Gemcitabine–radiotherapy in patients with locally
advanced pancreatic cancer
S.M. de Langea,*, C.J. van Groeningena, O.W.M. Meijerb, M.A. Cuestac,
J.A. Langendijkb, J.M.G.H. van Rield, H.M. Pinedoa, G.J. Petersa,
S. Meijerc, B.J. Slotmanb, G. Giacconea
aDepartment of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands
bDepartment of Radiotherapy, University Hospital Vrije Universiteit, Amsterdam, The Netherlands
cDepartment of Surgery, University Hospital Vrije Universiteit, Amsterdam, The Netherlands
dDepartment of Internal Medicine, St-Elisabeth Hospital, Tilburg, The Netherlands
Received 20 September 2001; received in revised form 2 January 2002; accepted 20 February 2002
A feasibility study was performed to assess the toxicity and efficacy of a combination of gemcitabine–radiotherapy in patients
with locally advanced pancreatic cancer (LAPC). 24 patients (15 females and 9 males) with measurable LAPC were included; the
median age of the patients was 63 years (range 39–74 years). The performance status ranged from 0 to 2. Gemcitabine was admi-
nistered at a dose of 300 mg/m2, concurrent with radiotherapy, three fractions of 8 Gy, on days 1, 8 and 15. When compliance
allowed, gemcitabine alone was continued thereafter, at 1000 mg/m2, weekly times 3, every 4 weeks, depending on the response and
toxicity. All patients were evaluable for toxicity and response. The objective response rate was 29.2% (1 complete remission+6
partial remissions); 12 patients had stable disease. However, 2 of the radiological partial remissions were shown to be complete
remissions by pathology assessment. Median duration of response was 3 months (range 1–35+months). Median time to
progression was 7 months (range 2–37+months). Median survival was 10 months (range 3–37+months). Dose reduction or
omission of gemcitabine was necessary in 10 patients. Non-haematological toxicity consisted of 87.5% nausea and vomiting grade
I-II, diarrhoea 54%, ulceration in stomach and duodenum 37.5% (20.8% ulceration with bleeding); 1 patient developed a fistula
between the duodenum and aorta, 5 months after treatment. Anaemia grade III-IV was observed in 8.3% of the patients. Neu-
tropenia grade III-IV was observed in 8.3%, thrombocytopenia grades III-IV in 16.7%. In 1 patient who underwent resection
postchemoradiation, no viable tumour cells were found. In addition, in the patient who suddenly died of a fistula between the
duodenum and aorta, no viable tumour cells were detectable at autopsy. Although the toxicity of this treatment was occasionally
severe, the response and survival are encouraging and warrant further studies of this combination. # 2002 Published by Elsevier
Keywords: Gemcitabine; Locally advanced pancreatic cancer; Radiotherapy
In the Western world, approximately 5% of the can-
cer mortality is due to pancreatic cancer . At pre-
sentation, only 10–20% of patients with pancreatic
cancer have localised disease that can be considered for
resection, but even when resection is performed pan-
creatic cancer has a poor prognosis. Most patients have
locally advanced or metastatic disease. Life expectancy
in these patients is very short, with a median survival of
approximately 3 months, and a one year survival of 2%
The course of pancreatic cancer is often very aggres-
sive and patients complain of significant weight loss
(95%), pain (75%), anorexia (64%), nausea (50%),
lethargy, depression, weakness, and consequently have
an impaired performance status .
Moreover, pancreatic cancer is very resistant to
chemotherapy . 5-Fluorouracil (5-FU), until recently
the most applied agent in pancreatic cancer, has a
response rate below 10%. Of the newer agents, paclitaxel,
docetaxel, topotecan, raltitrexed and temozolomide
0959-8049/02/$ - see front matter # 2002 Published by Elsevier Science Ltd.
European Journal of Cancer 38 (2002) 1212–1217
* Corresponding author. Tel.: +31-20-444-4300; fax: +31-20-444-
E-mail address: firstname.lastname@example.org (S.M. de Lange).
showed only limited activity with response rates of 5–
17% in phase II studies . Gemcitabine (20-20-difluor-
odeoxycytidine), a new deoxycytidine analogue, has
been shown to have an impact on disease-related symp-
toms and survival of advanced pancreatic carcinoma,
although the magnitude of this improvement was lim-
ited . It was noted that some patients experienced
clinical benefit, defined as 550% reduction in pain
intensity, and/ or 550% reduction in daily analgesics
consumption, or 520% improvement on the Karnofsky
Performance Scale that was sustained for 54 weeks, or
a weight gain of 57% .
In a randomised phase III clinical study in 126
patients, gemcitabine was compared with 5-FU. In the
gemcitabine arm, 24% of the patients experienced clin-
ical benefit, while only 5% of the patients randomised
to 5-FU did. However, objective response rates were
very low in both study arms, only 5% in the gemcita-
bine treated patients and 0% in the 5-FU treated
patients. Patients had a median survival of 5.6 months
when treated with gemcitabine, while patients treated
with 5-FU had a median survival of 4.1 months
(P=0.0025) . Chemoradiation studies, where the
combination of 5-FU and radiotherapy was used, did
not show significant improvement of local control or
survival in patients with pancreatic cancer .
Radiotherapy alone may be a treatment modality
with transient effect on pain which is often present in
patients with pancreatic cancer. However, the effect is
usually limited in time, and the overall survival is simi-
lar to non-treated patients .
Gemcitabine is a potent radiosensitiser [8,9]. Radio-
sensitisation by gemcitabine can be caused by different
mechanisms. First, at the genomic level, gemcitabine
inhibits the repair of chromosome damage induced by
irradiation, but has no demonstrable effect on the
repair of DNA double-strand breaks. Second, in both
in vitro and in vivo models, gemcitabine was reported to
induce cell cycle redistribution . Therefore, it is
likely that an accumulation of a cohort of cells into a
more radiosensitive phase of the cell cycle may con-
tribute to the radiosensitisation of gemcitabine. Third,
the preferential depletion of S-phase cells by apoptosis
tumour cell proliferation and enhance tumour reoxy-
genation due to increased cell loss . Fourth, radio-
sensitisation by gemcitabine has been associated with a
depletion of the deoxyadenosine triphosphate (dATP)
pool, suggesting that inhibition of ribonucleotide
reductase is of primary importance ; however, recent
evidence suggests that dATP depletion may contribute
to, but is not the main determinant of radiosensitisation
. Lastly, it has recently been observed in mouse
tumour cells that radiosensitisation by gemcitabine
might critically depend on the level of dCK expression
We have performed a clinical study to explore the
radiotherapy–gemcitabine interaction in patients with
non-metastatic, irresectable pancreatic cancer. In this
study, we assessed whether this combination was fea-
sible and has sufficient activity for further testing.
2. Patients and methods
This was a single-centre feasibility study to assess the
toxicity and efficacy of combined gemcitabine–radio-
therapy in locally advanced pancreatic cancer (LAPC).
Eligible patients had histologically- or cytologically-
confirmed adenocarcinoma of the pancreas and the dis-
ease had to be measurable on a Computed Tomography
(CT)-scan. The patients had to be aged 518 years, with
a World Health Organization (WHO) performance sta-
tus 42, and a life expectancy 53 months. Adequate
haematological, renal and liver function tests were
required, and were defined as white blood cell (WBC)
count 54?109/l, absolute neutrophil cell (ANC) count
52?109/l, platelets 5100?109/l, bilirubin 425 mmol/l,
(ASAT/ALAT) within 2? the upper normal limit, crea-
tinine 4120 mmol/l, or creatinine clearance 51 ml/s.
No patients with poor medical risks because of non-
malignant disease or uncontrolled infection could parti-
cipate in the study. This study was approved by the
institutional ethics committee, and all patients gave
2.2. Assessments and treatment
Pretreatment evaluation included a history and phys-
ical examination. Height, weight, performance status,
and tumour assessment were recorded. A chest film, an
abdominal CT scan and an electrocardiogram (ECG)
were also performed, as well as a pretreatment assess-
ment and laboratory studies. Gemcitabine was admi-
nistered at a dose of 300 mg/m2by intravenous (i.v.)
infusion over 30 min, 2–4 h before radiotherapy on days
1, 8 and 15. The radiotherapy dose was 24 Gy (3 weekly
fractions of 8 Gy) given concurrently with gemcitabine.
Gemcitabine alone was continued thereafter (after a
treatment-free interval of 1 week), weekly times 3, every
4 weeks, depending on the response and toxicity. This
was defined as 1 cycle. Gemcitabine alone was adminis-
tered at a dose of 1000 mg/m2for as long as indicated.
The radiation therapy consisted of a schedule of 24
Gy in three fractions of 8 Gy (1 fraction/week) and was
delivered to the tumour, peripancreatic nodal regions,
and a 1.0–2.0 cm margin (around the gross tumour
volume to account for microscopic tumour extension,
S.M. de Lange et al./European Journal of Cancer 38 (2002) 1212–12171213
set-up variation, patient motion and uncertainty). CT
scan-based treatment planning was performed and, in
general, a three- or four-field technique was used. To
decrease the irradiation of the kidneys, renography was
performed prior to therapy; in case of normal reno-
graphic findings, one kidney was left out of the irradi-
ation field completely, while the other kidney was
exposed as little as possible. Toxicities were graded
using the National Cancer Institute of Canada (NCIC)
common toxicity criteria . The dose of gemcitabine
was reduced (25–50%) in cases of grade III and IV
haematological and non-haematological toxicities. Eval-
uation during treatment included weekly history, phys-
ical examination, haematology and toxicity assessment.
Biochemical tests, including CA 19.9, were determined
every 4 weeks. CT scans were repeated every 2 months.
Patients were followed until death.
Responses were defined according to the WHO cri-
2.3. Statistical analysis
Duration of survival and time to progression were
calculated by the Kaplan-Meier method.
Table 1 shows the characteristics of the 24 patients
entered in the study. The inclusion period for this feasi-
bility study was January 1996 until December 1999. The
median Eastern Cooperative Oncology Group (ECOG)
performance status was 1. Two patients had received
prior chemotherapy, one for non-Hodgkin’s lymphoma,
three cycles of cyclophosphamide, doxorubicin, vincris-
tine and prednisolone (CHOP) and radiotherapy, 3
years before the diagnosis of pancreatic cancer. The
other patient received carboplatin-ethyol in a phase I
study. With this therapy, stable disease was achieved. A
few months later, progression occurred and gemcita-
bine–radiotherapy was started. Seven patients had prior
surgery, consisting of explorative laparotomy and bilio-
Twnety-three patients received all of the planned
three cycles of gemcitabine concurrent with radio-
therapy. One patient received only two cycles; the third
cycle was not given because of severe diarrhoea. After
chemoradiation, 218 weekly cycles of single agent gem-
citabine were administered with a median of 13 cycles
per patient (range 0–18). Gemcitabine was discontinued
in 15 patients because of progressive disease, in 4
patients because of toxicity, in 1 patient because of
abdominal pain and poor condition, in 1 patient
because a pancreaticoduodenectomy was performed,
and in 1 patient after an explorative laparotomy, which
revealed irresectable disease. One patient stopped
chemotherapy 12 months after the establishment of a
complete remission. One patient is still on study.
All patients were evaluable for non-haematological
and haematological toxicity. Side-effects have been
summarised in Table 2 and separated for toxicity
Total no. of patients
ECOG performance status
ECOG, Eastern Cooperative Oncology Group.
Grade (NCI Common
Gemcitabine plus radiotherapy
Fever in absence of infection
1214 S.M. de Lange et al./European Journal of Cancer 38 (2002) 1212–1217
resulting from chemo-radiation, subsequent gemcita-
bine alone, and late side-effects.
Dose reduction of 25–50% or omission of gemcita-
bine was necessary in 6 patients for grade III haemato-
haematological toxicity. The reduction during the con-
current treatment was 25% in 1 patient because of
myelosuppression and, in another patient, one dose of
gemcitabine and radiotherapy was omitted because of
severe diarrhoea. The other 8 patients had a 25–50%
reduction of the gemcitabine dose, when gemcitabine
was given as a single agent.
Haematological toxicity was mild, anaemia grade III-
IV was observed in 8.3%, neutropenia grade III was
observed in 8.3%, and thrombocytopenia grade III in
16.6% of the patients.
Non-haematological toxicity consisted of nausea and
vomiting grade I-II in 87.5% of the patients, diarrhoea
in 54%, and ulceration in the stomach and duodenum
in 37.5% (20.8% ulceration with bleeding). One patient
died of a haemorrhage due to ulceration of the stomach.
One patient suddenly died of a fistula between the duo-
denum and aorta, 5 months after treatment.
for gradeIII non-
3.2. Objective response
All patients were evaluable for response. One patient
had a complete remission and 6 patients had a partial
remission for an overall objective response rate of
29.2% (Table 3). 12 patients had stable disease, and 5
patients had progressive disease. The median duration
of response was 3 months (range 1–35+months). The
median time to progression was 7 months (range 2–37+
months). Treatment failure occurred in 19 patients and
consisted of local failure in 5 patients, local failure and
distant metastases in 7 patients and distant metastases
only also in 7 patients. Median survival was 10 months
(range 3–37+months) (Fig. 1). 19 patients died, 17
because of malignant disease and two due to toxicity.
One of these 2 patients died of a fistula between the
duodenum and aorta, and the second of bleeding due to
ulceration of the stomach.
CA 19.9 determinations were performed in all
patients before treatment (Table 3). In 19 patients, CA
19.9 was elevated (>22 U/ml). Serial CA 19.9 determi-
nations were performed in 17 patients. Of the 7
responding patients, 3 had abnormal baseline determi-
nations and all 3 patients had decreases of >50% in CA
19.9 for at least 8 weeks. All 12 patients with stable
disease had an abnormal CA 19.9 at baseline and 11 of
these patients had a decrease in CA 19.9 of >50%. Of
the 5 patients with progressive disease, 4 had an abnor-
mal CA 19.9 at baseline, and none of these patients had
a decrease in CA 19.9 of >50%. These data suggest
that there is an association between a decrease in CA
19.9 of >50% and the achievement of a tumour response
or stabilisation during treatment with gemcitabine–
radiotherapy followed by gemcitabine as a single agent.
Remarkably, in 1 patient who underwent resection of
the tumour postchemoradiation, no vital tumour cells
were found in the surgical specimen. Nevertheless, this
patient developed recurrent disease 5 months after sur-
gery and died 3 months later. In addition, the patient
who suddenly died of a fistula between the duodenum
and aorta did not have vital tumour detectable at
Gemcitabine–radiotherapy, followed by gemcitabine
alone, when delivered according to the present dosage
and schedule, resulted in objective responses, one com-
plete remission and six partial remissions in 24 patients
with non-metastatic irresectable pancreatic cancer.
However, the toxicity of this treatment was occasionally
severe. This included ulceration in stomach and duo-
denum in 37.5% of the patients, while in 20.8% of the
patients this was accompanied by bleeding. However,
gastroscopy was only performed when indicated, and
the incidence of ulceration may have been under-
estimated. Also of concern was the acute death in the
patient with a fistula between the duodenum and aorta,
Response and CA 19.9 determinations
Response Total no of
Initial Ca 19.9
of > 50%
CR/PR, Complete Response/Partial Response; SD, Stable Disease;
PD, Progressive Disease.
Fig. 1. Kaplan–Meier plot of survival of patients with locally
advanced pancreatic cancer.
S.M. de Lange et al./European Journal of Cancer 38 (2002) 1212–12171215
and the second sudden death in the patient with a
bleeding ulceration. It cannot be excluded that our
radiotherapy schedule with three high dose fractions of
800 cGy has been responsible for these late events. An
aorto-duodenal fistula after abdominal irradiation has
been described before by Zarembok and colleagues in
Hodgkin’s disease. The mechanism of this complication
seemed to be related to radiation-induced necrosis of a
mass invading the aorta and duodenum . After 18
patients were included in the study, prophylactic ome-
prazol was prescribed which seemed to result in less
severe upper gastrointestinal side-effects. This drug
might reduce this type of toxicity probably because it
may protect against the effect of gemcitabine–radio-
therapy on normal tissue. Of note, patients with pancrea-
tic cancer are more at risk for gastrointestinal bleeding.
The usual dose of gemcitabine as a single agent is
800–1250 mg/m2. When gemcitabine is combined
with radiotherapy, this dose is too toxic. In non-small
cell lung cancer, gemcitabine has been combined with
radiotherapy. At a dose of 600 mg/m2, severe pulmon-
ary toxicity consisting of acute pneumonitis and pul-
monary fibrosis was observed. Doses of 300 and 450
mg/m2appeared to be safe in combination with radio-
therapy in this disease . Another study of combined
treatment modality in non-small cell lung cancer was
performed by Vokes and colleagues. In this study, gem-
citabine was combined with cisplatin as induction ther-
apy followed by additional cycles of the same drugs
with concomitant radiotherapy (66 Gy). The dose of
cisplatin was 80 mg/m2, the dose of gemcitabine was
1250 or 600 mg/m2depending on the day of the cycle.
Toxicities were granulocytopenia, thrombocytopenia
and esophagitis. This combined treatment can be safely
used at this dose and schedule .
In our study, we used a gemcitabine doseof 300 mg/m2.
The radiotherapy dose normally used in pancreatic
cancer varies between 45 and 60 Gy in five daily frac-
tions, during 4–6 weeks. In rectal cancer, a study has
been conducted with a lower total dose of radiotherapy
of 25 Gy, but in high daily fractions of 5 Gy. This
radiotherapy scheme has demonstrated an impressive
reduction in cancer mortality and morbidity rates with
acceptable complication rates . To our knowledge,
there is no experience with the radiotherapy schedule
applied in our study, however, extensive experience also
exists with hypofractionated radiotherapy for the pal-
liative treatment of tumours at different sites. Addi-
tionally, this fractionation scheme was also chosen
because in the near future we will use extracranial ste-
reotactic radiotherapy using a few high dose radiation
fractions, in patients with pancreatic cancer. In addi-
tion, radiobiological studies have shown that pancreatic
tumour cells in vitro are radiosensitive . A non-ran-
domised phase II study by Ceha and colleagues with
high-dose conformal radiotherapy (70–72 Gy) in 44
patients showed more toxicity compared with a lower
dose in high daily fractions. Acute toxicity was mainly
grades I and II (in 70 and 57% of patients, respectively),
whereas grade III toxicity was seen in 9% of patients.
Late grades III and IV gastrointestinal toxicity was seen
in 3 and 2 patients, respectively. Late toxic death, due to
gastrointestinal bleeding was observed in 3 patients .
Gemcitabine–radiotherapy in pancreatic cancer has
also been studied by other investigators. In a phase I
study, Blackstock and colleagues applied gemcitabine
twice weekly for 5 weeks at doses of 20–60 mg/m2until
dose-limiting toxicity, concurrent with 50.4 Gy of
radiation therapy (in five daily fractions of 2 Gy for 5
weeks) in 19 patients . Side-effects consisted of nau-
sea and vomiting, thrombocytopenia and neutropenia.
The maximum tolerable dose (MTD) of gemcitabine in
this study was 40 mg/m2. Another phase I study by
McGinn and colleagues in 37 patients, applied gemcita-
bine at 1000 mg/m2on days 1, 8, and 15 of a 28 day
cycle. Radiation therapy was initiated on day 1. 15
fractions of 1.6–2.8 Gy until dose-limiting toxicity. A
second cycle of gemcitabine alone was given after a
week’s rest. Side-effects were neutropenia, thrombocy-
topenia, vomiting, and abdominal pain secondary to
gastric and duodenal ulceration. The MTD of radio-
therapy in this study was 2.4 Gy. The objective response
rate in this study was 30%. The median survival was
11.6 months . Another phase I study by McGinn
colleagues applied gemcitabine once weekly at a starting
dose of 300 mg/m2, concurrently with 50.4 Gy radio-
therapy in 13 patients . One patient experienced
dose-limiting toxicity at 300 mg/m2, consisting of grade
3 neutropenia. 10 patients have subsequently been trea-
ted without dose-limiting toxicity. The predominant
toxicity was nausea and vomiting. In 1 patient, late
toxicity was reported consisting of gastric/duodenal
ulceration occurring 3 months following completion of
the treatment. At the time of the report, the MTD had
not been reached and the study was planned to continue
with a gemcitabine dose of 500 mg/m2.
Crane and colleagues described a similar study of
chemoradiation in 51 patients with locally advanced
pancreatic cancer. Gemcitabine was given at a dose of
250–500 mg/m2weekly for 7 weeks and radiotherapy
30–33 Gy in 10–11 fractions over 2 weeks. The median
survival was 11 months, the median time to local pro-
gression was 6 months, and the median time to distant
progression was 9 months .
In our study, we decided not to further escalate the
dose of gemcitabine, because of severe local side-effects.
Studies have also been conducted with neoadjuvant
chemoradiation applying different chemotherapy and
radiotherapy regimens. In a study of White and col-
leagues applying 5-FU, mitomycin-C or cisplatin, or
both, with concurrent radiotherapy in 25 patients showed
that a potentially curative resection could be performed
1216 S.M. de Lange et al./European Journal of Cancer 38 (2002) 1212–1217
in 5 patients (20%) . Of these patients, 1 had a Download full-text
complete and 4 had a partial remission. Similarly, in a
study of Wanebo and colleagues that combined 5-FU
and cisplatin with concurrent radiotherapy in 14
patients, 9 patients had a resection, while in 2 patients a
pathological complete remission was achieved .
In terms of survival and response, the results of our
study are encouraging. Based on the results of this
study, we plan to assess this combined treatment in a
neo-adjuvant setting in patients with potentially resect-
able pancreatic cancer.
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