Kianmanesh 2021

Should we resect the primary tumor in metastatic NENs?

Prof. Reza Kianmanesh, MD, PhD.

(Hopital Robert Debre, Reims, France, University of Champagne Ardenne, France)

Kianmanesh 2021

A “reactualized” CONCEPT - Why to resect the PT in stage IV patients ?

PrimaryTumor

resection

Multicompartmental disease

siNENs pNENs

Stage IV

Unicompartmental disease

MWA MWA + RIGHT HEPATECTOMY

Liver Focused Therapies – PRRT…

Stage IV

MODERN THERAPIES

IMPROVED SURVIVAL ?

1. FOR MACROSCOPIC CURE ?

2. TREAT OR AVOID COMPLICATIONS ?

3. FOCUS ON LIVER TREATMENT ?

3 QUESTONS

Kianmanesh 2021

CONTROVERSIES

Primary tumor resection in stage IV NENs ?

No prospective RCT Retrospective

Unicenter Studies

Selection BiasEven in systematic reviews/metanalyzes!

Expert – Guidelines recommendations

Large Historic Data bases Potential benefit of PTR

Best Indications for PTR +++

Kianmanesh 2021

N=13 studies, 6 suitable for Meta-Analyse, no RCT !

Role of palliative resection of the primary tumour inadvanced pancreatic and small intestinalneuroendocrine tumours: A systematic review andmeta-analysisAlmond, L. M.; Hodson, James; Ford, S. J.; Gourevitch, David; Roberts, K. J.; Shah, Tahir;Coles, Jessica; Desai, Anant

DOI:10.1016/j.ejso.2017.05.016

License:Creative Commons: Attribution-NonCommercial-NoDerivs (CC BY-NC-ND)

Document VersionPeer reviewed version

Citation for published version (Harvard):Almond, LM, Hodson, J, Ford, SJ, Gourevitch, D, Roberts, KJ, Shah, T, Isaac, J & Desai, A 2017, 'Role ofpalliative resection of the primary tumour in advanced pancreatic and small intestinal neuroendocrine tumours: Asystematic review and meta-analysis', European Journal of Surgical Oncology (EJSO).https://doi.org/10.1016/j.ejso.2017.05.016

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2017

Almond, L. M.; Hodson, James; Ford, S. J.; Gourevitch, David; Roberts, K. J.; Shah, Tahir; Coles, Jessica; Desai, Anant

Pooled multivariate demonstrated significantly longer overall survival in patients undergoing resection of both

P-NETs (HR 0.43; 95% CI: 0.34 - 0.57, p<0.001) and SI-NETs (HR 0.47; 95% CI: 0.35 - 0.55, p=0.007).

Almond et al. EJSO 2017.

Why include these 2 studies ?

Not prospective, old, (2007, 2009)How to conclude or make Meta-analyze ?

DEBATABLE

Kianmanesh 2021

SiNENs & pNENs are different diseases ?

Kianmanesh 2021

Embryo /genetic Forgut / NEM1 Midgut

Grade G1,G2,G3-undifferenciated G1,G2 better prognosis

Size 1cm to > 10 < 2cm

Hormonal secretion F / NF Serotonine LN/LM

LN size small large

Ga-PET / F-DopaPET Ga Ga / F-Dopa

FDG-PET + for G2,G3, undifferentiated -

Drug (CT, Target) Sensitivity +++ +/-

Primary complications +/- + (10-30%)

Morbidity of primary resection +++ (PD 30% mb, up to 10% mt*) +/-

LM treatment options-SSA / Chemotherapy / Target therapy

-CEIA / Radioembolization

-Liver resection-ablation / liver Transplantation

GEP NENs – Different disease

pNEN siNEN

MULTIMODAL

Kianmanesh 2021

siNEN are «Complex Diseases»

Primary siNET

Ileon ++

MM-Lymph Nodes 80% -LN stages (I-IV)

Liver Metastases 30% to 80%

Small < 1 cm(20% to 30% multiple)

Small/large (± fibr. mesenteritis)

Multiple primaries 30%

Small or large

Multiple bilobar (> 70%)Diffuse disease?

Recurrence after liver resection: > 80%

Diffuse multicompartmental disease in > 50% of patients?

Surgical Macro. Cure

Is a LRT ++++

Primary + MM

LN > 8-12 is prognostic

Liver resection- Ablation

Analogue sensitive

Not chemosensitive

PRRT sensitive

TACE/TAE sensitive

Target T ± sensitive

-RADIANT-4 study

-NETTER trial

-CLARINET fort

siNET Stage Particularities Therapeutic options

Kianmanesh 2021

siNENs Complications are Life-threatening

Occlusive syndrome (20% to 30%)

Endoluminal obstruction of the primary

Exoluminal compression (MM, PC)

Mesenteric mass

• LN (with localized PC 15%)

• Fibrosis (desmoplasia)

Hemorrhage (5%)

Mesenteric ischemia (< 3%)

Images courtesy of Kianmanesh R.

a b

c d

Symptomatic patients with SiNENs at any stage Primary resection because life-threatening

Primary resection often required even in preclinic signs

What to do with Mesenteric Masses ?

Cure LocoRegional Resection Remove primary + LN + MM

Kianmanesh 2021

Pancreatic and/or Bile duct dilatation T3

pNENS Complications do not require Routine Surgery

Primary pNENs Complications (<10%):

• Venous thrombus (splenic, mesenteric, portal)• Sinitral (left) portal hypertension• Haemorrhage• Biliary obstruction (Jaundice)• Duodenum-colon compression• Wirsung dilatation

pNENs symptomatic patients Surgery is not always required

Place for heparine, stenting, …

Different tumor location from duodenum-head to tail of the pancreas

Different morbidity – mortality upon tumor location

Image courtesy of Kianmanesh R.

Kianmanesh 2021

Tierney JF, et al. Surgery. 2019;165:644-651.

N = 14510 stage IV patients

2019

460/6088=7.5%

2526/4252=59.4%

< 10% of stage IV pNENs had PTR versus 59% for siNENs

No propensity score used!

Kianmanesh 2021

Tsilimigras et al. J Gastrointestinal Surg 2020. doi.org/10.1007/s11605-020-04898-8

J Gastrointest Surg2020

Effectif N= 2219 GEP-NETs

4.9%62.6%

Resection of primary GI-NET among patients with stage IV

disease and unresected metastases should only be

performed in selected cases following multi-disciplinary

evaluation.

PSM cohort used forN=236 with PTR

For 5-y OSIncluding all primaries

The majority of patients with stage IV GI-NETs underwent

resection of siNETs or colon NET (539/889=60%)

PTR was associated with a survival benefit among patients

with metastatic GI-NETs across all anatomic sites, except for

rectal NETs.

PTR improved OS in patients with LMs who had liver-directed

therapy (median OS: 3.44 years [1.47–3.68] vs 1.44 [1.09–2.04],

p = 0.01), and patients with LMs who did not have liver-directed

therapies (2.07 years [1.34–2.64] vs 0.73 [0.64– 0.88], p < 0.001).

Kianmanesh 2021

Complications of primary resection pNENs from siNENs

Kianmanesh 2021

% PF DG emtying Hemorrhage In-hospitalmortality

5-year OSWithout LM

5-year DSSWithout LM

5-year DSS with LM

Enucleation 45 5 6 3

85 93 80

Distal pancreatectomy

14 5 1 4

Whipple (PD) 14 18 7 6

Centralpancreatectomy

58 16 4 4

Jilesen et al. World J Surg (2016) 40:729–748

Pancreatic surgery is associated to high rate of morbidity and MortalityParticularly Whipple (PD)

Kianmanesh 2021

PD Surgery higher morbidity

mortalityMajor complications

N=376 patients NENs, N=244 p & siNENs

Major complications

Kianmanesh 2021

Stage IV – Resectable or unresectable LMs ?

Kianmanesh 2021

Stage IV – Different stage IV patients may require PTR

56-year-old

Asymptomatic

Resectable LM asymptomatic

TNM staging. Rindi G, et al. Virchows Archiv. 2007;451:757-762.

Focus on liver treatment Potential benefit on Overall Survival ?

Primary Tumor ResectionBetter Survival ?

Liver directed Treatments Systemic Treatments

Type II

69-year-old

Occlusion

Unresectable LM symptomatic

Treat Life-threatening Complications +++ Potential benefit on Overall Survival ?

Type III

Kianmanesh 2021

Agressive management of LMs,

Assicated S-Analogues & PRRT ?

Kianmanesh 2021

Aggressive treatments:- resection+Ablation (RA)--- resection+TACE (TRA)

Non aggressive treatments

2005

Management of Stage IV NENs is Multimodal

N=60 LM from DETs, Milwaukee (1990-2004)

2005

Agressive Cytoreductive surgery & S-LAR

2015

Kianmanesh 2021

Management of Stage IV NENs is Multimodal

Fairweather et al. Ann Sureg Oncol 2017

N=939 NENs, N=649 with LMs

Better Outcome for:

-SiNENs vs pNENs-Liver resection vs other-WD tumors vs other

2017

Aggressive Treatments LMs fromSiNENs

Kianmanesh 2021

Management of Stage IV NENs is Multimodal

Bertani et al. Ann Sureg Oncol 2016

Unresectable LMs + Primary pNENs Primary Resection

2016

Primary pNET resected before PRRT

PRRT for LMs Better Survival

Kianmanesh 2021

N=889 Stage IV

Ann Surg2019

N=403 no PT before PRRTN=486 Primay removed before PRRT

pNETS=38%SiNTS=32%

pNETS siNETS

Kianmanesh 2021

2019

LMs + Primary siNENs or pNENs Primary resection PRRT Better Survival pNEN & siNENs

Reasons why primaries did not underwent resection ?, more advanced disease, poorer GC, larger primaries, more EHD ?

Kianmanesh 2021

Balazevic et al. Cancer 2020.

MM growth 13.5% patients over 3.4 years,PRRT reduced MM size in only 3.8% of patients!

2020

N=530 siNENs2/3 with MM

MM growth (>20%)Effect of PRRT on?

Kianmanesh 2021

Stage IV with extrahepatic disease (EHD)

Kianmanesh 2021

International Journal of Surgery2015

2 main prognostic factors:-Tumor burden-ExtraH disease

Bertani et al. International Journal of Surg 2015.

PTR of siNENs with LMs is less effective in patients with extahepatic disease

--- LMs & Extahepatic

Kianmanesh 2021

Ejaz et al. J Surg Oncol 2017.

J Surg Oncol 2017

Liver-directed therapies are not effectif in patients with extahepatic disease and >50% liver involvement

Kianmanesh 2021

Actual controversies – Recommendations

Scientific data

Kianmanesh 2021

SiNEN – Recommendations

Kianmanesh 2021

pNEN – Recommendations

PTR FOR UNRESECTABLE G1,G2 LMS NOT CLEARLY MENTIONED

Kianmanesh 2021

Recent Reviews and Larges Series

Kianmanesh 2021

Lewis et al. Ann Surg 2018.

2018

Even if the OS is better when LM are treated, Primary Resection seems improve OS of patients with untreated LMs !

N=854 GI stage IV NENs, N=430 LMs, N=392 PTRs

N=240 LMs treatment N=190 no LMs treatment

PTR for pNEN N=76/372 (20%)PRT for siNENs N=162/200 (81%)

No Propensity score Matching !

Conclusions:

consider PTR with or without LMs treatment on

an individualized basis until prospective findings

confirm the presence of a survival benefit for

these patients.

Selection Bias patients with slow growing LM were observed ?

Kianmanesh 2021

Partelli et al. HPB 2017.

HPB 2017

N=7 Studies, Compared 2 of them published more than 10 years ago!N=251 underwent primary surgery vs N=634 without primary resection

Kianmanesh 2021

Stage IV pNENs - After propensity score-adjusted N=359, PTR N=73 versus noPTR N=286

Kianmanesh 2021

Zhou et al. OncoTargets and Therapy 2018.

OncoTargets and Therapy

2018:11 975–982

Primary resection increases survival:

-Not for agressive surgery (morbidity)

-Good general condition

-Less advanced disease

-Body & tail pancreatic NENs

N=10 Studies, ComparedN=1226 underwent primary surgery vs N=1623 without primary resection

Bo Zhou1 canyang Zhan2 Yuan Ding1 sheng Yan1 shusen

Zheng1

4 included studies have more than 10 years publications !

3 included studies from the same center…

∂

Kianmanesh 2021

Tsoli et al. Cancer 2020.

2020

Conclusions:

PTR may exert a survival benefit in stage IV pNENs.

However, the included studies were subject to selection

bias, and special consideration should be given to PPTR

anchored to a multimodal treatment strategy.

N=5551 – 6 recent studies - Stage IV pNENs with LMs

PTR PT not resected5-year OS 56.6% 23.9%Complication rate PTR 27%

Kianmanesh 2021

Zheng et zal. Cancer Medicine 2019. DOI: 10.1002/cam4.2431

2019

Effectif N=1547 patients with GEP-NEN with LMPRT N=897

siNENs, N=556

pNENs, n=501

All NENs

N=511 unD or Poorly DN=310 Moderately Differentiated

N=726 Well Differentiated NENs !

N=821 !

Kianmanesh 2021

N=4076 metastatic midgut NENs (Primary resection 62%)

2020

Polz et al. Ann Surg Oncol 2020.

2004-2014 including different centers in USA

Interesting large population but retrospective and mainly comparative

Kianmanesh 2021

Daskalakis et al. JAMA Oncol. doi:10.1001/jamaoncol.2017.3326

Uppsala, Sweden, 1985-2015. N=363 Stage IV - SiNETs

No abdominal symptom within 6 months +++Emergency Surgery excluded.

Compared 2 groups:

N=161 prophylactic up-front LRSN=202 nonsurgical or delayed LRS

N=820 eligible N=363 included

2017

-Prophylactic up-front LRS conferred no survival

advantage in asymptomatic patients with stage IV

SI-NETs.

-Delayed surgery as needed was comparable in all examined

outcomes and was associated with fewer reoperations for

intestinal obstruction.

-The value of a priori LRS in the presence of distant

metastases is challenged and needs to be elucidatedin a randomized clinical study.

Kianmanesh 2021ENETS 2016 Guidelines

(1)

(2)

(3)

“ Routine resection of the siNETS primary ” has never been prospectively demonstrated to increase the overall survival in ASYMPTOMATIC stage IV patients with UNRESECTBLE LMs.

Need for RCT +++

Kianmanesh 2021

Take Home Messages and Conclusions

Kianmanesh 2021

Take Home Message “Primary resection in metastatic disease stage IV”

Andreasi et al. Curr Treat Options in Oncol 2020. Bertani et al. Surgery 2014. Neiderle et al. Current Oncology Reports 2021, 23, 85. Howe et al. Pancreas 2017. Howe et al. Pancreas 2020.

No Randomized Trial – Multiple selection bias in systematic reiews, meta-analyzes without RCT, retrospective data ?

● No survival benefit in case of G3 & poorly differentiated lesions (should be excluded from analyzes)

● PTR is recommended in all symptomatic siNET patients

● PTR may improve survival in selected patients with low-grade burden tumors, low risk resectableprimaries and in some patients with LMs in both pNENs and siNENs especially prior to PRRT.

● Patient selection in MDT remains mandatory in a multimodal long-term therapeutic strategy upon:

⁃ Patient’s general condition

⁃ Tumor grade/differentiation

⁃ Presence of extrahepatic disease / degree of liver involvement and resectability

⁃ Risks of PTR upon tumor nature and location, functionality, difficulties of lymphadenectomy (MM)

• for pNENs, body and tail pNENs rather than head of the pancreas (High morbidity)

• for SiNENs, remove the primary and LN and the MM (if possible, LN-stages I,II,IIIdown)

• Possibility of effective treatments including PPRT, LD-therapies, hepatectomy, TA and/or liver transplantation.