Prognostic Factors in Patients With Unresectable
Locally Advanced Pancreatic Adenocarcinoma
Treated With Chemoradiation
Sunil Krishnan, MD1
Vishal Rana, MD1
Nora A. Janjan, MD, MPSA1
James L. Abbruzzese, MD2
Morris S. Gould, MPAS1
Prajnan Das, MD, MS, MPH1
Marc E. Delclos, MD1
Shana Palla, MS3
Sushovan Guha, MD, PhD4
Gauri Varadhachary, MD2
Douglas B. Evans, MD5
Robert A. Wolff, MD2
Christopher H. Crane, MD1
1Department of Radiation Oncology, The Univer-
sity of Texas, M. D. Anderson Cancer Center,
2Department of Gastrointestinal Medical Oncol-
ogy, The University of Texas, M. D. Anderson
Cancer Center, Houston, Texas.
3Department of Biostatistics and Applied Mathe-
matics, The University of Texas, M. D. Anderson
Cancer Center, Houston, Texas.
4Department of Gastrointestinal Medicine and
Nutrition, The University of Texas, M. D. Anderson
Cancer Center, Houston, Texas.
5Department of Surgical Oncology, The Univer-
sity of Texas, M. D. Anderson Cancer Center,
BACKGROUND. Although patients with locally advanced pancreatic cancer (LAPC)
have an extremely poor prognosis, they are a heterogeneous group. Prognostic
factors are inadequately defined for disease-free survival and overall survival in
patients with LAPC who are receiving chemoradiation, so more definitive prog-
nostic factors would be very useful for designing clinical trials.
METHODS. Between December 1993 and July 2005, 247 patients with nonmeta-
static LAPC were treated at M. D. Anderson Cancer Center (Houston, Tex) with
concurrent chemoradiation (CRT). Median radiation dose was 30 Gy (range, 15–
52.2 Gy). Radiosensitizers included 5-fluorouracil (54%), gemcitabine (33%), and
capecitabine (13%). Actuarial univariate and multivariate statistical methods were
used to determine significant prognostic factors for disease-free survival and
RESULTS. Median follow-up was 4.3 months (range, 1–63 months). Median dis-
ease-free survival and overall survival were 4.2 months and 8.5 months,
respectively. On univariate analysis, prognostic factors for improved disease-
free survival were a Karnofsky performance scale (KPS) status of >80 (P <.01)
and a hemoglobin (Hgb)level at presentation of ?12 (P ¼.03). On multivariate
analysis, KPS was the only independent prognostic factor for disease-free sur-
vival. Median disease-free survival was 4.9 months among patients with a KPS
score of >80 and was 3.9 months among those with a KPS score of ?80. On
univariate analysis, prognostic factors for improved overall survival were an
Hgb level of ?12 (P ¼.02), KPS>80 (P < .001), and <5% weight loss (P ¼.03).
On multivariate analysis, Hgb and KPS were independent prognostic factors
for overall survival.
CONCLUSIONS. In the current study, KPS score was an independent prognostic fac-
tor for disease-free and overall survival among patients treated with chemoradiation
for LAPC. The pretreatment Hgb level was an additional independent prognostic
factor for overall survival. Cancer 2006;107:2589–96. ? 2006 American Cancer
KEYWORDS: locally advanced, pancreatic cancer, prognostic factors, chemoradia-
in western countries.1In 2006, estimates are that 33,730 new cases
of pancreatic cancer will be diagnosed and a roughly equal number
of deaths will be attributed to pancreatic cancer in the United
States.2Unfortunately, <10% of patients are eligible for a margin-
negative surgical resection, the only potentially curative treatment
ancreatic cancer is the third most common gastrointestinal
malignancy and the fifth leading cause of cancer-related death
Address for reprints: Sunil Krishnan, MD, Depart-
ment of Radiation Oncology, The University of
Texas M. D. Anderson Cancer Center, 1515 Hol-
combe Boulevard, Houston, TX 77030-4009; Fax:
(713) 563-2366; E-mail: skrishnan@mdanderson.
Received August 7, 2006; revision received
September 13, 2006; accepted October 2, 2006.
ª2006 American Cancer Society
Published online 2 November 2006 in Wiley InterScience (www.interscience.wiley.com).
for pancreatic cancer, which confers a 15% to 25%
rate of 5-year overall survival.3About two-thirds of
all pancreatic cancer patients have radiographically
detectable metastatic disease at presentation, and
the remaining patients have locally advanced unre-
sectable disease.4Typically in the United States,
standard treatment for locally advanced pancreatic
cancer consists of a combination of chemotherapy
and radiation therapy, but the integration of these
modalities and their respective dose schedules vary
Treatment with radiation therapy, with or without
chemotherapy, has not been prospectively compared
with best supportive care in a randomized study. Early
randomized trials by the Gastrointestinal Trials Study
Group (GITSG) have demonstrated that combining
chemotherapy and radiation therapy is more effective
than chemotherapy or radiotherapy alone.5,6These
trials used bolus 5-fluorouracil (5FU) chemotherapy
and split-course radiation therapy, which could be
considered suboptimal. Combined modality regimens
nearly double the median survival over radiation ther-
apy alone and marginally improve median survival
over chemotherapy alone. In contrast to these studies,
an Eastern Cooperative Oncology Group randomized
study that compared 5FU chemotherapy with com-
bined modality therapy showed no difference in me-
dian survival between the 2 groups, although toxicities
were significantly higher in the chemoradiation group.7
Other chemotherapy regimens used during this period
included streptozocin, mitomycin, methyl lomustine,
and doxorubicin.6,8None of these agents was shown to
be superior to 5FU. Since then, the promising antitu-
mor activity of gemcitabine in locally advanced and
metastatic pancreatic cancer and its potential for radio-
sensitization have led to renewed interest in combining
newer agents with radiation therapy.9–14In all of these
studies, no clear stratification of the cohort of treated
patients into low-risk and high-risk groups based on
pretreatment patient-specific and tumor-specific vari-
ables was performed.
The prognostic factors for pancreatic cancer de-
scribed in literature include performance status, car-
bohydrate antigen 19-9 (Ca 19-9) level, C-reactive
protein levels, and the degree of anaplasia.7,15–17There
are insufficient data on prognostic factors in patients
with unresectable pancreatic cancer who receive che-
moradiation as definitive therapy. To our knowledge,
there are only 2 small studies that discuss prognostic
factors in this population.7,15The current study was
undertaken to identify potential prognostic factors and
their relative contribution to survival in a large cohort
of locally advanced pancreatic cancer patients who
were treated with chemoradiation therapy. The current
study represents the largest cohort of unresectable
pancreatic cancer patients treated with concurrent
chemoradiation therapy with mature follow-up.
MATERIALS AND METHODS
Patient Identification and Selection
Between December 1993 and July 2005, 370 consecu-
tive patients received chemoradiation therapy for
locally advanced pancreatic cancer initially deemed
unresectable for cure at M. D. Anderson Cancer Center.
Of these patients, 76 received systemic gemcitabine-
based chemotherapy before they received chemoradia-
tion therapy. Forty-seven patients received concurrent
chemotherapy on protocol with bevacizumab. The
remaining 247 patients received chemoradiation with
either fluoropyrimidine-based or gemcitabine-based
chemotherapy as their initial and primary treatment
modality. To avoid the potential confounding impact
of either bevacizumab or the use of chemotherapy
before chemoradiation, this group of patients was
selected for analysis. The University of Texas M. D.
Anderson Cancer Center Institutional Review Board
approved this retrospective study. All rules and regula-
tion of the Health Insurance Portability and Account-
ability Act (HIPAA) were strictly followed during the
execution of this study.
Pretreatment evaluation included a complete history
and physical examination, biopsy, endoscopic retro-
grade cholangiopancreaticography (ERCP), dedicated
pancreatic cancer protocol abdominal and pelvic com-
puted tomography (CT 3-phase contrast-enhanced
thin-slice helical scan), and chest x-ray. Complete lab-
oratory tests included a full blood count, blood elec-
trolytes, creatinine, urea, liver transaminases, alkaline
phosphatase, and total bilirubin. Routine laparoscopy
was not performed. The treating physician(s) prospec-
tively recorded Karnofsky performance scale (KPS) status
and weight loss before therapy. A dedicated multidisci-
plinary team, including a medical oncologist and a
radiation oncologist, evaluated all patients; selected
patients were seen by surgical oncologists. Patients
were discussed at a weekly multidisciplinary confer-
ence. Tumors that extended to the celiac axis or the
superior mesenteric artery or tumors that occluded the
superior mesenteric (SMV)-portal venous confluence
were deemed locally advanced and unresectable based
on review of CT images. Tumors involving only the
SMV were deemed potentially resectable at our institu-
tion and, therefore, excluded from the current study.
Biopsy or cytology confirmation of diagnosis was
required for treatment in all patients. Patients who had
2590 CANCER December 1, 2006 / Volume 107 / Number 11
diagnostic pathology performed outside of M. D.
Anderson Cancer Center had their pathology findings
reviewed at our institution.
Among a total of 247 patients, there were 144 (58%)
men and 103 (42%) women. Median age was 64 years
(range, 39–85 years). Patient characteristics are sum-
marized in Table 1.
Treatment characteristics are summarized in Table 2.
Radiation therapy was administered by using mega-
voltage x-rays. Most (82%) patients received radiation
therapy that used a 4-field conformal technique. Other
techniques that were used included 2-field (15%), 3-field
(2%). Treatment volumes were nodal in most patients
(87%), and local fields (gross tumor volume with
margin) were used for the remaining patients. Most
(89%) patients received 30 Gy of radiation therapy in
2 weeks (range, 15–52.2 Gy). Concurrent chemother-
apy consisted of 5FU (n ¼ 133, 54%), gemcitabine
(n ¼ 81, 33%), and capecitabine (n ¼ 33, 13%). 5FU
was administered as a protracted venous infusion at a
dose of 300 mg/m2daily Monday through Friday. Gem-
citabine was administered at a dose of 350–400 mg/m2
infused over 30 minutes weekly for 7 weeks starting 24
hours to 48 hours after the first radiation dose. Capeci-
tabine was given at a dose of 800–900 mg/m2in divided
doses twice daily during the days when radiation ther-
apy was administered.
Chemotherapy dose adjustments were based on pre-
viously published criteria.18All patients were evaluated
every week during treatment, and all adverse effects
were monitored and recorded. Complete blood counts
and blood chemistries were obtained weekly during
Change in bowel pattern
% Weight loss
No. indicates number of patients; CEA, carcinoembryonic antigen; CA 19-9, carbohydrate antigen 19-
9; % Weight loss, percentage weight loss in 3 months before presentation; KPS, Karnofsky perform-
ance scale status.
* Where numbers do not add to 247, there were insufficient data for remaining patients.
Tumor and Treatment Characteristics
Characteristic No. (%)
30 Gy in 10 fractions
50.4 Gy in 28 fractions
Tumor size (area axial CT scan)
5FU indicates 5-fluorouracil; Gy, Gray(s); CT, computed tomography.
* Three patients who received a radiation dosage of 45 Gy and 1 who received 52.2 Gy were grouped
with the 50.4 Gy group. Seven patients who received 33 Gy and 1 patient who received 15 Gy were
grouped with the 30 Gy group.
Prognostic Factors For Pancreatic Cancer/Krishnan et al.2591
Patients were scheduled for follow-up visits with a
medical or radiation oncologist every 3–4 months.
Abdominopelvic CT scans and chest x-rays were per-
formed at these visits to monitor diseases status. Ther-
apy was individualized at the time of progression.
Various factors selected for investigation were chosen
on the basis of previously published reports.15,19–21In
addition, routine demographic, patient-specific, tumor-
specific, and treatment-specific variables were ana-
lyzed. Demographic variables included age, sex, and
Karnofsky performance scale score (KPS > 80 versus
KPS ? 80), pretreatment hemoglobin and bilirubin
levels, and weight loss >5% in 3 months before presen-
tation. Hemoglobin was analyzed as a continuous
variable and by dichotomizing at the median value of
12 g/dL. Bilirubin was analyzed as a continuous vari-
able and by dichotomizing at the traditional normal
level of 1 g/dL. We had insufficient data on tumor size,
tumor differentiation, and tumor markers including
Ca 19-9, CEA, and Ca125. We believed that the retro-
spective analysis of the presence or absence of various
presenting symptoms (including jaundice, anorexia,
nausea, abdominal and/or back pain, and fatigue) was
not sufficiently robust or necessarily biologically plau-
sible enough to warrant inclusion in our study of pot-
ential prognostic factors. We did analyze treatment-
specific factors and included radiation dose and the
type of chemotherapy given concurrently with radiation
The major endpoints of this study were overall survival
and disease-free survival. We also analyzed local recur-
rence (defined as any recurrence at or adjacent to the
initial primary site as determined by CT scans), lymph
node recurrence (any recurrence in the regional lymph
nodes on CT imaging), and metastatic recurrence.
Severe toxicity was defined as treatment-related toxicity
that resulted in hospitalization for supportive care for
>5 days; symptomatic gastrointestinal bleeding with
endoscopic evidence of gastric or duodenal ulceration
or with resultant transfusion; more than 3-dose dele-
tions during the planned 7 weekly gemcitabine infu-
sions; or treatment-related toxicity
surgical intervention or that resulted in death.18
Duration of overall survival was calculated in months
from the first day of radiation treatment to the time of
death or censorship. Survival time was censored at the
time of the last follow-up on record if death was not
observed. Disease-free survival time was censored at
the date of the last follow-up on record if no recur-
rences were observed, and death was not observed.
Dates of local and distant failure were determined by
using imaging studies, primarily abdominopelvic CT
scans. The significance of differences in proportions
was calculated with a chi-square test, and the differ-
ences in means with a Student t test.
Survival probabilities were estimated nonparame-
trically by using the Kaplan-Meier product-limit me-
thod.22Prospectively selected prognostic factors were
investigated by univariate and multivariate analyses.
Each variable identified as statistically significant on
univariate analysis was used in the multivariate model.
Comparisons between groups for overall survival and
disease-free survival were performed with a log-rank
test.23Cox proportional hazards modeling was used to
examine the effect of various prognostic factors on over-
all survival and time to local progression depending
upon results of the univariate analysis.24All tests were 2-
Median time from diagnosis to start of treatment was
0.6 months. The median clinical and radiographic fol-
low-up time was 4.3 months (range, 1–63 months).
Most (227 of 247, 92%) patients were deceased at the
time of this analysis. Median follow-up was 5.3 months
among the 20 survivors (range, 1–63 months).
Tumor and treatment characteristics are summarized
in Table 2. The median actuarial overall survival was
8.5 months (range, 1–78 months; Fig. 1). Estimated
rates of overall survival at the end of 1 year and 2 years
FIGURE 1. Overall survival and disease-free survival (Kaplan?Meier survival
2592 CANCER December 1, 2006 / Volume 107 / Number 11
were 25% and 8%, respectively. Median disease-free
survival was 4.2 months (range, 1–63 months) from the
start of radiation therapy (Fig. 1). Median time to local
failure was 6.0 months (range, 1–63 months), and me-
dian time to distant failure was 5.7 months (range, 1–
63 months). At the time of analysis, 227 patients had
died; 223 deaths were due to primary cancer, and 4
deaths were due to other causes. Seven (3%) patients
were able to undergo margin-negative resection after
chemoradiation therapy for pancreatic cancer that was
initially considered unresectable. These patients had a
median overall survival of 29.4 months (range, 5.6–63
months) and a median disease-free survival of 24.2
months (range, 5.6–63 months). At the time of analysis,
4 patients were alive.
Twenty-two (27%) of 81 patients treated with gemci-
tabine and 10 (8%) of 133 patients treated with 5FU
had severe acute toxicity (P ? .001). Only 1 patient
treated with capecitabine (Xeloda) had severe toxicity
and required total parenteral nutrition for intractable
nausea and vomiting. Among 10 patients treated
with 5FU, 8 had to be admitted for supportive care,
and 2 had gastrointestinal bleeding. The patients with
severe toxicity due to gemcitabine included 4 patients
with gastrointestinal bleeding and 14 patients ad-
mitted for management of intractable nausea and
vomiting, 3 of whom also had grade 3 hematologic tox-
icity. Eight patients treated with gemcitabine had grade
3 hematologic toxicity.
Table 3 provides results of the univariate analysis of
all factors considered to be prognostic for survival
outcomes. On univariate analysis, the prognostic fac-
tors for improved overall survival were Hgb ? 12
(P ¼.02; Fig. 2), KPS > 80 (P <.001; Fig. 3), and <5%
weight loss in the preceding 3 months (P ¼.03). The
significant prognostic factors for disease-free survival
were KPS > 80 (P < .01; Fig. 4) and Hgb ? 12
(P ¼.03). In particular, the concurrent chemotherapy
regimen had no impact on survival outcomes.
On multivariate analysis, Hgb<12 (hazard ratio [HR] ¼
1.48, P ¼.03) and KPS ? 80 (HR ¼ 1.55, P <.01) were
independent prognostic factors for overall survival.
Patients with a pretreatment Hgb of <12 had a median
overall survival of 7.3 months compared with 9.0
months for those with Hgb of ?12 (Fig. 2). Median
overall survival was 10.3 months among patients with
KPS > 80 and 7.6 months among those with KPS ? 80
(Fig. 3). On multivariate analysis (Table 4), KPS was the
only independent prognostic factor for disease-free
survival. Median disease-free survival was 4.9 months
among patients with KPS > 80 and 3.9 months among
those with KPS ? 80 (Fig. 4).
Univariate Analysis of Prognostic Factors for Outcomes
OutcomesP Hazard ratio (CI)
<5% Weight loss
CI indicates 95% confidence interval; KPS, Karnofsky performance scale score; Hgb, hemoglobin
FIGURE 2. Overall survival and hemoglobin (Hgb) level.
FIGURE 3. Overall survival and Karnofsky performance scale score.
Prognostic Factors For Pancreatic Cancer/Krishnan et al.2593
Pretreatment patient-related and tumor-related char-
acteristics that are prognostic for overall survival and
disease-free survival can be identified in patients
with locally advanced pancreatic cancer who are
treated with chemoradiation therapy. Our analysis
suggests that the KPS score and the pretreatment he-
moglobin level are independent prognostic factors
for overall survival, while KPS alone is an independ-
ent prognostic factor for disease-free survival.
A handful of small previous reports7,15,16,20,25–27
have evaluated prognostic factors that determine out-
come in patients with unresectable pancreatic cancer
(Table 5). Many of these studies included patients with
metastatic pancreatic cancer in addition to unresect-
able nonmetastatic pancreatic cancer. Only 1 of these
studies identified prognostic factors for disease-free
survival.7Performance status is the only prognostic
factor that is consistently shown to influence overall
survival in definitively treated patients. No definitive
prognostic factors for disease-free survival have been
consistently identified. Compared with the 2 studies
that evaluated prognostic factors in unresectable
patients receiving definitive chemoradiation as treat-
ment,7,15our study additionally showed that the pre-
treatment Hgb level was prognostic for overall survival.
The precise significance of the pretreatment Hgb level
is not immediately apparent. The fact that it merely
influenced overall survival and not disease-free sur-
vival would suggest that patients died of other causes.
However, only 4 patients died of causes other than
their primary cancer. It is possible that pretreatment
Hgb level is a partial surrogate for KPS. All the same,
these results would suggest that pretreatment Hgb
level may be factored into the determination of addi-
tional statistical endpoints (such as disease-free sur-
vival) for comparison in future prospective cancer
clinical trials. In addition, it may be worthwhile to ana-
lyze differences in pretreatment Hgb level between
trials when comparing outcomes of treatment groups
across clinical trials. Admittedly, this approach cannot
be used as a surrogate for prospective randomized
KPS score has been a recognized prognostic factor
for treatment outcomes in multiple cancers treated
with chemoradiation therapy with definitive intent.28–30
This may be due to the inherent aggressiveness of
tumors in patients with poorer KPS scores, increased
disease burden among these patients, or inability and/
or unwillingness of these patients to receive all pre-
scribed treatment. Similarly, Hgb level is a known prog-
nostic factor for treatment outcomes in other cancer,
such as cervical cancer, breast cancer, and head and
neck cancer.31–33Anemia related to malignancy is a
poorly understood phenomenon, and it is not immedi-
ately evident that correction of this anemia by using
growth factors reverses the poor prognosis conferred
by anemia. A few recent trials have shown that correc-
tion of anemia by using recombinant erythropoietin
has led to poorer outcomes.34,35Nevertheless in our
analysis, identification of anemia as a predictive factor
for overall survival further corroborates the hypothesis
that hemoglobin level has profound influences on
patient and tumor outcomes.
As with most retrospective analyses, multiple ca-
veats should be applied to interpretation of these find-
ings. First, the results of our study are not universally
applicable to patients with obvious metastasis or to
those having resectable disease. Second, as opposed to
definitive treatment comparisons from prospective
trials, retrospective analyses of patient-related and
treatment-related variables are exploratory, and, there-
fore, serve to generate testable hypotheses, not to prove
hypotheses. Such an exercise may identify variables
worthy of consideration, such as eligibility criteria and/
or randomization stratification variables, for future pro-
spective cancer clinical trials. In addition, it is some-
times possible to identify survival cohorts, which may
FIGURE 4. Disease-free survival and Karnofsky performance scale score.
Multivariate Analysis of Prognostic Factors
OutcomeP Hazard Ratio (CI)
.03 1.35 (1.02–1.78)
CI indicates 95% confidence interval; KPS, Karnofsky performance scale score; Hgb, hemoglobin
2594 CANCER December 1, 2006 / Volume 107 / Number 11
be helpful in determining more accurate statistical end-
points for comparison in future prospective cancer clin-
As with most retrospective studies, this study has
biases that deserve mention. Selection bias could have
been introduced by our exclusion of patients who were
on protocol therapy that included bevacizumab/biolo-
gics. Changes in imaging quality, radiation therapy
techniques, and use of additional supportive care mea-
sures in later years (such as the more prevalent use of
newer generation anti-emetics and colony-stimulating
factors) during this period might have introduced
unknown confounding factors. Another limitation was
the lack of data on tumor size, tumor differentiation,
and tumor markers like CEA and Ca19-9. In the absence
of adequate data on these tumor markers, the power to
detect 1 or more of them as significant predictors is
lacking. Last, because most patients (89%) received an
unconventional radiation dose and fractionation (30 Gy
in 10 fractions), significant conclusions cannot be drawn
regarding the prognostic value of dose.
The major strength of this study is its large sample
size. It is one of the largest series that has evaluated
this selected group of patients with unresectable pan-
creatic cancer who underwent treatment with defini-
tive chemoradiation therapy. Treatment criteria and the
treatment approach were relatively consistent through-
out this period. The multidisciplinary management of
patients by a dedicated team of clinicians who specia-
lize in pancreatic cancer management is also an asset
to such an investigation.
In conclusion, our study suggests that performance
status and pretreatment hemoglobin level are independ-
ent prognostic factors for patients with unresectable
pancreatic cancer being treated with chemoradiation
as definitive treatment. These results can be used for
designing future clinical trials, for stratifying patients
to various treatment strategies, and for predicting life
expectancy. The information could then be used by the
treating oncology team to define an optimal therapeu-
tic strategy for a particular patient, or to incorporate
stratification variables in a study design, or to analyze
future clinical trial findings for this group of patients.
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Klaassen DJ et al.7
91 (unresectable only) Definitive chemoradiation,
Performance status, degree of anaplasia, reduced appetite
Performance status, Ca19-9 level >1000 and regional
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Ikeda M et al.15
55 (unresectable only)
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Presence of jaundice predicted better prognosis
Absence of therapeutic intervention, CRP > 5 mg/dL,
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Performance status, CRP > 5 mg/dL, Ca19-9 level >10,000 U/mL
Engelken FJ et al.27
Ueno H et al.25
Sezgin C et al.16
103 (metastatic only)
67 (Unresectable & metastatic)
Performance status, CEA level <10 ng/mL, absence of
Ishii H et al.20
65 (unresectable & metastatic)
Ca 19-9 indicates carbohydrate antigen 19-9; CRP, C-reactive protein; GGT, gamma glutamyl transferase; CEA, carcinoembryonic antigen.
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2596 CANCERDecember 1, 2006 / Volume 107 / Number 11