Original Paper

Dig Dis 2006;24:207211

DOI: 10.1159/000090322

Treatment of Gastrointestinal Stromal Tumor

with Imatinib Mesylate: A Retrospective
Single-Center Experience in Heidelberg
Bernd Kasper a Birgit Kallinowski b Thomas Herrmann b Thomas Lehnert d
Gunhild Mechtersheimer c Thomas Geer e Anthony D. Ho a Gerlinde Egerer a
Departments of a Internal Medicine V, b Internal Medicine IV, and c Pathology, University of Heidelberg,
Heidelberg, d Department of Surgery, Klinikum Bremen-Mitte, Bremen, and e Diakonie-Krankenhaus,
Klinik fr Innere Medizin, Schwbisch Hall, Germany

Abstract
Background: Gastrointestinal stromal tumor (GIST) is
the most common mesenchymal neoplasm of the gastrointestinal tract. Surgery has been the only effective
therapy. However, many patients still eventually die of
disease recurrence. Chemotherapy and radiation therapy have been of limited value. Imatinib mesylate (Glivec)
is an orally administered competitive inhibitor of tyrosine kinases associated with the KIT, ABL protein, licensed for the treatment of metastatic GIST since 2002
in Germany. Methods: We summarized the data of 16
patients with advanced or metastatic GIST treated with
imatinib mesylate in palliative and neoadjuvant settings.
Results: Overall response was 81%, with no evidence of
disease (NED) in 3/16 (19%), partial response (PR) in 9/16
(56%) and stable disease (SD) in 1/16 (6%), whereas 3/16
patients (19%) suffered from progressive disease (PD).
Mean follow-up was 18.6 months [range: 430]. Mean
progression-free survival (PFS) was 17.6 months [range:
030], mean overall survival (OS) from initial diagnosis

2006 S. Karger AG, Basel

02572753/06/02420207$23.50/0
Fax +41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com

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was 32.3 months [range: 5122]. Most common side effects were periorbital edema and skin rash. Conclusion:
Imatinib mesylate is well tolerated in a dose of up to
800 mg/day and has significant activity during longterm treatment of patients with advanced or metastatic
GIST.
Copyright 2006 S. Karger AG, Basel

Introduction

Gastrointestinal stromal tumor (GIST) is a subtype of

soft-tissue sarcomas (STS) which represent 1% of all adult
malignancies and a heterogeneous group of neoplasms
deriving from mesenchymal tissues [1, 2]. The spontaneous outcome of malignant GIST is extremely poor [3].
Until recently, surgery has been the only effective therapy
and is still the rst-line treatment [4, 5]. However, surgery
is often inadequate for advanced GIST and even after
complete resection, many patients will die of disease recurrence or from metastatic disease. Conventional chemotherapy and radiation therapy have been of limited
value in GIST. Doxorubicin is the most active single
agent with response rates yielding from 20 to 25% [5].
Ifosfamide and dacarbazine have also demonstrated ac-

Dr. med. Bernd Kasper

University of Heidelberg, Department of Internal Medicine V
Im Neuenheimer Feld 410, DE69120 Heidelberg (Germany)
Tel. +49 6221 56 8008, Fax +49 6221 56 6824
E-Mail Bernd_Kasper@med.uni-heidelberg.de

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Key Words
Gastrointestinal stromal tumor
Imatinib mesylate

Palliative
Neoadjuvant

Patients and Methods

Patients
We analyzed the data of 16 patients with advanced or metastatic GIST treated with imatinib mesylate in our Departments of
Internal Medicine IV and V, University of Heidelberg, Germany.
The research was carried out according to the principles set out in
the Declaration of Helsinki 1964 and informed consent was obtained. GIST were histologically proven. The immunohistochemical expression of C-KIT (CD117) was assessed. Six of 16 patients
were female (37%), 10 patients were male (63%). Median age was
59.9 years (range: 3583). Three patients (19%) received imatinib
mesylate in a neoadjuvant setting (cases 7, 12 and 13) without primary surgery, 2 patients underwent surgery 7 (case 12) and 13 (case
13) months after starting with imatinib mesylate, the third (case 7)
was treated without surgery. 13/16 patients (81%) were initially
operated and received imatinib mesylate in a palliative clinical setting (cases 16, 811, 1416); other radiotherapy or other chemotherapy were not given as further treatment. Objective tumor response was evaluated by computed tomography and categorized
according to guidelines described by Therasse et al. [17]: no evidence of disease (NED), partial response (PR, 130% decrease in the

208

Dig Dis 2006;24:207211

greatest diameter of target lesion), stable disease (SD), progressive

disease (PD, 120% increase in the greatest diameter of the target
lesion or appearance of one or more new lesions). Five patients
(31%) were without metastases at initial diagnosis; initial metastatic sites were the liver in 8 patients (50%), and peritoneal or retroperitoneal sites in 5 patients (31%).
Treatment and Toxicity
Imatinib mesylate was supplied as 100 mg gelatine capsules obtained from Novartis, Basel, Switzerland. Medication was administered orally after meal. Patients received imatinib mesylate at
doses of 400800 mg/day. There was no prophylactic co-medication given.
Statistical Analysis
Overall survival was assessed from the time of initial diagnosis.
Progression-free survival was assessed from the start of treatment
with imatinib mesylate. Values are given as median and range.

Results

Response and Survival

Imatinib mesylate was active in the group of 13/16
patients with GIST (81%) with 19% NED, 56% PR and
6% SD (table 1). Only 3/16 patients showed PD (cases 10,
14 and 16) under therapy with imatinib mesylate, one of
them died 1 year (case 16) and the other 2 years (case 10)
after the start of treatment. Time interval from initial diagnosis to induction with imatinib mesylate was 14.4
months (range: 1102). Patients have been followed for
a median of 18.6 months (range: 430) under treatment.
Responses and stable diseases seem to be long-lasting,
with median PFS for all 16 patients of 17.6 months (range:
030) and 11 GIST patients (69%) free of progression at
1 year. Median OS assessed from the time of initial diagnosis was 32.3 months (range: 5122). In 3 of 16 patients
imatinib mesylate was given preoperatively in a neoadjuvant setting (compare cases 7, 12 and 13) in order to reduce tumor size, offering the opportunity for curative surgery of the primary tumor or metastases. Case 7 was an
old patient not eligible for an initial denitive surgery. In
cases 12 and 13, curative surgery could be performed after shrinkage of tumor size due to preoperative imatinib
mesylate therapy. Both patients continued treatment of
imatinib mesylate postsurgery in a dose of 400 mg daily
and are NED 24 and 21 months after the start of treatment.
Toxicity
None of the 16 patients in this study have developed
serious adverse events. No patient discontinued therapy

Kasper /Kallinowski /Herrmann /Lehnert /

Mechtersheimer /Geer /Ho /Egerer

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tivity [68]. However, conventional-dose, single-agent

chemotherapy still has to be considered as standard treatment for metastatic STS, but GIST is highly resistant to
this conventional chemotherapy.
GIST has been found to differentiate towards a pacemaker cell phenotype and to express the KIT tyrosine
kinase receptor uniformly [9, 10]. In addition, plateletderived growth factor receptor (PDGFR) is expressed in
mesenchymal tissues and the majority of other STS subtypes [11]. Activating gene mutations of the KIT protooncogene are frequently exhibited in GIST, which are
potential targets for therapeutic intervention with imatinib mesylate [12, 13]. Imatinib mesylate (Glivec) is an
orally administered competitive inhibitor of the tyrosine
kinases associated with the KIT protein, ABL protein and
PDGFR.
The rst successful treatment of a patient with metastatic GIST using imatinib mesylate has been reported
2001 by Joensuu et al. [14] and following trials indicated
the effectiveness and safety of imatinib mesylate in the
treatment of patients with unresectable or metastatic
GIST. The highest feasible dose of imatinib mesylate was
identied by an EORTC phase I study to be 400 mg administered twice daily with extensive activity in GIST
[15, 16].
In this paper, we assessed the response and survival of
16 patients with advanced and overtly metastatic GIST
treated with imatinib mesylate in palliative and neoadjuvant clinical settings.

Table 1. Remission and survival characteristics of all GIST patients treated with imatinib mesylate (n = 16)
Case

Age/sex

First
tumor
site

Metastases Interval: initial

at initial
diagnosis to
diagnosis
imatinib months

Disease
status at start
of imatinib

Clinical
indication

Response
by CT
evaluation

Progression- Overall
free survival survival
months
months

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16

76/M
34/M
73/F
60/F
55/F
61/M
82/F
60/M
70/F
58/M
73/M
46/M
55/F
43/M
45/M
51/M

S
S
A
A
S
S
S
A
SB
S
SB
S
S
SB
S
S

L
none
P
none
L
none
none
L
L
L
P
L, P
none
P
L
L, P

L
L
P
L
L
P
PT
PT, L
L
L
P
PT, L, P
PT
P
L
PT, L, P

palliative
palliative
palliative
palliative
palliative
palliative
neoadj.
palliative
palliative
palliative
palliative
neoadj.
neoadj.
palliative
palliative
palliative

PR
PR
PR
PR
PR
NED
SDa
PR
PR
PD
PR
NEDb
NEDb
PD
PR
PD

28
10
11
5
4
20
23
30
13
22
24
24
21
16
30
0

3
9
1
10
1
102
2
1
5
4
68
1
1
12
9
2

31c
19c
12c
15c
5c
122c
25c
31c
18c
29d
92c
25c
22c
20c
39c
12d

with imatinib mesylate due to toxicity. There was no side

effect of myelosuppression in this study. The most frequent side effects were periorbital edema (38%), skin rash
(19%), peripheral edema (19%), alopecia (19%), diarrhea
(19%), nausea/vomiting (6%), and fatigue (6%). According to WHO grade, most side effects were mild to moderate and tended to occur in the rst 8 weeks of treatment.
Periorbital edema was seen as puffy eyes and mainly involved the skin above the eye. Skin toxicity consisted of
erythema that sometimes became crusty. Despite continuous treatment, side effects were most frequently selflimiting.

The treatment of metastatic STS remains extremely

difcult because active chemotherapeutic agents are
missing. Conventional-dose, single-agent chemotherapy
has to be considered as the standard treatment for metastatic STS. However, the subgroup of GIST is highly resistant to conventional chemotherapeutic agents. Imatinib mesylate is an orally administered competitive inhibitor of the protein-tyrosine kinases associated with the

KIT protein, ABL protein and PDGFR [18] which was

found to be active in the treatment of GIST [14].
We investigated 16 patients with advanced GIST in
whom imatinib mesylate was given pre- and postoperatively. Daily dosing of imatinib mesylate was 400
800 mg per os. The effective dose of imatinib mesylate
is 400 mg according to the data of larger series [19]. All
patients started with imatinib mesylate in a dose of
400 mg daily and dose was increased up to 800 mg only
if progressive disease was observed. All doses were well
tolerated without serious adverse events. No patient discontinued therapy due to toxicity. Side effects were mild
to moderate and often self-limiting as already described
in the literature [15, 20]. A dose-nding phase III study
by the South West Oncology Group (SWOG) and the
EORTC for 400 vs. 800 mg imatinib mesylate per day
has been performed: If response induction is the only aim
of treatment, a daily dose of 400 mg of imatinib mesylate is sufcient; however, a dose of 400 mg twice a day
achieves signicantly longer progression-free survival
[19].
Imatinib mesylate induced an overall response of 81%
of our patients, similar to the results from the EORTC
studies [15, 20]. The majority of our patients treated with

Experience with Imatinib in GIST

Dig Dis 2006;24:207211

Discussion

209

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S = Stomach; A = abdomen; SB = small bowel; PT = primary tumor; L = liver metastasis; P = peritoneal metastasis; NED = no evidence of disease; PR = partial response; SD = stable disease; PD = progressive disease.
a
Without resection; b after nal resection; c patient is still alive; d patient died in this month.

imatinib mesylate were palliative. In 3 of 16 patients imatinib mesylate was given preoperatively in a neoadjuvant
setting resulting in reduced tumor size, offering an opportunity for curative surgery of the primary tumor or
metastases (compare cases 7, 12 and 13). A Swedish group
[21] even indicated a role for adjuvant treatment with
imatinib mesylate. However, this question is currently
being investigated in prospective randomized clinical
trials.
Primary or late resistance to imatinib mesylate has
been observed in GIST patients [15, 16]. Different mechanisms of resistance to imatinib mesylate could be identied in 16 GIST patients with initial or late resistance [22].
They include acquisition of new kit or PDGF-R mutations, kit genomic amplications as well as activation of
an alternate receptor tyrosine kinase protein. Mechanisms of resistance to imatinib mesylate were not evaluated in this clinical analysis; however, they are well described in a review article of our group [10].

Computed tomography (CT) and magnetic resonance

imaging (MRI) are the anatomic imaging techniques
most broadly used to assess the response to imatinib mesylate treatment. Standard positron emission tomography complements the anatomic imaging techniques.
FDG-PET was shown to be a rapid and sensitive indicator of response or resistance to imatinib mesylate, especially FDG-PET seems to be particularly useful for the
early identication of GIST responders [15, 16]. Nevertheless, since PET studies are not ubiquitously available
and cost-intensive, CT is most suitable for follow-up studies outside controlled clinical trials [10].
In conclusion, imatinib mesylate is generally well tolerated in doses of up to 800 mg per day and has signicant
activity during long-term treatment of patients with advanced or metastatic GIST. Moreover, this report indicates several new and interesting aspects of using imatinib mesylate in different clinical settings including neoadjuvant therapy.

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