotide (CLARINET study)

◆ G1 or G2 (Ki-67


Rinke A, et al. J Clin Oncol. 2009;27(28):4656–63; Caplin ME, et al. N Engl J Med 2014;371: 224–33.

Octreotide vs. Lanreotide (role beyond anti-hormone function)

Octreotide LAR

30 mg, im 4-weekly

(PROMID study; vs. placebo)

Lanreotide Autogel

120 mg; deep sc, 4-weekly

(CLARINET study; vs. placebo)

Population of patients

Advanced, functional or non-functional midgut

primary tumour or tumour of unknown.

PanNETs were excluded.

Advanced, non-functioning, somatostatin

receptor-positive, grade 1 or 2 (Ki-67

TARGETED THERAPIES

Two main pathways to target:

◆ mTOR (everolimus)

◆ Angiogenesis (sunitinib)

Adapted from Lamarca A, et al. J Oncopathol 2014;2(1):15–25

Potential pathways to target

Molecular biology in pNETs

TARGETED THERAPIES

Sunitinib

◆ G1 or G2 metastatic or locally advanced well

diff, functioning or non-functioning PanNETs

◆ Progressed within previous 12 m

◆ Randomisation 1:1 (n=171 patients

randomised*)

R

Sunitinib 37.5 mg PO OD

Placebo

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;364:501–13

TARGETED THERAPIES

Everolimus


diff, functioning or non-functioning PanNETs

◆ Progressed within previous 12 m

◆ Randomisation 1:1 (n=410 patients)

R

Everolimus 10 mg PO OD

Placebo

Primary endpoint: Progression-free survival

Yao JC, et al. N Engl J Med 2011; 364:514-523

TARGETED THERAPIES

Sunitinib and Everolimus

Sunitinib

37.5 mg once daily

(Phase 3 vs. placebo)

Everolimus

10 mg once daily

(Phase 3 vs. placebo)

Population of patientsUnresectable or metastatic, well- or moderately-

differentiated PanNETs

Unresectable or metastatic, well- or moderately-

differentiated PanNETs

Documented disease

progression at study entryYes Yes

Objective response rate 9.3% vs. 0% 5% vs. 2%

Median PFS (experiment vs.

placebo) (months)

11.4 vs. 5.5

HR 0.42 (95% CI 0.26, 0.66); p

TARGETED 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

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)

Benefit from chemotherapy in PanNETs: Objective response

Non-PanNETs

Response Rate

9.5%

PanNETs

Response Rate

26.3%

Vs.

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

Multiple different chemotherapy

combinations have been tested

over the years, most of them

in retrospective series of small

prospective studies

Treatment Type of Trial Patients’

characteristics

Number of pNET

patients

Response rate (%) Disease

control

rate (%)

Median PFS

(months)

Median overall

survival (months)

Year of publication

(References)

Chemotherapy

Chlorozotocin vs.

Streptozocin and

fluorouracil vs. Doxorubicin

and streptozocin

Phase III Previous chemo

allowed (no data)

33

33

36

30

45

69

No data 17

14

18

18

16.8

26.4

1992 (12)

Doxorubicin and

streptozocin

Retrospective

analysis

24% previous

chemotherapy

45 36 60 16 2-year survival rate:

50.2%

2004 (13)

Streptozocin, doxorubicin

and fluorouracil

Retrospective

analysis

5% second line 84 39 89 18 37 2004 (14)

5-fluororuracil, cisplatin and

streptozocin

Retrospective

analysis

Chemo naïve

patients

82 (49 pNETs) 38 86 9.1 31.4 2010 (15)

Capecitabine and

streptozocin +/-cisplatin

Randomised

Phase II

Previous chemo

allowed (no data)

86 (48% pNETs) 14/8 78/82 9.7/10.2 34.7 2012 (16)

Decarbazine Phase II 44% second line 50 34 No data No data 19.3 2001 (18)

Temozolomide and

thalidomine

Phase II 45% second line 29 (38%

pancreatic)

45 93 No data 2-year survival rate

61%

2006 (19)

Temozolomide and

capecitabine

Retrospective

analysis

Chemo naïve

patients

30 70 97 18 2-year survival rate

92%

2011 (21)

Temozolomide and

bevacizumab

Phase II 44% second line 35 (44%

pancreatic)

33.3 87 14.3 41.7 2012 (20)

Temozolomide, everolimus Phase I/II 33% second line 43 40 93 15.4 No data 2013 (37)

Capecitabine and

oxaliplatin

Retrospective

analysis

Second line 27 well-

differentiated NETs

included

27 well-

differentiated NETs

(unknown number

of pNETs)

30 78 20 40 2007 (23)

5-fluorouracil, oxaliplatin

and bevacizumab

Phase II No 6 of 13 patients

included

20 100 No data No data 2008 (24)

Capecitabine, oxaliplatin

and bevacizumab

Phase II No data 20 30 94 13.7 No data 2011 (25)

Chemotherapy and Targeted Therapy Studies for Well-differentiated Pancreatic NETs

Adapted from Lamarca A, et al.

J Oncopathol 2014;2(1):15–25

CHEMOTHERAPY

◆ Capecitabine (750 mg/m2 twice

daily day 1–14) + temozolomide

(200 mg/m2 once daily day

10–14); 28-day cycle

◆ Median PFS 18 months

◆ Radiological response rate:

70%

◆ Toxicity: myelosuppression

Strosberg JR, et al. Cancer 2011;117(2); 268–75. Courtesy of John Wiley and Sons. Copyright © 2010 American Cancer Society

Temozolomide + Capecitabine

% c

han

ge

Best radiographic response | 70% of patients achieved PR (RECIST)

CHEMOTHERAPY

Randomised phase II study in progressive PanNETS

Kunz P, et al. J Clin Oncol 36, 2018 (suppl; abstr 4004). By permission of Dr Pamela Kunz

Temozolomide Capecitabine vs. Capecitabine: E2211 clinical trial

Progressive,

G1 / G2, metastatic

pancreatic NETsR

Arm A:

Temozolomide 200 mg/m2 po QD days 1–5

Arm B:

Capecitabine 750 mg/m2 po BID days 1–14

Temozolomide 200 mg/m2 po QD days 10–14Stratified by:

◆ Prior everolimus

◆ Prior sunitinib

◆ Concurrent octreotide

Primary endpoint:

PFS (local review)

Secondary endpoint:

RR, OS, toxicity

Correlative endpoints:

MGMT by IHC, MGMT by

promoter methylation

1:1 n=72

n=72

Cycle length = 28 days; max 13 cycles.

Imaging performed every 12 weeks (RECIST 1.1)

CHEMOTHERAPY

Randomised Phase 2 study in progressive PanNETS

Kunz P, et al. J Clin Oncol 36, 2018 (suppl; abstr 4004) 2018. By permission of Dr Pamela Kunz.

Temozolomide Capecitabine vs. Temozolomide: E2211 clinical trial

Tem TemCap Comments

Grade 1

Grade 2

45.1%

54.9%

68.1%

31.9%

PFS (median) (months) 14.4 22.7HR 0.58 (95% CI 0.36, 0.93); p=0.023

If adjusted for grade results are

unchanged (HR 0.61 p=0.042)

OS (median) (months) 38.0 Not reachedHR 0.41 (95% CI 0.21, 0.82); p=0.012

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

PEPTIDE RECEPTOR RADIONUCLIDE THERAPY (PRRT)

◆ 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 Society

NETTER-1 clinical trial: PRRT vs. Octreotide 60 mg

PEPTIDE RECEPTOR RADIONUCLIDE THERAPY (PRRT)

◆ 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

Ramage J, et al. Semin Oncol 2018;45(4):236–48

Experience of PRRT in PanNETs

“The effect may be at least as great as in midgut NET”

THE FUTURE OF MANAGEMENT OF PANCREATIC NETSNew 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

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 2017

Cabozantinib, Sulfatinib

◆ Phase 3 trials ongoing in view of promising Phase 2 results

CHALLENGES FOR TREATMENT SEQUENCING

Targeted or PRRT: COMPETE study (n=300)


diff, functioning or non-functioning GEP-NETs

◆ SSTR +ve

◆ PD as per RECIST 1.1

◆ Randomisation 2:1

R

177Lu-DOTA-TOC 7.5 Gbq

(4 cycles; 1 dose/12 wks)


Primary endpoint: Progression free survival at 2 years

Primary completion date: Dec 2020

CHALLENGES FOR TREATMENT SEQUENCING

Targeted or Chemotherapy: SEQTOR study (n=180)


diff, functioning or non-functioning Pan-NETs

◆ Randomisation 1:1

R


Streptozocin + 5-FU

3/6-weekly

Primary endpoint: Progression free survival

Accrual completed: October 2018

Expected results: 2020

IMMUNOTHERAPY

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 burden

THANK YOU!

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