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Med. J. Cairo Univ., VoL 81, No. 2, March: 29-34, 2013
www.medicaljournalofcairouniversity.com
Concurrent Chemoradiation of Patients with Inoperable
Non-Metastatic Pancreatic Cancer
MOHAMED S. ELZAHI, M.Sc.; MOHAMED M. ELAWADI, M.D.; IBRAHIM A. AWAD, M.D. and
HANAN A. WAHBA, M.D.
The Departments of Clinical Oncology & Nuclear Medicine, Faculty of Medicine, Mansoura University
Abstract
cause of cancer death and one of the most difficult
malignancies to manage. Because of the usually
late onset of symptoms, only 10%-15% of patients
present with resectable disease, whereas the remaining 85%-90% present with locally advanced
unresectable or metastatic disease in.
Background: Inoperable non-metastatic pancreatic cancer
is a great challenge because the median survival is generally
less than 1 year and the impact of standard therapies is so
limited. All patients should be considered for protocol-based
therapy. The aim of this study is to determine the tolerability
and efficacy of Gemcitabine concurrent with 3D conformal
radiotherapy for locally advanced, unresectable, non-metastatic
pancreatic cancer.
Inoperable pancreatic cancer is a great challenge
that oncologists frequently encounter. Because the
median survival in patients with locally advanced
disease is generally less than 1 year, the goals of
treatment are to palliate symptoms and prolong
life [2].
Methods: Thirty three patients received the following
protocol in 3 phases; induction phase: Weekly Gemcitabine
at a dose of 1,000 mg/m2 over 30 minutes infusion for 7
weeks, chemoradiotherapy phase: Gemcitabine 600 mg/m2
weekly for 5 weeks concurrent with 3 dimensional (3D)
conformal radiotherapy for a total dose of 50.4 Gy in 28
fractions in 5.5 weeks, 5 days per week, and maintenance
phase: Gemcitabine at a dose of 1,000 mg/m2 weekly for 3
weeks with 1 week rest between 2 cycles.
Since the impact of standard therapies is so
limited, all patients with locally advanced pancreatic cancer should be considered for protocol-based
therapy. Patients with locally advanced disease are
usually eligible for clinical trials evaluating systemic therapy alone as well as trials evaluating
novel chemoradiation regimens. Some clinical
trials have established that the concurrent use of
chemotherapy with radiotherapy can improve the
median survival compared to radiation alone and
to chemotherapy alone [3].
Results: Forty eight patients with locally advanced unresectable pancreatic cancer were enrolled; only 33 patients
completed the treatment protocol. After a median follow-up
period of 20 months 15 patients were alive. The median
progression free survival (PFS) was 15 months; the median
overall survival was 19 months. The estimated 12 months, 18
months and 24 months survival was 79%, 42%, and 18%
respectively. Grade III toxicity were reported in 37.5% of
patients with no grade VI toxicity, vomiting were the most
common toxicity (32.5%) followed by fatigue (21.5%).
Because gemcitabine is superior to other agents
in patients with advanced pancreatic cancer, the
substitution of Gemcitabine with concurrent radiotherapy has been evaluated in several trials which
demonstrated encourage results as regards efficacy
and tolerability [4].
Conclusions: Gemcitabine concurrent with 3D conformal
radiotherapy is active, well tolerated and associated with
encouraging survival in patients with locally advanced pancreatic cancer.
Key Words: 3D conformal radiotherapy - Locally advanced
pancreatic cancer - Gemcitabine.
Aim of the study: To determine the tolerability
and efficacy of Gemcitabine concurrent with 3D
conformal radiotherapy for locally advanced, unresctable, non-metastatic pancreatic cancer.
Introduction
ALTHOUGH pancreatic cancer accounts for only
2% of all cancer diagnosis, it is the fourth-leading
Patients and Methods
Correspondence to: Dr. Mohamed S. Elzahi, The Departments
This prospective study included 33 patients
with locally advanced pancreatic cancer who at-
of Clinical Oncology & Nuclear Medicine, Faculty of
Medicine, Mansoura University
29
30
tended to Clinical Oncology and Nuclear Medicine
Department, Mansoura University Hospital in the
period from September 2009 to Mars 2012 inclusive.
Eligibility criteria:
- Age not less than 20 years and not more than 70
years.
- ECOG performance status from 0-2.
- Locally advanced unrespectable non-metastatic
pancreatic cancer with no lymph node involvement.
- Diagnosis is confirmed histologically or radiologically by triphasic CT or (MRI) with elevated
tumor marker CA19-9.
- Adequate hematological, hepatic and renal function.
- No prior anti- cancer treatment.
- No other malignancy.
Pretreatment evaluation:
All patients were evaluated by: Accurate full
personal, present, and past history; full clinical
examination including evaluation of performance
status, general and locoregional examination. Laboratory investigations included complete blood
picture, renal function, hepatic function, serum
CA19-9 and CEA. Radiological investigations
included base line triphasic CT or MRI abdomen
and pelvis and radiological investigations to exclude
metastasis included chest X-ray (or CT chest if
there is suspicious lesion) and bone scan if indicated.
Treatment protocol:
Concurrent Chemoradiation of Pancreatic Cancer
for all patients. Planning was done using 3D Precise
Treatment Planning System version 2.12. Optimization of 3DCRT plan was confirmed with cumulative dose volume histogram (DVH). Clinical
target volum (CTV) was cover by 95% of isodose
curves, inhomogenicity ranged from 95% to 105%,
and doses to organs at risk were limited to their
tolerances. 3D CRT was delivered by high energy
linear accelerator (Elekta, Precise Treatment System
TM), Version 5, with 6 MEV photon energy.
Post treatment evaluation was done at least 1
month after the end of chemoradiotherapy phase
using triphasic CT (or MRI) and tumor markers
CA19-9 and CEA. Patients were followed-up every
month by clinical examination, complete lab, tumor
markers and evaluation of toxic effects, every 3
months by CT or MRI for 1 year then every 6
months for the second year then annually.
Statistical analysis:
Drug and radiotherapy related toxicities were
graded using the NCI-CTC (version 2.0) [5]. Response was assessed by the RECIST criteria [6].
Progression free survival (PFS) was calculated as
the interval between the start of treatment and the
earliest event of disease progression. Overall survival (OAS) was calculated as the interval between
the diagnosis and last follow-up or death of the
patient. The Kaplan-Meier product limit method
was used to estimate PFS and OAS. Statistical
analyses were performed using SPSS 2004 (version
16) [7].
Results
All patients were planned to receive the following protocol in 3 phases; induction phase: Weekly
Gemcitabine at a dose of 1,000 mg/m2 over 30
minutes infusion for 7 weeks, chemoradiotherapy
phase: Gemcitabine 600 mg/m2 over 30 minutes
infusion, at least 1 hour before the radiotherapy,
weekly for 5 weeks concurrent with radiotherapy
for a total dose of 50.4 Gy in 28 fractions in 5.5
weeks, 5 days per week, using 3D conformal radiotherapy, and maintenance phase: After completion of chemoradiotherapy in the form of 2 cycles
of Gemcitabine at a dose of 1,000 mg/m2 over 30
minutes infusion weekly for 3 weeks with 1 week
rest between 2 cycles.
Patient characteristics:
Radiotherapy was delivered by 3D conformal
radiotherapy modality.
Prevalence of symptoms:
CT-based treatment planning (with a contrast
enhanced CT scan using 5mm slices) was required
Patient characteristics are summarized in (Table
1). Forty eight patients were eligible to start the
study, (66%) male and (33%) female with a median
age 52years. Fifteen patients (30%) were presented
with ECOG 0, 17 patients (37%) with ECOG 1,
and 16 patients (33%) with ECOG 2. The most
common site of the tumor was the head (72%).
Nearly 95% of the histologically assessed cases
were proved to be adenocarcinoma and 66% of
them were grade II. Only 40% of all cases had
elevated tumor marker CA19.9 (more than 37 u/l)
at the time of diagnosis.
Almost all patients were presented with more
than one symptom. In general, the most common
presenting symptoms were pain (66%), jaundice
(48%), and vomiting (36%).
31
Mohamed S. Elzahi, et aL
Toxicity:
The induction phase of the study was well
tolerated for most of patients, only 3 patients
developed grade III vomiting and diarrhea without
improvement on supportive treatment and they did
not complete the induction phase and were excluded
from the study. Patients were evaluated for adverse
events during chemoradiotherapy (Table 3). Four
patients out of 37 (11%) did not complete phase
II of the protocol; 2 patients (5.5%) developed
gastro-intestinal bleeding and another 2 patients
(5.5%) developed marked deterioration of general
condition with grade 3 vomiting and diarrhea.
Thirty three patients completed the phase. Five
patients (13.5%) developed grade I toxicity, 20
patients (54%) developed grade II toxicity, 14
patients (37.5%) developed grade III toxicity and
no one developed grade VI toxicity. The most
common toxicity was vomiting (32.5%) followed
by fatigue (21.5%). Only 3 patients (8%) needed
to stop the treatment due to grade III vomiting and
diarrhea (1 patient for 1 week and 2 patients for 2
weeks), they received supportive treatment and
then continued their therapy. In the other 30 patients, adverse effects were tolerable. About 80%
of these toxicities started to appear after the 3rd
week of therapy.
As regards phase III of the study, it was well
tolerated with no remarkable toxicity.
Response rate:
All 33 patients were assessed radiologically
and by tumor markers CA19-9 and CEA 1 month
after ending phase II. Radiologically; 2 patients
(6%) had complete response (CR), 6 patients (18%)
had partial response (PR), 22 patients (67%) had
stable disease (SD) and 3 patients (9%) had progressive disease (PD) (two patients developed liver
metastasis and 1 patient developed liver and lung
metastasis) (Table 4). As regards CA19-9, only 12
patients out of the thirty three patients had elevated
levels before starting the protocol. Six patients
(50%) had achieved 50% reduction relative to the
baseline value, 4 patients (33%) had stabilization
(<50% reduction to <25% increase) and 2 patients
(17%) had progression (>30% increase) [3].
Survival:
After a median follow-up period of about 20
months (range 10-27 months) and at the time of
analysis 15 patients were alive. The median PFS
time for patients in this study was 15 months (95%
CI, 11.958-18.042 months) (Fig. 1). The median
overall survival time was 19 months (95% CI,
14.312-23.688 months). The estimated 12 months,
18 months and 24 months survival was 79%, 42%,
and 18% respectively (Fig. 2). It was noticed that
the liver was the main site of relapse (95%), followed by abdominal lymph nodes and peritoneum
(20%), then the lung (15%), and bone (5%).
Table (1): Patient characteristics.
Number
(total)
Percentage
Male
Female
60
>60
32 (48)
16 (48)
29 (48)
19 (48)
66
34
60
40
0
1
2
Head
Body
Tail
15 (48)
17 (48)
16 (48)
35 (48)
11 (48)
2 (48)
30
37
33
72
23
5
Adenocarcinoma
Others
I
II
HI
37U/L
>37U/L
39 (41)
2 (41)
10 (41)
27 (41)
4 (41)
29 (48)
19 (48)
95
5
24
66
10
60
40
D.M
HTN
8 (48)
6 (48)
16
12
Characteristic
Sex
Age
Median 52y
Range (34-70)
ECOG
P.S
Site of Tumor
Pathology
Tumor Grade
Marker
(CA19.9)
Comorbidities
Table (2): Prevalence of symptoms.
Symptoms
Number (total)
Percentage
Pain
Jaundice
Vomiting
Weight loss
Anorexia
Nausea
32 (48)
23 (48)
17 (48)
15 (48)
11 (48)
8 (48)
66
48
36
31
23
17
Table (3): Toxicity of chemoradiation.
Toxicity
Vomiting
Fatigue
Diarrhea
Anorexia
Nausea
Stomatitis
Dyspepsia
G1
G2
G3
N
%
N
%
N
%
4
1
11
2.5
0
0
0
0
0
5
5
13.5
13.5
0
8
5.5
5.5
8
3
2
3
5
8
5.5
8
13.5
0
0
2.5
-
-
3
2
2
3
N.B: No patients developed G VI toxicities.
-
1
32
Concurrent Chemoradiation of Pancreatic Cancer
Table (4): Response rate (radiological).
CR
PR
SD
PD
Number
Percentage
2 (33)
6 (33)
22 (33)
3 (33)
6
18
67
9
Survival Function
1.0
' Survival Function
+ Censored
_ 0.8 - -
'
cd
•E 0.6
rn
g 0.4
0
Li ,
0.2
00
0.00
5.100
.
.
.
10.00 15.00 20.00
PFS
Fig. (1): PFS.
25:00 30.00
Survival Function
1.0
' Survival Function
+ Censored
0.8
7,1
,?:, 0.6
rn
0.4
0
0.2
g
0.0
1
5.00
10.00
1
1
15.00
20.00
OAS
Fig. (2): OAS.
1
25.00 30.00
Discussion
The optimal treatment of locally advanced
pancreatic cancer is still a matter of controversy.
Few studies have demonstrated median survival
durations longer than 12 months [4].
Our study aimed to assess the efficacy and
tolerability of concurrent use of Gemcitabine and
3D conformal radiotherapy for those patients with
locally advanced inoperable non- metastatic pancreatic cancer who showed a response or at least
a non progressive course after an induction phase
of weekly Gemcitabine.
The results of our study were better than the
results of a retrospective study done by Iciarashi
et al., [8] on 18 patient with locally advanced
pancreatic cancer utilizing Gemcitabine adminis-
tered twice weekly at a dose of 40mg/m2 concurrent
with total dose of 40-50.4Gy delivered using 1.82.0Gy daily fractions. Regarding response rate,
there was 5% complete response, 22% partial
responses, 50% stable diseases and 23% progressive
disease. The median survival was 15.0 months and
the overall 1-year survival rate was 60%, while
the median progression-free survival was 8.0
month. The higher dose of Gemcitabine given
concurrently with radiation may explain the better
results in our study.
Shibuya et al., [9] has studied a dose of 250
mg/m2 of Gemcitabine weekly given with a total
dose of 54Gy was delivered in 30 fractions of
1.8Gy/d on 21 patients. Radiological partial response was observed in 23%, stable disease was
noted in 52% and progressive disease was in 25%.
The 1-year survival rate was 74% and the median
survival time was 16.6 months. Again the higher
dose of Gemcitabine with radiation in our study
may explain the better results.
Gemcitabine was studied also concomitant with
radiotherapy by Cardenes et al., Rol on 28 patients.
Patients received GEM 600mg/m2 IV weekly, with
concurrent RT (50.4Gy in 28 fractions, 1.8Gy/d,
5 days per week) (the same as our study). The
median follow-up was 10 months (20 months in
our study) for all enrolled patients. Six patients
(21%) had a radiologic partial response, 16 patients
(57%) had stable disease, 5 patients (18%) had
progressive disease, and 1 patient (4%) had an
unevaluable response at last follow-up. Median
time to progression was 6 months. Median survival
time was 10.3 months. The 1- and 2-year actuarial
survival rates were 30% and 11%. The results were
disappointing as regards median survival and TTP.
Compared to our study, and although the researchers
of the previous study used the same dose of Gemctabine concurrent with the radiation, they did not
consider the induction phase before the concurrent
chemoradiotherapy phase and this may explain the
weak results of the that study. In the same time, it
gives an idea about the benefit of starting with the
induction phase aiming to exclude the non responsive and metastatic cases before the chemoradiation
phase which is reflected on the end result of the
study as regards the OAS and PFS.
This concept is confirmed by Gillmore et al.,
[iii who compared induction chemotherapy followed by chemoradiotherapy versus chemradiotherapy from the start. A multi-centre retrospective
analysis of 48 patients with biopsy-proven LAPC
treated with CRT from the start (n 24) or starting
with induction chemotherapy (n 24) in four regional
33
Mohamed S. Elzahi, et aL
oncology centers in the UK between March 2000
and October 2007. The disease control rate was
73.4% vs 81.3%. The median overall survival was
13 vs 17 months.
The same idea is supported in a published
nonrandomized series of 181 patients who were
treated with Gemcitabine-based chemotherapy for
3 months, and those with stable disease (128 patients) were treated with CRT or chemotherapy
alone. The median survival time was significantly
longer in patients receiving CRT (15 months versus
11.7 months). This shows a probable benefit of
CRT in patients who have achieved stable disease
with induction chemotherapy [12].
As regards the toxicity assessment of our study,
and compared to other studies used chemotherapy
alone for treatment of locally advanced pancreatic
cancer, the benefit of adding radiation to chemotherapy came at the cost of increased gastrointestinal toxicity as confirmed by Loehrer et al., [4]
who compared gemcitabine alone to gemcitabine
with radiation. Grade III gastrointestinal toxicity
was 23% and 38% respectively. Grade III toxicity
were 37.5 in our study.
But in comparison to other studies of chemoradiation using other agents than gemcitabine, our
protocol seems to be safer and less toxic. Oberic
et al., [13] studies 5 FU and docetaxel with radiation
on 40 patients. Twelve patients (60%) experienced
grade 3-4 toxicities during CRT treatment. The
most relevant severe toxicity involved the gastrointestinal tract in 34 patients (85%) including
vomiting (35%). Also, Saif et al., [14] studies
capicitabine concurrent with radiation on 82 patients. Sixty-six (80%) experienced grade III or
greater toxicity. There were three deaths reported
related to treatment.
Some studies explored the addition of another
agent to Gemcitabine with radiotherapy. Seventy
eight patients received radiation therapy (50.4Gy)
with concurrent infusional 5FU (200mg/m2 5
days/week) and weekly gemcitabine (200mg/m2).
After a 3-week break, patients received weekly
gemcitabine at 1000mg/m2 for 3 of 4 weeks, for
4 cycles. The median survival of the 78 eligible
patients was 12.2 months, the estimated one-year
survival was 51%, and the median TTP was 10
months [15]. In another study done by Arnolelli et
al. [15], Sixteen Patients with non-metastatic, locally
advanced pancreatic cancer were treated in a dose
escalation study with gemcitabine (0-300mg/
m2/week) given concurrently with cetuximab
(400mg/m2 loading dose, 250mg/m2 weekly main-
tenance dose) and irradiation (50.4Gy). The most
frequent Grade 3 toxicity was thrombocytopenia
73% and hyperkalemia 68%. The most Grade 4
toxicity was perforated duodenum (3 patients 19%)
and pulmonary embolism (2 patients 12.5%). The
overall survival was 10.5 months. These studies
suggest that addition of other agents to gemcitabine
during the radiotherapy leads to more toxicity to
the patients with no benefit or even worse results
as regards the response, median survival and PFS.
Conclusions:
Concurrent chemoraiotherapy using gemcitabine and 3D conformal radiotherapy with initial and
subsequent systemic gemcitabine is tolerable,
feasible, and effective, and offers good local control
for a substantial proportion of patients with locally
advanced pancreatic disease. This protocol showed
a significantly better progression free survival,
overall survival and a comparable toxicity profile
in comparison with other regimens. However,
further studies with larger numbers of patients are
needed to confirm our finding.
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