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495
Recommendations
Either PD or DPPHR can provide pain relief for the majority of patients with CP
who undergo these operations. Current evidence is inadequate to establish the superiority of either of these approaches over the other for pain relief.
Current evidence is inadequate to establish the superiority of either approach for
post operative morbidity or mortality . Delayed gastric emptying has been noted
more frequently following PD in several small RCTs. However, assessment of gastric emptying has not been standardized across studies and there has not been consistent distinction between PD with or without gastrectomy and pyloric
preservation.
Current evidence is inadequate to clearly establish superiority of either approach
for preservation of post operative pancreatic endocrine or exocrine function. The
functional benefi ts of DPPHR observed in earlier reports of RCTs were diminished
or nonexistent at longer term follow up. Methods for assessment of endocrine and
exocrine function were not standardized.
Current evidence is inadequate to establish superiority of either approach for
improved QoL. The suggestions that DPPHR may be associated with better QoL
must be tempered by the differences in methodologies used for assessment and by
the varied follow up intervals.
Based on this summary of the evidence available from RCTs and systematic
reviews, we can recommend pancreatic head resection for patients with pancreatic
head mass and intractable pain from CP. We can make no recommendation favoring
either PD or DPPHR. All of the available RCTs are limited by sample size, by interventions that were similar but not identical (ppPD and/or PD vs. Frey and/or Beger),
and by differences in the methodologies used for determining QoL and functional
outcomes . In the sequential follow-up reports of Izbicki’s study, a substantial proportion of the initial cohort was not included.
A Personal View of the Data
Pancreatic head resection is more benefi cial for pain relief than non-operative treatment for selected patients with CP. We make the assumption that the typical patient
suffering intractable pain from CP places higher value on pain relief and operative
survival and lesser value on potentially undesirable side effects. This would be particularly true if the side effects are treatable and where the magnitude of differences
in side effects between treatment options is limited. Furthermore, long term functional decline may more represent the natural history of disease progression rather
than any operative sequela.
In our opinion, the surgeons’ personal experience with peri -operative morbidity
and mortality and clinically relevant pain relief is the key determinant for selecting
PD or DPPHR in this circumstance, as it is for selection of the specifi c technical
43 Pancreatic Head Resection for Painful Chronic Pancreatitis
496
version of either approach. Surgeons will be biased by their training and practice.
These may or may not involve a highly specialized center and may or may not
include a substantial proportion of patients resected for CP rather than for pancreatic neoplasms. Objective interpretation of the current data will hopefully allow us
to acknowledge that alternative operations may be equally reasonable. Evidence
favoring one approach or another may waver. Observations from published studies
may not apply to an individual patient, particularly to a patient suffering with CP
with its varied morphologic, metabolic, social and medical nuances.
Recommendations
1. Patients with intractable pain associated with chronic pancreatitis and an infl am-
matory pancreatic head mass should undergo pancreatic head resection by PD or
DPPHR (evidence quality high, strong recommendation).
2. DPPHR may have early advantages with respect to gastric emptying (evidence
quality low, weak recommendation).
3. DPPHR may have advantages with respect to preservation of pancreatic exocrine
function and quality of life (evidence quality low, weak recommendation).
References
1. Buchler M, Malfertheiner P, Friess H, et al. Chronic pancreatitis with infl ammatory mass in the
head of the pancreas: a special entity? In: Beger HG, Buchler M, Ditschuneit H, Malfertheiner
P, editors. Chronic pancreatitis. New York: Springer; 1993. p. 41–6.
2. Beger HG, Schlosser W, Poch B, et al. Infl ammatory mass in the head of pancreas. In: Beger
HG et al., editors. The pancreas. London: Blackwell Science; 1998. p. 757–60.
3. Martin RF, Rossi RL, Leslie KA. Long-term results of pylorus-preserving pancreatoduodenec-
tomy for chronic pancreatitis. Arch Surg. 1996;131:247–52.
4. Sakorafas GH, Farnell MB, Nagomey DM, et al. Pancreatoduodenectomy for chronic pancre-
atitis: long-term results in 105 patients. Arch Surg. 2000;135:517–23.
5. Bittner R, Butters M, Buchler M, et al. Glucose homeostasis and endocrine pancreatic function
in patients with chronic pancreatitis before and after surgical therapy. Pancreas.
1994;9:47–53.
6. Malfertheiner P, Sarr MG, Nelson DK, Di Magno EP. Role of the duodenum in postprandial
release of pancreatic and gastrointestinal hormones. Pancreas. 1994;9:13–9.
7. Creutzfeldt W, Ebert R, Arnold R, et al. Gastric inhibitory polypeptide (GIP), gastrin and insu-
lin: response to a test meal in coeliac disease and after duodeno-pancreatectomy. Diabetologia.
1976;12:279–86.
8. Beger HG, Buchler MW. Duodenum-preserving resection of the head of the pancreas in
chronic pancreatitis with infl ammatory mass in the head. World J Surg. 1990;14:83–7.
9. Frey CF, Smith GJ. Description and rationale of a new operation for chronic pancreatitis.
Pancreas. 1987;2:701–7.
10. Muller MW, Friess H, Martin DJ, Hinz U, Dahmen R, Buchler MW. Long-term follow-up of a
randomized clinical trial comparing Beger with pylorus-preserving Whipple procedure for
chronic pancreatitis. Br J Surg. 2008;95:350–6.
M.B. Luu and D.J. Deziel
497
11. Izbicki JR, Bloechle C, Broeing DC, Knoefel WT, Kuechler T, Broelsch CE. Extended drain-
age versus resection in surgery for chronic pancreatitis. Ann Surg. 1998;228:771–9.
12. Buchler MW, Friess H, Muller MW, Wheatley AM, Beger HG. Randomized trial of duodenum-
preserving pancreatic head resection versus pylorus-preserving Whipple in chronic pancreatitis. Am J Surg. 1995;169:65–70.
13. Klempa I, Spatny M, Zenzel J, et al. Pancreatic function and quality of life after resection of
the head of the pancreas in chronic pancreatitis. A prospective, randomized comparative study
after duodenum preserving resection of the head of the pancreas versus Whipple’s operation.
Chirurg. 1995;66:350–9.
14. Strate T, Bachmann K, Busch P, Mann O, Schneider C, Bruhn JP, Yekebas E, Kuechler T,
Bloechle C, Izbicki JR. Resection vs drainage in treatment of chronic pancreatitis: long-term
results of a randomized trial. Gastroenterology. 2008;134:1406–11.
15. Bachmann K, Tomkoetter L, Kutup A, Erbes J, Vashish Y, Mann O, Bockhorn M, Izbicki JR. Is
the Whipple procedure harmful for long-term outcome in treatment of chronic pancreatitis?
Ann Surg. 2013;258:815–21.
16. Farkas G, Leindler L, Daroczi M, Farkas Jr G. Prospective randomized comparison of organ-
preserving pancreatic head resection with pylorus-preserving pancreaticoduodenectomy.
Langenbecks Arch Surg. 2006;391:338–42.
17. Keck T, Adam U, Makowiec F, Riediger H, Wellner U, Tittelbach-Helmrich D, Hopt UT. Short-
and long-term results of duodenum preservation versus resection for the management of
chronic pancreatitis: a prospective, randomized study. Surgery. 2012;152:95–102.
18. Deiner MK, Rahbari NN, Fischer L, Antes G, Buchler MW, Seiler CM. Duodenum-preserving
pancreatic head resection versus pancreatoduodenectomy for surgical treatment of chronic
pancreatitis: a systematic review and meta-analysis. Ann Surg. 2008;247:950–61.
19. Yin Z, Sun J, Yin D, Wang J. Surgical treatment strategies in chronic pancreatitis: a meta-
analysis. Arch Surg. 2012;147:961–8.
20. Lu WP, Shi Q, Zhang WZ, Cai SW, Jiang K, Dong JH. A meta-analysis of the long-term effects
of chronic pancreatitis surgical treatments: duodenum-preserving pancreatic head resection
versus pancreatoduodenectomy. Chin Med J. 2013;126:147–53.
43 Pancreatic Head Resection for Painful Chronic Pancreatitis
499© Springer International Publishing Switzerland 2016
J.M. Millis, J.B. Matthews (eds.), Diffi cult Decisions in Hepatobiliary
and Pancreatic Surgery, Diffi cult Decisions in Surgery: An Evidence-Based
Approach, DOI 10.1007/978-3-319-27365-5_44
Chapter 44
Is Total Pancreatectomy with Islet
Autotransplantation Indicated in Hereditary/
Genetic Pancreatitis?
Jeffrey B. Matthews
Abstract Total pancreatectomy with islet autotransplantation (TPIAT) has been
used in selected centers to treat intractable hereditary/genetic forms of recurrent
acute and chronic pancreatitis. It has theoretical advantages over continued medical
management or traditional endoscopic and surgical interventions because it entails
the complete removal of the infl amed and fi brotic organ to treat the symptoms of
pain while both eliminating the long-term risk of pancreatic ductal adenocarcinoma
and preserving islet mass and to limit post-pancreatectomy diabetes. While an
emerging consensus favors TPIAT in this setting, the evidence base largely relies on
retrospective patient series and expert opinion.
Keywords Chronic pancreatitis • Recurrent acute pancreatitis • Hereditary pancreatitis • Islet autotransplantation • PRSS1 • Total pancreatomy
Introduction
Recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) represent a spectrum of infl ammatory and fi brotic conditions of the pancreas and their associated
complications. Surgical intervention is most often considered for the indication of
pain , which can occur as a pattern of recurrent episodes or persistent symptoms
associated with progressive loss of pancreatic exocrine and endocrine function. The
morphological consequences are highly variable and may include ductal stricture ,
dilation, ductal and parenchymal calcifi cations, focal mass effects, and extension to
adjacent organs and vessels [ 1 ].
Treatment of the pain of chronic pancreatitis may be pharmacological, neuroab-
lative, and endoscopic , but these are of variable success for short- and long-term
J. B. Matthews (*)
Department of Surgery , University of Chicago Medical Center ,
5841 S. Maryland Avenue, MC 5029 , Chicago , IL 60637 , USA
e-mail:
jmatthews@surgery.bsd.uchicago.edu
500
control of symptoms. Surgical therapy may be an effective alternative in appropriately selected patients. The choice of operation generally refl ects assumptions about
the mechanism of pain. For example, duct decompression by lateral pancreaticojejunostomy may be recommended for patients with so-called large duct disease,
whereas pancreatic resection by pancreaticoduodenectomy or duodenum-sparing
pancreatic head resection may be indicated for patients with an infl ammatory head
mass [ 1 ].
Some patients have more complex situations, and the role of surgical therapy is
controversial. For example, the patient with a non-dilated pancreatic duct (smallduct disease) may have no duct to decompress and no mass to resect. Others may
have persistent or recurrent pain after prior pancreatic operation. Still others appear
to have genetic/hereditary syndromes, some of which appear to be associated with
increased risk of pancreatic cancer . Hereditary pancreatitis kindreds, over half of
whom are found to have mutations in PRSS1 (the gene that encodes for cationic
trypsinogen), are reported to have an over 50-fold increased risk of developing pancreatic cancer [ 2 ]. In smokers, the cumulative risk of cancer is 15 % by age 50 and
exceeds 50 % by age 75 [ 2 , 3 ], although in non-smokers the risk of cancer, while
still elevated, appears to be considerably lower. Pancreatitis associated with PRSS1
gene mutations has an autosomal dominant pattern of inheritance with incomplete
penetrance [ 4 ]. In contrast, RAP and CP associated with mutations in the CFTR or
SPINK1 genes shows autosomal recessive inheritance and do not appear to carry an
increased risk of pancreatic adenocarcinoma compared to other forms of CP [ 5 ].
The rationale for total pancreatectomy with islet autotransplantation (TPIAT) for
hereditary/genetic forms of pancreatitis includes the complete removal of the
infl amed and fi brotic organ to treat the symptoms of pain as well as to reduce or
eliminate the long-term risk of pancreatic ductal adenocarcinoma, while preserving
islet mass and preventing or limiting the extent of post-pancreatectomy type 3c
diabetes [ 6 , 7 ]. However, the consequences of total pancreatectomy in this setting
are not trivial and include not only persistent pain (often attributed to central sensitization as well as narcotic bowel syndrome) but also the metabolic and nutritional
impact of complete pancreatic exocrine insuffi ciency [ 6 , 7 ]. For patients with severe
and intractable symptoms, the main question is whether TPIAT truly improves
short- and long-term quality of life . For less severely affected patients, the question
is whether the long-term reduction in cancer risk suffi ciently changes the riskbenefi t ration to justify proceeding with TPIAT earlier, irrespective of the development of symptomatic incapacitation.
Search Strategy
A PubMed literature search of English language publications from 2000 to 2015
was used to identify series of patients with hereditary or genetic RAP or CP pancreatitis treated by TPIAT. Terms used in the search included “total pancreatectomy ”
J.B. Matthews
501
AND “ islet autotransplantation ” OR “autologous islet transplantation” AND
“chronic pancreatitis”, OR “ recurrent acute pancreatitis ” OR “ hereditary pancreatitis ” AND “genetic pancreatitis”. Articles were excluded if patients with hereditary/
genetic forms of RAP/CP were not specifi ed, or for reports that addressed fewer
than fi ve TPIAT patients. A PICO approach was used to frame the relevant question,
and the data were classifi ed using the GRADE system (Table 44.1 ).
Results
Patient Selection
There was considerable heterogeneity in the patient populations selected to
undergo TPIAT. Among the many factors that differed among the published series
included the demographics and comorbidities of the patients as well as the type
and number of prior pancreatic interventions. Several series did not specify the
number of patients with genetic/familial/hereditary disease, and only two series
reported the results of genetic testing for PRSS1 or other genes associated with
RAP and CP. Because genetic testing is not routine (or routinely recommended),
the total number of patients with PRSS1 gene mutations who have undergone
TPIAT is unclear. An uncertain number of patients were included multiple times
in various reports from the larger centers, notably the University of Minnesota and
the University of Cincinnati series [ 8 – 15 ], complicating interpretation of the
aggregate experience in hereditary/genetic RAP/CP. Some studies focused on
pediatric populations; others focused on small-duct (“minimal change”) chronic
pancreatitis.
In the Minnesota series of 484 patients that underwent TPIAT, the 80 patients
with hereditary/genetic forms of RAP and CP differed from those with nonhereditary forms in a number of respects: they were younger, had pancreatitis of
longer duration, a higher pancreatic fi brosis score, and a trend toward lower islet
yield [ 9 ]. Across all series, the vast majority of patients were described as having
failed prior medical, endoscopic , and, in many instances, surgical therapy.
Essentially all patients required substantial analgesic therapy and were in most
instances dependent on narcotics.
Table 44.1 PICO Table
P (Patients) I (Intervention)
C
(Comparator) O (Outcomes)
Patients with hereditary/genetic
recurrent acute and chronic
pancreatitis
Total
pancreatectomy with
islet
autotransplantation
Best medical
management
Morbidity; diabetes;
pain relief; QOL;
durability
44 Is Total Pancreatectomy with Islet Autotransplantation Indicated…
502
Perioperative Morbidity and Mortality
The largest series, from the University of Minnesota, reported a 1 % in-hospital
mortality rate [ 10 ], with other smaller series showing that postoperative mortality is
below 2 % [ 12 , 16 ]. A study based on data from the National Surgical Quality
Improvement Program confi rmed an approximately 1 % mortality rate and additionally identifi ed that major morbidity occurred in found a 41 % of patient [ 17 ]. The
most common signifi cant early postoperative complication was hemorrhage, occurring in about 10 % of cases. Partial portal vein thrombosis is also noted, but this
does not appear to adversely impact outcomes . Readmission rate was not consistently reported but in Wilson’s series was 37 % [ 15 ]. Actuarial survival is 90 % at
5 years and 81 % at 10 years in the Minnesota series, although the cause of late
deaths is not known in many instances [ 10 ].
Islet Function
Islet yield was highly variable between series, depending upon the age of the
patients, duration of CP, the condition of the pancreas, and the type(s) of prior pancreatic operation. Prior lateral pancreaticojejunostomy was associated with dramatically lower islet yield. There was not a consistent correlation between the number
of islet-equivalents isolated per kg body weight and ultimate insulin independence.
Insulin independence within the fi rst year was achieved in 20–41 % of patients
(Table 44.2 ). Typically, daily insulin requirements were reported to be less than
20U/day in most patients. Although a measurable drop-off of C-peptide was demonstrated over time in some series, with a corresponding decrease in the rate of
insulin-independence after 1 year, daily insulin requirements tended to otherwise
remain stable out to 10 years and beyond [ 10 , 14 ].
Data on the natural history of the development of endocrine insuffi ciency in
patients with genetic/ hereditary pancreatitis are sparse. In one study of patients carrying PRSS1 gene mutations, endocrine insuffi ciency was noted in 26 % of patients
at a median age of 38 years [ 4 ]. A small series of children treated by modifi ed
Puestow procedure for intractable pain showed two out of nine patients developed
insulin-dependent diabetes within 1 year of operation [ 18 ]. However, other small
series have not shown such rapid progression [
19 ].
Pain Relief/Narcotic Requirement
Following TPIAT, a signifi cantly decrease in subjective assessment of pain and the
need for narcotic pain medication was noted in all studies. Over 80 % of patients
reported either no pain or only mild pain (Table 44.2 ). Some reports quantifi ed the
J.B. Matthews
503
reduction of pain medication requirements as morphine equivalents, although the
details of reporting were highly variable. Achievement of the endpoint of narcoticindependence was inconsistent among the various series, ranging between 24 % and
80 % (Table 44.2 ).
QOL/Durability
A number of studies evaluated quality of life using several standard questionnairebased surveys (Table 44.2 ), most commonly short-form 36 (SF36). These were
administered at variable times after the procedure, and all published studies suffer
from at least some patients being lost to follow up. Several of the larger series
reported follow up over 5 years, and for some patients, over 10 years. These studies
demonstrated that narcotic independence and islet function, as well as improvements in QOL are sustained for at least 10 years following operation. For example,
Wilson [ 14 ] showed that the narcotic-independence rate rose from 55 % at 1 year to
73 % at 5 year follow up; although insulin-independence rates declined from 38 %
at 1 year to 27 % after 5 years, daily insulin requirements remained relatively constant and glycemic control measured by HgA1C levels were stable in all patients
evaluated.
Comparison to medical management is mostly implicit in that selection criteria
included failure of non-operative therapy. One study addressed cost-effectiveness
based on a series of indirect assumptions concluded that there was no cost disadvantage to TPIAT [ 16 ]. Wilson et al. [ 20 ] used a Markov model populated with data
Table 44.2 Series of TPIAT addressing hereditary/genetic etiology
Series (ref) Total n
Hereditary/
genetic PRSS1
Insulin
independent
Narcoticfree QOL
Sutton [
12 ] 16 16 4 25 % 63 % SF36
Bellin [
11 ] 19 (pediatric) 12 9 37 % 74 % SF36
Walsh [
24 ] 20 2 n.s. 20 % 30 % PDI
VAS
DASS
Morgan [
23 ] 33 3 n.s. 24 % 24 % SF12
Sutherland [
10 ] 409 58 n.s. 30 % 59 % SF36
Wilson [
13 ] 14 (pediatric) 4 1 29 % 79 % n.s.
Tai [
22 ] 9 4 2 22 % n.s. n.s.
Georgiev [
21 ] 53 8 n.s. n.s. n.s. SF36
McGill pain
Wilson [
15 ] 84 (“minimal
change”)
14 2 37 % 58 % SF36
Chinnakotla [
9 ] 80 80 38 ~20 % ~80 % SF36
Chinnakotla [
8 ] 75 (pediatric) 41 n.s. 41 % ~80 % SF36
n.s. not specifi ed
44 Is Total Pancreatectomy with Islet Autotransplantation Indicated…
504
from a series of 46 patients with small duct chronic pancreatitis who underwent
TPIAT to evaluate its cost-effectiveness compared to medical management.
Signifi cant reductions in the number of hospital admissions and the need for endoscopy and advanced imaging were noted following TPIAT, with signifi cantly
decreased cost per quality-adjusted life years. There are no data on long term nutritional status with respect to maintenance of body weight, anemia, vitamin defi ciencies, complications due to diabetes, and other possible sources of morbidity after
TPIAT.
Cancer Risk
TPIAT has been performed since 1977 and to date there have been no reports of a
single instance of intrahepatic pancreatic adenocarcinoma [ 6 ]. In the Minnesota
series of 80 patients with genetic/hereditary forms of pancreatitis, no cancers
occurred during the 2936 patient-years of follow-up [ 9 ]. It is unclear whether the
long-term risk of developing pancreatic cancer in hereditary CP in and of itself is
suffi cient justifi cation for proceeding with TPIAT; risk modifi cation by avoidance
of tobacco may have a substantial impact. The value of surveillance imaging is
unproven and may be diffi cult in a pancreas deformed by repeated damage and
progressive fi brosis.
Expert Consensus
Given the limited number of series, the heterogeneity of patients, and uncertainties
about both the natural history of RAP/CP (of any etiology) and the long term results
of TPIAT, a working group of expert pancreatologists and pancreatic surgeons
reviewed the relevant literature and compared their own clinical experiences to
develop a series of consensus statements to guide patient selection. There is a high
degree of consensus among these experts that TPIAT is indicated to treat intractable
pain in patients with impaired quality of life due to CP or RAP when medical, endoscopic , or previous surgical therapy have failed [ 9 ]. Moreover, it was recommended
by this group that special consideration be given to patients with genetic causes. The
National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) organized a workshop entitled “Total Pancreatectomy with Islet AutoTransplantation:
Gaps, Needs and Opportunities” in July 2014 in Pittsburgh. One of the critical
research gaps identifi ed was the need for multicenter collaboration through a data
registry [ 10 ].
J.B. Matthews
505
Recommendations Based on the Data
Patients with intractable pain or signifi cantly impaired quality of life due recurrent
acute or chronic pancreatitis who have otherwise failed medical, endoscopic , or
surgical therapy should be evaluated for TPIAT (evidence quality moderate; strong
recommendation).
TPIAT is preferable to continued medical management in patients with symptomatic hereditary pancreatitis associated with a PRSS1 gene mutation and a family
history of pancreatic cancer because of the virtual elimination of lifelong risk of
pancreatic adenocarcinoma (evidence quality high, strong recommendation).
TPIAT should be performed in the setting of a multidisciplinary team experienced in patient selection and postoperative management , at or in collaboration with
a center with experience in TPIAT (evidence quality high, strong
recommendation).
A Personal View of the Data
TPIAT should be considered in patients who are severely affected by the pain of
chronic pancreatitis and who have no conventional alternative. Patients with socalled “small duct” disease, or who have failed prior surgical interventions may be
good candidates so long as they are not yet C-peptide negative diabetics. Patients
with genetic predisposition (e.g., hereditary pancreatitis ), particularly younger
patients, are very well suited to this procedure. The outcomes for TPIAT are best
when performed in a center that has deep, multidisciplinary experience in caring for
the spectrum of benign and malignant pancreatic diseases. In addition to a signifi cant institutional commitment to an islet isolation laboratory, a successful program
requires close collaboration between medical pancreatologists, advanced endoscopists, and pancreatic surgeons in addition to experts in surgical nursing, nutrition,
and pain management .
The published literature suffers from considerable selection bias, framing effects,
and optimism bias. While earlier intervention may increase islet yield and the likelihood of insulin-independence, it eliminates the ability of the patient to benefi t from
future advances in islet isolation and preservation. This should temper enthusiasm
for TPIAT in the pediatric population. Fears over the eventual development of cancer in patients with hereditary pancreatitis should be tempered by a number of considerations, including tobacco as a modifi able risk, and the possibility of the
emergence of improved screening and treatment protocols for a disease that may not
develop for decades.
It is diffi cult to generalize which patients will have the best outcome from TPIAT
because of the high degree of variability in presentation, prior treatment, and anatomic circumstances. Potential patients differ not only in their clinical situations but
44 Is Total Pancreatectomy with Islet Autotransplantation Indicated…