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2010 SSAT PLENARY PRESENTATION
Repair of Symptomatic Giant Paraesophageal Herniasin Elderly
(>70 Years) Patients Results in ImprovedQuality of Life
Brian E. Louie & Maurice Blitz & Alexander S. Farivar
&Jeraldine Orlina & Ralph W. Aye
Received: 3 May 2010 /Accepted: 9 August 2010 /Published online:
19 January 2011# 2011 The Society for Surgery of the Alimentary
Tract
AbstractIntroduction Giant paraesophageal hernias (PEH) involve
herniation ofstomach and/or other viscera into the
mediastinum.These are usually symptomatic and commonly occur in the
elderly. The benefits and risks of operating on elderly
patientswith giant PEH have not been clearly elucidated.Materials
and Methods We performed a retrospective chart review of
consecutive patients aged 70 or greater with giantPEHs undergoing
repair.Quality of life data were gathered using QOLRAD, GERD-HRQL
and adysphagia severity score.Results Fifty-eight patients (34
females), median 78 years old, presented for repair. Nine patients
presented urgently. There wasno 30-daymortality. Major morbidity
was 15.5%. At mean follow-up of 1.3 years, 81%were symptom free
compared to baseline(p
-
junction to the diaphragmatic impressionswith a
paraesophagealcomponent and/or having a paraesophageal
configurationdefined as type IIIV.5 Patients admitted to the
hospital withsymptoms of incarceration or obstruction that
necessitated earlyendoscopy, nasogastric decompression, and repair
during thesame admission were included in this analysis. We
excluded allpatients with sliding hiatal hernias as well as those
requiringemergent operative intervention for strangulated PEH
orincarceration that did not respond to decompression.
Preoperative evaluation of each patient included adetailed
history and physical examination, an uppergastrointestinal
videoesophagogram, upper endoscopy, andhigh-resolution manometry
when possible. Wireless pHanalysis was done at the discretion of
the attending surgeon.Other imaging such as computed tomography,
pulmonaryfunction tests, and gastric emptying tests were obtained
asneeded on an individual basis.
Operative Techniques
All procedures were performed by a team including anattending
surgeon (R.A. or B.L.) with a senior resident orMIS fellow. The
laparoscopic approach is performed in lowlithotomy with five small
incisions following principlespreviously described.1 Esophageal
lengthening procedureswere not employed in any of our patients.
Cruralreconstruction was performed with simple
non-absorbable,braided 0 sutures (polyethylene terephthalate coated
withpolybutilate, Ethicon-Johnson and Johnson, Cincinnati,OH).
Bioabsorbable mesh reinforcement was used liberallyafter the trial
by Oelschlager was published.6
An open approach was used sparingly. A transabdominalapproach
was performed when the PEH was concomitantlyrepaired with another
intra-abdominal procedure. A transthoracicapproach was used if the
abdomen was hostile and inaccessibleto either laparoscopic or
transabdominal approaches. Meshreinforcement was not used in the
transthoracic repair.
An anti-reflux procedure was routinely performed aftercrural
reconstruction. Three procedures were used at thediscretion of the
operating surgeon. When a Nissenfundoplication was created, it was
performed over a 60-Frbougie and fashioned to 2 cm in length. When
a Hill repairwas created, it was done according to the
principlesdescribed by Aye.7 A special 43-Fr bougie with an open
tipto allow for a water perfused manometry catheter to beadvanced
was utilized to perform intraoperative manometry.The last
anti-reflux procedure was a hybrid procedurecombining the Nissen
fundoplication and the Hill repair.8 Atour center, we have surgeons
experienced in both the Nissenand Hill procedures. This hybrid
operation was conceivedand evaluated in an institutional review
board approved pilotstudy where the Nissen fundoplication is
performed over twoHill gastroplasty sutures placed through the
collar sling fibers
of the gastrointestinal junction and secured to the
pre-aorticfascia in hopes of mitigating axial tension and
cephaladdisplacement.
Quality of Life Instruments
Quality of life data were gathered using three diseasespecific
instruments: the Quality of Life in Reflux andDyspepsia
Questionnaire (QOLRAD), GERD-HRQL, and adysphagia score. These
instruments were completed by thepatient at the first office
consultation and postoperativelyfor short-term follow-up at 4 to 6
weeks and long-termfollow-up at 6 and 12 months and yearly
thereafter.
TheQOLRAD is a validated 25-item questionnaire designedfor
self-administration by patients with upper gastrointestinalsymptoms
with a maximum score of 7.9 Each item asks thepatients to reflect
on the impact of GERD or esophagealproblems over the past week and
to rate it on a 7-point scale.A higher score represents an improved
quality of life.Although it is a disease specific questionnaire
focusing onGERD and dyspepsia, it has been broadly applied
acrossmany upper intestinal disorders as an overall QOL
instrument.The 25 questions attempt to ascertain GI health in terms
ofemotional distress (six items), sleep disturbance (five
items),food/drink problems (six items), physical/social
functioning(five items), and vitality (three items).
The GERD-HRQL is a disease specific quality of lifeinstrument
that has been validated to measure symptomseverity in
gastroesophageal reflux.10 It has been used andvalidated to assess
response to medications, endoscopicprocedures, and surgery. The
self-administered instrumentconsists of ten questions and a
separate global satisfactionquestion. Likert-type responses are
possible, with 0 representingno symptoms to 5 reflecting
incapacitating symptoms andunable to do daily activities. The
scores can range from 54 to 0with a lower overall score equating to
better quality of life.
To assess the symptom of dysphagia, we used thevalidated
dysphagia score as described by Dakkak.11 Thisinstrument was
designed to be used with a standardizedmeal eaten within 7 days of
completing the questionnaireand combined with a blinded observer
documenting theactual food ingestion. Patients are asked about the
ease ofingesting certain textures of foods and defined amounts.
Ascore of 0 reflects that no food was ingested, whereas amaximal
score of 45 represents the ability to ingest theentire meal. To
simplify the use of the instrument, patientswere asked about their
ability to ingest each of the ninefoods and points are awarded
according to the standardizedweighting system. If a patient related
that no difficulty wasencountered full points were awarded.
Conversely, if thepatient admitted difficulty in ingesting a
certain food, nopoints were awarded. Half of the points were
awarded ifmoderate difficulty was encountered.
390 J Gastrointest Surg (2011) 15:389396
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Data and Statistical Analysis
Demographic, operative, clinical, and quality of life datawere
collected from the clinic chart and hospital medicalrecord.
Long-term quality of life analysis was conducted byphone interview
by one of the attending surgeons inpatients who were not able to
travel to the clinic. Statisticalanalysis was performed using SPSS
18. Continuousvariables were analyzed using Students t test.
Categoricalvariables were analyzed using chi-squared. Symptoms
wereanalyzed by McNemars test. The institutional review
boardapproved this study.
Results
A total of 58 patients were assessed and underwent
surgicalrepair of a symptomatic giant PEH. Median age was 78
years.Their baseline demographics and hernia characteristics
areoutlined in Table 1. The most common PEH was a type III(78%),
with an average size of 10 cm as measured fromdiaphragmatic hiatus
to the top of the gastric fundus onimaging. Nine patients presented
urgently with symptoms ofincarceration. There was no 30-day
mortality. Three patients
died in follow-up: one from lung cancer and two fromnatural
causes.
The three different repairs used in this series were
evenlyapplied with 18 Nissen fundoplications, 19 Hill
procedures,and 20 combined HillNissen repairs. One patient had
anAllison repair with PEG. A bioabsorbable mesh was placedin 38% of
cases. A laparoscopic repair was attempted in 55patients and
successfully completed in 53 with two cases(3.4%) converted to open
laparotomy. One conversion wasfor an intraoperative esophageal
perforation during a Hillrepair and the other for poor
visualization while attemptingto reduce a large complex type IV
hernia. Three casesutilized an open incision from the outset. Two
were done in thisfashion because a concurrent abdominal procedure
was alsoplanned. One was performed via a left thoracotomy because
thepatient had significant previous abdominal surgery.
Thirteen patients experienced morbidity (Table 2). Therewere
five (8%) minor morbidities including two patientsrequiring
mechanical ventilation for less than 24 h. Onerequired intubation
overnight for hypercarbia after repair ofa large type IV hernia,
and one was re-intubated brieflyafter developing re-expansion
pulmonary edema after repairof large type III hernia compressing
the left lower lobe.There were nine (16%) major morbidities. Four
patientsrequired readmission for dehydration. There were
twoesophageal perforations during passage of the bougie
forintraoperative manometry. One was repaired laparoscopicallyand
the other converted to an open procedure and thenrepaired. Both
patients were discharged without furthercomplications or
interventions.
At a mean follow-up 1.3 years (6 months5.5 years), 81%of
patients were entirely symptom-free compared to baseline(p
- 57% of patients. When compared to baseline preoperativescores,
the QOLRAD improved from 5.0 to 6.1 (p
-
required re-operation. Mesh was placed in three of
therecurrences. Mesh was not placed in one patient at thediscretion
of the surgeon and the other patients hadsurgery before mesh was
popularized. Despite thepresence of recurrence, the median
long-term QOLRADscore was 6.8, GERD-HRQL was 3.5, and the
dysphagiascore was 39. These were not statistically different
fromthe patients without recurrence.
Discussion
Herniation of the stomach into the chest in elderly
patients(>70 years of age) is a dilemma to many physicians.
Thesepatients often have associated comorbid disease that
delaysreferral to surgical specialists because of concerns about
theprohibitive risks of surgery. Secondly, the presentingcomplaints
such as chest pain or shortness of breath oftendirect the physician
to consider a cardiac or pulmonaryetiology for their symptoms.
Accordingly, these systems areevaluated. The PEH is often
discovered incidentally onimaging. Even when it is determined that
the PEH is thecause of their symptoms, both patients and physicians
arereluctant to seek surgical consultation for fear of
increasedmorbidity and mortality and a perception that
surgicalintervention will not resolve their symptoms or
improvetheir QOL.
However, in this series as well as others
publishedpreviously,1,2 it has been demonstrated that surgical
reductionof the hernia and its sac, crural reconstructionwith
bioabsorbablemesh, and an anti-reflux repair in an elderly patient
populationcan be performed safely, with a very low mortality rate
andacceptable morbidity. Even though no mortalities were reportedin
this series andmajor morbidity was 16%, it remains importantto
carefully evaluate the elderly patient since age greater than
70,BMI greater than 35 kg/m2, and multiple comorbidities havebeen
identified as factors that may increase the chances of anadverse
outcome.1
The symptoms derived from giant PEHs are oftensecondary to both
acid reflux and mechanical factors.5
Although the acid-related symptoms may be partially orless often
totally resolved with proton pump inhibitors, themechanical or
obstructive symptoms such as chest pain,aspiration, or shortness of
breath are not relieved bymedical therapy. Repair of the giant PEH
offers patientsthe opportunity to successfully control both the
acid refluxand mechanical symptoms in most cases. Patients appear
toexperience early benefit from repair and these benefitsappear to
improve further in longer-term follow-up.
It is not surprising that control of symptoms also
translatesinto an improvement in QOL. Many studies have focused
onQOL as a primary outcome. Previous studies have used ageneric
quality of life instrument (SF-36) combined with a
disease specific score such as GERD HQRL1 or a diseasespecific
instrument such as QOLRAD2 alone to determinequality of life
outcome measures. In our opinion, neither ofthese instruments
adequately assesses health in patients withPEH where overall status
is impacted by acid reflux,mechanical symptoms, and difficulty with
swallowing.Dysphagia is one particular area where QOLRAD
andGERD-HRQL are insufficient. Therefore, we have adoptedboth the
QOLRAD and GERD-HRQL to assess morecompletely aspects of health and
the disease state. We addedthe dysphagia score to directly evaluate
swallowing.
The QOLRAD and GERD-HRQL have clearly demon-strated an
improvement in quality of life both in the shortand long term
compared to their respective preoperativebaseline. However, unlike
prior studies, the dysphagia scorehas allowed us to quantify
dysphagia and demonstrate thatin short-term follow-up dysphagia is
worse, likely due toongoing healing and the reconstruction of the
hiatus with itsattendant edema. Dysphagia scores did return to
baseline inlong-term follow-up confirming that fear of
dysphagiashould not preclude patients from undergoing repair.
Thisknowledge allows us to prepare and educate our patientsbefore
and early after surgery, counseling them that in mostcases
dysphagia if present improves with time.
Observation has been proposed as a reasonable alternativein
elderly patients with a minimally symptomatic PEH.12
Using this paradigm, urgent or emergent surgery may berequired
if the patient develops rapidly worsening symptomsor acutely
incarcerates with or without the presence of agastric volvulus. The
nine urgent patients in our series whowere stabilized with
nasogastric decompression and earlyendoscopy to rule out
strangulation went on to successfullaparoscopic repair with minimal
morbidity and restoration ofquality of life. While the ability to
help these elderly patientsin an urgent setting is possible with
acceptable results, webelieve that decision should be made after
surgical consulta-tionwith physicians familiar with treating
andmanaging PEH.
The argument against observation is based on otherseries of PEH
repairs from respectable centers that havereported an increased
mortality and morbidity rate inpatients presenting urgently and
undergoing repair.1,3 Whilenot presented in this study, we did
exclude from thisanalysis all emergent operations for strangulated
PEH,which carries an inherently higher morbidity and mortalityrisk.
Our goal should be to avoid observing a patient untilthey present
in extremis and require emergent repair. Lastly,the ability to do
an appropriate workup for PEH in a stable,elective fashion is far
more likely to be successful than afteran urgent admission to the
hospital, when tests likemanometry are more difficult to
obtain.
The radiographic recurrence rate of 10% compares favor-ably with
other series in the literature.6,13 The recurrencesoccurred evenly
among our three repair groups suggesting that
J Gastrointest Surg (2011) 15:389396 393
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it is likely not the anti-reflux procedure that is central
todeveloping a recurrence. It is more likely that
adequatemediastinal mobilization of the esophagus and the
cruralclosure are central to the outcome of the repair and
likelywhether or not a recurrence will develop. Collis
gastroplastyhas been proposed as a method to reduce axial tension
aftermediastinal mobilization. Even with more liberal use of
theCollis gastroplasty, the observed recurrence rates are similar
toreports where a Collis was used more selectively. In general,our
group advocates using an esophageal lengtheningprocedure
selectively. The additional staple lines add in-creased risk for
postoperative leak and complications in thisfrail population, but
lengthening can be very important if shortesophagus is truly found
and there is a need to reduce axialtension on the repair.1,14
Although this study did not focus on the use ofbioabsorbable
mesh as an adjunct to the crural repair, weobserved that 50% of our
recurrences did not have meshplaced. Since the report by
Oelschlager,6 we have changedour practice to reinforce the
diaphragm reconstruction withbioabsorbable mesh. There remains some
controversy aboutthe utility of mesh1,15 particularly when an
esophageallengthening procedure is performed. These two adjuncts
toPEH surgery address different physiologic components ofthe
pathologic process, namely axial tension (gastroplasty)and radial
hiatal tension (mesh). The primary principle inall types of hernia
surgery has been to avoid tension.Certainly both adjuncts may be
important for an optimaloutcome, as long as the principle of a
tension free repair isthe foundation upon which those adjuncts are
utilized.
The standard anti-reflux repair associated with PEH repair
inNorth America has been the Nissen fundoplication. However,
avariety of repairs have been used in reconstruction of
thegastroesophageal junction after hiatal closure including
partialfundoplication,2,16 Hill repair,17 and the Belsey
operation.18
Since both Nissen fundoplication and the Hill repair
areperformed at our center, we have observed distinct advantagesand
disadvantages to both these operations. To capitalize on
theadvantages of both operations (reflux control in the Nissen
andaxial maintenance in the Hill), we combined aspects of
theseprocedures to see if a hybrid anti-reflux repair would
conferdistinct advantages over the traditional repairs (in
preparation).8
This study has several strengths and limitations.We believethe
use of three different QOL instruments better assesses thequality
of life in PEH patients who may have symptoms ofGERD, mechanical
symptoms and/or dysphagia. This studydetails consecutive patients
70 years and older undergoingprimarily laparoscopic repair but also
includes urgent and opencases. One of the limitations is that
dysphagia score used wasnot used in the manner that it was
validated. This limits theconclusions we can draw using this score.
However, we havefound it to be an important part of our quality of
life assessment.Lastly, our median follow-up 1.3 years is short
compared to
others even though the range extends out to 5.5 years. We hopeto
be able to report on the long-term QOL of this cohort todemonstrate
durability of the repair in the future.
Conclusions
These data support repair of symptomatic giant
paraesophagealhernias in patients aged 70 years or greater. These
hernias canbe repaired in the elderly with minimal surgical
mortality andacceptable morbidity in both the elective and urgent
setting. Asignificant number of patients undergoing repair can
expectresolution of the symptoms they suffered from
preoperatively.Similarly, patients should expect improvements in
both short-and long-term quality of life measures including
patients whopresented urgently or have small recurrent
herniation.
References
1. Luketich, J.D., et al., Outcomes after a decade of
laparoscopicgiant paraesophageal hernia repair. J Thorac Cardiovasc
Surg,2010. 139(2): p. 395404, 404 e1
2. Hazebroek, E.J., et al., Laparoscopic paraesophageal hernia
repair:quality of life outcomes in the elderly. Dis Esophagus,
2008. 21(8): p. 73741.
3. Polomsky, M., et al., Should elective repair of intrathoracic
stomachbe encouraged? J Gastrointest Surg, 2010. 14(2): p.
20310.
4. Nason, K.S., et al., Laparoscopic repair of giant
paraesophagealhernia results in long-term patient satisfaction and
a durable repair. JGastrointest Surg, 2008. 12(12): p. 206675;
discussion 20757
5. Schieman, C. and S.C. Grondin, Paraesophageal hernia:
clinicalpresentation, evaluation, and management controversies.
ThoracSurg Clin, 2009. 19(4): p. 47384.
6. Oelschlager, B.K., et al., Biologic prosthesis reduces
recurrenceafter laparoscopic paraesophageal hernia repair: a
multicenter,prospective, randomized trial. Ann Surg, 2006. 244(4):
p. 48190.
7. Aye, R.W., TheHill Procedure for Gastroesophageal Reflux, in
CurrentTherapy in Thoracic and Cardiovascular Surgery, S.C. Yang
and D.E.Cameron, Editors. 2004, Mosby: Philadelphia, PA. p.
400405.
8. Buduhan, G., et al., The Nissen-Hill "hybrid": Pilot study of
a newantireflux repair, in International Society for Diseases of
theEsophagus. 2008: Budapest, Hungary.
9. Wiklund, I.K., et al., Quality of Life in Reflux and
Dyspepsiapatients. Psychometric documentation of a new
disease-specificquestionnaire (QOLRAD). Eur J Surg Suppl,
1998(583): p. 419.
10. Velanovich, V., The development of the GERD-HRQL
symptomseverity instrument. Dis Esophagus, 2007. 20(2): p.
1304.
11. Dakkak, M. and J.R. Bennett, A new dysphagia score
withobjective validation. J Clin Gastroenterol, 1992. 14(2): p.
99100.
12. Stylopoulos, N., G.S. Gazelle, and D.W. Rattner,
Paraesophagealhernias: operation or observation? Ann Surg, 2002.
236(4):p. 492500; discussion 5001.
13. Karmali, S., et al., Primary laparoscopic and open repair
ofparaesophageal hernias: a comparison of short-term outcomes.Dis
Esophagus, 2008. 21(1): p. 638.
14. Houghton, S.G., et al., Combined transabdominal gastroplasty
andfundoplication for shortened esophagus: impact on
reflux-relatedand overall quality of life. Ann Thorac Surg, 2008.
85(6): p.194752.
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15. Champion, J.K. and D. Rock, Laparoscopic mesh cruroplasty
forlarge paraesophageal hernias. Surg Endosc, 2003. 17(4): p.
5513.
16. Rathore, M.A., et al., Intermediate-term results of
laparoscopic repairof giant paraesophageal hernia: lack of
follow-up esophagogramleads to detection bias. JSLS, 2007. 11(3):
p. 3449.
17. Jobe, B.A., et al., Laparoscopic management of giant type
IIIhiatal hernia and short esophagus. Objective follow-up at
threeyears. J Gastrointest Surg, 2002. 6(2): p. 1818; discussion
188.
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hernia:evaluation and surgical management. J Thorac Cardiovasc
Surg,1998. 115(1): p. 5360; discussion 612
Discussant
Dr. Piero Marco Fisichella (Maywood, IL): You show that with
anoperation of this high-risk group of patients that can be
treated, canachieve good results in terms of quality of life.
However, based on your results, one may think that the
operationis still safe. Still, you had a 10% recurrence rate and
two perforations.Moreover, the overall complication rate was 24% if
you combineminor and major complications. That means that more or
less onepatient out of four will have some sort of
complication.
I have three questions.First, I am interested in the surgical
technique. Based on your
experience, what are the technical elements that can allow you
toachieve good results?
You briefly mention in the paper the dissection of the sac,
theposterior mediastinal dissection. You also mentioned
lengtheningprocedures. Although, you did not use any lengthening
procedures, inthe discussion, you say that you used these
selectively. In addition,you also said that you used three
different techniques.
In summary, could you tell us what is the right approach that
youwould use for these patients?
Second. When did recurrence occur? Is there a specific time
thatyou saw the recurrence coming? Basically, is there a threshold
in thefollow-up beyond which patients may be safe from
recurrence?
Third. Do you know if mesh plays a role in the recurrence or
not?Last question. You had roughly 25 to 35 patients with
short-term
quality of life data, results before and after surgery. And you
have68% of patients with long-term results. Do you have any idea
what isthe complication rate in these patients?
Closing discussant
Dr. Brian E. Louie: To address your first question around
ourtechnique or what we think is important, I think we are like
mostlaparoscopic surgeons, we prefer entire sac reduction. We
believebringing the sac down is important and detaching it
circumferentiallyaround the esophageal hiatus. We spend a
considerable amount of timein the operation, probably two thirds of
the time mobilizing theintrathoracic esophagus. And our general
goal has been to reestablishat least 2 to 3 cm of intra-abdominal
esophagus once were satisfiedabout tension.
And if that means taking the dissection up above the
inferiorpulmonary veins, that generally means doing so. So we spend
aninordinate amount of time doing that. And I think that
esophagealmobilization is probably the key to the whole operation.
And I think,regardless of which anti-reflux procedure you add on to
mobilizationof the esophagus, at least in our series, it doesnt
seem to make muchdifference whether we used a Nissen, a Hill, or a
hybrid procedure; Ithink mobilization is key.
To answer your third question about the complications and
thequality of life and recurrences, the recurrences for us, when we
followthese patients, they are generally studied at 6 months and 12
monthswith the barium swallow and/or other tests, so the
recurrences generallyoccur between that 6 and 12 month interval. We
have seen a couple outlater than that, but I dont have a definite
time frame for that.
In terms of quality of life for that group, we didnt pull
thatspecifically out for the paper, but the patients that did have
theperforations or did get readmission, their general quality of
life in thisgroup is generally very good and very similar to the
elective group.
And then your other question was recurrence of mesh. So early
inthe series, we used no mesh until the report by Dr. Oeschlager
andcolleagues saying that mesh reduced the hernia rate, then we
began touse mesh much more liberally. Im not sure.
We looked at the data one way and said, you know, we
probablyshould be using mesh because of the six recurrences, three
didnt havemesh. But the other way to look at it is 60% of our
patients didnthave mesh and we still had the same recurrence rates.
And I know Dr.Luketichs group said the need for mesh is not as
great as everybodythinks it is. I think that is very controversial.
For now, I think we aregoing to continue to use mesh.
Discussant
Dr. Nathaniel Soper (Chicago, IL): This is something that we all
strugglewith. What do you do with the old patient who has a
paraesophagealhernia, because there is a significant morbidity and
mortality?
First of all, you state all of these patients had symptoms, so
you donot operate on asymptomatic patients who have
paraesophagealhernias; is that correct?
Dr. Brian E. Louie: That would not be quite correct because
Iwould think we have operated on them. They might not have beenover
70, but in this group they were all symptomatic that werein
theconsecutive series, that they all happened to have symptoms.
Discussant
Dr. Nathaniel Soper (Chicago, IL): You said you did not include
theemergency operations that were done for strangulation. Just to
give usa perspective, in this same period of time, how many of
those werethere in your medical center?
Closing Discussant
Dr. Brian E. Louie: In the medical center, we had about a dozen
overthe five-year period that the two senior surgeons have counted
thatcame in for strangulation and went to the operating room the
samenight for endoscopic findings of strangulation, so 12.
Discussant
Dr. Nathaniel Soper (Chicago, IL): And so its so hard to know
whatthe denominator is total in any of this series.
Last but not least, you had a 10% recurrence rate, but your
meanfollow-up was only about 1.3 years. Do you routinely
performanatomical tests to really assess what your true recurrence
rate is, orwere these symptomatic patients who happened to get
studied?
J Gastrointest Surg (2011) 15:389396 395
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Closing discussant
Dr. Brian E. Louie: Our follow-up protocol is generally to get
abarium swallow at about a year. And then if the patients are
willing,we will undergo full foregut evaluation with endoscopy, pH
analysis,
and manometry. We did not include that in this series because we
havenot gotten some of the patients out that far yet. But if we
follow themlong enough, I think well continue to have objective
data onrecurrences down the road.
But it is our protocol generally to get some imaging study,
whetherits upper GI esophagogram or an endoscopy.
396 J Gastrointest Surg (2011) 15:389396
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2010 SSAT PLENARY PRESENTATION
Preoperative Infliximab is not Associated with an IncreasedRisk
of Short-Term Postoperative ComplicationsAfter Restorative
Proctocolectomy and IlealPouch-Anal Anastomosis
Melanie L. Gainsbury & Daniel I. Chu & Lauren A. Howard
& Jennifer A. Coukos &Francis A. Farraye & Arthur F.
Stucchi & James M. Becker
Received: 2 August 2010 /Accepted: 22 October 2010 /Published
online: 19 January 2011# 2011 The Society for Surgery of the
Alimentary Tract
AbstractIntroduction Considerable controversy exists over
whether the preoperative use of infliximab (IFX) for refractory
ulcerativecolitis (UC) increases the risk for surgical
complications after restorative proctocolectomy and ileal
pouch-anal anastomosis(IPAA). The aim of this study was to assess
the association between preoperative IFX use and short-term
surgicalcomplications in a single-surgeon cohort at a tertiary care
academic center.Methods UC patients who underwent IPAA from
September 2005 through May 2009 were retrospectively
identified.Twenty-nine patients treated with IFX within 12 weeks of
surgery and 52 non-IFX control subjects were identified. Short-term
postoperative outcomes were compared between groups occurring
within 30 days of loop ileostomy closure.Results Patients were
similar with respect to demographics, co-morbidities, rate of
emergency surgery, hand-sewnanastomosis, and preoperative use of
cyclosporine, azathioprine, and high-dose steroids. IFX patients
were more likely tohave received a laparoscopic hand-assisted IPAA,
low-, medium-, and any-dose steroids, 6-mercaptopurine
(6-MP),methotrexate, and to have failed medical therapy. There was
no short-term mortality. Overall postoperative and
infectiouscomplications were similar between IFX and non-IFX
groups. Multivariate regression models revealed no
independentpredictors for postoperative complications when
including IFX [odds ratio (OR) 0.78, p=0.67], laparoscopic
hand-assistedIPAA, 6-MP, methotrexate, steroids, failure of medical
therapy, and body mass index.Conclusions Preoperative IFX use was
not associated with an increased risk of short-term postoperative
complications after IPAA.
Keywords Infliximab . Ulcerative colitis . Ileal
pouch-analanastomosis . Short-term complications
Introduction
Ulcerative colitis (UC) is a disease of the colonic
mucosacharacterized by recurrent inflammatory episodes.
Thetreatment of UC is to a large extent medical, using suchagents
as 5-aminosalicylic acid (5-ASA), corticosteroids,and the
immunomodulators 6-mercaptopurine (6-MP) andazathioprine. For those
patients unresponsive to theaforementioned medications, rescue
therapies such ascyclosporine and tumor necrosis factor alpha
(TNF-)inhibitors are available.
Approximately one half of chronic UC patients receivingmedical
treatment relapse per year. Nearly one fifth of UC
This study was presented, in part, at the 51st Annual Meeting of
theSociety for Surgery of the Alimentary Tract in New Orleans, LA
onMay 5, 2010 and published in abstract form in Gastroenterology
May2010; 138(5):S-867.
Source of financial support The Robert and Dana Smith
FamilyFoundation and the Smithwick Endowment Fund, Department
ofSurgery, Boston University School of Medicine
M. L. Gainsbury :D. I. Chu : L. A. Howard : J. A. Coukos :A. F.
Stucchi : J. M. Becker (*)Department of Surgery, Boston University
School of Medicine,88 East Newton Street, C500,Boston, MA 02118,
USAe-mail: [email protected]
F. A. FarrayeSection of Gastroenterology,Boston University
School of Medicine,Boston, MA, USA
J Gastrointest Surg (2011) 15:397403DOI
10.1007/s11605-010-1385-6
-
patients experience an acute severe colitis episode
requiringhospitalization. Of those, around 60% will respond
tointravenous corticosteroids within 72 to 96 h. An additional1520%
may improve following rescue medical therapy.Ultimately, however,
30% require surgical management within1 year and 80% will undergo
colectomy by 10 years.14
Proctocolectomy with ileal pouch-anal anastomosis (IPAA)remains
the surgical procedure of choice for UC patientsrefractory to
medical therapy. IPAA offers cure for theintestinal manifestations
of the disease while eliminating therisk for colonic malignancy.
Recent data from large volumeinstitutions suggest improved
health-related quality of lifefollowing IPAA with reliable
functional outcomes.4
Infliximab (IFX) is a chimeric IgG1 monoclonal anti-body that
targets TNF-, an important regulator of manychronic inflammatory
diseases such as UC.5 IFX receivedFDA approval in September 2005
for use in induction andmaintenance therapy for moderate to severe
UC. AlthoughIFX holds several boxed warnings, including the
increasedrisk of malignancy and opportunistic infections such
asdisseminated fungal infections and tuberculosis, its use
isconsidered safe and effective. Recent studies, however,have shown
that between 30% and 50% of patients treatedwith IFX still fail
rescue therapy and proceed to colec-tomy.4 Considerable controversy
exists in the literature onwhether such preoperative IFX use
increases short-termpostoperative complications for these patients
after procto-colectomy with IPAA.
As summarized in Table 1, a study by Selvasekar et al. atthe
Mayo Clinic found that IFX use in UC patients within2 months of
IPAA significantly increased the risk foranastomotic leak,
pouch-specific, and infectious complica-tions.6 Similarly, Mor et
al. from the Cleveland Clinicreported significantly increased rates
of anastomotic leak,pouchitis, abscess, and overall complications
in UC andindeterminate colitis patients with preoperative IFX
expo-sure.7 Conversely, Kunitake et al. at Massachusetts
GeneralHospital found similar rates of pouch-specific,
surgery-related, and infectious complications between
preoperativeIFX and non-IFX groups.8 These results were supported
byFerrante et al. who found no differences in anastomotic leak,
pelvic abscess, pouch-related or infectious complications
intheir study population.9 A recent meta-analysis by Yang et
al.further confounds the literature by reporting an
associationbetween IFX exposure and overall postoperative
complica-tions but no association individually between
preoperativeIFX use and infectious or non-infectious complications
forUC patients.10 These studies demonstrate that the
surgicalcommunity is still unclear as to whether patients
whoundergo medical rescue therapy with IFX prior to an IPAAcan
expect a safe and functional outcome.
Therefore, the aim of our study was to assess theassociation
between preoperative IFX use and short-termsurgical complications
in a single-surgeon cohort at ourtertiary care academic referral
center.
Methods
Data were collected from an IRB-approved IPAA Registryat Boston
University Medical Center. We identified 81consecutive UC patients
who underwent IPAA betweenSeptember 2005 and May 2009 by a single
surgeon (J.M.B.).Of the 81 subjects, 29 had received IFX treatment
within12 weeks of the first stage of their IPAA surgery.
Fifty-twocontrol subjects remained as the non-IFX group.
Short-termpostoperative outcomes were compared between the
twogroups as described below.
Inclusion and Exclusion Criteria
Patients with a diagnosis of UC registered in the IPAAdatabase
who underwent IPAA at Boston University MedicalCenter between
September 2005 and May 2009 wereincluded in this study. Patients
with other pre- or postoper-ative diagnoses such as Crohns disease,
familial adenoma-tous polyposis, or indeterminate colitis were
excluded.
Clinical Variables
Medical records of all included subjects were retrospec-tively
reviewed. Data abstracted from the medical recordsincluded the
following patient demographics: age, gender,body mass index (BMI),
smoking status, American Societyof Anesthesiologists (ASA) class,
and co-morbidities.Information regarding medications used 12 weeks
prior tosurgery included IFX, cyclosporine, methotrexate,
6-MP,azathioprine, oral low-dose steroids (40 mg/day). Surgical
factors evaluated includedindication for surgery, type of procedure
(two- versus three-stage), modality (open versus laparoscopic
hand-assisted),and ileal pouch-anal anastomosis technique (stapled
versushand-sewn).
Table 1 Literature-based comparison of postoperative
complicationrisk associated with preoperative use of infliximab
Authors Overall complicationsOR (95% CI)
Infectious complicationsOR (95% CI)
Selvasekar et al.6 1.7 (0.93.2) 2.7 (1.16.7)
Mor et al.7 3.5 (1.58.3) 13.8 (1.8105)
Kunitake et al.8 1.1 (0.62.0) 0.5 (0.21.4)
Ferrante et al.9 Not available 0.3 (0.071.4)
Yang et al.10 1.8 (1.12.9) 2.2 (0.68.0)
398 J Gastrointest Surg (2011) 15:397403
-
Outcome Measures
Our primary outcome was the rate of overall
short-termpostoperative complications between the IFX and
non-IFXgroups. Secondary outcomes included the rate of
short-terminfectious and non-infectious complications. Short-term
post-operative complications were defined as having occurredbetween
the first-stage IPAA surgery until up to within 30 daysafter the
last-stage IPAA surgery, the closure of the divertingloop
ileostomy. Complications were defined as pouch/anasto-motic leak,
pelvic/intraabdominal abscess, pouch-related com-plications, wound
infection, and other. Other complicationsincluded thrombosis
(pulmonary embolus, portal vein throm-bosis, and deep venous
thrombosis), small bowel obstruction,ileus, and one episode of
wound dehiscence. Pouch-relatedcomplications included one episode
of pouch dehiscence andone episode of a fistula originating from
the pouch. Pouch oranastomotic leaks were defined as contrast
extravasations seenon computed tomography or loop-o-gram studies.
Woundinfections occurring in the midline, port-site, or
ostomy-sitelocations were included in this study.
Statistical Analysis
Categorical variables were reported as frequencies
andpercentages. Continuous variables were reported as meanand
standard deviation (SD). Students t test for continuousvariables
and chi-square or Fishers exact tests for categor-ical variables
were used as appropriate in evaluating theassociations between IFX
use and patient factors such asdemographics, medications, and IPAA
data. Logisticregression analysis was used to assess
multivariableassociations between potential risk factors and the
follow-ing outcomes: overall postoperative complications,
infec-tious and non-infectious complications, and woundinfection.
Results are presented as odds ratios (OR) with95% confidence
intervals (CI).
A p value of 40 mg/day) use wereobserved (Table 2). Infliximab
patients, however, were morelikely to have received 6-MP,
methotrexate, low-dose steroids(
-
assisted IPAA, BMI, and use of any-dose steroid, 6-MP,
ormethotrexate (Table 4). Logistic regression models alsorevealed
no independent predictors of infectious or non-infectious
complications when including these same factors(Table 4). On
multivariate logistic regression, patients weremore likely to
develop wound infections with higher BMIs(OR 0.88, CI 0.780.99,
p=0.049) (Table 5). IFX, any-dosesteroids, 6-MP, failure of medical
therapy, and laparoscopichand-assisted procedures were not found to
be predictors ofwound infection (Table 5).
Subgroup Analysis
In a subgroup analysis in which all urgent/emergency
andthree-stage IPAA surgery patients were excluded, theresults
remained very similar. Logistic regression modelscontinued to
reveal no independent predictors of overall,infectious, or
non-infectious complications when includingIFX. On multivariate
logistic regression, however, BMI nolonger predicted the
development of wound infections (OR0.89, CI 0.781.01, p=0.06).
Complication IFX (n=29) Non-IFX (n=52) p value
Overall 13 (44.8%) 23 (44.2%) 0.96
Infectious 5 (17.2%) 14 (26.9%) 0.32
Pelvic/intraabdominal abscess 4 (13.8%) 7 (13.5%) 1.00
Wound infection 1 (3.5%) 10 (19.2%) 0.09
Non-infectious 12 (41.4%) 16 (30.8%) 0.34
Pouch/anastomotic leak 1 (3.5%) 5 (9.6%) 0.41
Pouch-related 0 (0.0%) 2 (3.9%) 0.53
Other 12 (41.4%) 13 (25.0%) 0.13
Table 3 Short-term complicationrates compared between
inflixi-mab and non-infliximab groups
Demographics IFX (n=29) Non-IFX (n=52) p value
Patient factors
Age, yearsa 36.212.6 42.012.7 0.06
BMIa 27.07.0 27.65.9 0.68
Gender, male 11 (37.9%) 22 (42.3%) 0.70
ASA score 2 21 (72.4%) 44 (84.6%) 0.68Smoker 5 (17.2%) 18
(34.6%) 0.10
Co-morbidities
Diabetes mellitus 2 (6.9%) 1 (1.9%) 0.29
Hypertension 6 (20.7%) 4 (7.7%) 0.16
Cardiac 4 (13.8%) 1 (1.9%) 0.06
Pulmonary 2 (6.9%) 4 (7.7%) 1.00
Renal 0 (0%) 3 (5.8%) 0.55
Surgical factors
Failed medical therapy 26 (89.7%) 36 (69.2%) 0.04
Emergent/urgent first stage 3 (10.3%) 5 (9.6%) 1.00
2-stage IPAA 28 (96.6%) 47 (90.4%) 0.41
Laparoscopic colectomy 13 (44.8%) 4 (7.7%)
-
Discussion
Our study indicates that preoperative IFX use 12 weeks prior
toundergoing IPAA for UC is not associated with an increasedrisk of
overall short-term postoperative complications. More-over, no
differences were observed in infectious or non-infectious
complications between IFX- and non-IFX-treatedpatients. These
findings suggest that for UC patients refractoryto medical therapy,
a rescue trial of IFX will not affect theshort-term postoperative
outcomes for those who subsequentlyrequire restorative
proctocolectomy and IPAA. To our knowl-edge, we are the first study
to examine only patients who hadreceived IFX after its FDA approval
in September 2005 for usein moderate to severe UC. Prior studies
have included patientswho received IFX during off-label usage,
which can makeresults difficult to interpret as these patients may
have been inpoorer condition prior to surgery.
Infliximab patients were more likely to have failed
medicaltherapy and to have received methotrexate, 6-MP, and
low-,medium-, and any-dose steroids. These observations were
notsurprising since IFX use is generally reserved for those
patientsfailing other medical therapies. Ultimately our data show
noincreased risk among IFX exposed patients for overall,infectious,
or non-infectious complications. Of note, the
proportion of ASA scores 2 at first-stage IPAA were similaramong
patients with an overall complication and those withoutany
complication (p=1.00, data not shown). We therefore donot believe
that overall health status is confounding thelikelihood of
developing a complication after surgery. In ourstudy population,
IFX patients were more likely to haveundergone laparoscopic
hand-assisted IPAA. This is anunusual association not previously
reported in the literature.Our institution does not have any preset
selection criteria forlaparoscopic hand-assisted procedures, which
makes thisfinding difficult to reconcile. Incidentally, a recent
studysuggests preoperative IFX treatment does not affect
outcomesafter laparoscopic restorative proctocolectomy with
IPAA.11
Interestingly, our data demonstrated a trend toward fewerwound
infections in the IFX treated group, however, this wasnot
statistically significant. Regression analysis revealed higherBMIs
to be predictive of developingwound infections, which iswidely
supported by the literature.1215 Logistic regression didnot show
laparoscopic hand-assisted proctocolectomy to beprotective against
wound infection in our study populationdespite reports in the
literature suggesting the contrary.16,17
Our findings are incongruent from those of Mor et al.7
and Selvasekar et al.,6 who reported increased risk
ofpostoperative complications after IFX use. In the Mor et
Table 4 Multivariate logistic regression analysis of factors
associated with postoperative complications after IPAA
Covariate Overall complication Infectious complication
Non-infectious complication
IFXa 0.78 (0.262.38) p=0.67 1.87 (0.467.57) p=0.38 0.59
(0.191.87) p=0.37
Steroid, any 1.29 (0.325.29) 2.41 (0.4612.7) 1.02 (0.234.46)
6-MP 1.05 (0.382.89) 1.02 (0.303.54) 0.81 (0.282.33)
Methotrexate 2.43 (0.2030.1) NAb 1.79 (0.1423.0)
Failed medical therapy 0.94 (0.243.61) 0.57 (0.113.03) 1.41
(0.355.65)
Laparoscopic colectomy 1.25 (0.305.10) 0.31 (0.061.72) 1.13
(0.274.82)
BMI 1.02 (0.941.10) 0.93 (0.851.03) 1.04 (0.951.14)
Results are expressed such that OR 1.0 predicts the absence of
the outcomea Results expressed as odds ratio, confidence interval,
and p value. All other results expressed as odds ratio and
confidence intervalb Due to the presence of zero cells, logistic
regression for methotrexate is not valid
Table 5 Multivariate logistic regression analysis of factors
associated with wound infection after IPAA
Covariate Odds ratio 95% Confidence interval p value
IFX 9.49 0.71126.6 0.09
Steroid, any 9.47 0.9396.2 0.06
6-MP 0.36 0.061.98 0.24
Methotrexatea NA NA NA
Failed medical therapy 0.21 0.022.42 0.21
Laparoscopic colectomy 0.31 0.024.73 0.40
BMI 0.88 0.780.99 0.049
Results are expressed such that OR 1.0 predicts the absence of
the outcomea Due to the presence of zero cells, logistic regression
for methotrexate is not valid
J Gastrointest Surg (2011) 15:397403 401
-
al.7 study, immunomodulators were more frequently usedamong the
IFX-treated group. Immunomodulator use wasone of the factors
adjusted for on multivariate analysis,which greatly minimizes but
can never completely elimi-nate its influence on study results.
They also looked atpatients with any preoperative exposure to IFX,
with a 37-week upper interquartile range. Upon subset analysis,
theauthors reported that whether patients received IFX within16
weeks of their surgery or after did not change the factthat sepsis
was significantly greater in the IFX group. Theduration of
infliximabs biological activity is not known,but with a half-life
of 7 to 12 days and onset of action ofapproximately 2 weeks, it
would seem unlikely that IFXalone could be responsible for this
increased risk after16 weeks. In the Selvasekar study,6 IFX
patients were morelikely to be on high-dose steroids, 5-ASA, and
azathioprine,which were also adjusted for on multivariate
analysis.
In the studies by Kunitake et al.8 and Ferrante et al.,9 IFXwas
not found to increase the risk of postoperative complica-tions.
Kunitake et al.8 investigated UC, Crohns disease, andindeterminate
colitis patients undergoing any abdominalsurgery. The results of a
mixed IBD cohort may be difficultto interpret since Crohns patients
do not seem to be atincreased risk for postoperative complications
from IFX.1820
In the study by Ferrante et al.,9 IFX-exposed patients
wereyounger, had shorter disease duration prior to surgery,
andlower C-reactive protein levels. Although these factors
wereexamined on univariate analysis, multivariate analysis was
notperformed. One could argue that these patients were
healthierthan their control counterparts, and perhaps less likely
todevelop complications. The Ferrante et al.9 study
populationincluded patients who underwent a single-stage
IPAAwithoutan ileostomy. It is therefore difficult to reconcile
results withthose at our institution, where two- or three-stage
procedureswith diverting loop ileostomies are consistently
performed.Furthermore, the authors reported IFX-exposed patients
weremore likely to receive an IPAA with ileostomy than controls.And
the patient cohort without ileostomies was found atincreased risk
for complications, further confounding the data.
Beyond UC, infliximab has been used in several otherpreoperative
clinical settings. There seems to be consensus inthe literature
regarding Crohns disease, as several studies haveshown no increased
postoperative risk associated with IFXuse.1820 Controversy is,
however, apparent in orthopedicliterature. Giles et al. reported
increased risk of infectiouscomplications following orthopedic
procedures in rheumatoidarthritis patients on IFX.21 Conversely,
others have found nosuch increased risk among IFX-exposed
rheumatoid arthritispatients after orthopedic surgery.22,23
Our study is not without its limitations. It is
retrospectivelydesigned, examines a single center study population
operatedon by a single surgeon, and has a small sample size. It
ispossible that our study is not powered enough to detect small
differences between the IFX and non-IFX groups. Laparo-scopic
hand-assisted IPAA, failure of medical therapy,low-, medium-, and
any-dose steroid use, methotrexate use,and 6-MP use were unequally
distributed among the groups.The effects of these differences were
minimized by inclusionin multivariate analysis models but never
eliminated. Further-more, there may be other potential confounders
we wereunable to assess such as UC disease severity,
malnutrition,duration of colitis prior to surgery, and total number
of IFXinfusions received. Other factors associated with
septiccomplications following IPAA have recently been reportedby
the Cleveland Clinic including BMI, blood transfusion,and
individual surgeon. This study was unable to find anassociation
between IFX use and septic outcomes.24
No study should be taken in isolation. The need for
amulti-centered prospective study or a collaborative retro-spective
study from multiple registries with well-definedvariables echoed in
the literature deserves to be re-mentioned. An end to the
controversy regarding IFX usein UC and postoperative complications
is unlikely to befound without such an undertaking.
Financial disclosures Dr. Farraye sits on the Advisory Board
forCentocor and recently resigned from Centocor's Speakers Bureau
8/2010.
Acknowledgement The authors would like to acknowledge
JeremyHetzel for his statistical advice.
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2. Baudet A, Rahmi G, Bretagne AL, et al. Severe ulcerative
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3. Becker JM, Stucchi AF. Treatment of choice for acute
severesteroid-refractory ulcerative colitis is colectomy. Inflamm
BowelDis 2009; 15(1):146149
4. Becker JM, Stucchi AF. Is surgery the best second-line
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5. Tracey KJ, Cerami A. Tumour necrosis factor: a
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6. Selvasekar CR, Cima RR, Larson DW, Dozois EJ, et al. Effect
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7. Mor IJ, Vogel JD, Moreira AL, Shen B, et al. Infliximab
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ColonRectum 2008; 51:12021210
8. Kunitake H, Hodin R, Shellito PC, Sands BE, et al.
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9. Ferrante M, DHoore A, Vermeire S, Declerck S, et al.
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10. Yang Z,Wu Q,WuK, Fan D.Meta-analysis: pre-operative
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11. Reinier BC, Berdah SV, Grimaud JC, et al.
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Discussant
Dr. Amy L. Halverson (Chicago, IL): I congratulate youon taking
on this controversial topic. And really one of themost important
issues is what are the baseline patientcharacteristics in terms of
impacting outcome versus whatis the impact of the infliximab. That
is, and is the use ofinfliximab just a marker for more severe
disease?
I want to focus on two questions.The first question involves
looking at the patients that
underwent the initial ileal pouch operation versus thosepatients
that were so sick they were deemed to undergo justthe colectomy and
then have an interval ileal pouchoperation. Now, I noticed that in
your control group, therewere some patients that underwent just a
colectomy and asubsequent ileal pouch. In contrast, with the
infliximabgroup, they all underwent the ileal pouch initially.
So can you talk a little bit about how you decide whogets the
pouch and who gets a colectomy and then a pouch,and then how you
think that those patients that underwentthe colectomy and then the
subsequent pouch affect theoutcomes? Do you think that maybe they
are at increasedrisk for complications because they were sicker, or
do youthink that they are at decreased risk because they had
theirpouch surgery long after the other morbidity related to
theulcerative colitis was sort of out of the picture and they hada
more elective pouch operation?
My second question relates to this laparoscopic surgery.Can you
give a little insight into how you think that there issuch a
difference in the infliximab versus the non-infliximabgroup and the
role that laparoscopic surgery plays with that?
Closing Discussant
Dr. Melanie L. Gainsbury: To address the first
question,certainly patients who underwent an emergency
first-stageprocedure, causing them to have a three-staged IPAA,were
verydifferent from their two-staged counterparts. Those
requiringemergency surgery are certainly much sicker and unable
totolerate the pouch creation at the time of their first
surgery.Whether inclusion of these patients would impact the
databecause they are at increased risk for complications or
perhapsat less risk because they were staged was difficult to
tell.
But wewere able to actually run a subset analysis where
weeliminated those patients who were emergency surgeries, andwe did
not find significant changes in the data. Essentially, therate of
overall complications, infectious complications, andnon-infectious
complications between the infliximab and non-infliximab groups
continued to be insignificantly different.
In terms of the second question, regarding the
laparoscopiccolectomies, it was rather surprising to us at first
when wediscovered that the rate of laparoscopic colectomies
wassignificantly different between the infliximab and
non-infliximab groups. We did not have any preset criteria at
ourinstitution for selecting patients for laparoscopic colectomy,so
it was rather difficult for us to reconcile this difference.
Weincluded it as a factor in all of our multivariate analyses to
tryto help offset some of that influence on the data.
J Gastrointest Surg (2011) 15:397403 403
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SSAT/AHPBA JOINT SYMPOSIUM 2010
SSAT/AHPBA Joint Symposium: Today's Approachesto Colorectal
Cancer (CRC) Liver Metastases
W. Scott Helton
Received: 2 January 2011 /Accepted: 11 January 2011 /Published
online: 1 February 2011# 2011 The Society for Surgery of the
Alimentary Tract
Each year in the USA, approximately 150,000 patients
arediagnosed with colorectal cancer with an associated
55,000attributable deaths.1 Colorectal cancer is the second
mostcommon cause of cancer-related death in the USA, withmost
patients dying of metastatic disease. Up to 4050% ofpatients with
colorectal cancer will develop metastasis,2
with about 1020% presenting with liver metastasis(CRLM) at the
time of diagnosis3,4 and another 2025%developing metachronous liver
metastasis some timelater.5,6 Despite this high incidence of
developing meta-static disease, the median survival of patients
with CRLMhas increased substantially over the past 10 years;
patientsare living with persistent or recurrent metastatic
diseaselonger and with better quality of life than those treated
inthe 1980s and 1990s.7,8 This improvement in outcome isrelated to
improved patient selection, newer and moreaggressive surgical
techniques,9,10 and more effectivechemotherapy agents and
regimens.11 Five-year survivalfollowing curative intent surgery of
CRLM now approaches4560%1215 and is as high as 20% at 10 years in
selectindividuals.16
Patients with extensive metastatic liver disease previous-ly
thought to be unresectable can now be rendered free ofdisease after
receiving multimodality therapy that includesboth systemic and
liver-directed therapies. Modern liver-directed therapy may include
simple or radical liver
resection, and second- and third-stage hepatectomies aswell as a
variety of nonresection therapies includingablation
(radiofrequency, microwave, cryoablation, electro-poration),
radiotherapy (external beam or transvascular),and hepatic artery
infusion chemotherapy.17 The laterapproaches can be employed
singularly or in combinationwith resection and systemic therapy to
reduce and/orcontrol the magnitude of metastatic disease and
rendermany patients completely free of disease.
Despite these advances, many patients with CRLM whocould
potentially benefit from multidisciplinary liver-directed therapy
alone or in combination with neoadjuvantand adjuvant therapy are
not seen by clinicians who areknowledgeable and experienced with
CRLM and hence arenot offered this opportunity for improved
survival. The lackof understanding by medical oncologists,
gastroenterolo-gists, and many surgeons on how liver-directed
therapies fitin with modern chemo and biological regimens
promptedthe American Hepatopancreatobiliary Association(AHPBA), the
Society of Surgical Oncology (SSO), andthe Society for Surgery of
the Alimentary Tract (SSAT) tohost a consensus conference on this
topic in 2006 duringthe Annual Meeting of the American Society of
ClinicalOncology (ASCO) meeting.18,19 Since 2006,
additionalexperience has been accrued with more widespread
aggres-sive multimodality therapy to convert patients
fromunresectable to resectable status. Kopetz and
colleaguespublished a review in The Lancet that discussed this
newparadigm for patients with both resectable and
initiallyunresectable disease (see Fig. 1).20 Despite these efforts
ofknowledge dissemination, the rapid evolution of so manynew
approaches and therapies has confused many practi-tioners and
patients. The rapid evolution of therapy andpaucity of adequately
powered randomized clinical trials todefine best therapy have led
patients and physicians to ask a
Presented at SSAT/AHPBA Joint Symposium: Today's Approaches
toColorectal Cancer Liver Metastases, Digestive Disease Week,
NewOrleans, LA 2010
W. S. Helton (*)Department of General, Vascular & Thoracic
Surgery,Virginia Mason Medical Center,1100 9th Ave,Seattle, WA
98101, USAe-mail: [email protected]
J Gastrointest Surg (2011) 15:404405DOI
10.1007/s11605-011-1425-x
-
number of questions surrounding therapeutic choices.These
include but are not limited to:
& Can we currently identify individuals who will benefitfrom
specific therapies and what factors, if any, arereliable predictors
of survival?
& With so many therapies, which one is best for
whichpatient?
& If chemotherapy is so much better today for CRLM,should
everyone receive it, regardless of havingresectable liver tumor(s)
upon presentation? If so,should they receive chemotherapy before or
after liverresection? For those who receive chemotherapy
beforeliver resection, does this increase subsequent
surgicalmorbidity or even preclude surgery?
& For patients who refuse or are ineligible for liver
resection,which other therapies are most effective or
reasonable?
& What are the limits of liver resection today and howmuch
residual liver reserve is necessary for survival?
& How do we balance the benefits and risks of
resectionagainst other less invasive therapies for a given
patient?
In an effort to address these questions, the scientific
andprogram committees of the AHPBA and SSAT agreed thatit would be
worthwhile to host a symposium on themanagement of CRLM during
Digestive Disease Week inthe Spring of 2010. The goals of this
symposium were toincrease knowledge of surgeons and
gastroenterologistsabout recommended best practice based upon
currentevidence for treating patients with CRLM and to bringclarity
to many of the questions above. Four experiencedsurgical oncologist
from four prominent cancer centersdelivered outstanding talks on
this subject. The AHPBAand SSAT are extremely pleased and
appreciative of the factthat they agreed to publish their comments
in the Journal of
Gastrointestinal Surgery. With this effort, our two
associ-ations hope to advance the care and improve the outcomesof
patients with CRLM.
References
1. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005.
CACancer J Clin 55:1030, 2005
2. Steele G, Jr., Ravikumar TS: Resection of hepatic metastases
fromcolorectal cancer. Biologic perspective. Ann Surg 210:12738,
1989
3. Cady B, Monson DO, Swinton NW: Survival of patients
aftercolonic resection for carcinoma with simultaneous liver
metasta-ses. Surg Gynecol Obstet 131:697700, 1970
4. Jatzko G, Wette V, Muller M, et al: Simultaneous resection
ofcolorectal carcinoma and synchronous liver metastases in a
districthospital. Int J Colorectal Dis 6:1114, 1991
5. Scheele J, Stang R, Altendorf-Hofmann A, et al: Resection
ofcolorectal liver metastases. World J Surg 19:5971, 1995
6. Altendorf-Hofmann A, Scheele J: A critical review of the
majorindicators of prognosis after resection of hepatic metastases
fromcolorectal carcinoma. Surg Oncol Clin N Am 12:16592, xi,
200
7. Adson MA, van Heerden JA, Adson MH, et al: Resection of
hepaticmetastases from colorectal cancer. Arch Surg 119:64751,
1984
8. Hughes KS, Rosenstein RB, Songhorabodi S, et al: Resection
ofthe liver for colorectal carcinoma metastases. A
multi-institutionalstudy of long-term survivors. Dis Colon Rectum
31:14, 1988
9. Abdalla EK, Resection of colorectal liver metastases.
Currentarticle in J Gastrointestinal Surgery, 2010.
10. Chun YS, Vauthey JN, Ribero D, et al. Systemic
chemotherapyand two-stage hepatectomy for extensive bilateral
colorectal livermetastases: perioperative safety and survival. J
Gastrointest Surg.2007 Nov;11(11):1498504.
11. Pawlik TM, Cosgrove D. The role of peri-operative
chemotherapyfor resectable colorectal liver mestastsis: what does
the evidencesupport? Current article in J Gastrointestinal Surgery,
2010.
12. Abdalla EK, Vauthey JN, Ellis LM, et al: Recurrence
andoutcomes following hepatic resection, radiofrequency
ablation,and combined resection/ablation for colorectal liver
metastases.Ann Surg 239:81825; discussion 8257, 2004
13. Choti MA, Sitzmann JV, Tiburi MF, et al: Trends in
long-termsurvival following liver resection for hepatic colorectal
metasta-ses. Ann Surg 235:75966, 2002
14. Pawlik TM, Scoggins CR, Zorzi D, et al: Effect of surgical
marginstatus on survival and site of recurrence after hepatic
resection forcolorectal metastases. Ann Surg 241:71522, discussion
7224, 2005
15. de Jong MC, Mayo SC, Pulitano C, et al: Repeat curative
intentliver surgery is safe and effective for recurrent colorectal
livermetastasis: results from an international multi-institutional
analy-sis. J Gastrointest Surg 13:214151, 2009
16. Tomlinson JS, Jarnagin WR, DeMatteo RP, et al: Actual
10-yearsurvival after resection of colorectal liver metastases
defines cure.J Clin Oncol 25:457580, 2007
17. Boutros C, Espat NJ, What how and when to offer
non-resectionaltherapy for colorectal cancer liver metastases.
Current article in JGastrointestinal Surgery, 2010.
18. Bartlett DL, Berlin J, Lauwers GY, Messersmith WA, Petrelli
NJ,Venook AP. Ann Surg Oncol. 2006 Chemotherapy and regionaltherapy
of hepatic colorectal metastases: expert consensusstatement.
Oct;13(10):128492. Epub 2006 Sep 6
19. JN Vauthey, M Choti, WS Helton. AHPBA/SSO/SSAT
ConsensusConference on Hepatic Colorectal Metastases: Rationale and
Over-view of the conference.. Ann Surg Oncol, 2006.
Oct;13(10):125960
20. Kopetz S, Vauthey JN. Perioperative chemotherapy for
resectablehepatic metastases. Lancet, 2008 Mar
22:371(9617):100716.
A New Paradigm for Colorectal Liver Metastases
Resectable Unresectable
Hepatectomy (One-stage or
Two-stage) PVE*
Preoperative Therapy
2-3 months First-Line
Chemotherapy Re-evaluate 2-3 months
Second-Line Chemotherapy
Third-Line Chemotherapy
Resectable
Postoperative Therapy
3-4 months
+/- liver-directed therapy
+/- liver-directed therapy
Fig. 1 A new paradigm for colorectal liver metastases. *Portal
VeinEmbolization
J Gastrointest Surg (2011) 15:404405 405
-
SSAT/AHPBA JOINT SYMPOSIUM 2010
Prognostic Markers and Staging Systems for Patientswith
Colorectal Liver Metastases
James J. Mezhir & Michael I. DAngelica
Received: 2 January 2011 /Accepted: 11 January 2011 /Published
online: 29 January 2011# 2011 The Society for Surgery of the
Alimentary Tract
Keywords Colorectal cancer . Hepatic metastasis .
Chemotherapy . Clinical risk score . Biomarkers
AbbreviationsCRLM Colorectal liver metastasesCEA
Carcinoembryonic antigenCRS Clinical risk score
Introduction
The treatment of colorectal liver metastasis has evolvedover the
last 20 years. What was previously thought to be acontraindication
to surgery, metastatic disease in the liverhas been demonstrated to
be amenable to locoregionaltherapy. Up to 70% of recurrences after
resection ofprimary colorectal cancer occur in the liver and up
to40% of these patients present with liver-only disease.
Thesepatients are amenable to potential cure following
metasta-sectomy as demonstrated by 10 year actual survival ofnearly
20% in selected patients.1
The treatment of colorectal liver metastasis (CRLM)
ismultidisciplinary and often includes treatment withregional or
systemic chemotherapy. The use of chemo-therapy as an adjunct to
surgical resection, however, is
debatable and the therapeutic impact is relatively small.The
optimal timing (before or after surgery) and durationof treatment
is unknown. To help guide the clinicianwhen evaluating patients
with CRLM, numerous groupshave developed prognostic scoring systems
based onretrospective analyses.25 These scoring systems
includeclinicopathologic factors that impact outcome such asnodal
disease in the primary tumor, timing of thedevelopment of
metastasis (synchronous vs. metachro-nous), size and number of
metastasis in the liver,carcinoembryonic antigen (CEA) level, and
the presenceof extrahepatic disease.
Despite these efforts, currently there is no idealpredictor of
outcome for patients with resectable CRLM.The ideal predictor of
outcome would include thefollowing characteristics: low cost and
easy to measure,reproducible across institutions, and measurable
bothbefore and after treatment. Most importantly, this factorwould
predict major differences in outcome that signif-icantly impact
treatment (Fig. 1a). A clinical example ofthis paradigm is K-ras
status as a predictor of response totherapy with cetuximab, a
monoclonal antibody againstthe epidermal growth factor receptor.6
In a prospectiverandomized controlled trial, patients with advanced
colo-rectal cancer were randomized to treatment with orwithout
cetuximab. When stratified for K-ras status,patients with wild type
K-ras tumors demonstrated asignificant survival advantage compared
to those withmutated K-ras tumors, who derived no benefit from
thechemotherapeutic agent (Fig. 1b). Therefore, patients
withmutated K-ras do not receive cetuximab therapy and arespared
the toxicity associated with a treatment with noproven benefit. To
date, there is no specific clinical risk
J. J. Mezhir :M. I. DAngelica (*)Department of Surgery, Section
of HepatopancreaticobiliarySurgery, Memorial Sloan-Kettering Cancer
Center,1275 York Avenue,New York, NY 10065, USAe-mail:
[email protected]
J Gastrointest Surg (2011) 15:406409DOI
10.1007/s11605-011-1424-y
-
score or biomarker that specifically prognosticates orguides
therapy for patients with resectable CRLM to thisdegree.
Clinical risk scoring systems are based on multivariateanalyses
of large clinical databases of patients selected forsurgical
resection. Multiple independent predictive factorsare combined into
a score that correlates with outcome.The Memorial Sloan Kettering
Cancer Center clinical riskscore (CRS) was established after review
of 1,001consecutive hepatic resections for CRLM.3 The
followingpreoperative factors were significant predictors of
disease-free survival on multivariate analysis (1 point is earned
foreach factor): node-positive primary tumor, disease freeinterval
5 cm, CEA >200 ng/mL. A score of 0 wasassociated with a 5-year
recurrence-free survival (RFS) of60% vs. a score of 5 which was
associated with a 5-yearRFS of 14%. However, high clinical risk
score does notpreclude 10-year survival in that patients with high
scoresstill demonstrate actual 10-year survival of up to 16%.1
Furthermore, with the exception of positive liver
resectionmargin, there is not a single clinical or pathologic
factorthat precludes 10-year survival (Table 1). These types
ofscoring systems serve as a general guide for prognosis butare not
ideal in that they do not specifically impacttreatment decisions
and do not predict universally good oruniversally bad outcomes.
Not surprisingly, some of the same clinical factors
(i.e.,node-positive primary tumor) are predictive of outcome
atother institutions. Despite this, these scoring systems arenot
always prognostic across institutions. The MayoClinic devised a
scoring system from their patient cohortthat included factors such
as positive hepatoduodenallymph nodes, perioperative blood
transfusion, node-positive primary tumor, disease-free interval,
and sizeand number of metastatic lesions.5 While validating
theirscoring system, they imported the data from their cohortinto
three other scoring systems, including the MemorialCRS.5 Survival
and recurrence were not stratified by anyof the scoring systems
from other institutions (concor-dance indexes for all systems
approximated 0.55). Clearly,there is significant variability which
highlights thecomplexity of developing a reliable and
reproduciblescoring system independent of surgeon and
institutionalbiases.
There are numerous possibilities for why scoring systemsare not
generalizable, and one of them is clearly an overallselection bias.
Surgeons are typically very good at choosingappropriate surgical
candidates who have demonstrated gooddisease biology, which limits
the ability to generalize topatients with very high or very low
clinical risk scores. Thereis also variability in the selection
bias in that at differentinstitutions patient selection, referral
patterns, and institutional
Years after resection
Ove
rall
Surv
ival
(%)
5 10
50
100
A
B
0
B
A
Months after randomization
Ove
rall
Surv
ival
(%)
Wild type k-ras
Mutated k-ras
Fig. 1 Prognostic markers in cancer and disease. a Theoretical
exampleof the ideal biomarker. The ultimate biomarker is a
predictor ofoutcome that is simple, cheap, easy to measure, and
predicts majordifferences in outcome in patients with a given
disease. b Overallsurvival of patients with advanced colorectal
cancer based on treatmentwith cetuximab and K-ras status. Patients
with wild type K-ras derived asignificant benefit from cetuximab
while those with mutated K-ras hadequivalent outcome. Adapted from
Karapetis et al.6 with permission
J Gastrointest Surg (2011) 15:406409 407
-
neoadjuvant and adjuvant paradigms differ. Another factor
istumor biology, which ultimately dictates outcome and ispoorly
understood. Taken together, selection bias and a poorunderstanding
of tumor biology leads to the development ofrisk scores that are
not generalizable and that do not impacttreatment decisions.
Overall, there is no scoring system to datethat fits the paradigm
demonstrated in Fig. 1 (the idealprognosticator).
Nomograms have been increasingly developed andutilized as
prognosticators in multiple malignancies. Anomogram for predicting
disease-specific survival afterresection of CRLM was recently
published from ourinstitution.7 Ten factors were weighted and
scored from ananalysis of 1,477 patients treated from 1986 to
1999(Fig. 2). The concordance index was 0.68 compared to
0.65 for the CRS. This nomogram has been recentlyvalidated at
another institution and was found to be morepredictive of outcome
than the CRS.8 Despite thesepositive findings, nomograms suffer
from the sameinherent biases as other scoring systems and are
notproven to be clinically helpful in guiding
treatmentdecisions.
Neoadjuvant chemotherapy is being utilized withincreasing
frequency and response to therapy is anotherpotential biomarker of
patients with CRLM. However, itis clear from prospective phase II
and III trials that therate of progression on neoadjuvant
chemotherapy is lessthan 10%. Older studies suggest a poor outcome
forpatients that progress on systemic chemotherapy. How-ever, newer
studies in the era of modern chemotherapy
Table 1 Clinicopathologic variables from 612 patients treated at
MSKCC with 10 year follow-up and impact on overall survival
Variable 10-Year survival (%)
Synchronous disease 13 11 5 7
Node-positive primary tumor 63 56 52 50
Preoperative CEA >200 ng/mL 16 11 8 7
Disease-free interval 1 59 51 32 39
Size of hepatic metastases >5 cm 53 41 41 35
Positive resection margin (liver) 20 10 9 0
Resection > or = lobectomy 63 63 62 68
> or = 4 hepatic metastases 23 16 11 5
Adapted from Tomlinson et al.1 with permission
CEA carcinoembryonic antigen
Fig. 2 Nomogram for predict-ing 96 months
disease-specificsurvival. Draw a straight line foreach patient
variable up to thepoint axis. The cumulativenumber of points
correlates tothe disease-specific survivalprobability for a given
patient.Taken from Kattan et al.7 withpermission
408 J Gastrointest Surg (2011) 15:406409
-
have shown that progression during neoadjuvant chemo-therapy
does not necessarily preclude a good outcomeafter resection.9
Therefore, response to neoadjuvantchemotherapy alone is of low
yield as a predictive markerand is not a reliable prognosticator
independent of otherclinical risk factors.
It is clear that we need something better that, in the era
ofmodern chemotherapy, can help guide treatment decisions.The hope
of an ideal prognostic marker will likely have tocome from the
benchtop where tumor biology can bepredicted independent of the
aforementioned selection biases.The answers likely reside in tissue
and serum banks which,with new technologies and better
understanding of tumorgenetics, are amenable to future study. Tumor
immunologicand inflammatory response, markers of sensitivity to
certainchemotherapies (i.e., thymidylate synthetase),
chemokines,and tissue microarray profiling have all demonstrated
theability to prognosticate tumor biology.10 However, thesestudies
have been small in number and at single institutionsand need
further validation.
In conclusion, better prognostic factors are needed toguide the
treatment of patients with resectable CRLM.Despite the numerous
staging and scoring systems that existto stratify outcomes, they
have limited utility in that theyare not reproducible and do not
define either universallygood or bad outcomes. To improve risk
stratification, weneed to explore the prognostic factors related to
tumorbiology that are independent of the currently utilizedclinical
and pathologic variables.
References
1. Tomlinson JS, Jarnagin WR, DeMatteo RP, et al. Actual
10-yearsurvival after resection of colorectal liver metastases
defines cure.J Clin Oncol 2007; 25(29):457580.
2. ReesM, Tekkis PP, Welsh FK, et al. Evaluation of long-term
survivalafter hepatic resection for metastatic colorectal cancer: a
multifacto-rial model of 929 patients. Ann Surg 2008;
247(1):12535.
3. Fong Y, Fortner J, Sun RL, et al. Clinical score for
predictingrecurrence after hepatic resection for metastatic
colorectal cancer:analysis of 1,001 consecutive cases. Ann Surg
1999; 230(3):30918; discussion 31821.
4. Iwatsuki S, Dvorchik I, Madariaga JR, et al. Hepatic
resection formetastatic colorectal adenocarcinoma: a proposal of a
prognosticscoring system. J Am Coll Surg 1999; 189(3):2919.
5. Zakaria S, Donohue JH, Que FG, et al. Hepatic resection
forcolorectal metastases: value for risk scoring systems? Ann
Surg2007; 246(2):18391.
6. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras
mutationsand benefit from cetuximab in advanced colorectal cancer.
N EnglJ Med 2008; 359(17):175765.
7. Kattan MW, Gonen M, Jarnagin WR, et al. A nomogram
forpredicting disease-specific survival after hepatic resection
formetastatic colorectal cancer. Ann Surg 2008; 247(2):2827.
8. Reddy SK, Kattan MW, Yu C, et al. Evaluation of
peri-operativechemotherapy using a prognostic nomogram for survival
afterresection of colorectal liver metastases. HPB (Oxford) 2009;
11(7):5929.
9. Gallagher DJ, Zheng JT, Capanu M, et al. Response to
Neo-adjuvant Chemotherapy Does Not Predict Overall Survival
forPatients With Synchronous Colorectal Hepatic Metastases.
Annalsof Surgical Oncology 2009; 16(7):18441851.
10. Katz SC, Pillarisetty V, Bamboat ZM, et al. T cell
infiltratepredicts long-term survival following resection of
colorectalcancer liver metastases. Ann Surg Oncol 2009;
16(9):252430.
J Gastrointest Surg (2011) 15:406409 409
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SSAT/AHPBA JOINT SYMPOSIUM 2010
The Role of Peri-operative Chemotherapyfor Resectable Colorectal
Liver Metastasis: What Doesthe Evidence Support?
Timothy M. Pawlik & David Cosgrove
Received: 2 January 2011 /Accepted: 11 January 2011 /Published
online: 21 January 2011# 2011 The Society for Surgery of the
Alimentary Tract
Introduction
With improved patient selection, better surgical techniques,and
more effective cytotoxic chemotherapy agents, 5-yearsurvival
following curative intent surgery of colorectalmetastasis now
approaches 4560%.14 While there havebeen significant advances in
prolonging overall survival ofpatients with colorectal liver
metastasis, many patients stilldevelop recurrent disease. De Jong
et al.5 reported acontemporary experience in which the 5-year
disease-freesurvival was only 30% following curative intent surgery
forcolorectal liver metastasis, with 60% of patients
developingextrahepatic disease at 5 years. Tomlinson et al.6 noted
thatapproximately one third of actual 5-year survivors succumbto
cancer-related death. Noting that the chance of cureafter
hepatectomy was roughly a one-in-six chance, theauthors estimated a
maximal cure rate of only about 25%for patients undergoing surgical
resection of colorectal livermetastasis. Given the persistent high
recurrence rates andthe overall poor true long-term survival
followingsurgical resection of colorectal liver metastasis, there
has
been great interest in the use of adjuvant chemotherapy
forpatients with resectable colorectal liver metastasis.
The role of adjuvant chemotherapy after resection ofcolorectal
cancer liver metastasis has recently beenreviewed by Power and
Kemeny.7 For both pedagogicaland practical purposes, peri-operative
chemotherapy forcolorectal liver metastasis can be divided into
threedifferent treatment strategies; neoadjuvant, peri-operative,
and adjuvant. We herein review each one ofthese peri-operative
chemotherapy treatment strategies forresectable colorectal liver
metastasis.
Adjuvant Chemotherapy
The use of adjuvant chemotherapy for colorectal cancer hasbeen
well studied in stage III disease. Specifically, multiplerandomized
clinical trials have noted a survival benefitassociated with the
use of adjuvant chemotherapy forpatients with colorectal cancer and
lymph node metasta-sis.811 Sargent et al.8 reported that surgery
plus adjuvant 5-flurouracil (5-FU) versus surgery alone was
associated withan overall survival benefit (8-year overall
survivalsurgery+5-FU-based chemotherapy, 53% versus surgeryalone,
43%; P
-
adjuvant chemotherapy in the management of stage IIIcolorectal
cancer.
Multiple phase I and II studies have similarly shownimproved
efficacy of modern-era chemotherapy in the treat-ment of
unresectable stage IV colorectal liver metastasis. Whilemonotherapy
with 5-FU previously resulted in response ratesonly in the range of
2025%,12 current regimens that includeoxaliplatin or irinotecan
have response rates in the range of4555%.1317 More effective
cytotoxic chemotherapy hastranslated into a significant increase in
the median survival ofpatients with unresectable colorectal liver
metastasis from6 months with best-supportive care to 1215 months
withmonotherapy 5-FU to now 2024 months with oxaliplatin-
oririnotecan-based therapies. Additional advances have
beenassociated with the addition of biologic agents, such
asbevacizumab or cetuximab, to cytotoxic chemotherapy, asoutlined
in the BEAT18 and CRYSTAL studies.19
Given the robust data on the role of systemic chemo-therapy for
both resected stage III and unresectable stage IVcolorectal cancer,
there has been interest in the potential useof adjuvant
chemotherapy in the setting of resected stage IVcolorectal liver
metastasis. Unfortunately, data on the roleof adjuvant chemotherapy
for resected colorectal livermetastasis are scant.2023 Of the four
randomized trialspublished to date, two were published only in
abstract formand each had fewer than 52 patients analyzed.20,22 Of
thetwo other randomized trials,21,23 both suffered from pooraccrual
and had fewer than 175 patients analyzed. In theLanger et al.21
study, only 107 patients were analyzed andthere was no noted
difference in overall survival when dailybolus 5-FU was compared
with observation alone followingresection of colorectal liver
metastasis. In the Portier et al.23
trial, 173 patients were randomized to surgery alone
versussurgery+5-FU. In this study, two patients were lost
tofollow-up, leaving 85 patients randomized to the surgeryalone arm
versus 86 patients to the surgery+5-FU arm.Among the patients
randomized to adjuvant 5-FU, 94% ofassigned patients received
post-operative chemotherapy. Nodifference in overall survival was
noted between the studyarms (5-year overall survivalsurgery alone,
42% versussurgery+5-FU, 51%; P=0.13). The authors did note,however,
that adjuvant 5-FU conferred a disease-freesurvival benefit (5-year
disease-free survivalsurgeryalone, 27% versus surgery+5-FU, 34%;
P=0.028). Coxmultivariate analysis confirmed a statistically
significantbeneficial effect of chemotherapy on disease-free
survival(HR=0.66, 95% CI, 0.460.96).23 While this study didshow an
improvement in disease-free survival, it failed toshow an overall
survival benefit with adjuvant therapy. Thereasons for this lack of
effect were undoubtedly multi-factorial and included the relatively
small study sample sizeand lack of statistical power. In an attempt
to increase theoverall number of patients available for analysis,
Mitry et
al.24 performed a pooled analysis of the Langer et al.21
andPortier et al.23 studies. In this pooled analysis, a total of
278patients were analyzed, 140 of whom had been randomizedto
surgery alone and 138 of whom had been randomized tosurgery+5-FU.
Among those patients randomized toadjuvant chemotherapy, 95% of
assigned patients receivedchemotherapy. In this study, the authors
again noted nodifference in overall survival and a trend
towardimproved disease-free survival associated with
adjuvanttherapy. On multivariate analysis, after controlling
forother competing risk factors, a marginal
statisticallysignificant associated benefit of adjuvant 5-FU
chemo-therapy was noted (P=0.046).
There have been several large retrospective, non-randomized
studies that have also examined the issue ofadjuvant chemotherapy
for resectable colorectal livermetastasis.2527 Each of these
studies have reported asurvival benefit for adjuvant 5-FU versus
surgery alonefor patients with resectable colorectal liver
metastasis. Ingeneral, these studies have noted a relative
2560%decreased risk of disease-specific death associated
withreceipt of adjuvant 5-FU. Obviously, these retrospectivestudies
have serious threats to validity including selectionbias and
treatment bias, not to mention issues with possibleconfounding. As
such, any causal inferences drawn fromsuch data need to be
carefully considered.
There has been one study that has examined the use ofmodern era
chemotherapy in the adjuvant setting forresected colorectal liver
metastasis. Ychou et al.28 reported arandomized phase III study
comparing adjuvant 5-FU versusFOLFIRI among patients having
undergone complete resec-tion of liver metastases from colorectal
cancer. In this study,321 patients were randomized to receive
either 5-FU alone orFOLFIRI. Of those patients assigned to FOLFIRI,
95%received the assigned post-operative chemotherapy. Theauthors
noted no benefit for FOLFIRI compared with 5-FUwith regards to
either diseas