Aggressive local treatment containing intraoperative radiation therapy (IORT) for patients with isolated local recurrences of pancreatic cancer: a retrospective analysis.

Abstract

To evaluate the use of intraoperative radiation therapy (IORT) in the multimodality treatment of patients with isolated local recurrences of pancreatic cancer.
We retrospectively analyzed 36 patients with isolated local recurrences of pancreatic cancer who have been treated with a combination of surgery, IORT and EBRT. Median time from initial treatment to recurrence was 20 months. All patients were surgically explored. In 18 patients a gross total resection was achieved, whereas the other half received only debulking or no resection at all. All patients received IORT with a median dose of 15 Gy. Additional EBRT was applied to 31 patients with a median dose of 45 Gy, combined with concurrent, mainly gemcitabine-based chemotherapy.
Median follow-up in surviving patients was 23 months. Local progression was found in 6 patients after a median time of 17 months, resulting in estimated 1- and 2-year local control rates of 91% and 67%, respectively. Distant failure was observed in 23 patients, mainly in liver or peritoneal space. The median estimated progression-free survival was 9 months with 1- and 2-year rates of 40% and 26%, respectively. We found an encouraging estimated median overall survival of 19 months, transferring into 1- and 2-year rates of 66% and 45%. Notably 6 of 36 patients (17%) lived for more than 3 years. Severe postoperative complications were found in 3 and chemoradiation-related grade III toxicity in 6 patients. No severe IORT related toxicity was observed.
Combination of surgery, IORT and EBRT in patients with isolated local recurrences of pancreatic cancer resulted in encouraging local control and overall survival in our cohort with acceptable toxicity. Our approach seems to be superior to palliative chemotherapy or chemoradiation alone and should be further investigated in a prospective setting specifically addressing isolated local recurrences of pancreatic cancer.

Full text

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RESEARCH ARTICLEOpen Access
Aggressive local treatment containing
intraoperative radiation therapy (IORT) for
patients with isolated local recurrences of
pancreatic cancer: a retrospective analysis
Falk Roeder1,2*, Carmen Timke1, Matthias Uhl1, Gregor Habl1, Frank W Hensley1, Markus W Buechler3,
Robert Krempien4, Peter E Huber1,2, Juergen Debus1,2†and Jens Werner3†
Abstract
Background: To evaluate the use of intraoperative radiation therapy (IORT) in the multimodality treatment of
patients with isolated local recurrences of pancreatic cancer.
Methods: We retrospectively analyzed 36 patients with isolated local recurrences of pancreatic cancer who have
been treated with a combination of surgery, IORT and EBRT. Median time from initial treatment to recurrence was
20 months. All patients were surgically explored. In 18 patients a gross total resection was achieved, whereas the
other half received only debulking or no resection at all. All patients received IORT with a median dose of 15 Gy.
Additional EBRT was applied to 31 patients with a median dose of 45 Gy, combined with concurrent, mainly
gemcitabine-based chemotherapy.
Results: Median follow-up in surviving patients was 23 months. Local progression was found in 6 patients after a
median time of 17 months, resulting in estimated 1- and 2-year local control rates of 91% and 67%, respectively.
Distant failure was observed in 23 patients, mainly in liver or peritoneal space. The median estimated progression-
free survival was 9 months with 1- and 2-year rates of 40% and 26%, respectively. We found an encouraging
estimated median overall survival of 19 months, transferring into 1- and 2-year rates of 66% and 45%. Notably 6 of
36 patients (17%) lived for more than 3 years. Severe postoperative complications were found in 3 and
chemoradiation-related grade III toxicity in 6 patients. No severe IORT related toxicity was observed.
Conclusion: Combination of surgery, IORT and EBRT in patients with isolated local recurrences of pancreatic cancer
resulted in encouraging local control and overall survival in our cohort with acceptable toxicity. Our approach
seems to be superior to palliative chemotherapy or chemoradiation alone and should be further investigated in a
prospective setting specifically addressing isolated local recurrences of pancreatic cancer.
Keywords: Pancreatic cancer, Isolated local recurrence, IORT
* Correspondence: F.Roeder@dkfz.de
†Equal contributors
1Clinical Cooperation Unit Radiation Oncology, German Cancer Research
Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
2Department of Radiation Oncology, University of Heidelberg, Heidelberg,
Germany
Full list of author information is available at the end of the article
© 2012 Roeder et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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Background
Pancreatic cancer is the fourth leading cause of cancer-
related death in western countries [1]. Only about 15-20
% of the patients are diagnosed in resectable stages [2].
In Europe, the standard of care for those patients con-
sists of surgery followed by adjuvant chemotherapy [3].
But despite some improvements in overall survival by
adding adjuvant chemotherapy [4], the vast majority of
the patients still develops an incurable treatment failure.
While in most patients the overall outcome is limited by
the development of distant metastasis or combined
locoregional and distant failure, about 10-35% of
patients will develop an isolated local recurrence without
evidence for distant spread after curative intended sur-
gery [4, 5]. While surgical resection is the only potential
curative treatment approach for pancreatic cancer, and
although an isolated local recurrence represents a poten-
tially curable situation, the majority of these patients will
be treated with palliative chemotherapy or chemoradia-
tion alone. This raises the question, if a more aggressive
local therapy could be beneficial at least for some of
these patients. We therefore retrospectively reviewed
our patients with isolated local recurrences of pancreatic
cancer after primary resection, who have been treated at
our institution with a more aggressive approach consist-
ing of surgery, IORT and EBRT.
Methods
We identified a total of 42 patients with isolated local
recurrences of pancreatic cancer in the database of the
University of Heidelberg, who have been treated with
IORT between 2002 and 2009. Thirty-six of these
patients met the premise of a curative intended treat-
ment, which was defined as surgery without gross re-
sidual disease + IORT regardless of additional EBRT, or
IORT + EBRT regardless of gross residual disease. These
patients formed the basis of current analysis.
The majority of patients were male and median age at
first diagnosis was 62 years. The primary treatment in all
patients included surgery without macroscopic residual
disease. The histological subtype was adeno-carcinoma
except in three patients. The majority of patients suf-
fered from locally advanced tumors (T3; n=29), located
in the pancreatic head (n=29) and showed positive
nodal disease (n=21). The most frequent surgical
approaches were Whipple´s procedures (n=27). About
two thirds of the patients received adjuvant chemother-
apy, mainly gemcitabine-based (82%). None of the
patients received chemoradiation in their primary treat-
ment course. For detailed patient and treatment charac-
teristics in primary situation see Table 1.
Local recurrence was identified by the appearance of
clinical symptoms, a growing mass on repeated CT or
MRI during regular follow up with a parallel increase of
tumor markers or a positive PET-Scan in case of nega-
tive tumor markers. After diagnosis of a local recur-
rence, all patients were restaged with at least chest and
abdominal CT to exclude distant metastasis. The median
time interval between primary treatment and local re-
currence was 20 months (range 6 to 76 months).
All patients were surgically explored and at least biop-
sied. In 18 patients a gross total resection was achieved,
whereas the other half received only a tumor debulking
or no resection at all, resulting in gross residual disease.
IORT was applied to all patients either to the tumor bed
or the region of gross residual disease with a median
dose of 15 Gy, using a median electron energy of 8 MeV
and a median cone size of 6 cm.
The technique of intraoperative radiation therapy used
at the University of Heidelberg has already been
described [6, 7]. In brief, IORT was performed in a dedi-
cated surgical theatre with an integrated Siemens Meva-
tron ME linear accelerator (Siemens, Concord, USA)
capable of delivering 6-18 MeV electrons and thus cov-
ering a depth up to 6 cm. After the surgical procedure,
an applicator of appropriate size was chosen to encom-
pass the target area which was defined in correspond-
ence with the treating surgeon. The applicator was
manually positioned and attached to the table. Unin-
volved radiosensitive tissues like small bowel were dis-
placed or covered by lead shielding. The applicator was
aligned with the linear accelerator using a laser guided
air-docking system. The IORT dose was prescribed to
90% isodose, which covered the gross residual disease or
the region of suspicious surgical margins with a safety
margin of 1 cm.
After staging, 25 patients were judged at least border-
line resectable and scheduled for surgery, IORT and
postoperative chemoradiation. Of these, 5 patients did
not receive postoperative EBRT because of complica-
tions or patients refusal (see Figure 1). The remaining 11
patients were initially judged as not resectable, but
responded to neoadjuvant chemoradiation and were
scheduled for surgical exploration and IORT (see
Figure 1).
EBRT was performed by linear accelerators using 3D-
conformal or intensity-modulated techniques. Patients
were treated in supine position using multiple field tech-
niques. The target volume included the gross tumor vol-
ume or the surgical tumor bed with a safety margin of
1-2 cm. No elective nodal irradiation was performed.
The median EBRT dose was 45 Gy (range 39.6 to
59.4 Gy), applied in conventional fractionation (1.8-2 Gy
per fraction, 5 fractions a week). EBRT was combined
with concurrent chemotherapy, usually gemcitabine
weekly (300 mg/sm), except in one patient. For detailed
patient and treatment characteristics for recurrence see
Table 2.
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Regular follow up visits took place either at our institu-
tion or at the referring center, including at least clinical
examination and abdominal CT scans every three months
for the first year after treatment. In case of Ca 19-9 in-
crease or clinical evidence for local re-recurrence or dis-
tant spread, additional tests or imaging modalities were
performed to confirm or exclude disease progression at
the discretion of the treating physician. Acute toxicity was
scored according to CTCAE V3.0, late toxicity was scored
according to RTOG criteria. In case of missing follow-up
examinations, data was completed by calling the patient
or the treating physician. Time to event data was calcu-
lated from the first day of radiation treatment until the last
follow up information or until death. Local control was
defined as absence of tumor regrowth in the region of the
treated recurrence on repeated CT or MRI scans. Local
control (LC), Progression-free-survival and Overall Sur-
vival (OS) were calculated using the Kaplan-Meier
method. In patients without further assessment of local
control e.g. after development of distant spread, the date
of the last information about the local status was used for
calculation Differences in subgroups were tested for statis-
tical significance by the log rank test. Differences were
considered statistically significant for a p-value of ≤0.05.
The study is in compliance with the Declaration of
Helsinki (Sixth Revision, 2008). Furthermore our study
was approved by the Independent Ethics Committee of
the Medical Faculty Heidelberg (ref. nr.: S-491/2010).
Results
The median follow up for the entire cohort was 16 months
and 23 months in surviving patients. Considering surgery,
the gross total resection rate for the entire cohort was
50%. Of the 11 patients receiving neoadjuvant chemora-
diation, gross total resection was achieved in 7 patients
(64%). Of the 25 patients scheduled for upfront surgery,
gross complete resection was achieved in 11 patients
(44%), whereas 6 patients suffered from localized macro-
scopic residual disease (R2-situation) and in 6 patients no
resection was possible at all. The difference in gross total
resection rate after neoadjuvant treatment compared to
upfront surgery was not statistically significant.
Local control
Local recurrence/progression was observed in 6 patients
(17%) after a median time of 17 months (range 7-
Table 1 Primary disease and treatment characteristics
Primary disease and treatment characteristics
n%
age at FD
median62
min35
max 75
gender
male2569
female11 31
histology
adeno-ca33 92
other38
localisation
head2981
body4 11
tail38
surgery
pp-whipple 2056
whipple7 19
left resection5 14
total pancreatectomy4 11
resection margin
R0 21 58
R16 17
unknown9 25
pT stage
pT26 17
pT329 81
unknown13
pN stage
pN01439
pN121 58
unknown13
pTNM stage
T2N038
T2N138
T3N0 1131
T3N11850
unknown13
adj. chemotherapy
yes2364
no1336
Gem1878
Gem/Cis14
Table 1 Primary disease and treatment characteristics
(Continued)
5-FU/LV29
5-FU/FA29
FD: first diagnosis, age [years], pp-whipple: pylorus-preserving whipple
procedure, adj.: adjuvant, Gem: Gemcitabine, Cis: Cisplatin, 5-FU: 5-
Fluororuracil, LV: Leucovorin, FA: Folinic Acid.
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25 months). The resulting estimated 1- and 2-year local
control rates were 91% and 67%, respectively (Figure 2).
Local recurrence was isolated in one patient, followed by
subsequent distant failure in one patient and accompan-
ied by synchroneous distant failure in 4 patients. All
patients with a local re-recurrence have died, except one
with an isolated local recurrence who remained stable
with palliative chemotherapy until the last follow up
visit. In univariate analysis, none of the tested prognos-
tics factors (resection margin gross total vs. gross re-
sidual, schedule of EBRT neoadjuvant vs. adjuvant, age,
gender, time to recurrence, adjuvant chemotherapy) had
a significant impact on local control.
Distant failure and progression-free survival
Distant failure was observed in 23 patients after a me-
dian time of 7 months (range 1-25 months). The first
site of distant failure was liver and peritoneal space in 7
patients respectively, followed by lung in 4 patients,
supraclavicular nodes in one patient and combinations
of these locations in 4 patients. Overall disease progres-
sion was detected in 24 patients, resulting in an esti-
mated median progression-free survival of 9 months.
The estimated 1- and 2-year rates of progression-free
survival were 40% and 26%, respectively (Figure 3). None
of the tested prognostic factors ((resection margin gross
total vs. gross residual, schedule of EBRT neoadjuvant
vs. adjuvant, age, gender, time to recurrence, adjuvant
chemotherapy)showeda
progression-free survival in univariate analysis, however
a trend to improved progression-free survival was
observed in female patients (p=0.058).
significantimpacton
Overall survival
Considering overall survival, a total of 22 deaths have
been observed. The estimated median overall survival
for the entire cohort was 19 months. The estimated 1-
and 2-year rates of overall survival were 66% and 45%,
respectively (Figure 4). Notably, 6 of the 36 (17%)
patients lived for more than 3 years. At univariate ana-
lysis, none of the tested prognostic factors (resection
margin gross total vs. gross residual, schedule of EBRT
neoadjuvant vs. adjuvant, age, gender, time to recur-
rence, adjuvant chemotherapy) showed a significant in-
fluence on overall survival.
Toxicity
Severe postoperative complications were observed in three
patients (8%). Two patients developed intraabdominal ab-
scess formations which resolved after re-intervention. One
patient developed a perforating gastric ulcer 10 days after
surgery followed by hemorrhagic peritonitis and conse-
quently died after multiple surgical revisions, accounting
for a 90-day mortality rate of 3% for the entire cohort.
Minor postoperative complications, mainly wound healing
disturbances and infections, were seen in 6 patients. No
acute or late side effects directly related to IORT were
found. Accurate data on acute toxicity during external
beam radiotherapy was available in 24 of the 31 patients
including complete blood cell counts for the whole treat-
ment time in 20 of them. A total of 8 grade 3 toxicities
were observed in 6 patients, mainly as gastrointestinal
(nausea, vomiting, diarrhea) and hematologic side effects
(see Table 3). Considering late toxicity we found severe
gastrointestinal side effects in terms of diarrhea and ab-
dominal spasms in two patients.
neoadj. EBRT
OP + IORT
gross total: 11
gross residual: 14
OP + IORT
gross total: 7
gross residual: 4
adj. EBRT
n=20
n=11 n=25
no EBRT
n=5
Figure 1 Treatment schedule. OP: operation, neoadj. : neoadjuvant, adj. : adjuvant, EBRT : external beam radiation therapy, IORT : intraoperative
radiation therapy.
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Discussion
Pancreatic cancer remains one of the diseases with the
worst prognosis in oncology [2]. According to stage at
presentation, patients are usually divided into three
groups: resectable disease (~20%), locally advanced dis-
ease (~40%) and metastatic disease (~40%) [2]. Even in
the most favourable group of patients with resectable
cancer, the 5-year overall survival is limited to about
20% [4], and the vast majority of these patients still
develops an incurable treatment failure, mainly distant
metastasis. However, in 10-35% of the patients an iso-
lated local recurrence without evidence for distant
spread occurs [4, 5]. Although an isolated local recur-
rence represents a potentially curable situation, little
interest has been paid to specifically address this situ-
ation, no generally accepted standard treatment exists,
and a special follow-up for patients after resection of
pancreatic cancer is not recommended by international
guidelines. Consequently these patients are treated
within a variety of concepts initially developed for differ-
ent stages of primary pancreatic cancer, ranging from ag-
gressive surgical approaches as in primary resectable
disease stages or chemoradiation as in locally advanced
pancreatic cancer to palliative chemotherapy as in meta-
static situations. However, there are some arguments for
addressing this situation as a specific stage of disease. In
our cohort, the median time to local recurrence from
primary treatment was 20 months. In contrast to pri-
mary resectable pancreatic cancer, these patients did ob-
viously not develop early distant metastasis, which is a
common feature after curative intended surgery. For ex-
ample, in the Conco-001 trial [4], which addressed the
issue of adjuvant chemotherapy in resectable primary
pancreatic cancer, the median disease-free survival in the
experimental arm was only 13 months, mainly due to
early distant failure, while local recurrence was observed
only in about 20% of the patients. In contrast to meta-
static disease, these patients could rationally benefit
from a local treatment component as they suffer from a
locoregional confined situation. Although they share
some features with LAPC patients like aggressive local
invasion into adjacent structures, they differ to some
Table 2 Recurrent disease and treatment characteristics
Recurrent disease and treatment characteristics
n%
age at rec.
median64
min37
max76
time to rec.
median20
min6
max76
surgery
gross total18 50
gross residual6 17
Explo. lap.1233
IORT dose
median15
min10
max15
IORT energy
median8
min6
max 18
IORT cone
median6
min5
max13
EBRT
neoadj RT1131
adj. RT 2056
no RT514
EBRT dose
median45
min39,6
max 59,4
EBRT technique
3D 2997
IMRT27
conc. CHT
yes30 97
no 13
Gem2583
Gem/Cis13
5-FU27
Table 2 Recurrent disease and treatment characteristics
(Continued)
5-FU/LV13
5-FU/Cis13
Rec.: recurrence, age [years], time to rec. [months], explo. Lap.: explorative
laparotomy, IORT: intraoperative radiation therapy EBRT: external beam
radiation therapy, neoadj.: neoadjuvant, 3D: three-dimensional CT-based
conformal treatment, IMRT: intensity-modulated radiation therapy, all
radiotherapy doses [Gy], conc.: concurrent, CHT: chemotherapy, Gem:
Gemcitabine, Cis: Cisplatin, 5-FU: 5-Fluorouracil, LV: Leucovorin, Ox: Oxaliplatin,
Erl: Erlotinib, Cap: Capecitabine, FA: Folinic Acid, Mito: Mitomycin C, Cet:
Cetuximab.
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extent from this patient group as they have already been
exposed to surgery and frequently chemotherapy. There-
fore, it seems reasonable to assume (at least to some ex-
tend) a different disease biology in these patients, and to
specifically address this situation as a unique stage of
disease.
To our knowledge, our cohort represents one of the
largest series published in peer reviewed literature that
specifically addresses the treatment and outcome for iso-
lated local recurrences of pancreatic cancer. With our
treatment approach which includes radical surgery,
IORT and chemoradiation, we observed encouraging
rates of local control, disease-free survival and overall
survival with acceptable toxicity. Notably, 6 of our 36
patients lived for more than 3 years and the estimated
median survival of 19 months after the treatment of
local recurrencefoundin
favourable with the results published by other groups
addressing LAPC (which seems to be the best available
benchmark in the absence of randomized trials or larger
cohort series specifically addressing isolated local recur-
rences). Using chemotherapy alone, modern phase III
trials consistently reported median overall survival rates
of only 9 to 10 months [8–10] for LAPC and about 6 to
8 months for metastatic disease [10–12]. The evaluation
of chemoradiation approaches within modern phase II
and III trials resulted in improved locoregional control
our analysis compares
rates but only in slightly improved median overall sur-
vival rates of 11 to 12 months [8, 13–15], although some
single center studies reported median overall survival
rates of 17-19 months due to intensification of treatment
[16–18].
Similar to primary pancreatic cancer, long term sur-
vival is hardly imaginable in patients with isolated local
recurrences without the achievement of locoregional
control. But even in resectable primary pancreatic can-
cer, local recurrences occur in up to 75% of the patients
based on autopsy findings due to the always narrow
and often positive margins [5]. Adjuvant chemoradia-
tion using fractionated external beam radiation therapy
(EBRT) has proven to reduce local recurrence rates
compared to chemotherapy alone regardless of its con-
flictingly reported influence on overall survival [19].
However, the dose that can be safely applied with exter-
nal beam radiotherapy is limited due to the tolerance of
surrounding structures at risk, mainly small bowel. Even
with the use of intensity-modulated therapy (IMRT),
doses beyond 60 Gy, which are potentially needed to
sterilize at least microscopic residual disease [20], can
hardly be achieved without unacceptable toxicity. Espe-
cially surrounding bowel structures cannot be adae-
quately spared due to the narrow anatomical relations
and the intra- and interfractional movements. There-
fore, other radiation techniques, namely stereotactic
Time [months]
0 2040 6080
Probability
0,0
0,2
0,4
0,6
0,8
1,0
Figure 2 Local control.
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radiosurgery (RS) and intraoperative radiation therapy
(IORT) have been investigated as sole treatment or as
boost techniques in combination with EBRT to achieve
further dose escalation in LAPC. Notably, most of these
trials also included small numbers of isolated local
recurrences, but subgroup analyses were not available
[21–23]. In the initial experience with RS published by
the Stanford group, RS resulted in excellent short term
local control rates (80-100%), but did not improve me-
dian survival (median OS 8-11 months) compared to
fractionated chemoradiation and raised some concerns
about late toxicity of high single doses in the pancreatic
region [21, 22]. However, Mahadevan et al. [23] recently
reported a series of 36 patients with unresectable pan-
creatic cancer treated with 3 fractions of stereotactic
radiotherapy up to total doses of 24-36 Gy followed by
gemcitabine using an adaptive tolerance-based dose pre-
scription approach dependent on the distance of the
target to duodenal structures. After a median follow-up
of 24 months, a local control rate of 78% with a median
disease-free survival of 9 and a median overall survival
of 14 months was found [23].
In our study, we observed comparable results (local
control 83%) using intraoperative radiation therapy
(IORT) as a boosting strategy in combination with max-
imal surgery and moderate doses of external beam radio-
therapy to overcome the dose limitations mentioned
above. In contrast to all external radiation therapy tech-
niques, IORT enables the unique opportunity of dis-
placing organs at risk from the irradiation field by
simple removal during the surgical intervention. Further
on, the target area is defined and treated under visual
control, which minimizes the risk of a geographic miss
and no additional safety margins are needed to compen-
sate for interfraction movements. Although the applic-
ability of the linear-quadratic model for high single
doses as used in IORT has been questioned to some ex-
tend [24], it can be assumed from clinical and experi-
mental data that a combination of 15 Gy IORT boost
with 45 Gy EBRT dose as used in our study is biologic-
ally equivalent to ≥70 Gy EBRT in conventional fraction-
ation [25]. The translation of dose escalation into
improved local control found in our study has also been
reported by other investigators using IORT in locally
advanced unresectable pancreatic cancer: For example,
Garton et al. [26] found 1- and 2-year local control rates
of 86% and 68% and a median overall survival of
15 months in a series of 51 patients with unresectable
pancreatic cancer treated with neoadjuvant EBRT fol-
lowed by IORT. Roldan et al [27] compared patients
with locally advanced pancreatic cancer scheduled either
for IORT+EBRT or EBRT alone and observed a signifi-
cant advantage in local control in favour of the IORT
group. Mohiuddin et al. [28] found a local control rate
Time [months]
0 2040 60 80
Probability
0,0
0,2
0,4
0,6
0,8
1,0
Figure 3 Progression-free survival.
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of 69% with a median overall survival of 16 months in
49 patients with unresectable pancreatic cancer treated
by IORT and postoperative chemoradiation followed by
maintenance chemotherapy. Moreover, Willett et al. [29]
reported a median survival of 13 months in a large series
of 150 patients with unresectable pancreatic cancer trea-
ted with a combination of IORT and EBRT. These and
our results compare favourable with approaches of che-
moradiation or chemotherapy alone in terms of local
control and strengthen the value of locally controlled
disease for overall survival as supported by a recent
pooled analysis on behalf of the International Society of
Intraoperative Radiation Therapy (ISIORT) in Europe
[30]. This described a prolonged survival in resectable
pancreatic cancer patients who remained free of local
recurrence for more than two years after surgery and
IORT (5-years OS 28%) compared to those who failed
locally (5-year OS 0%).
However, beside the encouraging local control rate
found in our series, distant failure occurred in the ma-
jority of patients. In contrast to primary pancreatic can-
cer, the value of adjuvant chemotherapy after resection
of a local recurrence or the use of additional chemother-
apy after chemoradiation has not been clearly estab-
lished. Therefore, only a minority of our patients
received additional chemotherapy directly after comple-
tion of local treatment at the discretion of the treating
medical oncologist. Given the known advantages of adju-
vant chemotherapy in terms of disease-free and overall
survival after gross total resection of primary pancreatic
cancer [4], additional adjuvant systemic therapy might
be beneficial also after local treatment of an isolated
local recurrence. This should be evaluated, although a
recent retrospective analysis by Baschnagel et al. [31]
failed to show a benefit from additional systemic therapy
after postoperative chemoradiation in primary pancreatic
cancer cases. The possible value of additional systemic
therapy seems to be further supported by the fact, that
those studies which report encouraging results with che-
moradiation for locally advanced pancreatic cancer, add-
itional or maintenance chemotherapy was used after
completion of local therapy [13, 15].
Time [months]
0 20406080
Probability
0,0
0,2
0,4
0,6
0,8
1,0
Figure 4 Overall survival.
Table 3 Acute toxicity during chemoradiation
Acute Toxicity during Chemoradiation
all gradesgrade 3
nausea73
diarrhea91
anemia 171
leukopenia 162
thrombopenia61
other30
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Another issue in pancreatic cancer is treatment toxicity.
In our study, we observed a 90-day postoperative mortal-
ity rate of 3% (1 patient). Severe postoperative complica-
tionswerefound in8%
gastrointestinal (GI) grade III toxicities attributable to che-
moradiation were observed in 10% and grade III
hematological toxicities in 20% of the evaluable patients.
No severe IORT related toxicity was found. These figures
compare favorable with data from the literature. Calvo
et al. [32] reported 33% grade III GI-toxicity and 6% se-
vere hematological toxicity with neoadjuvant chemoradia-
tion+IORT. Aristu et al. [33] observed 12% severe
gastrointestinal and 16% hematological toxicity during
neoadjuvant chemoradiation followed by IORT in unre-
sectable cases. IORT can be safely applied in patients with
pancreatic cancer without an increase of postoperative
morbidity or mortality compared to surgery alone as
shown by Reni et al. [34] in a comparative series of 203
patients. Considering toxicity of external beam chemora-
diation, it has to be emphasized, that severe toxicity is
closely associated with the radiation technique and the
irradiated volume. If modern radiation techniques are
used, and the radiation fields are restricted to the gross
tumor volume with small safety margins, the incidence of
severe GI-toxicity appears to be much lower than in previ-
ous trials using elective nodal irradiation as well. A recent
EORTC trial comparing chemotherapy with gemcitabine
mono versus concurrent chemoradiation with gemcitabine
in the adjuvant setting of pancreatic cancer observed no
significant difference in toxicity between the treatment
arms [19].
of the patients.Acute
Conclusion
In summary, to our knowledge this analysis represents
the largest series published in peer-reviewed literature
dealing exclusively with the treatment and outcome of
isolated local recurrences of pancreatic cancer using
IORT. Given the retrospective nature of our study, con-
clusions should be drawn with caution. However, aggres-
sive local treatment including surgery, IORT and
chemoradiation resulted in encouraging local control,
median overall survival and a substantial proportion of
long term survivors in our cohort with acceptable tox-
icity. Given the high rates of distant failure, the use of
additional systemic therapy after completion of local
treatment should be discussed. Nevertheless, the results
with our treatment approach seem to be superior to pal-
liative chemotherapy or chemoradiation alone and
should be further tested in a prospective setting specific-
ally addressing isolated local recurrences of pancreatic
cancer.
Competing of interest
The authors declare that they have no conflicts of interest.
Author details
1Clinical Cooperation Unit Radiation Oncology, German Cancer Research
Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
2Department of Radiation Oncology, University of Heidelberg, Heidelberg,
Germany.3Department of Surgery, University of Heidelberg, Heidelberg,
Germany.4Department of Radiation Oncology, Helios Clinic, Berlin, Germany.
Authors contributions
FR planned the analysis, participated in data acquisition, data analysis,
literature review, patient treatment, and drafted the manuscript. CT, MU, GH,
FWH, RK, PH, MWB participated in data aquisition, data analysis, literature
review and patient treatment. JD and JW participated in planning of the
analysis, patient treatment, manuscript draft and revised the manuscript
critically. All authors read and approved the final manuscript.
Received: 3 April 2012 Accepted: 18 July 2012
Published: 18 July 2012
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doi:10.1186/1471-2407-12-295
Cite this article as: Roeder et al.: Aggressive local treatment containing
intraoperative radiation therapy (IORT) for patients with isolated local
recurrences of pancreatic cancer: a retrospective analysis. BMC Cancer
2012 12:295.
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