Pancreaticoduodenal Resection for Malignancy in a Low-volumeCenter: Long-term Outcomes from a Developing Country

Abu Bakar Hafeez Bhatti • Mohammad Aasim Yusuf •

Syed Ather Saeed Kazmi • Aamir Ali Syed

� Societe Internationale de Chirurgie 2014

Abstract

Background The technical complexity of pancreatic

resection has made it a specialized procedure performed in

high-volume centers. It has been shown that patients

operated on in high-volume pancreatobiliary centers have

fewer complications and better survival. The purpose of

this study was to share our experience with and report long-

term outcomes of pancreaticoduodenal resections per-

formed in a low-volume center in Pakistan.

Methods Data of patients who underwent pancreati-

coduodenal resection for adenocarcinoma at our institute

from 1999 to 2012 were reviewed. A total of 39 patients

were included in the study. Variables included patients’

clinical and histopathological characteristics. Outcome was

determined based on complication rate, 30- and 90-day

mortality, disease-free survival, and overall survival. For

survival analysis, Kaplan–Meier curves were used and

significance was determined using a log rank test. Uni-

variate Cox analysis was performed to determine signifi-

cant factors for multivariate analysis.

Results The majority of tumors [20 (51 %)] were mod-

erate grade, T1/T2 [20 (51 %)], ampullary adenocarcino-

mas [18 (46 %)]. Mean hospital stay was 14 ± 8 days. The

mean number of nodes removed was 13.9 ± 6.9, while

mean number of positive nodes was 1 ± 1.7. Expected

5-year overall survival and relapse-free survival were 38

and 48 %, respectively. Overall 5-year survival was sig-

nificantly different with respect to nodal involvement, i.e.,

47 vs. 28 % (P = 0.018). On univariate analysis, nodal

involvement was the only factor associated with an

increased risk of death (P = 0.02, hazard ratio [HR] 2.9,

confidence interval [CI] 1.1–7.8).

Conclusion Low-volume centers are an acceptable alter-

nate to high-volume centers for performing pancreati-

coduodenal resection in carefully selected patients. Efforts

should be directed at developing specialized hepatobiliary

centers in developing countries.

Introduction

Pancreaticoduodenal (PD) resection is one of the most

complex procedures in gastrointestinal surgery [1].

Although Whipple is credited with performing the first

successful pancreatic head resection for ampullary cancer,

it was Alexander Brunschwig who performed the first

successful pancreaticoduodenectomy for pancreatic cancer

[2, 3]. High morbidity and mortality rates plagued this

procedure throughout the 20th century, leading to questions

regarding its effectiveness [4, 5]. Developments in various

aspects of patient care and refinement in the surgical

technique have helped improve the outcomes of this

complex procedure and impressive results have been

achieved in the last decade. More recently, a mortality rate

as low as 1 % has been reported [1]. The morbidity rate is

still high and ranges between 30 and 66 % [1, 6–8]. An

inverse relationship between hospital volume and morbid-

ity and mortality has been observed [9]. High-volume

A. B. H. Bhatti (&) � A. A. Syed

Department of Surgical Oncology, Shaukat Khanum Memorial

Cancer Hospital and Research Centre, Lahore, Pakistan

e-mail: Abubakar.hafeez@yahoo.com

M. A. Yusuf

Department of Gastroenterology, Shaukat Khanum Memorial

Cancer Hospital and Research Centre, Lahore, Pakistan

S. A. S. Kazmi

Department of Medical Oncology, Shaukat Khanum Memorial

Cancer Hospital and Research Centre, Lahore, Pakistan

123

World J Surg

DOI 10.1007/s00268-014-2644-6

centers have reported superior results with pancreatico-

duodenectomy, not only with respect to postoperative

complications and mortality but also for long-term survival

[10–12]. In recent years, low-volume centers have also

demonstrated acceptable short- and long-term survival

rates for PD resections [13, 14]. Long-term survival data

from low-volume centers in developing countries is lim-

ited. Although no standard definition exists as to what

constitutes a low-volume center; hospitals that perform

fewer than five resections a year are generally considered

low volume. The purpose of this study was to share our

experience with and report long-term outcomes of PD

resection for malignancy performed at a low-volume center

in Pakistan.

Methods

Patient selection

A retrospective review of patients who underwent pan-

creatic resection for suspected malignancy from December

1999 to December 2012 was performed. A total of 39

patients who underwent PD resection and were diagnosed

with adenocarcinoma on final histopathology were inclu-

ded in the study. Three patients with histopathological

diagnosis of neuroendocrine tumor (1), intraductal papil-

lary mucinous neoplasm (1), and chronic pancreatitis (1)

were excluded to control for potential favorable effects on

survival.

Institutional details

Shaukat Khanum Cancer Hospital performs close to 50

upper and lower gastrointestinal operations each per year.

The number of PD procedures is low (average of \3 per

year) due to the advanced stage at presentation in a sig-

nificant number of patients which renders them inoperable.

All pancreatic surgeries were performed by a single sur-

geon and the most common technique employed was the

standard Whipple’s procedure. Figure 1 shows the man-

agement plan for patients treated at our institute. Patients

were initially seen at the walk-in clinic to determine eli-

gibility for treatment at SKM. If eligible, they were refer-

red to the Gastroenterology Service where essential lab,

diagnostic (if not already established), and staging workup

was performed. All patients underwent a CT scan with

pancreatic protocol for local and distant staging, and an

endoscopic ultrasound exam (starting in 2005) to determine

local resectability, particularly with respect to vascular

involvement. All patients with biochemical evidence of

obstructive jaundice underwent endoscopic retrograde

cholangiopancreatography (ERCP) and stent placement.

We tend to stent all our patients because many present with

advanced disease with more pronounced jaundice than is

usually the case in the West, and because we often have a

significant waiting time between diagnosis/workup and

surgery. It is our institutional policy to confirm a histologic

diagnosis in all our patients prior to initiation of cancer

treatment. Moreover, we have seen a few patients with

chronic pancreatitis and also with tuberculosis where it was

impossible to distinguish between cancer and chronic

inflammation on imaging. Therefore, we feel it appropriate

in our clinical environment to establish a histologic diag-

nosis with certainty prior to major surgery. All patients

were discussed in tumor boards involving surgeons, med-

ical and radiation oncologists, pathologists, gastroenterol-

ogists, and radiologists. Percutaneous transhepatic

cholangiographic drainage of the biliary system was per-

formed in patients in whom ERCP was unsuccessful. If

patients were deemed resectable, they were scheduled for

surgical resection. Criteria for resectability included no

distant metastases, no radiographic evidence of superior

mesenteric vein (SMV) or portal vein (PV) distortion, and

clear fat planes around the celiac axis, hepatic artery, and

SMA. Patients with borderline resectable/locally advanced

unresectable tumors were not considered for primary sur-

gery and were referred for downstaging with chemother-

apy. Tumors were considered borderline if there were no

distant metastases but distortion or narrowing of the SMV

or PV was present. Similarly, patients with hepatic artery

or superior mesenteric artery were not considered for pri-

mary surgery and referred for chemotherapy. Patients with

Initial workup

CT/EUS/ERCP

Tumor board

Resectable

Surgery +/-chemotherapy

Borderline resectable/locally

advanced

Preoperative chemotherapy followed by assessment

Resectable Irresectable

Metastatic

Palliative chemotherapy+/-palliative surgery

Fig. 1 Diagrammatic representation of management plan for patients

with periampullary tumors

World J Surg

123

metastatic disease and poor functional status were not

considered surgical candidates. Postoperatively, patients

were kept in the intensive care unit for 1 day and shifted to

the floor if stable. Patients were seen every 3 months in the

first postoperative year with a CT scan and tumor markers

performed at 6 months. Patients were seen 6 months into

the second postoperative year and yearly after that, with

tumor markers and CT scan performed every year. The

protocolized follow-up was conducted for early detection

of a local recurrence (which might be amenable to surgical

excision) and to assess general well-being of our patients.

Preoperative chemotherapy was used in patients with bor-

derline resectable/locally advanced disease; gemcitabine/

fluorouracil-based chemotherapy was commonly used.

Adjuvant chemotherapy was used in pathologically node-

positive tumors, poorly differentiated tumors, or tumors

with perineural invasion. The standard adjuvant chemo-

therapy was six cycles of gemcitabine. Radiotherapy was

used in a very few patients based on the recommendations

of the multidisciplinary meeting.

Statistical analysis

Patient characteristics, including demographics, clinico-

pathological details, treatment modalities, and postopera-

tive course were assessed. Patients were followed until

June 2013. The primary objective of the study was to

determine 5-year disease-free survival (DFS) and overall

survival (OS) of PD resection and to identify statistically

significant variables. In addition, we also evaluated post-

operative complications, their management, and 30- and

90-day mortality rates. DFS was calculated by subtracting

date of surgery from date of relapse. OS was calculated by

subtracting date of surgery from date of death or last fol-

low-up. Expected 5-year survival was calculated using

Kaplan–Meier survival curves, and the log rank test was

used to determine significance. For categorical variables,

Fischer’s exact test and the v2 test were used, while for

interval variables, the t-test was applied. Univariate Cox

analysis was performed to identify variables for multivar-

iate analysis. Our institutional ethics committee granted

exemption from formal IRB review of this study prior to

submission.

Results

Patient characteristics

The mean number of resections performed per year was

less than 3. Figure 2 shows the number of procedures

performed in each year of the study period. The median age

of the patients was 55 (30–72) years and the median

follow-up was 15 (0–140) months. The male:female ratio

was 2.5:1. The most common predominant symptom at

presentation was jaundice in 27 (69 %) patients. Majority

of patients had good functional status and were categorized

as American Society of Anesthesiologists (ASA) class I–II.

Ampullary adenocarcinoma was the most common under-

lying malignancy, in 18 (46 %) patients. Preoperative

diagnosis of adenocarcinoma was established in 37 (95 %)

patients. Table 1 presents the demographics, clinical

details, and diagnostic modalities used in patients.

Treatment modalities

The standard Whipple procedure, used in 35 (90 %)

patients, was the most common pancreatic resection pro-

cedure. Two patients with colonic adenocarcinoma under-

went unplanned PD resection along with colonic resection.

One patient underwent a Whipple procedure while the

other required total pancreatectomy and right nephrectomy.

Table 2 presents the various treatment options used. Che-

motherapy was used in 14 (36 %) patients. In 11 (28 %)

patients, it was used as adjuvant treatment, while 2 (5 %)

patients received preoperative chemotherapy. One patient

received both neoadjuvant and adjuvant chemotherapy.

This was a 35-year-old patient with a locally advanced

tumor at presentation in whom adjuvant chemotherapy was

given to maximize chances of cure after successful surgery.

Preoperative combined chemoradiotherapy was used in one

patient with initial vascular involvement but good func-

tional status. In this patient, 5-fluorouracil-based chemo-

therapy and 50-Gy radiation in 25 fractions were given

Fig. 2 Number of pancreaticoduodenectomies in each year of the

study period

World J Surg

123

before surgical resection. Adjuvant radiation was given in a

patient with margin-positive resection and in another with

involvement of bile duct serosa with tumor cells. Palliative

radiotherapy was used in one patient with painful sacroiliac

metastasis in the first year of follow-up after surgery.

Histopathological variables

The majority of patients [31/36 (86 %)] had well to

moderately differentiated tumors. Lymphovascular [3/29

(10 %)] or perineural invasion [9/29 (31 %)] was identi-

fied in a small number of patients. Tumors were equally

distributed in terms of nodal involvement [N0 vs. N1 (54

vs. 46 %)] and tumor size [T1/T2 vs. T3/T4 (51 vs.

49 %)]. Margins were negative in all but one patient. For

the actual number of observed relapses, the distribution of

histopathological variables was not significantly different.

For actual number of observed mortalities, nodal

involvement was the only significant variable (P = 0.008)

(Table 3).

Complications and 30-day and 90-day mortality rates

Seventeen patients developed 19 (48.7 %) postoperative

complications. There were three deaths within 30 days for

a mortality rate of 7.6 % and six deaths within 90 days for

a rate of 15 %. The overall complication rate was 48.7 %.

Common complications included pancreaticojejunal (PJ)

leak in seven patients and wound infection in four patients.

Table 4 presents the various complications, their manage-

ment, and success rates. Three patients required completion

pancreatectomy for management of a PJ leak due to

Table 1 Patient characteristics and diagnostic modalities in study

group

n %

Age (years)

(mean ± SD)

54.9 ± 10.8

Gender Male 28 71.1

Female 11 28.9

ASA classa I 5 14.7

II 19 55.9

III 10 29.4

Predominant

symptom

Jaundice 27 69.2

Abdominal pain 9 23

Others 3 7.5

Preoperative ERCP Yes 34 87.1

No 5 12.9

Endoscopic

ultrasound

Yes 27 69.2

No 12 30.8

Preoperative

diagnosisaERCP ? biopsy 27 73

ERCP ? brush cytology 1 2.7

OGD ? biopsy 3 8.1

EUS ? biopsy 3 8.1

Percutaneous abdominal US-

guided biopsy

1 2.7

Colonoscopy ? biopsy 2 5.4

Diagnosis Ampullary adenocarcinoma 18 46.2

Duodenal adenocarcinoma 12 30.8

Pancreatic adenocarcinoma 7 17.9

Colonic adenocarcinoma 2 5.1

a Variables with missing data

Table 2 Various treatment modalities used in the study group

n %

Surgical

procedure

Whipple’s procedure 35 89.7

Total pancreatectomy 2 5.1

Right hemicolectomy ? Whipple’s 1 2.6

Right hemicolectomy ? right

nephrectomy ? total

pancreatosplenectomy

1 2.6

Chemotherapy Adjuvant 12 75

Neoadjuvant 2 12.5

Palliative 2 12.5

Radiation

therapy

Adjuvant 3 60

Neoadjuvant 1 20

Palliative 1 20

Table 3 Histopathological variables and their significance with

respect to disease relapse and death

n P value

Disease

relapse

Mortality

Gradea Well 11 NS NS

Moderate 20

Poor 5

p Tumor T1/T2 20 NS NS

T3/T4 19

p Nodal

involvement

N0 21 NS 0.008

N1 18

Nodes removed Mean 13.9 ? 6.9 NS NS

Nodes positive Mean 1 ? 1.7 NS NS

Margins Negative 38 NS NS

Positive 1

LV invasiona Present 3 NS NS

Absent 26

Perineural

invasionaPresent 9 NS NS

Absent 20

P value represented in italic is not statistically significant (P C 0.05 )

NS not significant, p pathologicala Variables with missing data

World J Surg

123

complete disruption of anastomosis. There were two

patients with partial disruption of the PJ anastomosis that

required resuturing of the disruption point in one patient

and omental buttress repair in the other. Superior mesen-

teric artery repair was performed in one patient with early

postoperative intra-abdominal bleeding. There was one

patient with a choledochojejunostomy leak that was man-

aged successfully with T-tube repair. One patient devel-

oped a myocardial infarct in the postoperative period that

was managed successfully with medical treatment.

Disease-free and overall survival

Fifteen (38 %) patients had a disease relapse, with liver

being the first site of relapse in 11 (73 %) patients. Other

common relapse sites were lungs and para-aortic lymph

nodes in two patients each (Table 5). Median recurrence-

free survival was 9 (0–140) months. The expected 5-year

DFS was 48 %. There were 22 deaths in the follow-up

period. The median OS was 12 (0–140) months. The

expected 5-year OS was 38 %. Overall 5-year survival was

significantly different with respect to nodal involvement

(N0 vs. N1), i.e., 47 vs. 28 % (P = 0.018), as shown in

Fig. 3. Median OS for pancreatic versus nonpancreatic

adenocarcinoma was 10 (1–108) and 16 (0–140) months,

respectively. On univariate analysis, nodal involvement

was the only factor associated with a decrease in OS.

Patients with nodal involvement had threefold increase in

the risk of death (P = 0.02, hazard ratio [HR] 2.9, confi-

dence interval [CI] 1.1–7.8). Multivariate analysis could

not be performed as nodal involvement was the only sig-

nificant variable on univariate analysis.

Discussion

A number of studies have reported outcomes of PD

resections in low-volume centers [13–16]. They have

shown acceptable outcome for this complex procedure

when compared with specialized centers. Similar results

have been reported in the current study, with acceptable

Table 4 Postoperative complications with subsequent management

and success rates

n Management n Success

rate

(%)

Pancreaticojejunal leak 7 Completion

pancreatectomy

3 57

Omental buttress

repair

1

Conservative 1

Refashioning 1

CT-guided aspiration 1

Choledochojejunostomy

leak

1 T-tube repair 1 100

Wound infection 4 Antibiotics 3 100

100Debridement 1

Gastroparesis 2 Conservative 1 100

Stomal ulceration 1 Injection

sclerotherapy

1 100

Myocardial infarct 1 Medical management 1 100

Intra-abdominal

hematoma

1 Superior mesenteric

artery repair

1 0

Intra-abdominal

collection

2 CT-guided drainage 1 100

Conservative 1

Overall complications 19 19 79

Table 5 Pattern of relapse in patients after pancreaticoduodenal

resection for adenocarcinoma

Site of recurrence n %

Liver 8 15

Lungs 2 5

Para-aortic lymph nodes 1 2.5

Bones 1 2.5

Liver ? para-aortic nodes 1 2.5

Liver ? surgical bed 1 2.5

Liver ? lungs 1 2.5

Overall 15 38.4

Nodal involveNo nodinvolve

Log ran

ement dal ement

nk P value:

1 year 2

41

78

: 0.01

2 year 3 y

24

70

year 4 y

24

70

year 5

24

70

year

24

47

Fig. 3 Kaplan–Meier survival curves for overall survival with

respect to nodal involvement in patients who underwent pancreati-

coduodenectomy for adenocarcinoma

World J Surg

123

short-term outcomes and long-term survival. The unique

features of the present study were the high percentage of

patients with ampullary/duodenal carcinoma and exclusion

of patients with benign/borderline tumors or patients who

did not have pancreatic head resection. Limitations of the

study included the retrospective nature of study, small

sample size, and relatively short follow-up.

The overall complication rate of \50 %, mortality rate

close to 7 %, and mean hospital stay of 14 days parallels

the results from many low- and some high-volume centers

[6, 9, 13–19]. In the last decade, low-volume centers have

reported a morbidity rate close to 60 % and a mortality rate

around 10 % [6, 14, 20]. Despite improvements in short-

term outcomes of pancreatic resections, long-term results

after surgical resection for pancreatic cancer remain

unchanged, with a 5-year survival rate of 20–25 % [14, 21–

23]. Survival for ampullary cancer is better at 40–60 % for

low- and high-volume centers [15, 24, 25]. Significant

factors reported to affect outcome after pancreatic resection

for malignancy include tumor stage, margin status, grade,

nodal involvement, perineural invasion, and underlying

pathology [26–28]. A high number of nonpancreatic can-

cers probably led to the better OS rate in the current study.

There is no consensus on how margin status is defined in

pancreatic cancer. In North America, tumor cells at the

surface of resection margins are considered positive, while

at other places tumor cells within 1 mm of the resection

margin are taken as positive [29–31]. It has been shown

that a negative margin of [1.5 mm translates into

improved survival outcomes in patients with pancreatic

resection for malignancy [32]. In the present study, no

tumor cells on resected margins microscopically were

considered negative and nearly all patients had negative

margins. Since pancreatic malignancy was not the most

common underlying malignancy, the effect of negative

margins on survival becomes less important. Nodal

involvement was identified as the only independent factor

significantly affecting survival. Perineural and lympho-

vascular invasion was identified in a small number of

patients and its significance could not be determined.

Indications for adjuvant chemotherapy include margin-

positive disease or nodal positivity. For locally advanced

tumors, chemoradiotherapy in a neoadjuvant setting is

being used extensively [33]. A recent meta-analysis

reported improved 12-month survival in patients who

received postoperative gemcitabine in combination with

radiotherapy [34]. Nearly 40 % patients in the present

study received chemo- or radiotherapy.

Schell et al. [14] compared outcomes following PD

resections between high- and low-volume centers affiliated

with the University of California. Over a period of 15 years

the postoperative complication rate (58.8 vs. 63.1 %),

mortality rate (4 vs. 4 %) and 5-year survival rate (19 vs.

18.3 %) were not significantly different between the two

groups. Although no definition of negative margins was

provided, positive margins were encountered in 25 % of

surgical specimens in both high- and low-volume centers.

Patients with a broad range of underlying pathologies like

adenocarcinoma, neuroendocrine tumors, intraductal pap-

illary mucinous neoplasm (IPMN), and chronic pancreatitis

were included. They concluded that low-volume centers

can achieve comparable results provided the expertise and

care facilities match those of high-volume centers. The

authors believed that the matching was possible due to

continuous sharing of operative techniques and periopera-

tive care pathways. Variable perioperative mortality rates

have been reported from low-volume centers, reaching up

to 20 % [6, 14, 18, 20]. A systematic review reported a

perioperative mortality rate of 5.5 vs. 11 % in high- and

low-volume centers, respectively [20]. Another systematic

review reported the postoperative mortality rate in hospi-

tals that performed fewer than five resections to be as high

as 16 % [35]. A complication rate of \50 % and 30-day

mortality rate of 7.6 % in the present study is comparable

to those of many low-volume centers [6, 14, 20].

In the current study, a 5-year DFS rate of 48 % and OS

rate of 38 % were observed. The high number of periam-

pullary tumors probably accounts for the improved survival

outcome. Patients with pathologies other than adenocarci-

noma were excluded from the study and thus issues of

selection bias were addressed and survival was determined

specifically for periampullary adenocarcinoma. Surgical

margins were positive in only one patient. We feel that this

low rate of margin positivity was due to surgical standards.

However, the variable definitions of margin positivity in the

literature and the high number of pancreatic head cancers,

which increase the risk of positive pancreatic resection

margins, in other studies may have confounded the results

of these studies. Uniformity in surgical technique (all pro-

cedures were performed by a single surgeon), careful

patient selection ([60 % of patients were ASA I and II),

absence of complex vascular resections, and accurate pre-

operative planning ([94 % of patients had a preoperative

tissue diagnosis, [85 % had preoperative stenting, and

70 % had preoperative EUS staging) could have contributed

to the improved short- and long-term outcomes that we

report here. Not all low-volume centers are as well equipped

as ours, follow a uniform surgical technique, and have

stringent patient selection criteria. Metreveli et al. [6]

reported outcomes from a low-volume community hospital.

Twenty-five surgeons performed a total of 63 pancreatic

resections; EUS was performed in only 11 % and ERCP in

44 % of patients. Preoperative tissue diagnosis was estab-

lished in 41 % of patients included in their study. Although

acceptable results were achieved in the current study, the

patient cohort was very selective and several issues remain

World J Surg

123

unanswered. Low-volume centers may provide acceptable

outcomes in carefully selected patients who have good

functional status and localized tumors not requiring com-

plex resections, but how are the high-risk surgical candi-

dates with vascular/partial arterial involvement managed?

In Pakistan, there was no center performing complex vas-

cular resections during the study period. Since most patients

investigated at Shaukat Khanum Hospital could not afford

treatment, travel outside the country was not possible for

these patients. We treated these patients with chemotherapy

with the intention of downstaging them in the hope that their

tumors became resectable. Unfortunately, there were very

few patients who ultimately had a pancreaticoduodenecto-

my. For the majority of low-volume centers, there is sub-

stantial room for improvement. The limitations in

preoperative planning, early detection of complications, and

standardization of surgical technique in low-volume centers

cannot be overemphasized. The present study showed that if

these limitations can be addressed, results comparable to

those of high-volume centers can be achieved for a specific

patient group.

Conclusion

The present study reports survival outcomes in addition to

short-term morbidity and mortality rates in patients who

underwent PD resection for malignancy in a low-volume

center for pancreatobiliary procedures. To our knowledge,

this is the first study reporting long-term survival in a

Pakistani cohort after PD resection for adenocarcinoma.

The study demonstrates that low-volume centers can

achieve acceptable results for complex PD resection in a

carefully selected patient cohort. The need to develop

specialized centers with high volume cannot be overem-

phasized since surgical resection is the only form of cure

for this aggressive malignancy.

Conflicts of interest The authors have no conflicts of interest or

financial ties to disclose.

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