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djuvant Chemoradiation Therapy for Pancreaticdenocarcinoma: Who Really Benefits?

ipun B Merchant, MD, FACS, Jennifer Rymer, BS, Elizabeth AS Koehler, MS, G Daniel Ayers, MS,ason Castellanos, BS, David A Kooby, MD, FACS, Sharon H Weber, MD, FACS, Clifford S Cho, MD,

Max Schmidt, MD, PhD, MBA, FACS, Atilla Nakeeb, MD, FACS, Jesus M Matos, MD,harles R Scoggins, MD, MBA, FACS, Robert CG Martin, MD, FACS, Hong Jin Kim, MD, FACS,yed A Ahmad, MD, FACS, Carrie K Chu, MD, Rebecca McClaine, MD, Brian K Bednarski, MD,harles A Staley, MD, FACS, Kenneth Sharp, MD, FACS, Alexander A Parikh, MD, FACS

BACKGROUND: The role of adjuvant chemoradiation therapy (CRT) in pancreatic cancer remains controversial.The primary aim of this study was to determine if CRT improved survival in patients withresected pancreatic cancer in a large, multiinstitutional cohort of patients.

STUDY DESIGN: Patients undergoing resection for pancreatic adenocarcinoma from seven academic medical institu-tions were included. Exclusion criteria included patients with T4 or M1 disease, R2 resectionmargin, preoperative therapy, chemotherapy alone, or if adjuvant therapy status was unknown.

RESULTS: There were 747 patients included in the initial evaluation. Primary analysis was performedbetween patients that had surgery alone (n � 374) and those receiving adjuvant CRT(n � 299). Median followup time was 12.2 months and 14.5 months for survivors. Medianoverall survival for patients receiving adjuvant CRT was significantly longer than for thoseundergoing operation alone (20.0 months versus 14.5 months, p � 0.001). On subset andmultivariate analysis, adjuvant CRT demonstrated a significant survival advantage only amongpatients who had lymph node (LN)-positive disease (hazard ratio 0.477, 95% CI 0.357 to0.638) and not for LN-negative patients (hazard ratio 0.810, 95% CI 0.556 to 1.181). Disease-free survival in patients with LN-negative disease who received adjuvant CRT was significantlyworse than in patients who had surgery alone (14.5 months versus 18.6 months, p � 0.034).

CONCLUSIONS: This large multiinstitutional study emphasizes the importance of analyzing subsets of patientswith pancreas adenocarcinoma who have LN metastasis. Benefit of adjuvant CRT is seen onlyin patients with LN-positive disease, regardless of resection margin status. CRT in patients withLN-negative disease may contribute to reduced disease-free survival. ( J Am Coll Surg 2009;
208:829–841. © 2009 by the American College of Surgeons)
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here will be an estimated 37,170 new cases of pancreasancer, with nearly as many deaths in the US in 2008.

isclosure Information: Nothing to disclose.resented at the Southern Surgical Association 120th Annual Meeting, Westalm Beach, FL, December 2008.

eceived December 11, 2008; Accepted December 12, 2008.rom the Departments of Surgery (Merchant, Rymer, Castellanos, Sharp,arikh) and Biostatistics (Koehler, Ayers), Vanderbilt University Medicalenter, Nashville, TN; the Department of Surgery, Emory University Hos-ital, Atlanta, GA (Kooby, Chu, Staley); the University of Wisconsin Hospi-al, Madison, WI (Weber, Cho); Indiana University Medical Center, India-apolis, IN (Schmidt, Nakeeb, Matos); the University of Louisville Hospital,ouisville, KY (Scoggins, Martin); the University of North Carolina Medicalenter, Chapel Hill, NC (Kim, Bednarski); and the University of Cincinnatiedical Center, Cincinnati, OH (Ahmad, McClaine).orrespondence address: Nipun Merchant, MD, FACS, Vanderbilt Univer-

ity Medical Center, 597 Preston Research Building, 2220 Pierce Ave, Nash-
eille, TN 37232–6860.
8292009 by the American College of Surgeons

ublished by Elsevier Inc.

lthough this accounts for only 2% of all newly diagnosedalignancies, pancreas cancer is the fourth leading cause of

ancer death.1 Most patients with pancreatic cancer presentith advanced disease at the time of diagnosis, and only0% to 15% of patients are candidates for potentially cur-tive resection.2-4 The rationale for adjuvant therapy isased on the high incidence of tumor recurrence both lo-ally and at distant sites, presumably because of the pres-nce of micrometastatic disease after surgical resection.

The Gastrointestinal Study Group (GITSG) first stud-ed the role of adjuvant chemoradiation therapy (CRT) forancreas cancer.5 The study was closed early because of thelow accrual of only 43 patients over 8 years, and the in-erim analysis showed a statistically significant benefit forhe adjuvant therapy arm. Based on this, the GITSG trial
stablished CRT as a viable option after pancreatic cancer
ISSN 1072-7515/09/$36.00doi:10.1016/j.jamcollsurg.2008.12.020

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830 Merchant et al Adjuvant Chemoradiation for Pancreas Cancer J Am Coll Surg

esection within the US, but less so elsewhere. Since theITSG trial, other trials have suggested that adjuvant che-otherapy alone may be beneficial in the adjuvant setting

or pancreas cancer,6-8 but no randomized trial has beenble to convincingly support the role of radiation therapy,nd this issue sparks considerable debate throughout theorld.Multiple reasons exist as to why these trials have failed to

btain a greater understanding of the role of CRT in pan-reas cancer. Limitations of these randomized trials includemall numbers of patients in the treatment arms,5 poorompliance with the treatment regimens,5,7 variable patho-ogic criteria for study entry including combining patientsith pancreatic adenocarcinoma with other periampullaryalignancies,6,7 and flawed randomization schemes.7 In

ddition, patients with positive (R1) and negative (R0)argins of resection and positive and negative lymph

odes (LN) are assessed as a uniform group. So patientopulations vary considerably among these trials and com-arative analysis becomes impossible.Recent large single-institution studies9,10 and data from

he Surveillance, Epidemiology, and End Results (SEER)atabase,11 however, have suggested a significant benefit fordjuvant CRT after surgery for pancreas cancer. Thesetudies, although analyzing large numbers of patients, areimited by institutional biases and by analysis of patientsreated over many years, during which time our diagnosticapabilities, operative morbidity and mortality, and tech-iques for delivery of radiation and chemotherapy have

mproved substantially.4,12

The primary aim of this study was to determine if adju-ant CRT improves survival in patients with resected pan-reatic cancer in a large, multiinstitutional cohort ofatients. This analysis dilutes the biases of individual insti-utions and allows for independent analysis of subsets ofatients. We sought to determine if adjuvant CRT benefitsnly a subset of patients who are LN positive or those with1 resection margins.

ETHODShis is an institutional review board-approved, multiinsti-

Abbreviations and Acronyms

CRT � chemoradiation therapyDFS � disease-free survivalESPAC � European Study Group for Pancreatic CancerGITSG � Gastrointestinal Study GroupLN � lymph nodeOS � overall survival

utional review of prospectively maintained databases from p

even academic medical centers of the Central Pancreasonsortium. Patients with pancreas adenocarcinoma whonderwent surgical resection from January 2000 to De-ember 2006 from five centers and from January 1996 toecember 2006 from two centers were analyzed. Patientsere excluded if they were found to have T4 or M1 diseaser R2 resection margins at the time of operation, if theyeceived preoperative therapy, or if their adjuvant therapytatus was unknown. A total of 747 patients were includedn the initial evaluation. Of these, 374 patients had surgerylone, 299 patients received adjuvant CRT, and 74 patientseceived adjuvant chemotherapy alone. Adjuvant radiationherapy alone was identified as a treatment regimen in sixatients; these patients were included in the CRT group.rimary analysis for this study was performed between pa-ients who had surgery alone (n � 374) and those receivingdjuvant CRT (n � 299). Patients receiving chemother-py alone were excluded from the primary analysis.

All pathology and operative reports were reviewed toetermine the extent of resection. Resection margins wereonsidered positive (R1) if the carcinoma was close (withinmm) or present at the final pancreatic neck, uncinate

rocess, bile duct, or duodenal or retroperitoneal soft tissueargin, consistent with American Joint Committee onancer (AJCC) definitions.13 Perineural and lymphovascu-

ar invasion were not recorded routinely, so were not in-luded in the final analysis. Tumor grade was consistentlyeported and included. Because of the update to the Amer-can Joint Committee on Cancer staging manual in 2002,taging was inconsistent throughout the study period, soas not evaluated.All patients underwent surgical resection at the centers

nvolved in this study. Being tertiary referral centers, manyatients received their adjuvant therapy at outside hospi-als, so specific adjuvant therapy regimens were not able toe determined for all patients, but the majority of patientseceived 5-fluorouracil (5-FU)-based chemotherapy withonformal radiation therapy. Only patients who had veri-ication of their therapy were included the study.

tatistical analysishe Wilcoxon test and the Fisher’s exact test were used as

ppropriate to test for differences in patient characteristicsetween the two treatment groups. Overall survival (OS)as defined as the time from operation to death for any

eason. For OS, patients alive at last contact were censoredt their last followup time. Disease-free survival (DFS) wasefined as the time of operation to time of first recur-ence or death for any reason. Patients alive and recurrence-ree were censored at last followup. Survival distributionsere estimated using the method of Kaplan and Meier. The
roportions of individuals surviving up to 2 and 5 years

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831Vol. 208, No. 5, May 2009 Merchant et al Adjuvant Chemoradiation for Pancreas Cancer

ere estimated, and standard errors for 95% confidencentervals were estimated using Greenwood’s formula. Sur-ival comparisons by treatment arm were performed usinghe log rank test. The impact of multiple prognostic vari-bles on OS and DFS were assessed using the Cox (propor-ional hazards) regression model stratifying by institution.omparisons with p values � 0.05 were considered statis-

ically significant.

ESULTSedian followup time for all patients was 12.2 months and

4.5 months for survivors. Demographic data for patientsre shown in Table 1, including the number of patients inach treatment arm by institution. The mean age for thentire cohort of patients was 65.0 � 11.3 years. Patients

able 1. Demographics

ariableOperation alone

(n � 374)CRT

(n � 299) p Value

ge at operation, y* 67 � 11.7 63 � 10.3 �0.001ale gender, n (%) 211 (56) 160 (54) 0.586

nstitution, n (%)1 12 (3) 20 (7)2 80 (21) 60 (20)3 103 (27) 75 (25)4 106 (28) 22 (7)5 13 (3) 13 (4)6 42 (11) 37 (12)7 22 (6) 72 (24)

umor size, cm* 3.03 � 1.36 3.28 � 1.45 0.048umor grade, n (%)1 32 (9) 27 (9) 0.4762 223 (59) 163 (55)3 108 (29) 100 (34)4 13 (3) 7 (2)

ocation of tumor, n (%)Head 352 (93) 269 (90) 0.135Body 6 (2) 12 (4)Tail 20 (5) 18 (6)

ein resection, yes, n (%) 45 (12) 45 (15) 0.255argin, positive, n (%) 76 (20) 99 (33) �0.001

ymph nodes, positive,n (%) 210 (56) 193 (65) 0.027

ymph nodes resected,n (range) 8.5 (0–58) 10 (0–41) 0.280

lood loss, mL* 797 � 826 832 � 834 0.405ransfusions, yes, n (%) 105 (28) 88 (30) 0.668omplications, yes, n (%) 132 (35) 101 (34) 0.807ength of stay, d* 10 � 9.4 9 � 6.0 �0.001

Mean � SD.RT, chemoradiation therapy.

eceiving adjuvant CRT were younger than those undergo- t

ng surgery alone (CRT, 63.0 � 10.3 years versus surgery,7.0 � 11.7 years, p � 0.001). There was an equal distri-ution of men and women. Tumors were larger in patientsho received CRT (3.03 � 1.36 cm versus 3.28 � 1.45

m, p � 0.048). Other tumor characteristics such as gradend location were similar between the two groups. Patientsn the CRT arm had a greater incidence of LN-positiveisease (CRT, 65% versus surgery, 56%, p � 0.027) and R1esections (CRT, 33% versus surgery, 20%, p � 0.00014).he complication rates were similar between both groups.ength of stay was significantly longer in patients whonderwent surgery alone compared with those who re-eived adjuvant CRT (CRT, 9 � 6.0 days versus surgery,0 � 9.4 days, p � 0.001).

verall survivalable 2 shows the median OS for the entire group of pa-ients treated with adjuvant CRT or surgery alone andatients stratified by resection margin status (R0 versus R1)nd by LN status (LN positive versus LN negative). Whenomparing the entire cohort of patients by treatment arm,S was significantly improved for patients receiving CRT

fter surgery compared with those undergoing surgerylone (20 months versus 14.5 months, p � 0.001). Com-arison of the subset of patients with R0 versus R1 resec-ion margin and LN-positive or LN-negative disease allowsor analysis of which patients may truly benefit with adju-ant CRT. Patients receiving adjuvant CRT showed signif-cantly improved OS compared with patients undergoingurgery alone, regardless of margin status. Patients who hadither R0 (CRT, 23.4 months versus surgery, 15.9 months,� 0.001) or R1 (CRT, 15.9 months versus surgery,

.9 months, p � 0.003) resection margins benefitted sig-ificantly with adjuvant CRT. On the other hand, thereere no statistically significant differences in OS betweenatients with LN-negative disease who received adjuvantRT and those who underwent operation alone (22.9 monthsersus 24.2 months, respectively, p � 0.774); patients withN-positive disease showed a significant improvement in OSith adjuvant CRT compared with those undergoing opera-

ion alone (19.4 months versus 10.4 months, p � 0.001).Figure 1 shows the Kaplan-Meier survival curves for OS

y treatment group. Two and 5-year OS rates for patientseceiving adjuvant CRT were 43.2% (95% CI, 37.2% to0.2%) and 15.6% (95% CI, 10.0% to 24.4%), respec-ively, and for those undergoing surgery alone were 33.5%95% CI, 28.5% to 39.5%) and 19.0% (95% CI, 14.3% to5.4%), respectively. Figure 2 shows the overall survivalurves for treatment groups stratified by resection marginnd LN status.

To assess the impact of resection margin and LN status
ogether, we stratified patients into the following sub-

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roups: R0, LN�; R0, LN�; R1, LN�; and R1, LN�Table 2). This analysis showed that LN-negative patientsad no statistically significant benefit with adjuvant CRTompared with those undergoing surgery alone, regardlessf their resection margin status. Lymph node-negative pa-ients with either R0 (CRT, 29.6 months versus surgery,4.4 months, p � 0.441) or R1 (CRT, 15.6 months versusurgery, 15.4 months, p � 0.761) resection margins had sim-lar OS in both treatment arms. On the other hand, LN-ositive patients showed a statistically significant benefit toeceiving adjuvant CRT compared with patients undergoingurgery alone with either R0 (CRT, 23.3 months versus sur-ery, 10.8 months, p � 0.001) or R1 (CRT, 14.4 monthsersus surgery, 8.5 months, p � 0.002) resection margins.

To adjust for competing risk factors, we performed aultivariate analysis to assess whether adjuvant CRTould remain a predictor of OS among LN-positive pa-

ients (Table 3). After adjusting for age, gender, tumorocation, size, grade, blood loss, transfusions, surgical com-lications, and margin and node status as an interactionerm, adjuvant CRT still demonstrated a significant sur-ival advantage compared with surgery alone among pa-ients who were LN positive (hazard ratio 0.477, 95% CI.357 to 0.638). There was insufficient evidence to suggesthat adjuvant CRT provided a survival advantage com-ared with surgery alone among patients who were LNegative (hazard ratio 0.810, 95% CI 0.556 to 1.181).ther prognostic variables for OS included age, tumor size,

dvanced tumor grade, increased blood loss, and R1 resec-ion margin. Variables that did not affect OS included tu-

able 2. Overall and Disease-Free Survivalatients Treatment n Overall survival, mo 95%

ll CRTSurgery

299374

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0, LN� CRTSurgery

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RT, chemoradiation therapy; inf, infinity; LN, lymph node.

or location, need for blood transfusion, vein resection, or m

omplications within 30 days. CRT, as seen in Table 2,ignificantly improved median OS in R0 patients by.5 months (p � 0.001) and by 6.1 months in R1 patientsp � 0.003). This differential treatment (interaction) ef-ect with resection status of 1.4 months was tested in a

igure 1. Kaplan-Meier survival curves for overall survival by treatmentroup. Two and 5-year overall survivals for patients receiving adjuvanthemoradiation therapy (n � 299) were 43.2% (95% CI, 37.2% to 50.2%)nd 15.6% (95% CI, 10.0% to 24.4%), respectively, and for those under-oing surgery alone (n � 374) were 33.5% (95% CI, 28.5% to 39.5%) and9.0% (95% CI, 14.3% to 25.4%), respectively. Overall survival with che-

p Value Disease-free survival, mo 95% CI p Value

0.001 12.810.8

11.2–15.09.3–12.6

0.552

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12.3–18.210.4–14.6

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0.774 14.518.6

11.6–18.414.5–27.9

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0.441 15.018.8

10.8–19.116.5–27.9

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0.761 13.411.6

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oradiation therapy versus surgery, p � 0.001 by log rank analysis.

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eparate regression model and was not statistically signifi-ant (p � 0.980).

isease-free survivalhere was no significant difference seen in DFS betweenatients receiving adjuvant CRT compared with those un-ergoing surgery alone when assessing the entire cohort ofatients (CRT, 12.8 months versus surgery, 10.8 months,� 0.552), (Table 2). No differences in DFS were seenith either R0 or R1 resection margin status by treatment

rm (R0 CRT, 15.0 months versus surgery, 12.0 months,� 0.429; R1 CRT, 10.1 months versus surgery, 6.5 months,� 0.156). Interestingly, patients with LN-negativeisease showed a significantly worse DFS with adju-ant CRT compared with those undergoing surgerylone (CRT, 14.5 months versus surgery, 18.6 months,� 0.034). Patients with LN-positive disease, however,

howed a significantly improved DFS with adjuvant CRTCRT, 12.3 months versus surgery, 7.2 months, p �.001).When assessing the impact of resection margin and LN

tatus together, no differences in DFS were seen in patients

able 3. Cox Proportional Hazards Model for Overall Survivalnd Radiationariable Hazard 95% CI p Value

RT versus operation, LNnegative 0.810 0.556–1.181 0.270RT versus operation, LNpositive* 0.477 0.357–0.638 �0.0001

ositive lymph nodes, yes/no 1.765 1.313–2.372 0.0002ge at operation, y 1.012 1.002–1.023 0.021ender, versus female 1.028 0.827–1.278 0.800umor size, cm 1.103 1.015–1.199 0.021umor grade 2 versus 1 1.912 1.217–3.002 0.005umor grade 3 versus 1 2.720 1.691–4.376 �0.0001umor location body versushead 1.064 0.419–2.703 0.900umor location tail versushead 1.078 0.647–1.798 0.770

lood loss per 100U change 1.018 1.004–1.031 0.010ransfusion versus none 1.189 0.916–1.542 0.190ein resection versus none 0.924 0.663–1.288 0.640omplications in 30 d 1.169 0.911–1.499 0.220ymph nodes resected 0.995 0.977–1.012 0.540argin, positive versusnegative 1.510 1.192–1.913 �0.001

A single model with an interaction term between LN status and treatmentenerated the estimates in this table, and provided estimates of the treatmentffect within LN groups. Although not shown in this table, this term had aazard of 0.589, with a 95% CI of 0.378 to 0.916 and a p value of 0.0190.RT, chemoradiation therapy; LN, lymph node.

igure 2. Kaplan-Meier survival curves for overall survival for treat-ent groups stratified by resection margin and lymph node (LN)

tatus. (A) Patients with either R0 or R1 resection margin benefittedignificantly from adjuvant chemoradiation therapy (CRT) comparedith those undergoing surgery alone (R0 CRT [n � 200] versus R0urgery [n � 298], p � 0.001; R1 CRT [n � 99] versus R1 surgeryn � 76], p � 0.003). (B) Only patients with LN-positive diseaseenefitted from adjuvant CRT compared with patients undergoingurgery alone; LN-negative patients showed no benefit with adjuvantRT (LN� CRT [n � 193] versus LN� surgery [n � 208], p � 0.001;

ith LN-negative disease regardless of resection margin

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tatus between the two treatment arms (Table 2). A trendoward worse DFS was seen in R0 and LN-negative pa-ients who received adjuvant CRT, but this did not achievetatistical significance (CRT, 15.0 months versus surgery,8.8 months, p � 0.072). Patients with LN-positive dis-ase who had an R0 resection showed a significant im-rovement in DFS with adjuvant CRT (CRT, 15.4 monthsersus surgery, 9.0 months, p � 0.001), however, LN-ositive patients with R1 resections showed no differencen DFS between the two treatment arms.

Kaplan-Meier survival curves for DFS by treatmentroup are shown in Figure 3. Two- and 5-year DFS rates foratients receiving adjuvant CRT were 25.2% (95% CI,0.3% to 31.2%) and 10.3% (95% CI, 6.6% to 16.0%),espectively, and for those undergoing surgery alone were8.7% (95% CI, 24.1% to 34.3%) and 15.9% (95% CI,1.7% to 21.6%), respectively. Figure 4 shows the survivalurves for treatment groups stratified by resection marginnd LN status.

Although there was no difference in DFS between pa-ients receiving adjuvant CRT and those undergoing sur-ery alone by log rank analysis, on multivariate analysis,fter adjusting for the variables listed in Table 4, and oncegain including an interaction term for lymph node status,djuvant CRT demonstrated a significant DFS advantage

igure 3. Kaplan-Meier survival curve for disease-free survival byreatment group. Two- and 5-year disease-free survivals for patientseceiving adjuvant CRT (n � 299) were 25.2% (95% CI, 20.3% to1.2%) and 10.3% (95% CI, 6.6% to 16.0%), respectively, and forhose undergoing surgery alone (n � 374) were 28.7% (95% CI,4.1% to 34.3%) and 15.9% (95% CI, 11.7% to 21.6%), respectively.isease-free survival with chemoradiation therapy versus surgery,� 0.552 by log rank analysis.

ompared with surgery alone among patients with positive c

Ns (hazard ratio 0.566, 95% CI 0.437 to 0.733). Thereas no evidence to suggest adjuvant CRT provided a sur-ival advantage compared with surgery alone among pa-ients who were LN negative (hazard ratio 1.170, 95% CI.832 to 1.645). Other prognostic variables for DFS wereimilar to those for OS and included age, tumor size, ad-anced tumor grade, increased blood loss, and R1 resectionargin. Variables that did not affect DFS included tumor

ocation, need for blood transfusion, vein resection, oromplications within 30 days. CRT, as can be seen in Table, improved median DFS by 3 months and 3.6 months for0 (p � 0.429) and R1 patients (p � 0.156), respectively.his differential treatment (interaction) effect with resec-

ion status of 0.6 months was tested in a separateegression model and was not statistically significantp � 0.600).

ISCUSSIONhis large multiinstitutional study emphasizes the impor-

ance of analyzing subsets of patients with pancreas adeno-arcinoma who have LN metastasis and R1 resection mar-ins. This study suggests that patients receiving adjuvantRT after surgical resection for pancreatic adenocarci-oma achieve a significant OS benefit as compared withhose undergoing surgery alone. Subset analysis, however,evealed that the benefit of adjuvant CRT is seen only inatients with LN-positive disease. Although patients with0 or R1 resection margin showed a significant survivaldvantage with adjuvant CRT, this benefit was not seen inatients with LN-negative disease and was seen only inN-positive patients. Similarly, for DFS, comparison ofhe entire group of patients revealed no significant differ-nces between patients receiving adjuvant CRT comparedith those undergoing surgery alone, but on subset analy-

is, a DFS advantage is seen only in patients who haveN-positive disease and are receiving adjuvant CRT. Inddition, the DFS in patients with LN-negative diseaseho received adjuvant CRT was actually significantlyorse than that in patients who had surgery alone.Significant risk factors for recurrence after surgical resec-

ion for pancreas adenocarcinoma include LN-positive dis-ase and involved surgical margins.7,8,10 Outcomes for theseatients are significantly worse than those for patients withegative resection margins and LN-negative disease. Thisinding was confirmed in our study. Clinical trials of adju-ant therapy for pancreas cancer include 17% to 45% ofatients who had an R1 resection and 45% to 80% ofatients who have LN-positive disease.Other pathologic criteria for study entry into clinical

rials have also varied significantly. The GITSG trial ex-
luded LN-negative patients,5 the European Organization

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or Research and Treatment of Cancer (EORTC) trial ex-luded patients with T3 or T4 tumors,6 and the Chariténkologie (CONKO)-001 trial excluded patients with

ostoperative CA19–9 or carcinoembryonic antigen valuesreater than 2.5 times normal.8 The comparison of theseeterogeneous patient populations limits the evaluation ofhe role of adjuvant CRT in pancreas cancer.

Results from the several published prospective and ret-ospective series evaluating the role of adjuvant CRT arehown in Table 5. In the US, adjuvant CRT has been con-idered to be the standard of care for more than 20 years byany clinicians. The rationale for this, however, lies in the

indings of the randomized GITSG study initially pub-ished in 1985.5 This trial has been extensively criticizedecause of its small numbers, slow accrual, and use of out-ated split course radiation, and should, at this time, beonsidered only in historical context.

The only other prospective study in the US that com-ared adjuvant CRT with surgical resection alone for pan-reas adenocarcinoma is a nonrandomized study fromohns Hopkins.14 Patients were allowed to choose betweentandard therapy (similar to that used in the GITSGtudy), intensified therapy (intensified radiation therapy to

able 4. Cox Proportional Hazards Model for Disease-Freeurvival and Radiationariable Hazard 95% CI p Value

RT versus operation, LNnegative 1.170 0.832–1.645 0.370RT versus operation, LNpositive* 0.566 0.437–0.733 �0.0001

ositive lymph nodes, yes/no 1.971 1.491–2.605 �0.0001ge at operation, y 1.011 1.001–1.020 0.028ender, versus female 0.992 0.815–1.208 0.940umor size, cm 1.083 1.008–1.163 0.030umor grade 2 versus 1 1.915 1.291–2.842 0.001umor grade 3 versus 1 2.560 1.681–3.901 �0.0001umor location body versushead 1.534 0.807–2.918 0.190umor location tail versushead 1.104 0.715–1.705 0.650

lood loss per 100U change 1.031 1.016–1.047 0.0001ransfusion versus none 1.022 0.802–1.302 0.860ein resection versus none 1.083 0.806–1.456 0.600omplications in 30 d 1.167 0.934–1.459 0.170ymph nodes resected 0.997 0.982–1.013 0.740argin, positive versusnegative 1.437 1.156–1.787 0.001

A single model with an interaction term between LN status and treatmentenerated the estimates in this table and provided estimates of the treatmentffect within LN groups. While not shown in the table above, this term had aazard of 0.484, with a 95% CI of 0.324 to 0.724 and a p value of 0.0004.RT, chemoradiation therapy; LN, lymph node.

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ation alone. The majority of patients chose standardherapy and those that received adjuvant CRT showedn improvement in OS (CRT, 19.5 months versus sur-ery, 13.5 months, p � 0.003), with no difference seenetween the two CRT arms.Data from European trials show a significant role for

djuvant systemic chemotherapy, but fail to support a roleor adjuvant CRT in pancreatic adenocarcinoma. The ran-omized EORTC trial, consisting of both pancreatic can-ers and periampullary tumors, also failed to show a signif-cant benefit with the use of CRT.6 Even when analyzed foratients with pancreatic adenocarcinoma alone, there waso benefit with the use of CRT.In the European Study Group for Pancreatic Cancer

ESPAC-1) trial,7 patients in the 2 � 2 factorial design whoeceived adjuvant CRT actually fared significantly worsehan those undergoing surgery alone. In contrast, however,hose who received adjuvant systemic chemotherapy hadn increased OS compared with those who underwent sur-ery alone. When both the 2 � 2 factorial arm and single-andomization arms were analyzed for prognostic factors,he benefit of chemotherapy appeared most pronounced inatients with well-differentiated tumors, LN-positive dis-ase, and margin-negative resection. The detrimental ef-ects of CRT, meanwhile, appeared to be most pronouncedn patients with moderately differentiated tumors, LN-ositive disease, and negative resection margins. Althoughhis study has led to the virtual abandonment of adjuvantRT in Europe, it has been widely criticized in the USecause of its complicated design, the lack of statisticalower in the 2 � 2 design, and the lack of radiation qualityontrols.

Recently, large retrospective series from Johns Hopkinsnd Mayo Clinic have suggested that use of adjuvant CRTignificantly improves OS compared with that in patientsndergoing surgery alone.9,10 In the study from Johns Hop-ins, analysis of 616 patients showed that the benefit ofRT was independent of several risk factors including tu-or size, grade, margin, and nodal status. Similar to results

f this study, adjuvant CRT improved survival for bothargin-negative and margin-positive patients. In addition,N-positive patients appeared to have a significant benefitith adjuvant CRT, and LN-negative patients did not. Buty multivariate analysis, the interaction between nodal sta-us and treatment was not significant.

The recently reported Mayo Clinic experience of 472atients who underwent R0 resection also showed a signif-cant survival benefit with the use of adjuvant CRT. Thisenefit was present for both LN-positive and LN-negative

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enefit of adjuvant CRT, they were both nonrandomizedingle-institution studies.

In this study, the presence of involved LNs was 60%,onsistent with several other randomized and nonrandom-zed series shown in Table 5. Also consistent with otherublished series, the presence of positive LNs was associ-ted with decreased survival. The survival benefit of adju-ant CRT was seen only in LN-patients and not in LN-egative patients and was consistent with the findings ofohn Hopkins study. In the Mayo Clinic study, which eval-ated only R0 resected patients, adjuvant CRT led to an

mprovement in survival in both LN-negative and LN-ositive patients. However the randomized ESPAC-1 trialdjuvant CRT was actually harmful in both LN-positivend LN-negative patients. The decrease in DFS with adju-ant CRT for LN-negative patients seen in our study is anntriguing finding and similar to the findings of theSPAC-1 trial suggesting that these patients may actuallye harmed or certainly not helped with the use of adjuvantRT.The incidence of positive microscopic margins (R1) was

6% in this study. An R1 resection margin was indepen-ently associated with worse OS and DFS, consistent withhe findings in several other studies.7,8,10 Although the usef adjuvant CRT improved OS in patients with R0 and R1argins in this study, this benefit was seen only in patientsith LN-positive disease. In the study from Johns Hop-ins, the use of adjuvant CRT also showed a survival ad-antage in patients with both positive and negative resec-ion margins independent of nodal status.

Despite the maturation of a number of randomized tri-ls, little improvement in overall survival or understandingf the appropriate adjuvant therapy in pancreas cancer haveaterialized.This lack of progress is not simply the result of

neffective systemic therapies, but in part, the result of poorrial design and calls for a more disciplined approach toesigning future trials.15,16 Other critical factors necessaryo improve the quality of data obtained from future studiesf adjuvant therapy include a systematic approach to theelection of patients for surgery with the use of high qualityretreatment imaging and defined radiographic criteria foresectability,17,18 and the use of a meticulous and reproduc-ble system for pathologic evaluation of resection mar-ins.18 A recent consensus conference sponsored by theociety of Surgical Oncology and the American Hepato-ancreatico-Biliary Association addressed these importantssues and this article is forthcoming. Future trials mustlso carefully define inclusion criteria and ensure betteruality control of treatment delivery, including standard-
zed surgical technique, especially for dissection along the
uperior mesenteric artery, where the majority of positiveargin resections occur.This multiinstitutional study helps to overcome many of

he limitations associated with studies exploring the role ofdjuvant CRT described earlier. It limits institutional bi-ses and evaluates large numbers of patients who had theirurgical resection at experienced, high-volume centers thatreat pancreas cancer using a multidisciplinary approach. Its, however, limited by its inherent retrospective approach.

any of the quality measures discussed earlier could not bevaluated prospectively and could not be confirmed, par-icularly for the adjuvant treatments, because many pa-ients received their treatment at facilities other than therimary institution where the surgical resection waserformed.Although no randomized trial has demonstrated the

enefit of adjuvant CRT in resected pancreas cancer, sub-tantial data exist in a large number of patients to suggesthat it may be beneficial in certain high-risk subsets ofatients (R1 resection margin and/or LN-positive disease)nd does not exclude the possibility of a therapeutic con-ribution of this treatment strategy. Our results suggest thathis benefit is limited to patients with LN-positive disease.ata also exist from our study and that of the ESPAC-1

rial to suggest that in some patients, particularly LN-egative patients, adjuvant CRT may actually be harmful.hese data emphasize the importance of determininghich subsets of patients truly benefit from this therapy

nd are not harmed by the morbidity of ineffective therapy.Future studies will need to continue to assess the benefits

f adjuvant chemotherapy and CRT and should includetratification schemes to investigate the effects of adjuvantherapy depending on resection margin status and LN sta-us. Optimal staging, standardization and quality controlf surgical technique, pathologic evaluation and treatmentelivery will also need to be key components of trial design.he design of these trials should take into account the

essons learned from previous trials so that data generatedre not flawed by the same limitations.

uthor Contributions

tudy conception and design: Merchant, Rymer, Kooby, We-ber, Schmidt, Nakeeb, Scoggins, Martin, Kim, Ahmad,Parikh

cquisition of data: Merchant, Rymer, Kooby, Weber, Schmidt,Nakeeb, Scoggins, Martin, Kim, Ahmad, Parikh, Castella-nos, Cho, Matos, Chu, McClaine, Bednarski

nalysis and interpretation of data: Merchant, Rymer, Kooby,Weber, Cho, Schmidt, Nakeeb, Scoggins, Martin, Kim,
Ahmad, Parikh, Koehler, Ayers, Staley, Sharp

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rafting of manuscript: Merchant, Rymer, Kooby, Weber,Schmidt, Nakeeb, Scoggins, Martin, Kim, Ahmad, Parikh,Castellanos, Sharp, Staley, Koehler, Ayers

ritical revision: Merchant, Kooby, Weber, Parikh, Sharp,Koehler, Ayers

EFERENCES

1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CACancer J Clin 2006;56:106–130.

2. Lim JE, Chien MW, Earle CC. Prognostic factors followingcurative resection for pancreatic adenocarcinoma: a population-based, linked database analysis of 396 patients. Ann Surg 2003;237:74–85.

3. Geer RJ, Brennan MF. Prognostic indicators for survival afterresection of pancreatic adenocarcinoma. Am J Surg 1993;165:68–73.

4. Cameron JL, Riall TS, Coleman J, et al. One thousand consec-utive pancreaticoduodenectomies. Ann Surg 2006;244:10–15.

5. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant com-bined radiation and chemotherapy following curative resection.Arch Surg 1985;120:899–903.

6. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapyand 5-fluorouracil after curative resection of cancer of the pancreasand periampullary region: phase III trial of the EORTC gastroin-testinal tract cancer cooperative group. Ann Surg 1999;230:776–782; discussion 774–782.

7. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trialof chemoradiotherapy and chemotherapy after resection of pan-creatic cancer. N Engl J Med 2004;350:1200–1210.

8. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy withgemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlledtrial. JAMA 2007;297:267–277.

9. Corsini MM, Miller RC, Haddock MG, et al. Adjuvant ra-diotherapy and chemotherapy for pancreatic carcinoma: theMayo Clinic experience (1975–2005). J Clin Oncol 2008;26:3511–3516.

0. Herman JM, Swartz MJ, Hsu CC, et al. Analysis of fluorouracil-based adjuvant chemotherapy and radiation after pancreaticoduo-denectomy for ductal adenocarcinoma of the pancreas: results of alarge, prospectively collected database at the Johns Hopkins Hospi-tal. J Clin Oncol 2008;26:3503–3510.

1. Greco J, Castaldo E, Feurer I, et al. Survival benefit with adjuvantradiation therapy in surgical resected pancreatic cancer. Paper pre-sented at: American Society of Clinical Oncology GastrointestinalCancers Symposium; January 19–21, 2007; Orlando, FL.

2. Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consec-utive pancreaticoduodenectomies in the 1990s: pathology, com-plications, and outcomes. Ann Surg 1997;226:248–257, discus-sion 257–260.

3. Greene F, Page DL, Fleming ID, et al, eds. AJCC cancer stagingmanual (edition 6). New York, NY: Springer-Verlag; 2002.

4. Yeo CJ, Abrams RA, Grochow LB, et al. Pancreaticoduodenectomyfor pancreatic adenocarcinoma: postoperative adjuvant chemora-diation improves survival. A prospective, single-institution experi-ence. Ann Surg 1997;225:621–636.

5. Wolff R, Varadhachary G, Evans D. Adjuvant therapy for ade-
nocarcinoma of the pancreas: analysis of reported trials and rec- r
ommendations for future progress. Ann Surg Oncol2008;15:2773–2786.

6. Chua YJ, Cunningham D. Adjuvant treatment for resectablepancreatic cancer. J Clin Oncol 2005;23:4532–4537.

7. Pawlik T, Laheru D, Hruban R, et al. Evaluating the impact of asingle-day multidisciplinary clinic on the management of pan-creatic cancer. Ann Surg Oncol 2008;15:2081–2088.

8. Raut CP, Tseng JF, Sun CC, et al. Impact of resection status onpattern of failure and survival after pancreaticoduodenectomyfor pancreatic adenocarcinoma. Ann Surg 2007;246:52–60.

iscussion

R CHARLES J YEO (Philadelphia, PA): I rise to congratulate Drerchant and his multi-institutional cast of coauthors for providing

s with these intriguing data on a very important topic. Very wellresented, Dr Merchant, and very, very well done.The study positives I think are quite obvious to all in the audience.

his is a multi-institutional experience with large numbers of pa-ients, very well analyzed, and it asks an important and really very,ery key question, a fundamental question in pancreas cancer, whohould receive postoperative therapy?

The study, though, does have a few negatives. It’s not randomized,o key parameters between the groups are clearly significantly differ-nt. For example, age, tumor size, margin status, and lymph nodetatus were all significantly different on univariate analyses. There’so central pathologic review of these specimens so it’s open to someuestion what the primary tumor was. Chemoradiation was notiven in a study environment, so we may very well be comparingpples to oranges, perhaps to lemons. And a high percentage ofatients are reported in this study as being lymph node negative. Iave some skepticism about that. Probably many of these lymphode negative patients are molecularly lymph node positive. So Iave four questions.First, one would imagine that disease free survival is a very soft

utcomes variable. We all review postpancreatectomy CT scans ande provide guidance, reassurance and education to our patients and

o the CT radiologists who mistake bowel loops in the right upperuadrant for tumor recurrence, et cetera. So how is disease free sur-ival defined? And was tissue confirmation required?

Question number two. Tell us more about the chemoradiationroup. I find it hard to believe that in the last few years 5 FU was therimary chemotherapeutic agent used. What percentage of these pa-ients actually saw Gemzar or gemcitabine, what percent saw two drugs,or example gemcitabine plus Xeloda, bevacizumab or erlotinib?

Third, and I think critical here, decision counseling plays a verymportant role in our assessment and in the patient advocate assess-

ent of responses to issues of therapy for postpancreatectomy pa-ients. Who should be treated with postoperative therapy? That’seally one of the questions we are being asked here.

From your data can you calculate for us the benefits of adjuvantherapy for pancreatic cancer in quality adjusted life years; ie, what’she annual cost per quality adjusted life year (QALY) in patients
eceiving such therapy? As many of you may have seen just a few