Orthovoltage intraoperative radiation therapy for pancreatic adenocarcinoma.

Abstract

To analyze the outcomes of patients from a single institution treated with surgery and orthovoltage intraoperative radiotherapy (IORT) for pancreatic adenocarcinoma.
We retrospectively reviewed 23 consecutive patients from 1990-2001 treated with IORT to 23 discrete sites with median and mean follow up of 6.5 and 21 months, respectively. Most tumors were located in the head of the pancreas (83%) and sites irradiated included: tumor bed (57%), vessels (26%), both the tumor bed/vessels (13%) and other (4%). The majority of patients (83%) had IORT at the time of their definitive surgery. Three patients had preoperative chemoradiation (13%). Orthovoltage X-rays (200-250 kVp) were employed via individually sized and beveled cone applicators. Additional mean clinical characteristics include: age 64 (range 41-81); tumor size 4 cm (range 1.4-11); and IORT dose 1106 cGy (range 600-1500). Post-operative external beam radiation (EBRT) or chemotherapy was given to 65% and 76% of the assessable patients, respectively. Outcomes measured were infield control (IFC), loco-regional control (LRC), distant metastasis free survival (DMFS), overall survival (OS) and treatment-related complications.
Kaplan-Meier (KM) 2-year IFC, LRC, DMFS and OS probabilities for the whole group were 83%, 61%, 26%, and 27%, respectively. Our cohort had three grade 3-5 complications associated with treatment (surgery and IORT).
Orthovoltage IORT following tumor reductive surgery is reasonably well tolerated and seems to confer in-field control in carefully selected patients. However, distant metastases remain the major problem for patients with pancreatic adenocarcinoma.

Full text

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RESEARCHOpen Access
Orthovoltage intraoperative radiation therapy
for pancreatic adenocarcinoma
Pavan Bachireddy1†, Diane Tseng1†, Melissa Horoschak1, Daniel T Chang1, Albert C Koong1, Daniel S Kapp1,
Phuoc T Tran2*
Abstract
Purpose: To analyze the outcomes of patients from a single institution treated with surgery and orthovoltage
intraoperative radiotherapy (IORT) for pancreatic adenocarcinoma.
Methods: We retrospectively reviewed 23 consecutive patients from 1990-2001 treated with IORT to 23 discrete
sites with median and mean follow up of 6.5 and 21 months, respectively. Most tumors were located in the head
of the pancreas (83%) and sites irradiated included: tumor bed (57%), vessels (26%), both the tumor bed/vessels
(13%) and other (4%). The majority of patients (83%) had IORT at the time of their definitive surgery. Three patients
had preoperative chemoradiation (13%). Orthovoltage X-rays (200-250 kVp) were employed via individually sized
and beveled cone applicators. Additional mean clinical characteristics include: age 64 (range 41-81); tumor size
4 cm (range 1.4-11); and IORT dose 1106 cGy (range 600-1500). Post-operative external beam radiation (EBRT) or
chemotherapy was given to 65% and 76% of the assessable patients, respectively. Outcomes measured were infield
control (IFC), loco-regional control (LRC), distant metastasis free survival (DMFS), overall survival (OS) and treatment-
related complications.
Results: Kaplan-Meier (KM) 2-year IFC, LRC, DMFS and OS probabilities for the whole group were 83%, 61%, 26%,
and 27%, respectively. Our cohort had three grade 3-5 complications associated with treatment (surgery and IORT).
Conclusions: Orthovoltage IORT following tumor reductive surgery is reasonably well tolerated and seems to
confer in-field control in carefully selected patients. However, distant metastases remain the major problem for
patients with pancreatic adenocarcinoma.
Background
Pancreatic cancer is the fourth leading cause of cancer
mortality in the United States, afflicting more than 32,000
people annually. A 5-year survival rate less than 5% high-
lights the dismal prognosis accompanying this disease [1].
The majority of patients present with locally advanced or
metastatic disease, precluding complete surgical resection.
Even the minority of patients able to achieve complete
surgical resection can only expect a 5-year survival rate of
approximately 20% [2,3]. The natural history of resected
pancreatic adenocarcinoma has led to introduction of the
use of adjuvant chemoradiotherapy regimens following
surgery [4,5]. Initial randomized trials demonstrated a sur-
vival benefit with adjuvant chemoradiation compared to
observation alone, but subsequent trials have suggested
either potential harm when compared to adjuvant che-
motherapy or lack of benefit [6-10]. However, these nega-
tive trials have been criticized for serious flaws in design
and quality control [4,11-13]. Issues with tolerance and
completion of chemoradiation regimens as well as lack of
efficacy of low doses of adjuvant radiation therapy indicate
the need to investigate dose escalation [14].
Intraoperative radiation therapy (IORT) is a specialized
modality that offers the precise delivery of a high dose of
ionizing radiation targeted to the tumor bed and regions
at risk to eliminate microscopic disease in situ while
simultaneously allowing for the displacement and protec-
tion of surrounding normal tissue from the treatment. As
a result, IORT is well suited as a technique to dose esca-
late in an attempt to increase local control from radiation
* Correspondence: tranpt21@sbcglobal.net
† Contributed equally
2Department of Radiation Oncology and Molecular Radiation Sciences, the
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University,
Baltimore, MD, USA
Full list of author information is available at the end of the article
Bachireddy et al. Radiation Oncology 2010, 5:105
http://www.ro-journal.com/content/5/1/105
© 2010 Bachireddy 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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therapy. Recent studies suggest that IORT may have a
positive impact on local control and possibly even overall
survival in patients with localized pancreatic cancer
[15-18]. The objectives of this study are to review our
experience in patients treated with surgery and orthovol-
tage IORT for pancreatic adenocarcinoma.
Methods
We conducted an institutional review board-approved
retrospective review of consecutive patients treated
between August 1993 and August 2002 with IORT and
surgery for pancreatic adenocarcinoma by the Depart-
ment of Radiation Oncology, Stanford University Medical
Center, Stanford, CA. Our cohort consisted of 23 patients
selected for IORT on the basis of tumor resectability as
well as high likelihood of local-regional recurrence.
Pretreatment evaluation included patient history; com-
plete physical examination; routine laboratory studies;
and imaging by computed tomography scan of the abdo-
men. Informed consent was obtained from all patients
before treatment.
Hospital medical records, clinic charts, and radiation
oncology records were reviewed. We updated follow-up
information in all patients within 1 month before the
present study by using examination, data from the refer-
ring physician, or direct correspondence with patients or
relatives. Follow-up for surviving patients was deter-
mined from the day of IORT.
Treatment of Patients
The majority of patients (83%) had IORT at the time of
their definitive surgery. Three patients had preoperative
chemoradiation (13%). Surgery was carried out in a dedi-
cated operative suite containing a Philips RT-250 IORT
radiation unit (Philips Medical Systems, Best, and The
Netherlands). Treatment was delivered with 200-250-
kVp orthovoltage X-rays directly over the tumor bed
and/or regions at risk including vessels via individually
sized and beveled cone applicators. Choice of half-value
layer (HVL) filters, 0.57-2.45 mm copper, was based on
consideration of dose rate (50-100 cGy/min), residual
tumor thickness and underlying tissues. For example,
when there is normal bone in the exit of the beam, higher
HVL beam (with higher kvp) was used to minimize
excess bone dose due to the contribution from the
photoelectric effect. Treatment fields were designed to
encompass a 0.5- to 1-cm margin around the tumor bed.
IORT was administered employing a series of specially
designed nickel plated brass circular cones with dia-
meters ranging from 2.5-12.5 cm and bevels of 0°, 15°,
30°, and 45°. The mean IORT dose was 1106 cGy (range
600-1500). All doses were prescribed to the surface, and
no bolus was used. Before administration of IORT, maxi-
mal efforts were made to mobilize and pack uninvolved
small and large intestines and major uninvolved nerves
or vessels out of the proposed radiation field. If this was
not possible, customized lead shielding was employed to
prevent overdosing of vital structures. IORT dose to nor-
mal bowel and major nerves was limited to ≤12.5 Gy
whenever possible. Post-operative external beam radia-
tion (EBRT) or chemotherapy was given to 65% and 75%
of the assessable patients, respectively. Post-operative
EBRT total dose ranged from 4500-5400 cGy given over
2-3 months. Chemotherapy consisted of concurrent infu-
sion of 5-fluorouracil (5-FU) with one patient receiving
both 5-FU and gemcitabine.
Follow-up
After completion of treatment, patients were evaluated
at 1, and 3- to 6-month intervals for disease status and
treatment-related complications. Routine evaluation
included physical examination, hematology and chemis-
try profiles. In general chest radiography and abdominal
CT were performed every 6 months.
Outcomes analyzed were infield control (IFC), loco-
regional control (LRC), distant metastasis free survival
(DMFS), overall survival (OS) and treatment-related
complications. Intervals were defined from day of IORT
to last follow-up or first reported site of failure or death
from cancer. Disease relapse in the IORT field was
defined as an infield failure, whereas relapse within the
compartment of IORT was defined as locoregional fail-
ure. The DMFS was defined as survival without distant
recurrence (outside the locoregional compartment), and
other events were censored. Similarly, OS was scored as
death from pancreatic cancer or, if information was
lacking, death likely from pancreatic cancer; other com-
peting causes of death were censored.
Margin status was confirmed by pathology report of
frozen/permanent sections, and if not available or non-
informative, IORT and/or surgical reports were used.
Microscopic residual disease was defined as the presence
of tumor cells at the surface of the resection margin
(0 mm definition), and thus greater than 0 mm margin
was considered negative [19]. Patients were also grouped
into R0 (gross complete resection with negative mar-
gins), R1 (gross complete resection with positive mar-
gins), and R2 (macroscopic residual disease) resections.
Complications were scored according to National
Cancer Institute Common Terminology Criteria for
Adverse Events, version 3.0. The interval for Grade 3-5
(G3-5) complications (complication-free survival [CFS])
CFS was defined as day of IORT to first reported G3-5
complication.
Statistics
Survival graphs were generated by the product limit
method of Kaplan and Meier and log-rank analysis was
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utilized for differences between proportions. Analysis
was facilitated using Prism, version 4.0, by GraphPad
(San Diego, CA).
Results
Patient Characteristics
Our cohort of 23 patients treated with IORT at 23 sites
included 12 women and 11 men. Racial distribution
included 15 Caucasians (65%), 4 Asians (17%), 1 Afri-
can-American (4%), 1 Tongan (4%), 1 Native American
(4%), and 1 not otherwise specified (4%). The majority,
18 (78%), endorsed a history of smoking; only 2 (8%)
reported extensive alcohol use. Primary sites of disease
and original stages for patients in our series were 14
patients with involvement of the pancreatic head only,
10 Stage II, 3 Stage III, 1 Stage IV and one not other-
wise specified; two involving head and uncinate process,
1 Stage II and 1 Stage III; one involving head and body,
Stage III; one involving head and tail, Stage II; 2 invol-
ving body alone, 1 Stage 1 and 1 Stage II; one involving
body and tail, Stage 1; one involving tail alone, Stage III;
and one arising at the ampulla of Vater. Two patients
had failed prior surgeries (8%), one (4%) of which had
had prior chemoradiation therapy. Preoperative CA19-9
was obtained on 14 (61%) patients, ranging from 1-2020
(median 123, mean 477). Additional pre-IORT charac-
teristics are listed in Table 1.
Surgery, IORT, and post-IORT treatment
Whipple procedure (pancreaticoduodenectomy) was per-
formed on 17 tumor sites (74%) and of these, 10 (43%)
were felt to have positive gross margins intraoperatively
(for summary see Table 2). Margin status showed that
11 sites (all 10 sites with positive gross margins and 1
with a negative gross margin) had microscopic residual
disease. Most tumors were located in the head of the
pancreas (83%) and sites irradiated included: tumor bed
(57%), vessels (26%), both the tumor bed/vessels (13%)
and other (4%). IORT was administered with a mean
dose of 11.1 Gy and median cone size of 6.25 cm.
Post-operative external beam radiation (EBRT) or che-
motherapy was given to 65% and 76% of the assessable
patients, respectively. The mean EBRT dose was 48.8 Gy,
ranging from 45-54 Gy. Of the assessable patients who
did not receive post-operative EBRT, 3 (18%) had
received prior EBRT (either neoadjuvant or subsequent
to prior surgery), two (12%) had either locally advanced
or metastatic disease discovered after surgery, and one
(6%) died from post-operative complications (intra-
abdominal hemorrhage). Two patients that had neoadju-
vant chemoradiation (8%) resulted in measurable
responses.
Outcomes analysis and complications
Median and mean follow-up of patients was 6.5 and 21
months, respectively. At the time of analysis, 1 out of 16
assessable patients (6%) was alive, and 1 (6%) died from
postoperative complications. Kaplan-Meier (KM) 2-year
IFC, LRC, DMFS and OS probabilities for the whole
group were 83%, 61%, 26%, and 27%, respectively (Fig-
ure 1). Our cohort had three G3-5 complications asso-
ciated with treatment (surgery and IORT) translating
into a 2-yr KM G3-5 complication free survival (CFS) of
68%. The G3-5 complications included myocardial
infarction [post-operative day (POD) 6], death from
intraabdominal hemorrhage (POD 0), neutropenic fever
and sepsis (two months post-operative).
Discussion
We present our analysis of a consecutive series of
patients with pancreatic adenocarcinoma treated with
surgery and orthovoltage IORT. The 2-year LRC (61%)
and 2-year OS (27%) in our series of patients are consis-
tent with previously published series for this historically
poor prognostic group of patients [10,16]. We have
found that surgery combined with IORT followed by
adjuvant chemoradiation seems to improve local control
of the tumor, although this may not have necessarily
translated into a survival benefit.
The largest single center retrospective cohort study of
203 pancreatic adenocarcinoma patients examined the
clinical effectiveness of IORT after surgical resection and
found that there was a significant survival benefit in addi-
tion to improved local control rates in localized pancrea-
tic cancer [15]; however, the improvement in survival has
not been consistent among other studies and may be
applicable only to patients with localized disease. In other
retrospective studies, it appears that addition of IORT
may provide a slight overall survival benefit of 1-2
months in the subset of patients with localized pancreatic
cancer [17]. The survival benefit and impact of local con-
trol of IORT in pancreatic adenocarcioma has been
addressed in an older prospective randomized clinical
trial, but the sample size was likely too small to ade-
quately address the question of benefit [20]. The only
other prospective clinical trial published involving IORT
Table 1 Patient characteristics prior to IORT (n = 23)
Age, mean, years (range)
Prior surgery, n (%)
Prior radiotherapy, n (%)
Prior systemic therapy, n (%)
Tumor size, mean, cm (range)
Primary site, n (%):
65 (41-81)
2 (9)
3 (13)
4 (17)
4.1 (1.4-11)
14 (61)
4 (17)
5 (22)
Head of pancreas
Head and uncinate/body/tail
Other*
* - Ampulla of Vater (1), body (2), body and tail (1), tail (1).
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for pancreatic cancer was designed to test the efficacy of
a radiosensitizing drug; even then, the question in the
study was not focused on the clinical benefit of IORT
[21]. While it is difficult to compare between retrospec-
tive series, our data appear consistent with the other
reported studies [17].
Residual disease following pancreatic cancer surgery is
an important prognostic factor [2,3]. The benefit of
IORT is likely from improved local control particularly
on minimal-microscopic disease that remains following
resection. We did not find residual disease status, R0,
R1 or R2, to be an important determinant of IFC, LRC
or OS in our study (data not shown). This may reflect
the already highly selected population in our series,
small cohort size and/or cohort heterogeneity.
Intraoperative orthovoltage units are less commonly
used than either mobile or non-mobile linear accelera-
tors, which deliver electron beams [22]. The use of
intraoperative orthovoltage RT has been previously
described and the dosimetric properties of a unit similar
to the one used in our study characterized [23,24].
While the steepness of the fall-off of dose with depth is
slower than that for electron beams as reviewed pre-
viously [25], our unit provides flexible access to localiza-
tions deep in the abdomen, which would be more
difficult to treat intraoperatively with linear accelerators.
Moreover, the initial costs, shielding requirements, and
maintenance of orthovoltage units are less than those of
linear accelerators.
The limitations of our retrospective series of IORT for
pancreatic adenocarcinoma are inherent in all retrospec-
tive clinical study designs. These include, but are not lim-
ited to, selection bias, recall bias, heterogeneity of patients
and a small number of patients. In addition, the 10-year
time span over which our cohort was collected might have
allowed for confounding factors associated with improve-
ments with diagnosis, surgical technique, and treatment.
Our study of post-IORT outcomes may include a biased
patient population with even more advanced disease who
are not typical candidates for surgery because of Stanford’s
surgical expertise and experience with pancreaticoduode-
nectomies. In our series, 7/23 (30%) of our patients had
either stage III or stage IV disease and 11/23 (48%) had
gross and/or microscopic residual disease following pan-
creaticoduodenectomy. However, if anything, this would
have biased our results toward poorer outcomes compared
to other studies. Because retrospective data is hypothesis
generating at best, we fully endorse efforts toward larger
randomized clinical trials using IORT, such as the efforts
of the International Society of Intraoperative Radiotherapy
(see http://www.isiort.org)
In our cohort, we observed a 2-yr KM G3-5 complica-
tion free survival of 68%. The complications included
Figure 1 Outcomes of patients treated with orthovoltage IORT.
Kaplan-Meier (KM) plot of the entire cohort for infield control (IFC),
loco-regional control (LRC), distant metastasis free survival (DMFS) and
overall survival (OS). Twenty-three patients were treated with surgery
and IORT.
Table 2 Treatment characteristics
Type of surgery, n (%):Pancreaticoduodenectomy (Whipple)
Distal pancreatectomy
Other*
R2
R1
R0
17 (74)
2 (9)
4 (17)
8 (35)
6 (26)
9 (39)
6.25 (5-10)
11.1 (6-15)
12.1 (6-15)
11 (8-12)
10.3 (8-12)
11 (65)
49 (45-54)
13 (76)
Resection status, n (%):
IORT cone size, median cm (range)
R0-R2, mean (range)
R2, mean (range)
R1, mean (range)
R0, mean (range)
External beam radiotherapy, n (%)
XRT dose, mean, Gy (range)
Systemic therapy**, n (%)
IORT dose, Gy
Post-IORT Treatment:
* - resection of recurrence (1), surgical bypass (roux-en-y) (2), cholecystecomy/gastrojejunostomy/choledochojejunostomy (1).
** - 5-fluorouracil +/- gemcitabine.
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myocardial infarction, death from intraabdominal hemor-
rhage, neutropenic fever, and sepsis. The intraabdominal
hemorrhage was unlikely to be from the IORT as the
source of the bleeding was clearly outside of the treat-
ment field. These other peri-operative complications are
not likely from IORT alone, however, it is not clear
whether or not these complications are a result of the
surgery itself or if there is a possible contribution of
IORT to these complications. Pancreaticoduodenec-
tomies by themselves are large operations that place dra-
matic stress on the cardiovascular system, predispose the
patient to infection, and place them at risk for intraab-
dominal bleed due to the rich vasculature at the surgical
site. In most of the previous studies of IORT for pancrea-
tic adenocarcinoma, IORT does not increase the risks
associated with surgery [26-28]. In addition a recent
multi-institutional case series, which had the largest sam-
ple of patients treated with IORT to date, observed a low
frequency of adverse late events after IORT [29] (3%).
These were late grade 3-4 gastrointestinal events com-
prised of colitis, ileus and bleeding.
Finally, for the benefits in local control rates to trans-
late into improvements in survival will require further
improvements in systemic therapy. Retrospective studies
supporting this notion have recently been published
[29-31].
The addition of IORT to cytoreductive surgery requires
the balance of the potential for improved local control
and survival enhancement with the risk for added toxi-
city. IORT for pancreatic adenocarcinoma has the poten-
tial to improve LRC and clinical outcomes for patients
with advanced disease and residual local tumor following
surgery.
Conclusions
Orthovoltage IORT following tumor reductive surgery is
reasonably well tolerated and seems to confer in-field
control in carefully selected patients. Distant metastases
remain the major problem for patients with pancreatic
adenocarcinoma.
Conflicts of interest Notification
The authors declare that they have no competing
interests.
Acknowledgements
PTT was a recipient of a Henry S. Kaplan Research Fellow award (SUMC
grant 1046297-100-KAVWO).
Author details
1Department of Radiation Oncology, Stanford Cancer Center, Stanford
University, Stanford, CA, USA.2Department of Radiation Oncology and
Molecular Radiation Sciences, the Sidney Kimmel Comprehensive Cancer
Center, Johns Hopkins University, Baltimore, MD, USA.
Authors’ contributions
PB and DT carried out the clinical review required in the study, analyzed the
data and drafted the manuscript. MH helped to carry out the clinical review
required in the study. DC and AK participated in the review of the drafted
manuscript. DSK and PT conceived of the study, participated in its design,
performed the analysis and coordinated and helped to draft the manuscript.
All authors read and approved the final manuscript.
Received: 18 August 2010 Accepted: 8 November 2010
Published: 8 November 2010
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