is there an added value of surgery in the treatment … · tumor van het intestinale type, waarbij...

IS THERE AN ADDED VALUE OF

SURGERY IN THE TREATMENT OF

OLIGOMETASTATIC PANCREATIC

CARCINOMA?

Jakob Vandeveire Student number: 01207797

Supervisor(s): Prof. Dr. Karen Geboes, Dr. Marc De Man, Dr. Tom Holvoet

A dissertation submitted to Ghent University in partial fulfilment of the requirements for the degree of

Master of Medicine in Medicine

Academic year: 2017 – 2018

Acknowledgments

First and foremost, I would like to thank my promotor Prof. Dr. Karen Geboes for her assistance in

the realization of this thesis and her greatly appreciated feedback. Despite her busy schedule, she

always managed to find time to help me with my problems. She gave me the freedom and

responsibility to take care of things myself but was always available to answer my questions. At

meetings, she always gave me useful information I could really appreciate. In general, writing this

thesis was a positive and educational experience.

Secondly, I would also like to thanks my mentor Dr. Tom Holvoet for his constructive feedback and

friendly attitude, even though we only communicated through e-mail.

Furthermore I would like to thank my family, for carefully listening to me when I was stressing out

and for giving me positive energy and courage to keep going. Thank you for supporting me and

always trying to keep me motivated.

Last but not least my close friends in general also deserve a sincere thanks for helping me with all

of my questions concerning this thesis and for supporting me through this period of establishing

this final task before concluding the theoretical part of my medicine study.

Jakob Vandeveire

Ghent, December 2017

Table of contents

Abstract ................................................................................................................................. 1

Abstract (Nederlands) ........................................................................................................... 3

Introduction ........................................................................................................................... 5

Methods ................................................................................................................................ 7

Results .................................................................................................................................. 9

1. Systemic therapy ........................................................................................................ 9

2. Surgery ......................................................................................................................11

2.1. Pancreatic Ductal Adenocarcinoma (PDAC) .......................................................11

2.1.1. Decision for resection ..................................................................................15

2.1.2. Median operative time .................................................................................17

2.1.3. Blood loss ....................................................................................................21

2.1.5. Duration of hospitalization and ICU stay ......................................................24

2.1.6. Survival ........................................................................................................25

2.1.7. Adjuvant surgery ..........................................................................................30

2.1.8. Case reports ................................................................................................30

2.2. Periampullary cancer ..........................................................................................34

2.2.1. Complication rate .........................................................................................35

2.2.2. Survival ........................................................................................................35

2.3. Acinar cell carcinoma ..........................................................................................36

3. Radiotherapy .............................................................................................................37

Discussion ............................................................................................................................39

Conclusion ...........................................................................................................................47

Reference list .......................................................................................................................48

Appendix ............................................................................................................................... 1

Characteristics of studies: .................................................................................................. 1

Attachments .......................................................................................................................... 1

1

Abstract

Background

Pancreatic carcinoma has a relatively low incidence in Europe but at the same time is ranked

4th in the list of most deadly cancers. 50% of patients are already in a metastatic stage of

disease at the time of diagnosis. Without treatment, these patients have a median survival of

4-6 months and a 5-year survival rate of about 1-2%. The current standard therapy for this

group of patients is the initiation of a palliative treatment with chemotherapy.

Objectives

A systematic review of literature analysing the outcome of different approaches in the

treatment of patients with oligometastatic pancreatic carcinoma. This literature study

specifically compares morbidity, mortality and survival of these different treatment strategies

in order to assess a potential added value of surgery in comparison to other treatment

strategies for patients with oligometastatic pancreatic carcinoma.

Search methods

Pubmed, Embase and Web of Science were searched for eligible publications. In order to find

some additional articles, additional searches on Google Scholar were done. Only articles from

1995 and later were included. Most articles were obtained through the references of articles

found via the databases mentioned above.

Results

Most patients included in studies assessing the value of surgery in metastatic pancreatic

carcinoma are highly selected because the decision to proceed to surgery is only made when

the patient is in good general condition and has low overall tumor burden with a high chance

of R0 resection. Significant differences in perioperative morbidity and mortality were observed

between simultaneously resected patients and patients who underwent palliative bypass

surgery. Median overall survival in patients who underwent resection for metastatic pancreatic

ductal adenocarcinoma ranged from 5.9 months to 31.0 months. Specifically, patients who

underwent staged resection or metachronous resection had a better overall survival in

comparison to synchronously resected patients. Survival observed in case reports is

remarkably higher since surgery was only done following an exceptionally good response to

chemotherapy. When differentiating between tumor histology, a better survival in patients with

periampullary tumours was observed, specifically when it concerned an intestinal type tumor

2

with survival ranging up to 23 months. Also, acinar cell carcinomas tend to have a better overall

survival in general in comparison to PDACs.

Conclusion

Surgery can be considered a valuable treatment strategy in the treatment of oligometastatic

pancreatic carcinoma but only in highly selected cases that are in good general condition, have

low overall tumor burden and show a good response to chemo(radio)therapy. Specifically,

staged resection and metachronous resection seem to have the biggest potential to prolong

survival. More studies assessing the role of surgery in metastatic pancreatic carcinoma should

be conducted, preferably multicentre, as well as studies assessing the value of staged

resection and studies assessing the impact of (neo)adjuvant treatment on survival. In the

future, neoadjuvant chemotherapy may be used for patients presenting with metastatic

carcinoma to select appropriate candidates for surgery since only patients that respond to the

neoadjuvant treatment might also benefit from an aggressive surgical approach.

3

Abstract (Nederlands)

Achtergrond

Pancreascarcinoom heeft een relatief lage incidentie in Europa maar staat tegelijkertijd op de

vierde plaats in de lijst van meest dodelijke kankers. 50% van de patiënten bevindt zich reeds

in een gemetastaseerd ziektestadium op het moment van de diagnose. Zonder behandeling

hebben deze patiënten een mediane overleving van 4-6 maanden en een 5-jaars overleving

van ongeveer 1-2%. De huidige standaardtherapie voor deze patiënten is het opstarten van

een palliatieve behandeling met chemotherapie.

Doelstelling

Een systematische review van de wetenschappelijke literatuur waarin de uitkomst van

verschillende benaderingen voor de behandeling van patiënten met oligometastatisch

pancreascarcinoom wordt geanalyseerd. Deze literatuurstudie vergelijkt specifiek de

morbiditeit, mortaliteit en overleving van deze verschillende behandelstrategieën om een

potentieel toegevoegde waarde van chirurgie te beoordelen in vergelijking met andere

behandelingsstrategieën voor patiënten met oligometastatisch pancreascarcinoom.

Methodologie

Pubmed, Embase en Web of Science werden doorzocht op publicaties die mogelijks in

aanmerking zouden komen voor inclusie in deze review. Om extra publicaties te vinden, zijn

aanvullende zoekopdrachten op Google Scholar uitgevoerd. Alleen artikelen uit 1995 en later

zijn geïncludeerd in deze review. De meeste artikelen zijn verkregen via de referenties van

artikelen die zijn gevonden via de bovengenoemde databases.

Resultaten

De meeste patiënten die deelnamen aan studies waarin resultaten van chirurgie bij

gemetastaseerd pancreascarcinoom werden geanalyseerd zijn streng geselecteerde

patiënten omdat de beslissing om tot chirurgie over te gaan pas wordt genomen als de patiënt

in goede algemene conditie is en een lage totale tumorbelasting heeft met een grote kans op

R0-resectie. Significante verschillen in perioperatieve morbiditeit en mortaliteit werden

waargenomen tussen gelijktijdig gereseceerde patiënten en patiënten die een palliatieve

bypass-operatie ondergingen. De mediane overleving bij patiënten die een resectie hadden

ondergaan voor metastatisch ductaal adenocarcinoom van de pancreas (PDAC) varieerde van

5,9 maanden tot 31,0 maanden. Specifiek hadden patiënten die een resectie in meerdere

fasen of een metachrone resectie ondergingen een betere mediane overleving in vergelijking

4

met synchroon gereseceerde patiënten. De overleving geobserveerd in case reports is

opmerkelijk hoger omdat chirurgie alleen werd uitgevoerd na een uitzonderlijk goede respons

op chemotherapie. Bij differentiatie op basis van tumorhistologie werd een betere overleving

gerapporteerd bij patiënten met periampullaire tumoren, met name wanneer het ging om een

tumor van het intestinale type, waarbij een overleving tot 23 maanden werd gezien. Acinaire

carcinomen hadden over het algemeen ook een betere overleving in vergelijking met PDAC's.

Conclusie

Chirurgie kan worden beschouwd als een waardevolle behandelingsstrategie bij de

behandeling van oligometastatisch pancreascarcinoom, maar alleen in streng geselecteerde

patiënten die in een goede algemene conditie zijn, een lage algehele tumorbelasting hebben

en een goede reactie op chemo(radio)therapie vertonen. Specifiek lijken gefaseerde resecties

en metachrone resecties het grootste potentieel te hebben om de overleving te verlengen.

Meer studies die de rol van chirurgie bij metastatisch pancreascarcinoom beoordelen moeten

worden uitgevoerd, bij voorkeur multicenter, evenals studies die de waarde van gefaseerde

resectie beoordelen en studies die de impact van (neo)adjuvante behandeling op overleving

beoordelen. In de toekomst kan neoadjuvante chemotherapie worden gebruikt voor patiënten

die zich presenteren met gemetastaseerd carcinoom om geschikte kandidaten voor chirurgie

te selecteren, omdat alleen patiënten die goed reageren op de neoadjuvante behandeling ook

baat kunnen hebben bij een agressieve chirurgische aanpak.

5

Introduction

Pancreatic cancer has a relatively low incidence in Europe compared to colorectal, lung and

breast cancer. However, pancreatic cancer is ranked as the fourth most deadly cancer

worldwide. This demonstrates the particularly poor prognosis associated with the disease.

Only 5% of patients diagnosed with pancreatic cancer in Europe are still alive after 5 years (all

stages together) and patients lose 98% of their life expectancy at the time of diagnosis. This

prognosis is even worse when metastatic disease is present, with a 5-year survival rate of only

1% (1).

The poor prognosis of pancreatic cancer is explained by the fact that the disease is often

discovered rather late because the patient usually only presents symptoms in an advanced

stage. Small lesions in the head of the pancreas can cause obstruction of the common bile

duct, thus leading to an early diagnosis in an icteric patient. This occurs rather unfrequently.

To date, no valuable screening method has been found. All of this causes a malignancy in the

pancreas to already be in a metastatic stage at the time of diagnosis in 50% of cases. Often

there are multiple metastases (in different organs), but in some exceptional cases one speaks

of an oligometastasis, with only one (or some) metastasis/metastases present in one other

organ.

Today the only curative-intended therapy is surgical resection. However, in clinical practice

this method is used only in selected cases with localized disease (stage I or II) (2-4).

Unfortunately, only 15-20% of patients with pancreatic cancer meet the criteria for localized

and resectable disease (stage I or II). Specifically, a pancreaticoduodenectomy (Whipple

procedure) with standard lymphadenectomy and a distal pancreatectomy with splenectomy is

performed for cancer located in caput and corpus/cauda of the pancreas, respectively. In

patients with resected pancreatic cancer, median survival is 17 to 27 months with a 5-year

survival rate of 15-20% (5, 6). However, in those patients who undergo surgical resection, 66-

92% will have recurrent disease within 2 years after resection involving local recurrence in 35-

60% and systemic recurrence in 80-90% of cases (6, 7). A number of studies have already

shown that adjuvant therapy could potentially prolong survival after curative resection. At

present, the standard in patients with a resected pancreatic tumor is six months of adjuvant

chemotherapy with gemcitabine or fluorouracil (5-FU), and very recently also GemCap which

is a combination of gemcitabine and capecitabine. The role of neoadjuvant therapy is currently

under investigation and could potentially yield survival benefit, especially in patients with

borderline resectable tumors (8).

6

In about 30% of patients diagnosed with pancreatic cancer, it concerns a locally advanced

tumor and non-resectable tumor (stage III). These patients have a median survival of 8-12

months and a 5-year survival rate of approximately 6% (8). In several trials, the possibilities of

neoadjuvant therapy for initially non-resectable tumours are studied, since neoadjuvant

therapy may provide the opportunity to downstage the tumor before surgical intervention to

increase the amount of R0 resections. For this purpose, mainly FOLFIRINOX (a composition

of leucovorin, fluorouracil, irinotecan and oxaliplatin) and nab-paclitaxel plus gemcitabine are

used. Regardless of the use of neoadjuvant therapy, however, no official advice has yet been

formulated for its standard use due to a lack of evidence provided by prospective trials and a

lack of randomized trials comparing neoadjuvant with adjuvant therapy.

In the remaining 50% of patients with pancreatic cancer, the disease was already in a

metastatic stage (stage IV) at the time of diagnosis. Without treatment, these patients have a

median survival of 4-6 months and a 5-year survival rate of about 1-2%. The current standard

therapy for this group is palliative chemotherapy. Gemcitabine is used for patients with a poor

performance score and is able to extend survival for these patients to about 6-7 months (9).

Meta-analyses suggest that FOLFIRINOX and gemcitabine / nab-paclitaxel may have a

positive effect on overall survival (with a median survival of 11 months and 8.5 months

respectively) in patients with a better performance score, regardless of the greater toxicity

associated with the treatment (9, 10). As a result, the latter are now used as standard in

patients with metastatic disease and a good performance score.

A specific therapy aimed at oligometastases could possibly have an effect on the overall

survival of patients already diagnosed in stage IV, as has already been demonstrated for

patients with colorectal cancer with metastases, mainly in the liver. The pancreas

predominantly metastasizes to the liver, followed by peritoneum, lung and pleura and bone (1).

However, the value of resection of metastases, and in particular the resection of liver

metastases, remains a point of intense discussion. Therefore in this review results will be

analysed to see if combinations of extensive surgery and new treatment concepts could

provide a survival benefit, mainly in younger and fitter patients. Current guidelines advise

metastasectomy only when 1) a negative surgical resection (R0) can be obtained with

pancreatectomy, 2) the pancreatic tumor responds to neoadjuvant systemic therapy, 3) the

oligometastases are resectable, 4) the patient is in good general condition with limited

comorbidities (1).

The purpose of this review is to study the literature already existing on the topic of treatment

of oligometastatic pancreatic cancer and possibly to formulate a new advice for the therapeutic

approach of this rare subset of metastatic disease. Results of resection of oligometastases,

7

whether or not in combination with (neo)adjuvant chemotherapy and/or radiotherapy will be

analysed. This will take into account overall survival and specific parameters that may have a

beneficial effect on survival. Eventually, a specific advice may be formulated for a well-defined

type of patient that might benefit from a specific treatment for oligometastases. In addition to

surgery, the literature on Stereotactic Body Radiotherapy (SBRT) will be investigated.

Methods

All articles containing mainly cases with oligometastases were included, but no articles older

than 1995. A language restriction was set so only articles written in English, Dutch or French

were included. It was also intended that the investigations used were already beyond the

experimental phase on animals so all results could be directly applicable to a human population

and that one or more conclusions could be drawn regarding the treatment of oligometastases

of pancreatic tumors that are relevant in clinical practice.

The articles for this review were collected based on a number of searches in various internet

databases including Pubmed, Web of Science and Embase. Additionally, similar searches

were performed in Google Scholar, which allowed a number of additional articles.

The main source for finding articles were the references of major publications on the topic. Via

this route most small studies were found, with only a few cases being treated for

oligometastases of pancreatic tumours.

Relevant studies were sought in the above-mentioned databases based on highly specific

search terms. No use was made of MESH terms because they did not provide satisfactory

results specifically related to the treatment of oligometastases. The search terms used in

Pubmed include “pancreatic metastasis chemo”, “oligometastasis pancreatic cancer”,

“oligometastatic pancreatic cancer”, “hipec pancreatic cancer”. In Embase, more structured

search terms were used: “'pancreas cancer'/exp OR 'pancreas cancer' AND oligometastasis”,

“'pancreas cancer'/exp OR 'pancreas cancer' AND ('metastasis'/exp OR metastasis)”,

“'pancreas metastasis'/exp OR 'pancreas metastasis' AND ('chemotherapy' OR

'chemotherapy'/exp OR chemotherapy)”, “'pancreas tumor'/exp OR 'pancreas tumor' AND

('peritoneum metastasis'/exp OR 'peritoneum metastasis')”. However, these searches often

yielded hundreds to thousands of results, so only the first pages of results, sorted by relevance,

were examined. In Web of Science, more structured search terms were used to find relevant

publications as well: "TOPIC: (pancreatic cancer) AND TOPIC: (oligometastases)".

8

As mentioned earlier, Google Scholar was also searched for additional publications about the

subject. Similar searches were used as above, mostly yielding tens of thousands of results.

Of all studies, the abstract was thoroughly reviewed and evaluated for relevance. All reviews

and meta-analyses found were considered as background information. Results from all case

reports, RCTs and cohort studies were included in this review. If no decision could be made

regarding whether or not to include the article in the study after reading the abstract, the entire

article was reviewed and revaluated.

Specifically, after screening all above mentioned databases, 83 records were identified. An

additional 50 records were identified through ‘similar articles’ and via references of articles

found through database screening. After duplicates were removed, the abstract of a total of

124 records was screened for relevance. Another 75 records could be excluded based on the

abstract. Eventually, 49 full-text articles were assessed for eligibility, 9 of which were excluded

after thoroughly reviewing and evaluating the full-text for relevance. Reasons for exclusion

included irrelevance, the unavailability of the full text or no specific results for pancreatic

carcinoma. This resulted in a total of 40 references used for the realization of this review. For

the Prisma flow chart, see attachment 1.

In this review, overall survival following treatment of patients with oligometastases derived from

pancreatic tumours is assessed. Specifically for surgery also median blood loss, operative

time, duration of hospitalization, perioperative morbidity and mortality are assessed. Any data

relating to quality of life will also be evaluated when available.

9

Results

1. Systemic therapy

Since the current gold standard for patients with pancreatic cancer in a metastatic stage (stage

IV) is the initiation of palliative chemotherapy, first the results of these chemotherapeutic

approaches is assessed in order to provide a reference to which the results of surgery will be

compared.

In a randomized trial comparing gemcitabine and 5-fluorouracil, median survival was 5.65

months in patients receiving gemcitabine and 4.41 months in patients receiving 5-FU patients.

The 1-year survival rate was 18% for gemcitabine and 2% for 5-FU patients. The survival

advantage for gemcitabine was highly statistically significant (P=0.0025) (11).

A large study from France compared efficacy and safety of FOLFIRINOX and gemcitabine.

The primary endpoint was overall survival, which appeared to be 11.1 months in the

FOLFIRINOX group and 6.8 months in the gemcitabine group (P<0.001). Moreover, the

median progression-free survival was 6.4 months in the FOLFIRINOX group as compared with

3.3 months in the gemcitabine group (P<0.001). The objective response rate (ORR)1 was also

superior in the FOLFIRINOX group with 31.6% of patients showing a response versus 9.4% in

the gemcitabine group (P<0.001). However, there was a disadvantage regarding the

FOLFIRINOX therapy, seeing as it had a tendency to induce adverse events in more patients

when compared with gemcitabine. Neutropenia occurred in 45.7% of patients in the

FOLFIRINOX group as compared to only 21% of patients in the gemcitabine group (P<0.001).

Moreover, 5.4% of patients in the FOLFIRINOX group developed febrile neutropenia as

compared to 1.2% in the gemcitabine group (P=0.03). Concerning quality of life at 6 months

into treatment however, 31% of patients had a definitive decrease in the scores on the Global

Health Status and Quality of Life versus 66% in the gemcitabine group (P<0.001) (9).

When comparing treatment with gemcitabine and nab-paclitaxel versus gemcitabine alone, a

median survival of 8.5 months versus 6.7 months was observed respectively (P<0.001). The

1-year survival was 35% in the nab-paclitaxel-gemcitabine group and 22% in the gemcitabine-

only group (P<0.001) and a 2-year survival of 9% and 4% was observed respectively (P=0.02).

The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group

1 ORR is defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period. Response duration usually is measured from the time of initial response until documented tumor progression.

10

and 3.7 months in the gemcitabine group (P<0.001). The most common adverse events of

grade 3 or higher were neutropenia (38% vs. 27%), fatigue (17% vs. 7%) and neuropathy (17%

vs. 1%). So, while the addition of nab-paclitaxel contributes to a better median survival, it

appears to cause more adverse events (10).

In a multicentre Phase II study from Satoi et al. the efficacy and tolerability of intravenous and

intraperitoneal paclitaxel combined with S-1 in patients with PDAC and peritoneal metastasis

was evaluated. S-1 is a combination of three pharmacological compounds (tegafur, gimeracil,

and oteracil potassium) that is designed to improve the antitumor activity of 5-fluorouracil (5-

FU) concomitantly with an intent to reduce its toxicity. The median survival time was 16.3

months and the 1-year survival rate and 2-year survival rate were 62% and 23% respectively.

Grade 3 or 4 hematologic events included neutropenia (6%) and anaemia (3%). Grade 3 or 4

nonhematologic adverse events included appetite loss (12%), nausea (9%), vomiting and

diarrhoea (6%) and mucositis (6%) (12).

Table 1: Median survival in case series assessing chemotherapy in the treatment of metastatic pancreatic cancer.

Author (ref.) Number of

participants

Type of

chemotherapy

Median OS

(months)

P-value

Burris (11) 126

Gemcitabine vs. 5-

FU

Gemcitabine: 5.65

5-FU: 4.41 P=0.0025

Conroy (9) 342

FOLFIRINOX vs.

gemcitabine

FOLFIRINOX: 11.1

Gemcitabine: 6.8 P<0.001

Von Hoff (10)

861

Nab-paclitaxel +

gemcitabine vs.

gemcitabine

Nab-paclitaxel +

gemcitabine: 8.5

Gemcitabine: 6.7

P<0.001

Satoi (12) 33 Paclitaxel + S-1 16.3 N/A

N/A: not available; 5-FU: Fluorouracil.

11

2. Surgery

2.1. Pancreatic Ductal Adenocarcinoma (PDAC)

Table 2: Case series assessing results of surgery in patients with PDAC.

Year

(ref.) First author

Patients

with

PDAC/

total

patients

Median

survival for

pancreatic

carcinoma

(months)

Morbidity 30-day

mortality Metastasis Study design

Additional therapy for

pancreatic carcinoma

2007

(13) Gleisner 17/22 5.9 (all) 45.5% 9.1% H: 17 Retrospective

3x 5-FU

3x gemcitabine

2006

(14) Shrikhande 29/29

13.8

[11.4-20.5]

ILN: 27

H: 11.4

P: 12.9

24.1% 0%

H: 11 (7

solitary, 3

multiple, 1 not

specified)

ILN: 11

P: 8

Retrospective

Neoadjuv.:

1x RCTx

Adjuvant (23 total):

1x RCTx

13x gemcitabine

6x 5-FU

2x experimental tumor

vaccinations

1x unknown

12

2010

(15) de Jong 20/40

Overall: 17

Synchr: 16

Metachr: 19

Pancreatico-

biliary: 13

30% 0% H: 40 Prospective

Neoadjuv.: 4

Adjuv.: 22 (all types)

14x gemcitabine

4x 5-FU

2x cyclophosphamide

injections

3x combination

irinotecan-based

1997

(16) Takada 109/109

Metastases

(+):

SR: 6

Bypass: 4

Metastases

(-):

PD: 24

Bypass: 5

N/A 0% H: 33 Retrospective Not specified

2010

(17) Seelig 18/20 10.7 (all) 45% (all) 0% (all)

H: 14

P: 6

Mesocolon

transversum: 2

Stomach: 2

Omentum

majus: 1

Prospective

All patients:

Adjuvant CTx: 20

Neoadjuv. RCTx: 2

13

Diaphragm: 1

Ovary: 1

2016

(18) Hackert 128/128 Median: 12.3

Synchr:

45%

Metachr.:

21.7%

Synchr: 2.9%

Metachr: 4.3%

ILN: 43

H: 85 Prospective

20x neoadjuv.

73 adjuv.:

79.5% gemcitabine

8.2% 5-FU

12.3% other

2016

(19) Tachezy 69/69

Median: 14.5

[10.8-18.2] 68% 1% H: 69 Retrospective

70% gemcitabine

7% FOLFIRINOX

1x RCTx

2006

(20) Adam

41/1452

(all)

Median: 20

(all)

Not

specified Not specified H: 41 (all) Retrospective Not specified

2010

(21) Singh 3/7

Median: 14

(7-18) 0% 0% H: 3 Prospective Adjuvant (not specified)

2013

(22) Satoi 58/58 Median: 25 47% 1.7%

H: 19

P: 17

ILN: 7

Lung: 2

Retrospective

58 adjuv. CTx

91.4% gemcitabine

8.6% others

26 RT

2 immunotherapy

14

2012

(23) Klein 22/22

Median: 7.6

(±9.9) 18% Not specified H: 22 Retrospective Adjuv. gemcitabine

2009

(24) Yamada 63/63

Median:

H: 10.1

(2.5-12.8)

P: 9.6

(0.8-11.7)

N3: 8.3

(0.1-45.4)

Not

specified Not specified

H: 11

N3: 48

P: 6

Retrospective

Adjuvant

33x IORT

18x gemcitabine

8x others

2010

(25) Dünschede 23/23

Synchr.: 8

Metachr.: 31

Synchr:

33%;

Metachr:

0%

Synchr.: 0%

Metachr.: 0% Liver: 23 Retrospective

Synchr.: 2x

gemcitabine ajduv.

Metachr.: 7x

gemcitabine adjuv.

All: results of patients with periampullary tumours are also included; Synchr: synchronous; metachr: metachronous; ILN: interaortocaval lymph node metastasis; Periton.: peritoneal metastasis; Adjuv.: adjuvant; Neoadjuv: neoadjuvant; RCTx: radiochemotherapy; CTx: chemotherapy; RT: radiotherapy; IORT: intraoperative radiation therapy; 5-FU: Fluorouracil; SR: simultaneous pancreatic and partial hepatic resection; N/A: not available; H: hepatic metastases; P: Peritoneal metastases; N3: paraaortic lymph node metastasis; Metastases (+): patients with metastatic disease; Metastases (-): patients without metastatic disease.

15

Results concerning survival in studies including periampullary tumours will be discussed

separately because some other tumor histologies can occur periampullary and these could

potentially have different survival figures in comparison to pancreatic ductal adenocarcinomas.

See the paragraph ‘characteristics of studies’ in the appendix for further details on each study

assessing the value of surgery in the treatment of metastasized pancreatic carcinoma.

2.1.1. Decision for resection

The decision to proceed to surgery in a patient with metastatic disease is made based on

multiple factors. For example, Takada et al. considered hepatic resections to be curative

through macroscopic and intraoperative ultrasonic findings. Two criteria were used to select

patients for palliative bypass surgery: reasonable certainty that a resection of the primary

carcinoma of the pancreatic head or the liver would not result in a cure, and that the patient

would be unable to tolerate aggressive surgery (16). When metastatic disease was found

intraoperatively, Seelig et al. based their decision for resection on the impression to reach a

R0 resection with synchronous resection of metastasis and a good clinical performance status

of ASA III or better (17). Reasons for resection in patients with suspected metastatic disease

preoperatively were good performance status and patient’s will to receive maximal treatment

(17, 19). Shrikhande et al. used similar criteria in patients with intraoperatively known

metastatic disease, only proceeding to resection when the following criteria were met: the

patient was considered to be in good general condition, the patient preferred resection despite

preoperative counselling regarding possibility of metastatic disease, peripherally located one

or two isolated liver metastases, the impression of “low overall tumor burden”, a high probability

of R0 resection, and an ASA grade of III or better (14). Singh et al. only performed synchronous

liver resection if a R0 resection of the pancreatic or periampullary tumor was possible.

Resection of the primary tumor was performed first and only then resection of the liver

metastasis attempted (21). Satoi et al. only performed surgery following the achievement of

stable disease, partial response, or complete response2 over 6 months after initiating non-

2 Based on the definition by Response Evaluation Criteria In Solid Tumors (RECIST version 1.1). Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Source: 26. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European journal of cancer. 2009;45(2):228-47.

16

surgical anti-cancer treatments (22). Often in studies assessing the results of surgery in

patients with metastatic pancreatic cancer, metastases are only discovered at the time of

surgery and thus the decision to proceed to resection is often made by the surgeon in a case-

by-case evaluation while taking into consideration the local resectability and comorbidity (23).

17

2.1.2. Median operative time

Table 3: Surgical technique, median operative time and average blood loss in patients who underwent surgery for metastatic PDAC.

Year

(ref.)

First author Surgical technique Median operative time

(minutes)

Average blood

loss (mL)

2007

(13) Gleisner

PD: 15 (68.2%)

DP: 7 (31.8%)

Hepatic resection:

- Wedge resection: 20 (90%)

- Segmentectomy: 1 (4.5%)

- Hemihepatectomy: 1 (4.5%)

370

Range: 338-444 625

2006

(14) Shrikhande

PD: 18 (62%)

- Hepatic resection (segmentectomy): 4

- ILN resection: 9

- Peritoneal nodules resection: 5

DP: 9 (31%)


- ILN resection: 1

- Peritoneal nodules resection: 3

TP: 2 (7%)


- ILN resection : 1

N/A 600

18

2010

(15) de Jong

PD: 38 (95%)

Ampullectomy: 2 (5%)

Hepatic resection:

- Wedge resection: 22 (69%)

- Segmentectomy: 6 (25%)

- Hemihepatectomy: 4 (10%)

N/A 560

1997

(16) Takada

Extended PD

Lymphadenectomy

Partial/wedge hepatic resection

N/A N/A

2010

(17) Seelig

PD: 2 (10%)

Pylorus preserving PD: 8 (40%)

DP: 8 (40%)

TP: 2 (10%)

N/A 1000

2016

(18) Hackert

PD: 66 (52%)

TP: 22 (17%)

DP: 39 (30%)

Hepatic resection:

- Atypical: 86%

- Formal: 14%: segmentectomy, hemihepatectomy

N/A N/A

2016

(19) Tachezy

PD

Pylorus-preserving PD

Distal splenopancreatectomy

Subtotal or TP

N/A N/A

19

Lymphadenectomy

Hepatic resection: atypical wedge

2006

(20) Adam

N/A N/A N/A

2010

(21) Singh

PD: 7 (100%)

Hepatic resection (segmentectomy): 7

420

Range: 379-461 372

2013

(22) Satoi

(Pylorus preserving) PD: 7 (41%)

DP: 9 (53%)

DP with celiac axis resection: 1 (6%)

Hepatic resection:

- Metastasectomy: 5

- Liver biopsy: 2

- No liver tumor found at time of surgery: 6

Peritoneal metastasis (not found at time of surgery): 1

N/A N/A

2012

(23) Klein

PD: 1 (5%)

Pylorus preserving pancreatectomy: 16

DP: 1 (5%)

TP: 4 (18%)

Liver-directed therapy:

- Segmentectomy: 7 (32%)

330.2

Range: 249.3 – 411.1 750

20

- Metastasectomy: 15 (68%)

2009

(24) Yamada

PD: 181

Pylorus-preserving PD: 45

DP: 63

TP: 70

Pancreatic head resection with segmental

duodenectomy: 1

IORT was administered to the retroperitoneal fields.

N/A N/A

2010

(25) Dünschede

Synchronous resection:

Partial PD: 3

DP: 6

Hepatic resection:

- atypical resection: 6

- lobectomy: 2

- segmentectomy: 1

Metachronous resection:

Segmentectomy: 1

Atypical liver resection: 3

Synchronous resection:

320

Range: 170-520

Metachronous resection:

196

Range: 150-275

500

PD: Pancreaticoduodenectomy; DP: Distal Pancreatectomy; TP: Total pancreatectomy; N/A: not available; IORT: intraoperative radiation therapy.

21

Analysis of data pointed out that the median operative time for patients undergoing

simultaneous resection of the pancreatic primary tumor and the metastatic liver disease ranged

from 320 minutes to 420 minutes (13, 21, 23, 25). When comparing these results with patients

undergoing resection of their primary lesion alone, conflicting results were found. Gleisner et

al. and Klein et al. found the median operative time to be similar to patients who underwent

synchronous resection, reporting a median operative time ranging from 349.3 minutes to 357

minutes (13, 23). Singh on the other hand, found operative time to be significantly longer for

patients undergoing synchronous resection in comparison to patients who underwent surgery

for their primary tumor alone with a median operative time of 420 minutes and 362 minutes,

respectively (P<0.001) (21). However, these median operative times seem to be remarkably

longer than the median operative time observed by Gleisner et al. in patients who underwent

standard surgical palliation, which entailed a traditional “double-bypass” characterized by a

hepaticojejunostomy as well as a gastrojejunostomy. The median operative time in these

patients was 218 minutes, which was significantly shorter than the group of patients who

underwent simultaneous resection (P<0.001) (13). Dünschede et al. showed a median

operative time of 320 minutes for patients undergoing simultaneous resection but a median

operative time of only 196 minutes in patients with metachronous disease who underwent

metastasectomy sometime after the resection of their primary tumor (25).

2.1.3. Blood loss

Blood loss observed in patients who underwent resection of the primary tumor and the

associated metastatic disease ranged from 372 mL to 1000 mL (13-15, 17, 21, 23, 25).

Shrikhande et al. found similar median perioperative blood loss between M1 resected patients

and M0 resected patients, with a median intraoperative blood loss of 600 mL and 700 mL,

respectively (P=0.432) (14). Klein et al. found similar results, with a median intraoperative

blood loss of 750 mL in patients undergoing simultaneous resection versus 700 mL in patients

who did not have hepatic metastasis and thus underwent resection of their primary pancreatic

tumor alone (P=0.333) (23). The same accordance in results was found by Singh et al., with a

median intraoperative blood loss of 372 mL in simultaneously resected patients versus 320 mL

in patients without metastatic disease who underwent resection of their primary tumor

(P=0.107) (21). Gleisner et al. also observed the same tendency with a median perioperative

blood loss of 625 mL in patients who underwent simultaneous resection and 725 mL in patients

who underwent resection of their primary lesion alone (P=0.53). In contrast, patients who

underwent palliative bypass had significantly less blood loss during surgery (150 mL) in

comparison to patients who underwent simultaneous resection (P<0.001) (13).

22

2.1.4. Perioperative morbidity and mortality

Figure 1: Surgical morbidity and 30-day mortality in PDAC patients. Synchr: synchronous disease; Metachr: metachronous disease.

The surgical morbidity in patients who underwent synchronous or metachronous resection for

metastatic pancreatic cancer ranged from 0% to 68% (13-19, 21-25). The perioperative

complication rate noted by Gleisner et al. was 45.5%, which was similar to the complication

rate found in patients who underwent resection of their primary tumor alone (47.7%) (P=1.00).

Several complications were minor and were not necessarily related to the hepatic resection.

This included urinary retention, refractory pain and superficial wound infection. Intermediate

complications included events such as pleural effusion and perihepatic abscess. Pancreas-

specific complications included delayed gastric emptying, pancreatic fistula, superior

mesenteric vein injury and postoperative bleeding. In contrast, the complication rate found in

patients who underwent a palliative bypass was significantly lower (27.7%) in comparison to

patients who underwent simultaneous resection (P<0.001). Two patients in the simultaneous

resection group died within 30 days of surgery, yielding a perioperative mortality rate of 9.1%.

Although the difference was not significant, the 30-day postoperative mortality tended to be

higher in comparison with patients who underwent resection of only their primary tumor (4.5%)

or the patients who received a palliative bypass (3.0%) (13). In contrast to Gleisner et al., other

studies analysing complication rates and operative deaths showed no significant differences

between a group of patients who underwent simultaneous resection of the pancreatic tumor

and associated liver metastasis and a group of patients with metastatic liver disease who

underwent a palliative bypass, nor was a difference observed when the same simultaneous

resection group was compared with a group that did not have metastatic disease and thus

underwent resection of their primary tumor alone (14, 16, 23). For example, the postoperative

45

.5%

24

.1%

30

.0%

N/A

45

.0%

45

.0%

21

.7%

68

.0%

42

.9%

47

.0%

18

.0%

N/A

33

.0%

0.0

%9.1

%

0.0

%

0.0

% 9.1

%

0.0

%

2.9

%

4.3

%

1.0

%

0.0

%

N/A

N/A

N/A

0.0

%

0.0

%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Surgical morbidity 30-day mortality

23

complication rate observed by Shrikhande et al. in patients presenting with M1 disease (24.1%)

was similar in patients presenting with M0 disease (24.4%). Shrikhande et al. even reported a

30-day perioperative mortality of 0% and they found this to be less, however not significantly,

than the 30-day postoperative mortality for a group of patients who underwent R0/R1 resection

for M0 disease of 4.2% (14). Tachezy et al. also reported a relatively low 30-day mortality rate

of 1% and also found this not to be differing from the 1% 30-day mortality rate in non-resected

patients. They reported a total morbidity of 68%, which was significantly higher compared to

a group of patients who did not undergo resection but an abdominal exploration instead, in

which a total morbidity of 48% was observed (P=0.025) (19). According to Klein et al. the

difference in results between resection in M1 and M0 disease was more clear, with a

complications rate of 41% in patients who underwent resection of a primary pancreatic tumor

alone and a complication rate of only 18% in patients who underwent simultaneous resection.

However, this difference reached reach no significance (P=0.099) (23). In general, comparison

of perioperative morbidity and mortality between different authors should be done with great

caution however, since a difference in tumor burden could be present. For example, between

Takada et al. and Gleisner et al. a big difference in tumor burden should be taken into account.

Patients included in the study from Takada et al. had a relatively high tumor burden with the

size of resected liver metastases ranging from 0.5 to 5 cm and the amount of metastases

resected ranging up to 7 per patient (16). This in contrast to the much lower tumor burden

found in patients included in the study from Gleisner et al. with a median size of the largest

metastasis being 0.6 cm with a 95% confidence interval of [0.3-1.2]. Also, 19 out of 22 patients

(86%) in the study from Gleisner et al. presented with a solitary liver metastasis (13). When

comparing results from patients with synchronous disease and patients with metachronous

disease, Hackert et al. observed a surgical morbidity after synchronous resection of 45.0% and

a surgical morbidity of 21.7% in patients after metachronous resection, as well as a 30-day

perioperative mortality rate of 2.9% in synchronous resections and 4.3% in metachronous

resections (18). Dünschede et al. on the other hand, reported a postoperative complication

rate 33% in patients who underwent one-stage resection of the primary tumor and liver

metastases and a postoperative complication rate of 0% in patients with metachronous

disease who underwent metastasectomy after initial resection of their primary pancreatic

tumor. Data on the complication rate from resection of the primary tumor in metachronously

resected patients was not available (25). Concerning reoperation rate, Tachezy et al. observed

6% in the resection group versus 3% in the non-resection group (19). Revision surgery was

performed 2 patients (9%) in the study from Klein et al. This differed from patients who

underwent surgery of the primary pancreatic tumor alone by whom a revision surgery was

done in 4 patients (18%) (23).

24

2.1.5. Duration of hospitalization and ICU stay

Figure 2: Hospitalisation time following surgery of metastatic PDAC. N/A: Not available.

Median duration of hospitalisation ranged from 8.0 to 23.3 days. The median duration of

hospitalization and ICU stay observed by Tachezy et al. tended to be longer for the patients

who underwent simultaneous resection (16 days) compared to patients who did not undergo

resection but received an abdominal exploration instead (12 days). ICU stay was also similar,

with a median stay of 0 days (range: 0-20 days) in the resected group and 0 days (range: 0-5

days) in the non-resected group. So both hospitalization and ICU stay tended to be longer in

the resected group (19). The median time of hospitalization observed by Shrikhande et al. was

identical between patients who underwent resection for M0 disease and patients who

underwent resection for M1 disease with a median of 12 days in both groups (14).

N/A

N/A

23.3

4.5

9.7

16.0

N/A

20.7

N/A

8.0

12.0

8.0

0 5 10 15 20 25

Dünschede (25)

Yamada (24)

Klein (23)

Satoi (22)

Singh (21)

Tachezy (19)

Hackert (18)

Seelig (17)

Takada (16)

de Jong (15)

Shrikhande (14)

Gleisner (13)

Hospitalisation time (days)

Au

tho

r

25

2.1.6. Survival

Figure 3: Survival rates in PDAC. ILN: metastatic disease to the interaortocaval group of lymph nodes; Liver: metastatic disease to the liver; Before: survival figures measured from the start of chemotherapy. After: survival figures measured from the time of adjuvant surgery. For further details on the study by Satoi et al. see ‘characteristics of studies’ in the appendix.

0.0%

8.1%

10.1%

15.0%

14.3%

29.0%

34.0%

0.0%

0.0%

6.7%

18.0%

0.0%

20.0%

28.6%

33.0%

53.0%

5.0%

9.0%

13.3%

58.9%

55.0%

0.0%

60.0%

71.4%

76.0%

95.0%

42.0%

36.0%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Gleisner (13)

Shrikhande (14)

de Jong (15)

Takada (16)

Seelig (17)

Hackert (18) Liver

Hackert (18) ILN

Tachezy (19)

Singh (21)

Satoi (22) After

Satoi (22) Before

Klein (23)

Dünschede (25)

1-year survival 3-year survival 5-year survival

26

Figure 4: Median overall survival in patients who underwent simultaneous resection for metastatic PDAC. H: Hepatic metastatic disease; P: Peritoneal metastatic disease; N3: interaortocaval lymph node metastatic disease; synchr.: Patients with synchronous disease; metachr.: patients with metachronous disease, measured from the detection of metastases.

The median overall survival found by Gleisner et al. was 5.9 months and the 1- and 3-year

overall survival rates were 13.3% and 6.7% respectively. No factors were found to be

associated with the overall survival, including primary tumor or hepatic margin status, tumor

diameter, or primary lymph node status. This study also included some non-pancreatic,

periampullary tumours originating from duodenum (n=2), distal bile duct (n=2) or ampulla

(n=1). The pancreatic primary tumor histology (median overall survival of 5.9 months) versus

nonpancreatic primary tumor histology (median overall survival of 9.9 months) was not

associated with a significant difference in overall survival (p=0.43). The longest survival at the

time of writing (2007) was 39.5 months but this patient had a duodenal adenocarcinoma and

received adjuvant FOLFIRI therapy. It has to be noted that in total in this study seven patients

(31.8%) received some form of adjuvant therapy, 6 of whom presented with a pancreatic

adenocarcinoma primary lesion. The chemotherapy used in these patients with a pancreatic

adenocarcinoma was systemic 5-fluorouracil (n=3) or gemcitabine (n=3). Compared to the

other patient groups in this study they found the median overall survival to be shorter than in

the resected controls (who did not have metastatic disease and thus underwent resection for

their primary tumor alone) with a median overall survival of 14.1 months but they found it to be

comparable with the palliative controls (patients with histologically proven liver metastases who

underwent standard surgical palliation) reaching a median overall survival of 5.6 months. As

mentioned before, some patients in this study received some form of adjuvant therapy but it is

not possible to assess the impact of it on survival due to a lack of data (13). A Japanese study

5.9

13.8

17.0

6.0

10.712.3

14.5 14.0

25.0

7.610.1 9.6

8.3 8.0

31.0

0

5

10

15

20

25

30

35M

edia

n o

vera

ll su

rvia

l (m

on

ths)

Author (ref.)

27

found similar results with a median survival time of 6 months for patients who underwent

simultaneous resection of pancreatic cancer and metastatic liver disease and the longest

survival being 10 months. All patients in this study died because of multiple recurrent liver

metastasis. However, patients who underwent a palliative bypass had a median survival time

of only 4 months and the longest survivor lived for only 6 months. These results are significantly

worse than the ones found in a group of patients who did not have metastatic liver disease and

underwent a pancreaticoduodenectomy for their primary pancreatic tumor (P<0.01). They had

a median survival time of 24 months and the longest survival was greater than 114 months

(16). A slightly different study, conducted by Dünschede et al., observed a median survival of

8 months in a group of patients with synchronous disease who underwent simultaneous

resection and 11 months in a group of patients who only received chemotherapy in the form of

gemcitabine for the treatment of their metastatic pancreatic cancer. For patients presenting

with metachronous disease on the other hand, they observed a median survival of 31 months

in the group of patients who underwent metastasectomy and 11 months in the group of patients

only receiving gemcitabine for the treatment of their metastatic disease. Every patient in this

study died of the progression of the disease (25).

A prospective cohort study conducted at the university of Heidelberg by Hackert et al. assessed

the impact of resection in stage IV PDAC patients with limited metastases located in the liver

or the interaortocaval lymph nodes in terms of surgical outcome and long-term survival. 128

patients were submitted to surgery for stage IV PDAC with spread to the liver or the

interaortocaval lymph nodes. Measured from the time of liver resection (whether it was

resected synchronously or metachronously), the median survival of the 85 patients who

underwent liver resection was 12.3 months. This was similar to the 43 patients who underwent

resection of the interaortocaval lymph nodes with an identical median survival of 12.3 months.

The 5-year survival for patients with liver metastasis and patients with interaortocaval lymph

nodes metastases was 5.9% and 7.0% respectively. It’s important to note that 20 patients had

undergone neoadjuvant treatment prior to surgery. All of the interaortocaval lymph node

resections were performed synchronously, whereas only 72.9% of the liver resections were

performed synchronously. There was no significant difference in survival when comparing

synchronously and metachronously resected patients when measured from the time of liver

resection. There also was no survival difference observed after neoadjuvant therapy in both

patients with metastatic disease to the liver and patients with metastatic disease to the

interaortocaval lymph nodes. Tumor localisation as well had no influence on survival in patients

with liver metastases, nor did either number or size of liver metastases have a significant

impact on survival. Patients with metachronous disease underwent liver resection following

PDAC surgery after an average interval of 18.4 months. Among the patients in the study by

28

Hackert et al., 73 completed their adjuvant therapy. The most commonly administered forms

of chemotherapy include gemcitabine (79.5%) and 5-fluorouracil (8.2%). The other 12.3% were

administered other schemes (18).

Tachezy et al. did a multicentre analysis of 6 European pancreas centres and hereby also

assessed the value of surgery in the treatment of metastatic pancreatic cancer. They found a

median overall survival of 14.5 months in 69 patients who underwent synchronous resection

of pancreatic tumor and hepatic metastasis. This was significantly longer than the matched

control group of 69 patients who did not undergo resection but received an abdominal

exploration instead, which reached a median overall survival of only 7.5 months (P<0.001).

Neoadjuvant treatment was administered in 14% of the resected patients and 1% of the

nonresected patients. About 80% of patients of whom data on adjuvant therapy was available

received postoperative, tumor-specific treatment (19). Similar observations were made in the

study of Shrikhande et al. with a significant difference in survival curves between R0/R1 M1

(liver metastases) and M1 (liver metastases) without any resection (exploration or bypass) with

a median survival time of 11.4 months and 5.9 months respectively (P=0.0384). The estimated

median overall survival time for all 29 patients included in this study (this includes patients with

metastases in liver, peritoneum and lymph nodes) was 13.8 months and the estimated 1-year

overall survival rate was 58.9%. Specifically, the estimated median survival time of 23 patients

who received adjuvant treatment was 15.8 months. When differentiating between location of

metastasis, they observed an estimated median survival time of 27 months in patients with

metastatic disease to the interaortocaval group of lymph nodes, 11.4 months in the patients

with liver metastasis and 12.9 months in patients with peritoneal metastatic disease. The

difference in survival between these groups of patients was not significant however (14). A

study conducted by Yamada et al. at the Nagoya university in Japan found a median survival

time of 8.3 months for patients with synchronously resected paraaortic lymph node

metastases, 10.1 months for patients with synchronously resected hepatic metastases and 9.6

months for patients with synchronously resected peritoneal metastases. In this study no

neoadjuvant therapy was administered but almost every patient received adjuvant therapy in

the form of intraoperative radiation therapy (IORT)3 and chemotherapy. When looking

unresected controls with paraaortic lymph node metastasis they saw a poorer prognosis with

a median survival of 5.9 months. The same trend was observed in unresected patients with

hepatic metastases (median survival time of 6.8 months in patients with hepatic metastases in

one of the hepatic lobes, 4.1 months in patients with hepatic metastases in both hepatic lobes

3 An intensive radiation treatment that's administered during surgery. IORT allows direct radiation to the target area while sparing normal surrounding tissue.

29

and 2.5 months in patients with multiple metastases in both hepatic lobes) or peritoneal

metastatic disease (median overall survival of 5 months in patients with metastases to near

peritoneum, 8.7 months in patients with a few metastases to distant peritoneum and 3.7

months in patients with multiple metastases to distant peritoneum). None of the differences in

survival between resected and unresected patients were significant. When comparing median

survival time in patients who underwent surgery for M0 disease (12.7 months) and M1 disease

(8.3 months in patients with synchronously resected paraaortic lymph node metastases, 10.1

months for patients with synchronously resected hepatic metastases and 9.6 months for

patients with synchronously resected peritoneal metastases), they observed significant

differences for each group (P<0.0001, P=0.01, P=0.003, respectively) (24).

In the study by Klein et al. the overall median survival in patients who underwent synchronous

resection was only 228 days (7.5 months) with a 2-year survival of 5% (1 patient). No 5-year

survival was reached within this group of patients. When comparing this with patients who did

not have metastatic disease and therefore only underwent resection of their primary pancreatic

tumor they saw a median survival of 437 days (14.6 months), which was significantly longer

than the patients who underwent synchronous resection (P=0.015). 2-year survival in this non-

metastatic group was reached in 8 patients (36%) and 5-year survival in 3 patients (14%).

When a R0 resection was reached, the median survival rose to 390 days (13 months) in

patients with metastatic disease and rose to 794 days (26.5 months) in patients without

metastatic liver disease. When looking at patients in whom a R1 resection was executed,

survival dropped to 194 days (6.5 months) and 255 days (8.5 months) respectively. When

lymph nodes were involved median survival was 215 days (7.2 months) and 754 days (25.1

months) respectively (23). Seelig et al. also compared M1 patients and M0 patients but they

found no significant difference in median postoperative survival between both groups, with

patients with M1-disease reaching a median survival of 10.7 months versus patients with M0-

disease reaching a median survival of 15.6 months (P=0.11). All deaths in this study were

caused by recurrent metastatic disease (17). The overall median survival observed by de Jong

et al. was 17 months, with a 1- and 3-year survival rate of 55% and 18% respectively. These

results should be interpreted with caution however, since 20 out of 40 patients included in this

study had periampullary tumours from which survival figures could potentially differ because

some of these tumours are intestinal type tumours and therefore have a different histology and

survival. No specific factors, including metastatic tumor number and size, were associated with

overall survival. Median survival was similar among patients who had synchronous versus

metachronous disease, with a median survival of 16 months and 19 months respectively (15).

30

2.1.7. Adjuvant surgery

A Japanese study, conducted by Satoi et al., assessed the role of adjuvant surgery for patients

with initially unresectable pancreatic cancer with a long-term favourable response to non-

surgical anti-cancer treatments. 58 cases who underwent adjuvant surgery were compared

with 101 controls who did not undergo adjuvant surgery because of unresectability. The cases

consisted of 41 patients with locally advanced disease and 17 patients with distant metastasis.

Of these patients with initial metastatic disease, 7 patients did not have metastatic disease

anymore at the time of surgery (6 of whom had liver metastases, 1 of whom had peritoneal

metastasis), 5 patients underwent resection (all had liver metastases). In the remaining 2

patients a biopsy of the liver was performed (from which results were also included in the

analysis). Another three patients had metastatic disease to the paraaortic lymph nodes. Satoi

et al. found that the median time from initial therapy to surgical resection was 274 days (182-

1418). The median observation period of the controls in this study was 51 months. The overall

survival rates at 1, 3 and 5 years were 88%, 18% and 10% respectively and the median survival

time was 39.7 months. For the cases a median observation period and post-operative

observation period of respectively 54 months and 41 months were found. Similarly, the 1, 3

and 5-year survival rates were 95%, 53% and 34% respectively with a median survival of 39.7

months. Measured from the time of surgery, the overall survival rates at 1, 3 and 5 years were

76%, 33% and 29% respectively with a median survival of 25 months. Survival curves for the

adjuvant surgery group was significantly better than for the control group (P<0.0001).

Concerning optimal timing of adjuvant surgery, this study showed that the longer the duration

of the initial treatment prior to surgical resection, the longer the survival time (22).

2.1.8. Case reports

A case report from Neofytou et al. reports about a 65-year male with a pancreatic tumor located

in the tail of the pancreas in combination with an MRI confirmed solitary 16mm metastatic

lesion in the liver. Six cycles of FOLFIRINOX were administered and were well tolerated by

the patient. A follow-up MRI showed a partial response for both the primary pancreatic tumor

and the solitary liver metastasis. After this, 3 more cycles of FOLFIRINOX were administered

resulting in further reduction of the size of both lesions. Because of this favourable response

to the neoadjuvant therapy, the decision was made to proceed to a synchronous resection of

the primary pancreatic tumor and the liver metastasis. The patient’s postoperative course was

uneventful and 7 weeks postoperatively 3 final cycles of FOLFIRINOX were administered. The

patient in this case remains disease free 2 years following surgery and 28 months from the

diagnosis of metastatic pancreatic adenocarcinoma (27).

31

2 other case reports, both described by Schneitler et al., have a similar approach as in the

case report described above. Both patients also received FOLFIRINOX therapy prior to

surgery. Both patients had hepatic metastases but one of them also had additional peritoneal

carcinomatosis. In these cases however, the FOLFIRINOX treatment resulted in a complete

resolution of the hepatic metastases, with no lesions detectable on CT. Moreover, the diameter

of the pancreatic tumor decreased and the peritoneal carcinomatosis disappeared. Because

of these surprising results, the decision was made to proceed to surgery. Patient 1 is a 65-year

old female with a carcinoma in the tail of the pancreas with metastasis to the liver discovered

in August of 2012. Following a multidisciplinary deliberation resection of the tail of the pancreas

was advised. The surgery eventually resulted in a resection of the tail of the pancreas as well

as the spleen, a radical dissection of the lymph nodes, a gall bladder resection, and a non-

anatomical resection of liver segments II, VI and VII. Adjuvant therapy was administered in the

form of gemcitabine. The patient appeared to be cancer-free in the subsequent follow-ups with

CT. However, 5 months after the last check-up (April of 2014), new metastases were found in

a retroperitoneal lymph node and muscles of the back. As a follow-up to this, FOLFIRINOX

was restarted and the most recent CT-scan showed partial remission of the retroperitoneal

lymph node metastasis. At the time of writing (August of 2014) no liver metastases have been

detected since the initial diagnosis (August of 2012) (28).

The other patient in this case report is a 45-year old male. Ultrasound showed a tumor in the

tail of the pancreas that was in contact with the splenic artery. An abdominal CT confirmed this

diagnosis, as well as multiple hepatic, nodal and peritoneal metastases (January of 2013). A

decline in tumor growth was observed after 3 months of chemotherapy so the FOLFIRINOX

was continued. A subsequent CT showed the disappearance of the liver and peritoneal

metastases. Because of this, the decision to proceed to surgery was made. This resulted in a

multivisceral resection of the tail and body of the pancreas, a left adrenal gland resection, a

resection of the spleen, a left large bowel resection with transversodescendostomy, a resection

of the cranial part of the left kidney, a gall bladder resection, an atypical segment V liver

resection, an aortic lymph nodal dissection and a celiac lymph node dissection (September of

2013). 2 months after surgery the treatment with FOLFIRINOX was continued, albeit at 75%

of full dose to prevent the patient’s frequent presentation of leukopenia in the adjuvant phase.

This was discontinued 6 months later and the last CT scan (June of 2014) showed no

metastatic lesions (28).

Another case report documented by Shimada et al. from Japan involves a 44 year old female.

A low-density mass was revealed with dynamic CT. During intraoperative ultrasonography a

small solitary nodule was detected in the anterior segment of the liver. This metastasis was

removed with a wedge resection. Considering no other distant metastases were present, the

32

patient consequently underwent distal pancreatectomy, splenectomy, and left adrenectomy,

with regional lymph node dissection. Pathologic examination of the pancreatic tumor revealed

moderately differentiated tubular adenocarcinoma, partially including poorly differentiated

adenocarcinoma. The postoperative course was uneventful. Two courses of adjuvant systemic

therapy were administered with a regimen of 5-fluorouracil and cisplatin. The patient is doing

well 7 years post-surgery with no clear evidence of recurrence (29).

In this final case report from Costa Neves et al. a 72-year old female is presented. CT showed

a 4 cm mass in the head of the pancreas. When staging was first performed this patient was

staged T4N1M0 and the patient was considered fit for surgery, during which a common hepatic

artery and coeliac axis encasement was found. Therefore a new staging was executed and

two new masses in the left liver were discovered, confirmed on FDG-PET scan. As a result of

the discovery the patient was entered into a Phase II clinical trial randomizing inoperable

pancreatic cancer patients to gemcitabine alone versus the addition of the immunomodulator

IMM-101 and was allocated to the active arm. After six cycles of gemcitabine and IMM-101,

nab-paclitaxel was added to the combination. The patient then showed an excellent and

sustained partial response for the following six cycles. After this a consolidation

chemoradiation with concomitant capecitabine and IMM-101 was offered to the patient.

Following completion of radiotherapy, capecitabine and IMM-101 were continued as a

maintenance therapy. Because of the exceptionally favourable response to these forms of

chemotherapy and radiotherapy a new attempt on surgery was done. She underwent a

pylorus-preserving pancreaticoduodenectomy with portal vein resection, left hepatectomy, and

coeliac and retroperitoneal nodal dissection. Postoperatively the patient continued to receive

IMM-101 and capecitabine was restarted 10 weeks after surgery. Unfortunately at 12 months

from surgery 2 metastatic bilateral lesions were found in the lungs and a new solitary hepatic

metastasis was also discovered. No data on survival was published in this case report (30).

33

Table 4: Case reports

Year

(ref.)

First

author

Age

(years)

Primary

tumor

Therapy Histology Site of

metastasis

Survival

2015

(27)

Neofytou 65 Tail of

pancreas

(Neo)adjuvant

CTx

Poorly

differentiated

PDAC

(pT3N1M1)

Segment VI:

synchronous

>2 years

(alive)

2015

(28)

Schneitler 65 Tail of

pancreas

(Neo)adjuvant

CTx

PDAC

pT3N0M0

(postop)

Right lobe:

synchronous

>1.5

years

(alive)

45 Tail of

pancreas

(Neo)adjuvant

CTx

PDAC:

pT4N1Mx

(preop),

pT3N0M0

(postop)

Liver,

peritoneal:

not specified

>9

months

(alive)

2015

(31)

Sumiyoshi 77 Tail of

pancreas

Adjuvant CTx ACC Peritoneal >6 years

(alive)

2004

(29)

Shimada 44 Tail of

pancreas

Adjuvant CTx Moderately

differentiated

PDAC

Anterior

inferior

segment

>7 years

(alive)

2015

(30)

Costa

Neves

72 Head of

pancreas

Neoadjuvant

CTx and

RCTx

T4N1M1 Left lobe >16

months

(alive)

PDAC: Pancreatic Ductal Adenocarcinoma; CTx: Chemotherapy; RCTx: radiochemotherapy; preop: preoperative; postop: postoperative

34

2.2. Periampullary cancer

Table 5: Case series for periampullary tumours

Year

[ref.] First

author

Patients with

periampullary

carcinoma/

total patients

Median survival

for pancreatic

carcinoma

(months)

Morbidity 30-day

mortality

Meta-

stasis

Study design (Neo)adjuvant therapy

2007

(13) Gleisner 15/22 5.9 (all types)

45.5% (all

types)

9.1% (all

types) Liver: 5 Retrospective

1x FOLFIRI

2010

(15) de Jong 40/40

Overall: 17

Synchr.: 16

Metachr.: 19

Intestinal: 23

Pancreatico-biliary:

13

30% 10% Liver: 40 Prospective

Neoadjuv.: 3

Adjuv.: 22 (all types)

14x gemcitabine

4x 5-FU

2x cyclophosphamide

injections

3x combination irinotecan-

based

2010

(17) Seelig 2/20 10.7 (all types) 45% (all types)

0% (all

types)

LN: 1

Liver: 1 Prospective

All patients:

Adjuvant CTx: 20

Neoadjuv. RCTx: 2

2010

(21) Singh 4/7 Median: 14 (7-18) 25% 0% Liver: 4 Prospective

Adjuvant (not specified)

Synchr: synchronous disease; metachr: metachronous disease; CTx: chemotherapy; RCTx: radiochemotherapy; neoadjuv: neoadjuvant therapy; adjuv: adjuvant therapy; FOLFIRI: Folinic acid, fluorouracil and irinotecan; 5-FU: fluorouracil; LN: lymph nodes.

35

Periampullary tumours encompass a spectrum of carcinomas which are unified by their

anatomic location but differentiated by their histological origin including: pancreatic head, distal

bile duct, duodenal, and ampullary adenocarcinomas.

2.2.1. Complication rate

In a study from de Jong et al. 1902 patients underwent surgical resection of a periampullary

carcinoma, 40 of which underwent curative intent surgery for liver metastasis as well. In these

40 patients, pancreatic head adenocarcinoma was the most common type of tumor (n=20;

50%). 95% of patients underwent a pancreaticoduodenectomy, the other 5% underwent an

ampullectomy. The majority of patients had lymph node metastasis associated with their

primary tumor (n=30; 75%). Most patients (n=27; 68%) presented with synchronous disease

and therefore underwent a simultaneous resection of both primary tumor and metastatic

disease. The other 13 patients (33%) presented with metachronous disease and were also

treated with surgery. Patients with synchronous disease were more likely to have smaller

lesions compared with patients presenting with metachronous disease. 78% of patients were

treated with resection only (n=31), 20% with radiofrequency ablation (RFA) only (n=8) and 2%

with a combination of resection and RFA (n=1). 7 patients received neoadjuvant chemotherapy

prior to hepatic resection, 4 of which had primary pancreatic cancer. Following surgery, 22

patients received some form of adjuvant chemotherapy in the form of gemcitabine (n=14), 5-

FU (n=4), cyclophosphamide injections (n=2), or combination irinotecan-based therapy (n=3).

The peri-operative complication rate observed by de Jong et al. was 30% and morbidity

following simultaneous resection was mostly associated with pancreas-related complications.

Complications associated with staged resection were limited to liver-related morbidity. Most

complications following liver surgery were major in nature (15).

2.2.2. Survival

2 patients (5%) in the study of de Jong et al. died postoperatively, both of whom underwent

simultaneous resection of the primary tumor and the metastatic liver disease. After a median

recurrence free interval of 10 months, 22 patients (55%) recurred. 1-year and 3-year disease-

free survival were 28% and 12% respectively. These numbers are better when comparing them

to disease-free survival numbers of patients who underwent a non-therapeutic laparotomy with

a median survival time of 7 months and 1-year and 3-year disease-free survival of 18% and

2% respectively (15). As mentioned earlier, Gleisner et al. achieved a median overall survival

of 5.9 months in patients with a pancreatic primary tumor histology versus 9.9 months in

patients with a non-pancreatic primary tumor histology. This difference in survival was not

significant however (13). This difference in survival between pancreatic carcinomas and

36

periampullary carcinomas was also observed by Adam et al., who reported about the results

after synchronous resection of primary tumor and associated metastatic liver disease in

noncolorectal nonendocrine tumours. In total 1452 patients with a primary tumor with

metastatic disease to the liver who underwent simultaneous resection of the primary tumor and

the associated metastatic disease were analysed. In the 84 patients with pancreaticobiliary

primary tumours participating in the study, they reported a 5-year survival of 27%. This included

41 patients with an exocrine pancreatic primary, 23 with gallbladder primary, 15 patients with

ampullary primary, and 5 patients with other biliary primary tumor locations. Remarkably, the

patients with ampullary primary tumours had a much more favourable survival, with a 5-year

survival figure of 46%. Patients with pancreatic primary tumours on the other hand achieved a

5-year survival of only 25% and even worse, in the subgroup of patients with a PDAC histology

specifically, a 5-year survival of ‘only’ 20% was noted (20). A 5-year survival of 20% in patients

with metastatic pancreatic cancer who underwent resection still is relatively good however,

seeing as this is similar to the survival of patients without metastatic disease who underwent

resection. This suggests that patients included in the study by Adam et al. are probably highly

selected patients.

The overall median survival observed by Seelig et al. was 10.7 months. This was not

significantly different from to the M0 control group who had a median survival of 15.6 months.

There also was no significant difference in survival between patients with liver metastasis

(median 11 months) and patients with metastasis in other locations (median 14.1 months) (17).

1-year and 3-year survival observed by de Jong et al. were 55% and 18% respectively. No

specific factors were associated with overall survival and median survival was similar among

patients who had synchronous (16 months) versus metachronous disease (19 months). The

histology of the primary tumor was of importance however, with a median survival following

surgery of 23 months for intestinal-type tumours compared with only 13 months for patients

with pancreaticobiliary tumours. Similarly, the 3-year survival was 33% versus 8%,

respectively. So it appears that the histology of the primary tumor has a very important

repercussion on survival (15). In a study conducted in New Delhi, India, 4 cases of

periampullary cancer with metastatic disease are described. All patients underwent a classic

Whipple procedure together with a simultaneous resection of the isolated liver metastasis. One

of these four patients died 9 months after surgery because of liver metastases. The other 3

patients are still alive at 16, 48 and 60 months after surgery (21).

2.3. Acinar cell carcinoma

Studies discussing acinar cell carcinoma (ACC) are discussed separately because these type

of tumours have the tendency to have a better overall survival. In a case report by Sumiyoshi

37

et al., a 77 year old man presented with an acinar cell carcinoma located in the tail of the

pancreas. Tumor invasion was suspected from the extrinsic compression of the posterior

stomach wall, as seen on gastrointestinal fiberscopic examination. Localised disseminated

nodules around the tumor were also discovered. A distal pancreatectomy, concomitant with

partial gastrectomy and resection of the disseminated nodules was performed. The patient

recovered well and was able to leave the hospital 11 days after surgery. Adjuvant S-1

chemotherapy was administered, with palliative intent. The patient does not show any signs of

recurrence and is in good health 73 months after surgery (31). Schmidt et al. showed that

acinar cell carcinomas have a significantly better prognosis after surgery across all stages of

pancreatic tumours in comparison to PDACs. Compared to patients with PDAC, those with

ACC had larger tumours (4.0 vs. 5.9 cm) but more frequently presented at an earlier Stage

(stage I/II 34.6% vs. 22.4%) and without distant metastases (66.5% vs. 61.0%). Stagespecific

survival was significantly better for resected ACC compared to PDAC: stage I: 52.9% vs. 30.9%

(P= 0.001), stage II: 39.9% vs. 10.6% (P<0.0001) and stage III: 20.4% vs. 6.7% (P=0.006)

(32).

3. Radiotherapy

In a study assessing the potential role of curative-intent stereotactic body radiotherapy in the

treatment of oligometastatic lesions, no specific data on primary pancreatic tumours was

available (33, 34). Lesions originating from primary pancreatic, biliary of liver cancer however,

had a significantly poorer local control in general (33).

Median survival of patients included in a study analysing the effects of palliative radiation

therapy was 4.2 months. Survival rates after 1, 3 and 6 months were 79.3%, 55.3% and 30.3%

respectively. Patients presenting with bone metastases had a median overall survival of 3.1

months and a 1, 3 and 6-month survival of 75.3%, 46.5% and 19.9% respectively. Most

patients were treated with 30 Gy in 10 fractions with a median treatment duration of 15 days.

Symptomatic response to radiotherapy was confirmed in at least 26 of 30 cases (87%). Mean

survival of patients with brain metastases was 6.3 months. All patients with liver metastases

deceased during follow-up and median overall survival was 8.3 months. 71.4% survived the

first 6 months after radiotherapy and after 12 months, 18% was still alive (2 patients) (35).

38

Table 6 Case series regarding radiotherapy

Year

(ref.) First author

Median overall survival

(months)

2008

(33) Milano N/A

2014

(35) Habermehl 4.2 (total)

2008

(34) Milano 24 (total)

N/A: not available; total: also including survival from tumours in other anatomic locations.

39

Discussion

The purpose of this review is to assess the value of surgery in the treatment of patients with

stage IV pancreatic cancer, more specifically those patients presenting with oligometastatic

disease. Eventually, the objective is to analyse if there is an added value of surgery in the

treatment of oligometastatic pancreatic carcinoma compared to the current gold standard,

which consists of chemotherapy.

In regards to operative details, similar results are observed between authors. Gleisner et al.

found the median operative time and median estimated blood loss to be comparable between

a group of patients who underwent simultaneous resection of primary tumor and associated

metastatic disease and a group of patients who did not have evidence of metastatic disease

and thus only underwent surgery for their primary tumor. Both operative time and blood loss

were significantly lower in a group of patients who underwent a palliative bypass though. The

same tendency in results was reported concerning perioperative morbidity and mortality.

Again, no significant difference was observed between simultaneously resected patients and

patients without metastatic disease who underwent surgery for their primary tumour alone but

both perioperative morbidity and mortality in the simultaneously resected group of patients

were significantly higher in comparison to patients who underwent a palliative bypass (13).

However, most authors didn’t find a significant difference in perioperative morbidity and

mortality comparing simultaneously resected patients with patients who underwent a palliative

bypass (14, 16, 23). Shrikhande et al., as well as Klein et al. and Singh et al., also didn’t find

any significant differences in blood loss, median operative time, perioperative morbidity or

mortality between resection for M1 disease and M0 disease (14, 23). So resection for

metastatic disease appears to be similar to resection of a primary tumor alone when looking

at median operative time, median estimated blood loss, perioperative morbidity and mortality.

Resection of primary tumor and associated metastatic disease is however more demanding

for the patient in contrast to bypass surgery. This difference between resection and bypass

surgery could be reduced by refining surgical techniques and by gaining specific experience

for these type of interventions.

Although several studies have reported successful outcomes after synchronous resection of

colorectal primary tumours and the associated hepatic metastatic disease, the role of

synchronous resection of primary tumor and associated metastatic disease in other tumor

histologies or other anatomic locations is not well defined. In a subset of patients presenting

with a resectable pancreatic primary tumor and low-burden metastatic disease or

metachronous metastatic disease after resection of the primary tumor for example, a different

40

therapeutic strategy may potentially yield better overall survival. Dünschede et al., Hackert et

al. and de Jong et al. all reported better survival results for patients who underwent

metachronous resection when compared to synchronous resection (15, 18, 25). This may have

something to do with the fact that patients who develop metachronous disease could

potentially have a more indolent form of disease or the fact that patients are subjected to a

resection of metastatic disease because they responded well to adjuvant therapy after the

initial resection of the primary tumor (as was the case in the case reports). Despite the fact

that 5-year survival figures of only 10% to 20% after surgery for pancreatic cancer with

metastatic disease are observed, surgery is the only treatment available in resectable

pancreatic cancer that could theoretically be curative. Though, it should be stressed that these

observed survival figures of 10-20% are only applicable in highly selected cases. Now,

according to international guidelines and widespread clinical practice, stage IV PDAC patients

are generally referred to palliative treatment with chemotherapy. With improving safety and

surgical expertise however, several authors have suggested more aggressive curative-

intended approaches in pancreatic surgery to improve long-term survival, even in patients with

(locally) advanced pancreatic adenocarcinoma (23).

The fact whether the patient presented with synchronous or metachronous disease and

therefore underwent simultaneous resection versus staged resection, respectively, appeared

to have important implications as regards to overall survival. Dünschede et al. observed a big

difference between these groups of patients. It is noteworthy though that the latter survival

figure is calculated from the moment when the metastases are detected. Also, 2 patients in the

group who underwent resection of the metachronous liver metastases first received

chemotherapy after the resection of the primary pancreatic tumor before advancing to liver

resection, making it a staged resection (25). Although not significant, Hackert et al. and de

Jong et al. also noted a difference in survival between synchronously and metachronously

resected patients, in favour of metachronous resection (15, 18). However, 5 out of 13 (38%)

patients in the study from de Jong et al. presenting with metachronous disease received

neoadjuvant chemotherapy prior to hepatic resection as compared to only 2 out of 27 (7%)

patients with synchronous disease receiving chemotherapy before simultaneous resection

(15). Overall, it’s clear to see that especially patients undergoing staged resection have a better

prognosis as compared to patients presenting with synchronous disease and therefore

undergoing simultaneous resection of primary tumor and associated metastatic disease. This

could however also have something to do with the fact that cancers in patients presenting with

synchronous disease are inherently more aggressive. Also, neoadjuvant chemotherapy

potentially plays an important role in these greatly different survival figures, although Hackert

et al. could not demonstrate a significant difference in survival between patients who received

41

neoadjuvant treatment and patients who did not receive neoadjuvant treatment (18). Given the

fact that patients undergoing staged resection have a better median overall survival, results of

these kind of patients should be interpreted carefully and should definitely not be directly

compared with survival figures of patients who underwent synchronous resection. The

difference in survival between patients undergoing simultaneous resection and patients

undergoing metachronous resection is less pronounced and does not reach statistical

significance, probably because of the fact that the majority of these patients did not necessarily

receive chemotherapy during the period between the resection of the primary tumor and the

resection of the associated metastatic disease (in contrast to patients who underwent staged

resection).

As regards to heterogenicity of data concerning tumor histology, some studies included in this

review make no difference between different types of tumor histologies when reporting results.

Patients with either PDAC or (peri)ampullary tumor histologies often end up in the same study

population while there is clear evidence, delivered by several studies, that there can be quite

significant differences in outcome between different types of tumours. For example, Klein et

al. made a clear distinction between periampullary tumours of intestinal type and periampullary

tumours of pancreaticobiliary origin. The difference in survival between intestinal type tumours

and pancreaticobiliary tumours was significant, emphasizing that when reporting about

periampullary tumours a clear distinction should be made in regards to tumor histology in order

to be able to formulate correct and specific conclusions concerning the results of surgery for

periampullary tumours. Another example is the study conducted by Adam et al. They observed

a much more favourable survival in patients with periampullary primary tumours (5-year

survival of 46%) in comparison to patients with pancreatic primary tumours (5-year survival of

25%). This is an indicator for the fact that pancreatic primary tumours have a much more

aggressive nature and/or therapeutic resistance and therefore should be analysed and

discussed separately from tumours originating from other anatomic locations in terms of

survival. These notable differences in survival are the reason why in this review the choice was

made to separately analyse and report outcomes of treatment in periampullary tumours and

pancreatic tumours, unlike some studies where endpoints like survival are being discussed in

general without differentiating between these apparently completely differently reacting types

of tumours.

Another, similar example concerns the localisation of metastatic disease. Often no specific

results are reported according to where the primary tumor has metastasized. However, some

authors assessed the impact of the location of the metastasis but with conflicting results.

Yamada et al. found no significant difference in survival when differentiating between

localisation of metastatic disease, with slightly worse survival figures for patients with

42

paraaortic lymph node metastases as compared to patients with liver metastases or peritoneal

metastases. This in contrast to survival figures observed by Shrikhande et al. who found a far

better prognosis for patients with interaortocaval lymph nodes in comparison to metastases in

other locations.

According to the results found in studies conducted by Takada et al. and Shrikhande et al.,

simultaneous resection of primary tumor and associated metastatic disease should be superior

to no resection at all. However, one should take in mind that one of the criteria for the patients

who underwent surgical resection was the impression of “low overall tumor burden”. So

automatically patients who underwent palliative bypass have a tendency to have a higher

overall tumor burden in comparison to those patients who underwent surgical resection.

Therefore, the results of patients undergoing surgical resection will automatically be better

because these patients already had a better prognosis from the beginning. Notwithstanding

these results, Gleisner et al. found different results when comparing results between patients

who underwent simultaneous resection of primary tumor and associated metastatic disease

and patients who underwent standard surgical palliation in the form of a bypass, as well as

comparing the results of both groups with the results of patients who underwent resection for

M0 disease. Regarding overall survival, Gleisner et al. did not find evidence to prove that

synchronous resection could have an added value in the treatment of metastatic pancreatic

cancer as compared to palliative bypass, nor did their results completely discourage the use

of surgery in these cases since they observed similar overall survival results between patients

who underwent simultaneous resection and patients who underwent palliative bypass (13).

These conflicting results between Takada and Shrikhande on one hand and Gleisner on the

other hand are due to the fact that Gleisner et al. only included patients who were considered

unresectable because of the presence of the liver metastases in their palliative control group.

Also, patients in the Takada et al. report had a more extensive burden of hepatic disease with

hepatic metastases ranging from 0.5 cm to 5 cm and some patients had as many as 7 lesions

(16). In contrast, the overwhelming majority of patients in the series from Gleisner et al. had

very limited metastatic disease, with a median tumor size of 0.6 cm, and 90.9% of patients

having only 1 lesion (13). Dünschede et al. also didn’t find convincing evidence for the

promotion of synchronous resection, as they compared a group of patients who underwent

synchronous resection with a group of patients who was treated with gemcitabine only and

saw a median survival of 8 months versus 11 months, respectively (25). So it is clear that the

value of synchronous surgery in metastatic disease remains doubtful with authors reporting

conflicting results. Looking at survival alone however, it seems that simultaneous surgery does

not yield a worse survival in comparison to palliative bypass but it doesn’t seem to be

convincingly superior either.

43

Despite the rather big difference in tumor burden found between Takada et al. on the one hand

and Gleisner et al. on the other hand, both studies found similar median overall survival figures

of approximately 6 months. This advocates for the fact that despite the patient presenting with

only one or a few metastases, pancreatic cancer is already a widespread disease by the time

the patient is diagnosed with metastatic disease. It is suspected that despite the fact that no

metastases are visible on imaging, there probably are multiple occult metastases present in

the body. Although it may be tempting to treat patients with solitary or at most a few localized

small metastases as patients with only ‘limited’ metastatic disease, these data indicate that a

pancreatic tumor with metastatic disease, regardless of number and size, is a marker for

existent, widespread, systemic disease (13). Another observation that may lead up to the same

conclusion is the fact that most patients who underwent resection, even when a R0 status is

achieved, tend to have a high recurrence rate, indicating that at the time of diagnosis of

metastatic disease there most probably already are some occult metastases present in the

body (17). Several authors reported the death in the majority of their patients to be the result

of recurrent metastatic disease (13, 16, 17, 24). This phenomenon is not treatable by surgery

but could possibly be tackled with chemotherapy. Satoi et al. conducted a multicentre study

analysing the role of ‘adjuvant surgery’ in patients with a long-term favourable response to non-

surgical anticancer treatments. Patients underwent surgical resection after a median of 274

days from initial therapy. Median survival time was 25 months, which is remarkably longer than

all other studies included in this review and significantly better than the control group containing

patients with unresectable pancreatic cancer, reaching a median overall survival of 20.8

months. When calculating the optimal timing for surgery they found that the longer the duration

of the initial treatment prior to surgical resection, the longer the survival time. A sub-group

analysis assessing the time from initial treatment to surgery showed significant differences in

the overall survival rates in favour of patients who were able to undergo adjuvant surgery more

than 240 days after initial treatment. Therefore, they recommended an optimal time for

adjuvant surgery of at least 240 days after the initial non-surgical anticancer treatment (22).

In some highly selected cases however, very high survival figures are achieved. In this review

several case reports are documented with survival times ranging from a minimum of at least 9

months up to more than 7 years and counting. Though, it should be mentioned that one of the

case reports used in this review, reported by Sumiyoshi, is one concerning an acinar cell

carcinoma (31). This type of pancreatic tumor tends to have a far better prognosis than other

tumor histologies in general so it should not be compared to survival figures of other tumor

types. That aside, the reason behind the relatively high survival figures found in case reports

concerning PDAC’s is probably due to the fact that these case reports are usually highly

selected patients with an exceptional response to systemic therapy. Most of the time patients

44

presented in these case reports are in a good general condition. Also, the vast majority of

patients described in these case reports have a pancreatic lesion located in the tail of the

pancreas. A study by Lorgis et al. examined the influence of tumor localisation on the

effectiveness of chemotherapy and found that carcinomas in the head of the pancreas tended

to be less responsive to FOLFIRINOX treatment than carcinomas in other locations (36).

Not only case reports are prone to containing only highly selected patients and thus having a

selection bias. All case series are susceptible to selection bias since patients included in

studies where surgery is used to treat metastatic pancreatic cancer are more likely to be in

better general condition than patients who underwent palliative bypass for example. Patients

included in these studies are often “super-responders” to non-surgical anti-cancer treatments

as well. As regards to metastatic disease, it is often the case in studies concerning metastatic

pancreatic cancer that at the time of surgery it is not known the patient effectively has

metastatic disease. In the majority of cases when the decision is made to subject the patient

to surgery, metastases are only discovered at the time of surgery or even retrospectively after

final histopathologic reporting (13, 14). A case control study conducted by Gleisner et al.

analysed the results of simultaneous resection of primary pancreatic cancer and metastatic

hepatic disease in 22 patients. Surgery was performed for known synchronous disease in only

1 patient. In the other 21 patients, hepatic metastases were only identified during laparotomy

(13). The same goes for a retrospective study conducted at the university of Heidelberg where

metastatic disease was identified or suspected intraoperatively before resection in 14 out of

29 patients and diagnosed only after histopathologic reporting in the remaining 15 patients.

Indications for resection despite the knowledge of the presence of metastatic disease include:

patient in good general condition, patient preference (this of course when preoperative

counselling had taken place regarding the possibility of metastatic disease), resection of

peripherally located one or two isolated liver metastases, the impression of ‘low overall tumor

burden’, a high probability of R0 resection, and a ASA grade III or better. This implies that

patients included in studies assessing the value of surgery in metastatic pancreatic carcinoma

are already in a better general condition since they have to meet these criteria before resection

is considered. Therefore results from these studies should not be generalized and should be

interpreted with caution (14).

An important note that needs to be made is the fact that in almost every study assessing the

outcome after surgery of primary tumor and metastatic disease, the majority of patients gets

administered some form of neoadjuvant or adjuvant systemic therapy. In order to understand

the role of chemotherapy on the outcome after surgery, results between patients who

underwent surgery in combination with the administration of some form of (neo)adjuvant

therapy and patients who only underwent surgery should be compared. Only a few studies

45

included in this review compared results from these different treatment strategies. As

mentioned before, Hackert et al. could not demonstrate a significant difference in survival

between patients who received neoadjuvant treatment and patients who did not receive

neoadjuvant treatment (18). Shrikhande et al. found a median overall survival of 13.8 months

for all 29 patients in their study and more specifically, they found an estimated median survival

of 15.8 months for patients receiving adjuvant treatment (14). Tachezy et al. on the other hand,

did not see an impact of neoadjuvant therapy on overall survival in a univariate analysis but

the sample size of their study was too small to reach statistical significance (19). The role of

chemotherapy is mainly to shrink the existing tumor and existing metastases. It can also be

effective against possible existing occult metastases present in the body and thus not

detectable by imaging.

One of the limitations of all studies used in this review is the sample size. The biggest study

assessing the results of surgery on metastatic pancreatic cancer contains 128 patients. Most

studies only contain a few dozen patients. Therefore these studies have limited statistical

power, which makes it difficult to draw conclusions that are applicable to large populations.

Another limitation of this study is the heterogenicity of data available in the different studies in

this review, making it impossible to make a decent quantitative analysis. This as well makes it

harder to formulate specific conclusions and potentially come up with specific guidelines for

treatment of metastatic pancreatic cancer. An example of this heterogenicity in data is the type

of operation performed (Whipple, pylorus-preserving pancreaticoduodenectomy, distal, and

total pancreatectomy) and the localisation of metastatic disease, as well as tumor histology

and total tumor burden. All these differences in data make it, as mentioned above, difficult to

draw specific conclusions.

Another limitation of quite a few studies included in this review is the retrospective nature of

them. Because of this it is often the case that not all details on (neo)adjuvant therapy are

available, making it more of a challenge to interpret results. Associated with the retrospective

nature of studies is the risk of selection bias since the reason for resection is often not known

anymore. Because of this often only highly selected patients in good general condition are

included. Another limitation is the fact that most studies are single centre, making it hard to

judge whether the accomplished results can be extrapolated to bigger populations or if they

are the result of (a lack of) specific expertise from this centre.

In order to get a complete view on the possible advantages of surgery in metastatic pancreatic

cancer, other important endpoints such as quality of life should also be assessed. This is

absent in the overwhelming majority of studies on surgery in metastatic pancreatic cancer.

Therefore it is impossible to get an understanding of how much surgery of metastatic

46

pancreatic disease has implications on the patient’s life, for example in comparison to palliative

bypass. Also, potential long-term complications and side effects in resected patients cannot

be completely excluded.

Quality of life is important though, seeing as complication rates in surgery with simultaneous

resection of primary tumor and associated metastatic disease are relatively high and mostly

severe in nature (Clavien grade ≥ 3) (15). There specifically appears to be a difference in risk

of developing certain complications, depending on whether it concerns synchronous or

metachronous disease, thus whether it concerns simultaneous resection or staged resection.

Specifically, patients who underwent liver resection following pancreaticoduodenectomy

tended to have a higher risk of developing a liver abscess compared with patients who

underwent simultaneous resection of primary tumor and associated hepatic metastasis (15,

23). Klein et al. found the surgical complication rate (Clavien grade ≥ 3) to be smaller in patients

with metastatic liver disease in comparison to patients without metastatic disease, with a

complication rate of 18% and 41% respectively (23).

47

Conclusion

Surgery in patients presenting with pancreatic carcinoma with associated metastatic disease

remains controversial among authors but results regarding overall survival seem to be

increasing as time evolves and centres are gaining specific experience and expertise in the

surgical approach of these type of patients. It is noteworthy however that all studies included

in this review in which results from staged resection and metachronous resection were

compared with results from synchronous resection unanimously showed a better median

survival for patients presenting with metachronous disease. Therefore, studies specifically

assessing the value of staged resection and metachronous resection in metastatic pancreatic

cancer should be conducted in order to investigate a potential survival benefit. Staged

resection in particular seems to have the biggest potential as regards to gaining survival. When

investigating the optimal timing for surgery it appeared that the longer the duration of the initial

treatment prior to surgical resection, the longer the survival time. Concerning systemic

chemotherapy, it is suggested that chemotherapy could play an important role in downstaging

the tumor and metastases before resection and in eliminating occult metastases that were not

resected during surgery. That’s why in most studies patients are administered (neo)adjuvant

systemic therapy. In order to assess the role of neoadjuvant administration of chemotherapy,

more studies in which the effects of adjuvant surgery are assessed should be carried out. In

the future, neoadjuvant chemotherapy may be used for patients presenting with a metastatic

carcinoma to select appropriate candidates for surgery since only patients that respond to the

neoadjuvant treatment might also benefit from an aggressive surgical approach. In general it

can be concluded that surgery can be considered a valuable treatment strategy for highly

selected patients, preferably for those who show an astonishingly good response to

chemo(radio)therapy, have a low overall tumor burden and thus limited metastatic disease (in

number and size). Specifically, patients with periampullary tumours seem to benefit more of a

surgical approach, especially when it concerns tumours of the intestinal type. As of now it’s too

early to generalize the use of surgery in the approach of metastatic pancreatic cancer however.

Part of the reason why is the small amount of studies assessing the results of resection in

patients with metastatic pancreatic carcinoma and the small sample size in these studies,

resulting in not enough statistical power to safely assume results reported in these studies are

applicable to large populations of patients.

48

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1

Appendix

Characteristics of studies:

GLEISNER 2007

Methods Matched cohort study

Participants Of the 1563 patients who underwent resection of periampullary or pancreatic

adenocarcinoma, 22 patients underwent simultaneous hepatic resection for

synchronous liver metastasis. The primary tumor site was ampullary (n=1),

duodenal (n=2), distal bile duct (n=2) or pancreas (head, n=10; tail, n=7). A

matched-controlled analysis was performed. Specifically, 2 matched groups

of patients were used for the purpose of analytic comparison: 1) 66 patients

with no evidence of hepatic metastases who underwent resection of their

primary tumor (eg, “resection controls”); and 2) 66 patients with histologically

proven liver metastases who underwent standard surgical palliation (eg,

“palliative controls”). Surgical palliation entailed a traditional “double-bypass”

characterized by a hepaticojejunostomy as well as a gastrojejunostomy.

Patients with extrahepatic disease, including those with serosal implants or

peritoneal disease, were not included in the study.

The majority of patients (n=19; 86.4%) had lymph node metastasis

associated with their primary tumor.

The majority of patients (n=20; 90.9%) had a solitary hepatic lesion, and 2

patients had 2 lesions each.

The mean size of the largest lesions was 0.6 cm (0.3-1.2 cm).

Surgery was performed for known synchronous disease in 1 patient (4.5%),

and hepatic metastases were identified incidentally at the time of laparotomy

in 21 patients (95.5%).

Interventions Cases

Pancreaticoduodenectomy (n=15; 68.2%) or distal pancreatectomy (n=7;

31.8%).

Extent of hepatic resection: wedge resection (n=20; 90%), segmentectomy

(n=1; 4.5%) and hemihepatectomy (n=1; 4.5%).

Resection controls

Resection of primary periampullary/pancreatic tumor.

Palliative controls

2

Traditional “double-bypass” characterized by a hepaticojejunostomy as well

as a gastrojejunostomy.

Outcomes Operative time, blood loss, perioperative morbidity and mortality, time to

recurrence, overall survival

Notes Study included participants with pancreatic and periampullary tumours.

Patients were not stratified according to primary tumor and thus no separate

results were reported.

7 patients (31.8%) received some form of adjuvant chemotherapy.

- PDAC (n=6): 5-FU (n=3) or gemcitabine (n=3).

- Duodenal adenocarcinoma (n=1): FOLFIRI (n=1)

SHRIKHANDE 2006


Participants 29 patients underwent pancreatic resection with resection of associated

metastatic disease (interaortocaval lymph node dissection, liver resection,

and/or multiorgan resections). Data of 287 patients with R0/R1 M0 disease

and of 118 patients not treated with resection but harbouring M1 (only liver)

disease were evaluated for purposes of comparison with the main study

group.

None of the patients was proven to be harbouring metastatic disease in the

preoperative evaluation. In 14 patients, metastatic disease was identified or

suspected intraoperatively before resection, whereas in the remaining 15

patients metastatic disease was diagnosed retrospectively only after

histopathological reporting.

Interventions 18 patients underwent pancreaticoduodenectomy for pancreatic head

cancer:

- 3 had solitary metastasis to the liver. They underwent single

segmentectomy.

- A 4th patient underwent resection of segments 7 and 8 for two,

separate lesions.

- 9 had metastatic disease to the interaortocaval group of lymph nodes.

- The remaining 5 patients had metastatic peritoneal nodules (colonic

mesentery, n=2; peritoneum lining the abdominal wall, n=3).

9 patients underwent distal pancreatectomy for pancreatic body and tail

cancer:

3

- 6 had metastatic disease to the liver. 4 of them underwent

segmentectomies for solitary lesions, 2 underwent resections of

segments 4b, 6 and 7 and segments 2 and 8, respectively, for two

separate lesions. One of these 6 patients had metastatic disease to

the interaortocaval group of lymph nodes along with a solitary liver

metastasis.

- 3 had metastatic peritoneal nodules.

2 patients underwent total pancreatectomy for locally advanced pancreatic

head cancer.

- 1 had metastatic disease to the liver and underwent a

segmentectomy.

- 1 had metastatic disease to the interaortocaval group of lymph nodes.

Outcomes Blood loss, complication rate, duration of hospitalization, perioperative

mortality, overall survival

Notes Median follow-up time of patients who were alive was 8.5 months.

1 out of 29 patients received radiochemotherapy as neoadjuvant treatment.

23 out of 29 patients received adjuvant treatment:

- Radiochemotherapy: 1

- Gemcitabine: 13 (2 of which also received experimental tumor

vaccinations)

- 5-FU: 6

- Experimental tumor vaccinations: 2

- Unknown: 1

DE JONG 2010

Methods Retrospective cohort study

Participants 40 patients underwent curative intent surgery (resection and/or

radiofrequency ablation (RFA)) for periampullary liver metastasis. Location

of the primary tumor was pancreas head (n=20), ampulla of Vater (n=10),

distal bile duct (n=5), or duodenum (n=5).

Most patients (n=27) presented with synchronous disease, while 13 patients

presented with metachronous disease following a median disease-free

interval of 22 months.

Most patients (n=25) presented with hepatic metastasis from

pancreaticobiliary origin (pancreatic or distal common bile duct) compared

4

with 15 patients who had metastasis from an intestinal-type primary

(ampullary or duodenal).

The majority had lymph node metastasis associated with their primary tumor

(n=30; 75%).

Interventions Pancreaticoduodenectomy (n=38; 95%)

Ampullectomy (n=2; 5%)

Hepatic surgery:

- Resection only (n=31; 78%)

- RFA only (n=8; 20%)

- Resection + RFA (n=1; 2%)

Hepatic resection:

- Wedge resection (n=22; 69%)

- Segmentectomy (n=6; 25%)

- Hemihepatectomy (n=4; 10%)

Outcomes Perioperative complication rate, surgical morbidity, recurrence, survival.

Notes There were no differences in metastatic tumor number or size between the

intestinal versus pancreaticobiliary groups.

Patients with synchronous presentation were more likely to have smaller

hepatic lesions (median: 0.5 cm) compared with patients who presented with

metachronous disease (median: 3.5 cm).

Seven patients received neoadjuvant chemotherapy prior to hepatic

resection (primary tumor: pancreatic, n=4; ampullary, n=2; duodenal, n=1).

Neoadjuvant chemotherapy was often administered more for metachronous

(n=5; 38%) disease than synchronous disease (n=2; 7%).

22 (55%) patients received some form of adjuvant chemotherapy:

- Gemcitabine (n=14)

- 5-fluruoracil (n=4)

- cyclophosphamide injections (n=2)

- combination irinotecan-based therapy (n=3).

TAKADA 1997


Participants 109 patients with adenocarcinoma of the pancreatic head were divided into

two groups:

5

- Group 1: 33 patients with liver metastasis: Group 1A (n=11)

underwent pancreaticoduodenectomy and partial liver resection.

Group 1B (n=22) underwent palliative bypass surgery.

- Group 2: 76 patients without liver metastasis: Group 2A (n=37)

underwent pancreaticoduodenectomy. Group 2B (n=39) underwent

palliative bypass surgery.

Size of the resected liver metastasis ranged from 0.5 to 5 cm, and from 1 to

7 lesions per patient were resected.

Interventions Group 1A (n=11): extended pancreaticoduodenectomy with

lymphadenectomy + partial/wedge hepatic resection.

Group 2A (n=37); pancreaticoduodenectomy

Group 1B (n=22)/group 2B (n=39): gastrointestinal and/or biliary-enteric

anastomosis.

Outcomes Postoperative mortality, survival.

Notes No mention of administration of (neo)adjuvant treatment.

SEELIG 2010


Participants 20 patients with proven stage IV periampullary cancer of the pancreas who

underwent pancreatic surgery with synchronous resection of hepatic,

adjacent organ, or peritoneal metastases.

Location of primary tumor:

- Pancreatic head (n=9; 45%)

- Pancreatic tail (n=9; 45%)

- Papilla Vateri (n=2; 10%)

Location of metastases:

- Liver (n=14; 70%)

- Peritoneum (n=5; 25%)

- Omentum majus (n=2; 10%)

- Lymph node metastases were present in 16 patients (80%)

The results of the study group were compared with a matched-pair control

group of 20 patients with pancreatic adenocarcinoma who underwent only

pancreaticoduodenectomy or distal pancreatic resection for stadium IIb or III

(= tumours without associated metastatic disease) pancreatic

adenocarcinoma.

Interventions Pylorus preserving duodenopancreatectomy (n=8)

6

Distal pancreatectomy (n=8)

Duodenopancreatectomy (n=2)

Total pancreatectomy (n=2)

Outcomes Perioperative mortality, complication rate, blood loss, length of hospital stay,

survival.

Notes No details on type of surgery specifically for metastatic disease.

All patients received some form of adjuvant chemotherapy.

2 patients (10%) also received some form of neoadjuvant chemotherapy.

HACKERT 2016

Methods Prospective cohort study

Participants 128 patients undergoing PDAC and metastases resection.

- Liver: n=85

- Interaortocaval lymph nodes (ILN): n=43

All ILN resections were performed synchronously with the pancreatic

resection, whereas 72.9% of liver resections were carried out at the time of

the pancreas resection. 22.4% of liver resections were performed following

prior PDAC surgery at an average time of 18.4 (range 1-58) months. In 4

patients (4.7%) liver metastases were removed during an initial exploration,

followed by chemotherapy and resection of the primary pancreatic tumor.

Metastases:

- Diameter <1 cm (43%)

- Diameter 1-2cm (31.7%)

- 3 lesions or less (96.4%)

- More than 3 lesions (n=3)

Interventions Pancreaticoduodenectomy (n=66):

- Liver metastases (n=36)

- ILN metastases (n=30)

Total pancreatectomy (n=22):



Distal pancreatectomy (n=39):



Resection of liver metastases:

- Atypical resections of one to four subcapsular lesions (86%)

7

- Formal resections (14%), including bisegmentectomies, and right and

extended right hepatectomies.

Outcomes Perioperative morbidity and mortality, survival.

Notes Patients were stratified with regard to synchronous or metachronous

metastases resection.

20 patients received neoadjuvant treatment.

The majority of major hepatic resections were carried out metachronously.

TACHEZY 2016


Participants 69 patients with pancreatic ductal adenocarcinoma (PDAC) and synchronous

liver metastasis who underwent simultaneous pancreas and liver metastasis

resections.

69 patients receiving exploration without tumor resection served as the

control group.

Interventions Classic pancreaticoduodenectomy

Pylorus-preserving pancreaticoduodenectomy

Distal splenopancreatectomy

Subtotal or total pancreatectomy

Lymphadenectomy was performed to a standard extent in all cases.

All liver resections were atypical wedge resections.

Outcomes Perioperative morbidity and mortality, duration of hospitalization, survival.

Notes Multicentre analysis

Preoperative neoadjuvant treatment was administered in 14% of the

resected and 1% of the nonresected patients.

- Gemcitabine-based (n=5)

- FOLFIRINOX (n=4)

- Unknown (n=2)

ADAM 2006


Participants 1452 patients with noncolorectal nonendocrine liver metastases treated with

hepatic resection, 84 of which had a primary tumor of pancreatic or biliary

origin.

- 41 exocrine pancreatic primary

- 23 gallbladder primary

8

- 15 ampullary primary

- 5 other biliary primary tumor locations

Hepatic metastases were solitary in 56%.

Interventions No specifics were given.

Outcomes Survival

Notes In general, the subgroup with pancreaticobiliary primary tumours

experienced an intermediate 5-year survival of 27%. Only those patients with

ampullary primary tumors had a favourable 5-year survival (46%). Patients

with liver metastases from pancreatic primary tumors had a 5-year survival

of 25%, and the subset with pancreatic adenocarcinoma had a 5-year

survival of 20%.

SINGH 2010

Methods Prospective cohort study

Participants Two-hundred and thirty patients underwent pancreaticoduodenectomy for

pancreatic and periampullary cancer. Eleven (4.8%) out of 230 patients

undergoing pancreaticoduodenectomy for pancreatic and periampullary

cancer were detected to have isolated liver metastases. Seven of these were

diagnosed preoperatively on CT scan while four were diagnosed

intraoperatively. Synchronous resection was not considered in four patients:

two with locally advanced tumours (both had a diagnosis of liver metastases

on preoperative CT) and another two with multiple liver metastases seen on

intraoperative ultrasound (both had intraoperative detection of liver

metastases). Results of the seven patients who underwent synchronous

resection were compared the other 223 patients who underwent

pancreaticoduodenectomy.

Interventions Seven patients (3.0%) underwent synchronous resection of the isolated liver

metastasis together with a pancreaticoduodenectomy. Four of these patients

had periampullary cancer while three underwent pancreaticoduodenectomy

for pancreatic cancer.

Resections were in the form of left lateral segmentectomies in two patients

and metastasectomy in five patients.

Outcomes Operative mortality, operative time, complication rate, duration of hospital

stay.

Notes No median survival available. Three patients are disease free at follow-up

times of 16, 48 and 60 months.

9

All patients who had synchronous liver resections received chemotherapy

versus 134 (60.1%) of the other 223 patients undergoing

pancreaticoduodenectomy.

SATOI 2013

Methods Retrospective multicentre cohort study

Participants 58 patients with initially unresectable pancreatic cancer who underwent

adjuvant surgery following the achievement of stable disease (SD), partial

response (PR), or complete response (CR) over 6 months after initiating non-

surgical anti-cancer treatments.

- 41 with locally advanced tumours

- 17 with distant organ metastases

The control group included 43 patients judged to have unresectable disease

on laparotomy:

- 18 witch locally unresectable tumours

- 13 with peritoneal dissemination

- 10 with liver metastasis

- 2 with distant lymph node metastasis

The control group also included 58 patients who did not undergo surgical

resection because of either unchanged unresectability, a poor performance

status, and/or the patients’ or surgeons’ wishes.

Interventions Primary tumor resection:

- (Pylorus preserving) pancreaticoduodenectomy (n=30)

- Total pancreatectomy (n=3)

- Distal pancreatectomy (n=15)

- Distal pancreatectomy with celiac axis resection (n=10)

Patients with liver metastases (n=13):

- Metastasectomy (n=5)

- Liver biopsy (n=2)

- No liver tumor found at time of surgery (n=6)

On patient had peritoneal metastasis (n=1) diagnosed on CT but was not

found during surgical resection of the primary tumor.

Outcomes Survival

Notes 53 patients received gemcitabine-based chemotherapy. 32 patients received

S-1 chemotherapy.

10

Median time from initial therapy to surgical resection was 274 days (182-

1418).

KLEIN 2012


Participants 22 patients who underwent simultaneous pancreatic resection and liver-

directed therapy for hepatic metastasized pancreatic adenocarcinoma

(HMPA) were compared to 22 patients who underwent classic pancreas

resection for nonmetastasized pancreatic carcinoma (NMPA).

Interventions Pancreatic resections (HMPA):

- Pancreaticoduodenectomy: 1 patient (5%)

- Pylorus preserving pancreatectomy: 16 patients (73%)

- Distal pancreatectomy: 1 patient (5%)

- Total pancreatectomy: 4 patients (18%)

Liver-directed therapy:

- Segmentectomy: 7 patients (32%)

- Enucleation of the hepatic metastases: 15 patients (68%)

Pancreatic resections (NMPA):

- Pancreaticoduodenectomy: 3 patients (14%)

- Pylorus preserving pancreaticoduodenectomy: 14 patients (64%)

- Distal pancreatectomy: 1 patient (5%)

- Total pancreatectomy: 4 patients (18%)

Outcomes Postoperative morbidity, preoperative and operative data, survival.

Notes All patients received adjuvant chemotherapy with Gemcitabin in the

postoperative course.

YAMADA 2009


Participants 542 patients with pancreatic cancer underwent surgery, including:

- 48 patients with paraaortic lymph node metastases

- 11 patients with hepatic metastases

- 6 patients with peritoneal metastases

Location of primary tumor:

- Head of pancreas (n=279)

- Body and tail of pancreas (n=72)

- Entire pancreas (n=9)

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Interventions Pancreaticoduodenectomy: 181

Pylorus-preserving pancreaticoduodenectomy: 45

Distal pancreatectomy: 63

Total pancreatectomy: 70

Pancreatic head resection with segmental duodenectomy: 1

Intraoperative radiation therapy (IORT, 30Gy) was administered to the

retroperitoneal fields.

Outcomes Survival

Notes Adjuvant chemotherapy: 5-fluorouracil (5-FU) portal injection, 5-FU based

chemotherapy or gemcitabine were given to some patients.

DÜNSCHEDE 2010


Participants 23 patients:

- Group 1: patients with isolated synchronous liver metastases of

pancreatic cancer and no evidence of locoregional or further

metastatic disease (n=14). Nine patients underwent one-stage

resection of the primary tumor and liver metastases. The other five

patients received chemotherapy with gemcitabine.

- Group 2: patients with isolated metachronous liver metastases of

pancreatic cancer and no evidence of locoregional or further

metastatic recurrence (n=9). Four patients underwent resection of

liver metastases after R0 resection of the pancreas carcinoma. The

other five patients received chemotherapy with gemcitabine after R0

resection of the pancreas carcinoma.

Median number of liver metastases (group 1):

- Resection group: 3 (1-5)

- Gemcitabine group: 1

Mean size of the largest metastases (group 1):

- Resection group: 3.5 cm (1-9 cm)

- Gemcitabine group: 2.5 cm (2-4 cm)

Median number of liver metastases (group 2):

- Resection group: 1.75 (1-2)

- Gemcitabine group: 1.75 (1-2)

Mean size of the largest metastases (group 2):

- Resection group: 2.2 cm (1-3 cm)

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- Gemcitabine group: 2.2 cm (1-3 cm)

Interventions Group 1:

- Partial pancreaticoduodenectomy for pancreatic head cancer (n=3).

- Distal pancreatectomy for pancreatic tail cancer (n=6)

- Liver resections: atypical liver resection (n=6), lobectomy (n=2) or

trisegmentectomy (n=1).

Group 2:

- Left lateral bisegmentectomy (n=1)

- Atypical liver resection (n=3)

Outcomes Operative time, blood loss, complication rate, mortality rate, survival.

Notes In group 2, two patients in each group received chemotherapy after resection

of the primary.

Attachments

Attachment 1: Prisma flow diagram.

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