Int. 1. Radiation Oncology Bid. Phys.. Vol 9, pp. 911-915 03~3016/83/060911~5503.00/0 Printed in the U.S.A. All rights rcscrvcd. Copyright 0 1983 Pergamon Press Ltd.

??Brief Communication

CURATIVE SURGERY FOR ADENOCARCINOMA OF THE PANCREAS/AMPULLA OF VATER: THE ROLE OF ADJUVANT PRE OR

POSTOPERATIVE RADIATION THERAPY

GENE KOPELSON, M.D.

Assistant Professor, Dept. of Therapeutic Radiology, Tufts University School of Medicine and Tufts-New England Medical Center, Boston MA 02111

From 1972 to 1981, 7 patients received a&vast external beam radiation therapy before (5 patients) or after (2 patients) a curative Whipple operation for adenocarcinoma of the pancreas (5 patients) or ampulla of Vater (2 patients). Via supervoltage, 4000-4520 rad/20-25 fractions/4-5 l/2 weeks were delivered to the tumor ked and draining lymphatics. Two patients (of 4 at risk) are Syear survivors; 3 are alive-without-disease at 1-2 years follow-up. Distant metastases have developed to date in 3 patients. A marginal miss occurred at the edge of a radiation portal in 1 patient, and no true in-field failures have occurred. Complications occurred in 2 patients. Because of the high incidence of local-regional failures after curative surgery alone for adenocarcinoma of the pancreas or ampulla of Vater, the above results suggest that adjuvant radiation therapy should he considered as a modality to potentially improve treatment results.

INTRODUCTION

Even after potentially curative surgery (i.e., Whipple operation or total pancreatectomy), 5-year survival rates for patients who survive the operation with adenocarci- noma of the pancreas or ampulla of Vater range from 3-18s 1.6.11.16.17 and 6_39%,‘0.” respectively. There has been little attention in the literature to the sites of tumor recurrence after radical surgery alone. Yet several recent analyses from the Massachusetts General Hospital found a high incidence of post-operative local-regional recur- rences for adenocarcinomas of the pancreas’ and ampulla of Vater.* Radiation therapy is a' regional modality in which postoperative adjuvant irradiation used after cura- tive surgery has been able to sterilize subclinical disease in ~90% of cases for adenocarcinomas of the rectum- rectosigmoid,7*9 sigmoid colon,’ uterus,’ ovary,‘* breast,” and lung.*

Thus the analogy to pancreatic adenocarcinoma is clear, and the present review was undertaken to assess the efficacy of the Whipple procedure coupled with adjuvant radiation therapy in an attempt to decrease the high regional recurrence rate after surgery alone and perhaps to improve survival.

METHODS AND MATERIALS

From 1972 to 1981, 7 patients at the Department of Therapeutic Radiology of the Tufts-New England Medi- cal Center received adjuvant radiation therapy pre- or

post-operatively in conjunction with a Whipple operation for adenocarcinoma of the pancreas or ampulla of Vater. Patients with initially unresectable disease were excluded as were those patients who were given preoperative irra- diation in an attempt to convert the lesion to being resectable.14 Patients with gross residual or microscopic residual (i.e., positive margins) disease are excluded, as are patients with potentially-resectable lesions in whom medical contraindications precluded radical surgery and in whom radical irradiation was given.

There were 4 women and 3 men; their age at diagnosis ranged from 45-72 years (median 57). Each patient had an adenocarcinoma (cystadenocarcinomas were ex- cluded). A summary of the clinical courses appear in Tables 1 and 2.

Of the 5 patients irradiated preoperatively (Table l), initial exploration revealed small-to-moderate sized lesions of the pancreatic head or ampulla of Vater. There was no radiographic nor palpable evidence of vessel fixation or other evidence of surgical unresectability. The one initially un-explored patient had small adenocarci- noma of the ampulla of Vater diagnosed at endoscopic retrograde cholangio-pancreatography (although at final pathology the origin of the tumor was felt to be in the pancreatic head). Biliary-enteric anastamoses were accomplished, and the patients were then irradiated prior to definitive surgery.

Supervoltage (@‘Co-l patient, 45MV X rays-4

Reprint requests to: Dr. G. Kopelson, Dept: of Radiation Oncology, Salem Hospital, 81 Highland Ave., Salem, MA 01970. Acknowledgements-The author would like to thank Mindy

and Barry Printz-Kopelson for their help in the preparation of this manuscript.

Accepted for publication 20 January 1983.

911

Tabl

e 1.

Pre

oper

ativ

e ad

juva

nt

radi

atio

n th

erap

y

Pt. n

o.

Site

Initi

al e

xplo

ratio

n R

adia

tion

deta

ils

Size

/Ext

ent

PKX

XdU

r~

Fiel

ds

Rad

/Fxn

/El

da

ys

Rad

iatio

n-&

post

Surg

ery

inte

rval

R

adia

tion

cour

se

Path

olog

y

Tum

or

Nod

es

Com

plic

atio

ns

Surv

ival

Fa

ilure

site

(s)

I P

3.5

x 4

cm;

inv

Ch-

J A

P-PA

44

00/2

2/30

4.

5 w

k.

“Tum

or s

hrun

k”

No

chan

ge (

mod

. diff

. N

eg.

Obs

truct

ed

Ch-

J: b

iliar

y-cc

- 8m

Pe

riton

eal

duod

enum

, C

BD

ad

encc

a)

Ioni

c fis

tula

se

edin

g 2

P 4x

5cm

C

h-J

AP-

PA

4500

/23/

39

3 w

k.

No

Cha

nge

Ung

rade

d ad

enoc

a.

Neg

. N

one

ly2m

Li

ver

3 P

4x6c

m

Chd

-J

4-fie

ld

4500

/25/

35

6.5

wk.

“M

arke

d 1”

N

o re

sidu

al t

umor

N

eg.

Non

e sly

3m

Non

e (p

rior

poor

ly d

iff.

aden

oca.

) 4

P’

“waln

ut”

Non

e*

AP-

PA

4ooo

/20/

26

4 w

k.

“Mar

ked

1”

Wel

l diff

. ade

noca

. N

eg.

Smal

l bo

wel

obs

truct

ion;

7y

3m

Mar

gina

l [C

hd-J

,G-J

] m

argi

nal

stom

ach

ulce

r re

curr

ence

5

AV

3c

m

Chd

-J,

G-J

A

P-PA

40

00/2

0/26

5

wk.

N

o C

hang

e M

od d

iff. a

deno

ca.

Neg

. N

one

sgy7

m

Non

e

P -

Panc

reas

; A

V -

A

mpu

lla o

f V

ater

; A

denc

ca.

- A

deno

carc

inom

a;

CL-

J -

Cho

lecy

stoj

ejun

osto

my;

C

hd-J

-

Cho

ledo

choj

ejun

osto

my;

H

pJ

- H

epat

iwje

juno

stom

y;

G-J

-

Gas

troje

jum

stom

y;

AP-

PA

_ A

nter

ior-

Post

erio

r pa

ralle

l-opp

c6ed

; >

- pa

tient

stil

l aliv

e.

*Dia

gnos

is m

ade

endo

scop

ical

ly;

tum

or f

elt t

o ar

ise

in p

ancr

eas

at f

inal

pat

holo

gy

(see

text

).

Tabl

e 2.

Pos

tope

rativ

e ad

juva

nt

radi

atio

n th

erap

y

Initi

al s

urge

ry

Rad

iatio

n de

tails

Su

rger

y-to

-radi

atio

n Pt

. no.

Si

te

Proc

edur

es

Size

/Ext

ent

Nod

es

Gra

de

inte

rval

Fi

elds

R

ad/F

sn/E

l da

ys

Com

plic

atio

ns

Surv

ival

Fa

ilure

site

s

6 P

HpJ

G

-J

2 cm

/inv.

pe

ripan

crea

tic

fat,

116

Pas.

Wel

l dilT

. 2.

5 m

o.

AP-

PA

4500

/25/

40

Non

e =-

2Y

Non

e du

oden

um a

nd p

ylor

ic

aden

oca.

sp

hinc

ter

7 A

V

Chd

-J G

-J

Inv.

hea

d pa

ncre

as a

nd

Neg

. M

od. d

itT.

2 m

o.

AP-

PA

4520

/24/

36

Non

e >l

Y

Non

e du

oden

um

adcn

oca.

Sam

e ab

brev

iatio

ns a

s in

Tab

le I

.

Surgery for adenocarcinoma of pancreas/ampulla of vater 0 G. KOPELSON 913

patients) was used to irradiate the primary tumor (in the ampulla, or in the pancreati’c head), areas of probable microscopic involvement such as pancreatic body and draining pancreaticoduodenal, celiac axis, and porta hepatis lymph nodes. The pancreatic tail, splenic hilum, and the lateral suprapancreatic nodes were not included because of efforts to maximize sparing of left renal parenchyma. Irradiation dose-time factors appear in Table 1. At the subsequent Whipple procedure (Table l), there was marked tumor shrinkage noted in 3/5 patients. Fibrosis causing a lengthy operation was found in one patient in whom there was a 6.5 week interval between the end of irradiation and surgery. All patients irradiated preoperatively had negative lymph nodes at final patholo- gY*

For the 2 patients irradiated postoperatively (Table 2), similar field sizes and doses were used as described above and in Table 1.

No patient received adjuvant chemotherapy. Survival was calculated from date of surgery.

RESULTS

Of 4 patients at risk, 2 were 5-year survivors. The 3 other patients are alive without disease at l-2 years follow-up. Distant disease developed in Patients No. 1, 2, and 4. There were no true in-field post-irradiation recur- rences, although a marginal miss occurred in Patient No. 4 (Fig. 1). One of 4 patients irradiated preoperatively for carcinoma of the pancreas (No. 3) showed no residual tumor.

Two patients to date have experienced complications. In Patient No. 1, the cholecystojejunostomy became obstructed postoperatively necessitating revision; unfor- tunately shortly thereafter a biliary-colonic fistula devel- oped and the patient died. No patient died of complica- tions resulting from the initial surgical procedures. In Patient No. 4, subsequent small bowel obstruction neces- sitated lysis of adhesions, and a marginal stomach ulcer was managed successfully conservatively. Thus the known complication rate to date is 2 of 7.

Fig. 1. Patient No. 4 was treated preoperatively to the tumor bed and draining lymphatics via AP-PA portals with 45MV X rays. The rectangular simulation field is outlined in wire. Seven years later (after the post-irradiation Whipple procedure), left ureteral obstruction developed. The right kidney was nonfunctional on intravenous pyelogram and renal scan (consistent with chronic radiation changes because of its inclusion within the portal). At exploration, a large recurrent biopsy-proven tumor was found at the junction of the left ureter, left renal vein, and para-aortic region (small white arrowhead) which was located at the edge of the prior portal. Antegrade pyelogram (superimposed upon the prior radiation simulator film) reveals the distal extent of recurrent tumor (large arrowhead). Although the liver and pancreatic remnant were free of tumor, she died 3 months later of the recurrence.

914 Radiation Oncology 0 Biology ??Physics June 1983, Volume 9, Number 6

DISCUSSION Although there has been much discussion in the litera-

ture as to the intent of surgery (i.e., curative vs palliative) and the choice of operation (i.e., Whipple procedure vs total pancreatectomy vs bypass alone) for patients with apparently localized carcinoma of the pancreas/periam- pullary region,‘*6~“*‘6~‘7 overall survival remains extremely poor as noted in the Introduction.

For carcinomas of the pancreas, at the Massachusetts General Hospital Tepper et ~1.‘~ found a minimum local regional failure rate of 50% after curative surgery, which was unrelated to tumor size or nodal involvement. In a series from Memorial Hospital, approximately ‘/3 of patients had positive regional nodes (microscopically) beyond the resected area (e.g., peripancreatic nodes around the pancreatic body), which were potentially encompassable within a regional irradiation fie1d.3 Simi- larly, investigators from the Peter Bent Brigham Hospital found similar microscopic involvement of the common duct or body or tail of the pancreas.” In the Memorial series, lesions of the pancreatic head (locations which are usually considered for a Whipple procedure) did not appear to involve peripancreatic nodes located at the pancreatic tail.

of the Whipple procedure. Indeed, the one anastamotic complication (Patient No. 1) [a similar incidence to surgery-alone series ‘*6*‘o*“~‘6*‘7] suggests that biliary- enteric or enteroenteric or gastro-enteric anastamoses may be constructed successfully after preoperative irra- diation and may tolerate postoperative irradiation to 4500 rad. The extensive fibrosis which was found at surgery (performed 6.5 weeks after preoperative irradiation) in Patient No. 3 suggest that a 4-5 week interval might be preferred.

Although survival results are better for lesions of the ampulla of Vater after curvative surgery,“,” at the Mas- sachusetts Genera1 Hospital, Kopelson et al.” found a 57% local-regional failure rate at that institution after curative surgery alone, and an even higher rate of 80% from 4 other series in the literature that had reported sites of postoperative recurrences.

The present series suggests that by the inclusion in a radiation portal of the tumor bed and draining unresected lymphatic regions (porta hepatis, celiac axis, peripan- creatic, some pancreaticoduodenal), that no in-field regional recurrences have occurred to date compared to a much higher incidence that would have been anticipated from the above surgery-alone series.‘0*‘6 The 5-year sur- vival of 2 of 4 patients at risk is encouraging. However, the occurrence of one marginal miss (Fig. 1) suggests that a more generous infero-lateral border to encompass more of the pancreatic body/tail (while maximizing left renal sparing) might be done in the future, possibly with shaped multiple fields as described by Shipley et al.” and Gun- derson.’

The relative advantages and disadvantages of preoper- ative vs postoperative adjuvant irradiation in this setting are discussed by Tepper et ~1.‘~ Practically, to avoid a second exploration, postoperative irradiation would be the most commonly used sequence. There is very sparse data on such adjuvant irradiation in pancreas/peri-ampullary carcinomas. In a follow-up series from the Massachusetts Genera1 Hospital, Shipley et al.” reported on 10 patients who had a Whipple procedure, 9 of whom survived the operation. Of this latter group of 9, 6 did not have adjuvant postoperative irradiation and 4/6 developed local-regional failure (confirming the prior report from the same hospital by Tepper et a1.16). Of the 3 postopera- tive survivors who received postoperative adjuvant irra- diation, ‘/J failed local-regionally, although the authors did not state whether this was a marginal recurrence or in-field failure. Nguyen et ~1.‘~ reported a small series of patients with carcinoma of the pancreas or ampulla of Vater who were irradiated primarily (9 patients) or adjuvantly after a Whipple procedure (9 patients). Although the median survival for the latter postoperative patients was 13 months for lesions of the head of the pancreas and was 17 months for lesions of the ampulla, unfortunately, detailed results of sites of failure and complications were not described for those patients irra- diated adjuvantly postoperatively (i.e. after the Whipple operation).

The relatively low complication rate and 0% peri- operative mortality rate (Patient No. 1 died after a second operation) are certainly comparable to surgery-alone series,‘*6*‘0v”*‘6*‘7 which have spanned this time period. In fact the data in Tables l-2 suggest that 4500 rad/ 180-200 rad fractions to the upper abdomen can be potentially well-tolerated, even when added to the rigors

It should be emphasized that the present study is a small, nonrandomized, retrospective analysis. The con- tinuing occurrence of distant failures suggests that adju- vant chemotherapy may be another alternative modality to improve results of surgery-alone series, or that com- bined adjuvant chemotherapy-radiation therapy be con- sidered. The point of the present paper is to suggest no increased patient morbidity/mortality when adjuvant external beam irradiation is added to a Whipple opera- tion, and that improved regional disease control rates and survival may occur also. These findings deserve consider- ation for a prospective randomized study; the Gastroin- testinal Tumor Study Group did such a study although results have not been published to date.

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