original article
Annals of Oncology 19: 1644–1649, 2008
doi:10.1093/annonc/mdn179
Published online 2 May 2008
Use of palifermin for the prevention of high-dose
methotrexate-induced oral mucositis
E. Schmidt, N. H. Thoennissen, A. Rudat, R. Bieker, C. Schliemann, R. M. Mesters, M. Zühlsdorf,
C. Müller-Tidow & W. E. Berdel*
Department of Medicine, Hematology and Oncology, University Hospital Muenster, Muenster, Germany
Received 28 November 2007; revised 26 March 2008; accepted 31 March 2008
original
article
Background: Oral mucositis is a frequent problem after high-dose methotrexate (HD-MTX), impairing patient’s
quality of life, leading to higher rates of infections and delaying subsequent chemotherapy. This report describes the
effect of palifermin in patients treated within the GMALL-B-ALL 2002 protocol containing HD-MTX who developed
a severe mucositis in cycle A1/B1.
Patients and methods: Ten patients, all with World Health Organization grades III–IV oral mucositis in cycles A1/B1,
obtained palifermin with subsequent similar or identical cycles to reduce mucositis. Thus, patients serve as their own
control for efficacy of palifermin.
Results: All 10 patients developed grades III–IV mucositis in cycles A1/B1 without palifermin, whereas only two of 10
developed grades III–IV mucositis in corresponding cycles A2/B2 with palifermin. Only four of 10 patients showed
infections in the cycles with palifermin compared with 10 of 10 patients without palifermin. The duration of mucositits in
patients who acquired a higher grade mucositis despite treatment with palifermin could be reduced from 12.9 days
(median) without to 11 days with palifermin. The amount of i.v. opioid analgetics could be significantly reduced.
Conclusion: Palifermin might reduce the incidence, severeness and duration of oral mucositis in HD-MTX-based
chemotherapy and may influence clinical sequelae such as infection and quality of life.
Key words: methotrexate, oral mucositis, palifermin
introduction
Oral mucositis is a severe and frequent adverse effect of highdose methotrexate (HD-MTX)-based chemotherapy. It is
caused by damage of the mucosal lining of the gastrointestinal
tract (GIT) as a result of a dynamic series of biological events
involving different cellular and tissue compartments of the
GIT mucosa. Understanding of the pathobiology has increased
rapidly during the last years [1–5]. Mucosal barrier injury is
based on a network of interactions involving the endothelium,
extracellular matrix, metalloproteinases, submucosal reactions
and connective tissue [1–3]. Sonis and coworkers developed
a pathophysiological model dividing the dynamical process of
mucositis in five phases: initiation, up-regulation, signal
amplification, ulceration and healing [2, 3].
Oral mucositis and myelosuppression represent doselimiting toxicity effects of HD-MTX. Mucositis is associated
with an increased risk of life-threatening infections [6, 7], with
the need for total parenteral nutrition, i.v. analgetic therapy,
and may lengthen hospital stay with increased economic
burden and consumption of health care resources [8–11]. Oral
*Correspondence to: Dr W. E. Berdel, Universitätsklinikum Muenster, Medizinische
Klinik, Albert-Schweitzer-Strasse 33, D-48149 Muenster, Germany. Tel: +49-2518347587; Fax: +49-251-8347588; E-mail: [email protected]
mucositis impairs the patient’s quality of life by pain, the
inability to eat, swallow and talk. For many patients with grades
III–IV mucositis, the subsequent cycle of chemotherapy is
delayed. A grade IV mucositis is an emergency situation in
oncology, ethically demanding to relieve the patient’s situation.
The recent evidence-based management guidelines from the
Multinational Association of Supportive Care in Cancer [12]
make several recommendations to provide a better patient
comfort including good oral hygiene, oral decontamination
with antibacterial and antifungal mouthwash and topical and
systemic pain management.
Numerous substances have been used in addition to treat
oral mucositis such as ice chips [13, 14], antioxidants as
glutamine, N-acetylcysteine, benzydamine hydrochloride and
antiinflammatory agents like prostaglandine E1 and E2 [15].
Until now none of them has proven an unequivocal clinical
benefit.
Palifermin is a recombinant human keratinocyte growth
factor (KGF) which is known to stimulate growth of epithelial
cells in a wide variety of tissues. In murine models, a beneficial
effect on mucositis could be shown [16]. In December 2004,
the Food and Drug Administration approved palifermin
(recombinant KGF from Escherichia coli, Amgen, Thousand
Oaks, CA, USA) on the basis of randomized data showing
ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected]
original article
Annals of Oncology
a decrease of incidence and duration of severe oral mucositis in
patients with hematologic malignancies receiving myelotoxic
therapy requiring hematopoietic stem-cell support [17].
Therefore, the updated guidelines of the Multinational
Association of Supportive Care in Cancer recommend the use
of palifermin in patients who are receiving high-dose
chemotherapy and total body irradiation with autologous stemcell transplantation (level 1, grade A recommendation) [12].
KGF receptors are present on epithelial cells in many tissues
including the tongue, buccal mucosa, salivary gland, esophagus,
stomach, intestine, lung, liver, pancreas, kidney, bladder,
mammary gland and eye lens as well as on tumor cells of
different histology [18]. Receptors could not be found on
lymphoma and lymphoblastic leukemia cell lines [18].
The mechanism of action of palifermin in mucositis is not
completely elucidated. It leads to a down-regulation of
proinflammatory cytokines [19] and increases
antiinflammatory cytokines such as IL-13 [20, 21]. Palifermin
protects the epithelium against reactive oxygen molecules by
modifying the expression of detoxifying transcription factors
and enzymes [22].
In this series, we observed patients who were treated in the
GMALL-B-ALL/B-NHL 2002 protocol, which is based on HDMTX and is used for certain aggressive B-cell lymphomas and
lymphoblastic leukemias. The incidence of grades III–IV
(World Health Organization, WHO, oral toxicity scale, Miller
et al. [23]) mucositis upon HD-MTX within this protocol
ranges from 56% (cycle A1) to 32% (cycle B1) as described by
Hoelzer et al. [24]. Another study shows a mucositis rate of
42% [25]. The data of the B-NHL90 trial (GMALL study
group) with 3 g MTX/m2 (>55 years 500 mg MTX/m2) showed
a grade III (Donelly scale) mucositis rate of 41%–54% in cycle
A1 and 61%–75% in cycle B1. In previous trials (B-NHL 83,
B-NHL 86), mucositis grades I–IV were observed in 50%–53%
of chemotherapy cycles [26].
All patients reported here developed a severe mucositis in
cycle A1 or B1. In order to prevent additional mucositis, these
patients received palifermin for the corresponding following
cycles of similar or identical chemotherapy. Thus, patients in
this retrospective series can serve as their own control for
efficacy of palifermin in preventing mucositis.
patients and methods
patients
We report on a retrospective series of 10 patients with B-cell acute
lymphoblastic leukemia (B-ALL) and aggressive B-cell lymphoma classified
according to the WHO classification. Patients’ characteristics are given in
Table 1. We have included only patients into this report who developed
severe mucositis in initial treatment cycle A1 or B1 without palifermin and
were then given palifermin in the subsequent treatment cycles.
treatment protocol
The patients were treated from September 2004 to March 2007 on protocol
GM-ALL-B-ALL/B-NHL 2002 (upon approval by ethical board and written
informed consent) and developed severe mucositis. The protocol outline
with age-related dose modifications is depicted in Figure 1. Two of
10 patients were treated in the protocol for patients >55 years of age with
a slightly reduced MTX dosage (500 mg/m2 compared with 1500 mg/m2).
One patient was treated in the ‘elderly protocol’.
Volume 19 | No. 9 | September 2008
Eight of 10 patients received a ‘run-in’ therapy (prephase) of 5 days
with prednisone 60 mg/m2 and cyclophosphamide 200 mg/m2 before the
cycle A1. Two patients with mediastinal B-cell non-Hodgkin’s lymphoma
(B-NHL) did not receive any prephase therapy.
Patients with mucositis in cycle A1 or B1 received prophylaxis and
supportive treatment including morphine, tetracaine-, panthenole and
camomile-containing mouthwashes, oral hygiene and amphotericin B
suspensions to prevent intestinal candidosis. All patients received
recombinant granulocyte colony-stimulating factor (G-CSF) to shorten the
time of grade IV neutropenia. Prophylactic oral hygiene, amphotericin B
and G-CSF were not changed during the subsequent cycles.
grading of mucositis
Mucositis grade was judged daily by the four-point WHO scale [23]. The
observation was carried out by the authors and, to ensure uniformity of
judgment, by the first and the last author during the time of mucositis
maximum. All these patients developed severe WHO grades III–IV oral
mucositis in the cycle A1 (seven of 10) or B1 (three of 10). One of these
patients (number 9, Table 1) did not get MTX in cycle A1 because of
a surgical bowel intervention.
palifermin application
Because of their mucositis, all 10 patients obtained palifermin (Kepivance,
Amgen) for 3 days before and another 3 days after the following
corresponding chemotherapy cycle (A2 or B2) to reduce the risk of further
higher grade mucositis. Prior written informed consent was obligatory.
Palifermin dose was 60 lg/kg/day, which is the full dose recommended or
a lower daily dose as outlined in Table 1.
results
Figure 2A and B depicts the maximum grade of mucositis
observed in chemotherapy cycles A1/B1 without palifermin
versus A2/B2 with palifermin support. Evaluated together, there
were 16 episodes of severe grade IV and one grade III mucositis
in the chemotherapy cycles without palifermin support. In
contrast, we have observed only one episode of grade IV, four
episodes of grade III and four episodes of grade II mucositis
during the chemotherapy cycles with palifermin support
(difference P < 0.05, Mann–Whitney–Wilcoxon test).
The amount of i.v. opioid analgetics could be reduced from
a total of 2403 mg morphine in cycle A1 (3380 mg cycle B1)
without palifermin to 640 mg in cycle A2 (480 mg cycle B2)
with palifermin (difference P < 0.05, Mann–Whitney–Wilcoxon
test). The intraindividual dose changes are presented in
Figure 3A and B.
Furthermore, the duration of mucositis in patients who
acquired a higher grade mucositis despite treatment with
palifermin could be slightly reduced. The median duration of
grade III/IV mucositis without palifermin was 12.9 days
(16 cycles with mucositis) with a range from 7 to 18 days. The
median duration of grades III–IV mucositis with palifermin
was 11 days with a range from 10 to 13 days (not significant,
Mann–Whitney–Wilcoxon test). In this evaluation, patients
not developing severe mucositis under palifermin protection
were not included.
Ten of 10 patients developed a severe infection in cycle A1 or
B1 without palifermin. Severe infection is defined as fever
(>38.5C) in neutropenia which had to be treated with empiric
systemic antibiotic therapy. In the palifermin-supported
chemotherapy cycles, only four of 10 patients showed a severe
doi:10.1093/annonc/mdn179 | 1645
original article
Annals of Oncology
Table 1. Patients treated in the GMALL-B-ALL/B-NHL 2002 protocol (severe infection is defined as body temperature >38.5C and use of systemic
antibiotics)
Patient ID No.
Diagnosis
Maximum grade
of mucositis (WHO)
Without palifermin
Maximum grade
of mucositis (WHO)
With palifermin
Dosage of palifermin
1
B-ALL
Grade 1 A2–C2 10 days
2
Burkitt-like
lymphoma
A2 60 lg/kg bodyweight
(BW); B2 and C2
30 lg/kg BW
A2–C2 60 lg/kg BW;
B1 30 lg/kg BW
3
Mediastinal B-NHL
Grade IV, A1, 12 days;
Grade III, B1, 8 days;
infection A1, B1
Grade IV, A1, 15 days;
grade III, C1, 14 days;
infection A1, C1
Grade IV B1, 15 days;
infection B1
4
Mediastinal B-NHL
5
B-ALL
6
Burkitt lymphoma
7
Atypical Burkitt
lymphoma
8
B-ALL, elderly
protocol
Burkitt lymphoma
9
10
B-ALL
A2–C2 60 lg/kg BW;
C1 30 lg/kg BW
d23 to 21; 60 lg/kg
BW d1–3 after
chemotherapy
A2–C2 30 lg/kg
BW
Grade II C1, 4 days
Grade I A2
Grade IV A1, 10 days;
grade III B1, 13 days;
infection A1–C1
Grade IV A1, 13 days;
grade III, B1 7 days;
infection A1
Grade II, A1, 4 days;
grade IV, B1 18 days;
grade III, C1, 18 days;
infection A1, C1
Grade IV B1, 12 days;
grade II A1, 5 days;
infection A1, B1, C1
Grade IV A1, 16 days;
infection A1
Grade IV B1, 12 days;
infection B1
Grade IV A1, 14 days;
grade IV B1, 8 days;
infection A1, B1
Grade II B1/B2, 3 days;
infection B2
Grade III C1 13 days;
grade III A2, 10 days
Grade I A2-C2, 7 days;
grade III C1, 10 days;
infection C1
infection. Interestingly, infection is associated with a higher
grade mucositis.
Since cycles A1 and A2 contain identical (with the exception
of the run-in phase of corticosteroids and cyclophosphamide
given to eight of 10 patients before A1) and cycles B1 and B2
contain identical chemotherapy, patients can serve as their own
controls for the antimucositis efficacy of palifermin. Figure 4
documents the maximum appearance of mucositis in three
patients at identical times following chemotherapy cycles
without (part A, C and E) or with palifermin (part B, D and F)
support. Only three individual cycle comparisons for two
patients (numbers 7 and 9, Figure 2, Table 1) did not show an
improvement of mucositis severity by palifermin. Patient
number 10 did receive palifermin in cycle C1, but showed
a grade III mucositis. However, in the corresponding cycle C2,
a mucositis of only grade I was observed.
As we report on an individual patient series, there was
some variation in the course of supportive palifermin
treatment concerning individual cases and these are depicted
in Table 1.
1646 | Schmidt et al.
Grade II, B1, 9 days;
grade II, B2, 7 days
Grade II cycle B2, 5 days
A2–C2 30 lg/kg
BW
Grade I, A2, 6 days;
grade I, B2, 7 days;
infection A2, B2
A2 40 lg/kg BW;
B2–C2 50 lg/kg
BW
Grade III, A2, 10 days;
grade IV, B2, 12 days;
infection A2
A2-B2, 60 lg/kg BW;
protocol could not be
finished because of
infectious complications
40 lg/kg BW B1–B3
60 lg/kg BW
60 lg/kg BW C1–C2
discussion
We report descriptive observation data from 10 patients who
were treated in the trial protocol GM-ALL-B-ALL/NHL 2002 or
the respective protocol for elderly patients (one patient) and
developed severe mucositis. In summary, we observed
a considerable effect of palifermin reducing the dosage of i.v.
morphine, severity, duration and clinical sequelae (such as
infection) of mucositis when similar (A1/A2) or identical
(B1/B2) chemotherapy cycles without palifermin support were
compared with those with palifermin support in identical
patients.
Recently, palifermin has been described to reduce the
prevalence and severity of oral mucositis in patients with
hematologic malignancies undergoing high-dose therapy with
autologous peripheral blood stem-cell transplantation [17].
However, there are also standard chemotherapy regimens not
requiring stem-cell support, which can be associated with
severe mucositis. In a placebo-controlled phase II study
published recently, it was demonstrated that palifermin is
Volume 19 | No. 9 | September 2008
original article
Annals of Oncology
Figure 1. Prephase: cyclophosphamide 200 mg/m2 d1–5, prednisone 60 mg/m2 d1–5. Cycle A1/A2: rituximab 375 mg/m2 d7 (A2 d77); dexamethasone
10 mg/m2 d8–12 (A2 d78–82); vincristine 2 mg d8 (A2 d78); MTX 1500 mg/m2 (500 mg/m2 > 55 years) d8 (A2 d78); ifosfamide 800 mg d8–12 (A2 d78–82);
cytarabine 2 · 150 mg/m2 d11–12 (A2 d81–82); VP16 100 mg/m2 d11–12 (A2 d81–82); cytarabine 40 mg i.th. d8, 12 (A2 d78, 82); MTX 15 mg i.th. d8, 12
(A2 d78, 82); dexamethasone 4 mg i.th. d8, 12 (A2 d78, 82). Cycle B1/B2: rituximab 375 mg/m2 d28 (B2 d98); dexamethasone 10 mg/m2 p.o. d29–33 (B2
99–103); vincristine 2 mg d29 (B2 d99); MTX 1500 mg/m2 (500 mg/m2 > 55 years) d29 (B2 d99); cyclophosphamide 200 mg/m2 d29–33 (B2 99–103);
adriamycine 25 mg/m2 d32–33 (B2 d102–103); cytarabine 40 mg i.th. d29, 33 (B2 d99, 103); MTX 15 mg i.th. d29, 33 (B2 d99, 103); dexamethasone 4 mg
i.th. d29, 33 (B2 d99, 103). Cycle C1/C2: rituximab 375 mg/m2 d49 (C2 d119); dexamethasone 10 mg/m2 p.o. d50–54 (C2 120–124); vindesine 3 mg/m2
maximum 5 mg d50 (C2 120); MTX 1500 mg/m2 (500 mg/m2 > 55 years) d50 (C2 d120); VP16 250 mg/m2 d53–54 (C2 d123–124); cytarabine 2 · 2 g/m2
(2 · 1 g/m2 > 55 years) d54 (C2 d124). Protocol for elderly patients: Prephase: cyclophosphamide 200 mg/m2 d1–5, prednisone 60 mg/m2 d1–5. Cycle
A1/A2/A3: rituximab 375 mg/m2 d7 (A2 d49, A3 d98); dexamethasone 10 mg/m2 d8–12 (A2 d50–54, A3 99–103); MTX 500 mg/m2 d8 (A2 d50, A3 99);
ifosfamide 400 mg d8–12 (A2 d50–54, A3 99–103); cytarabine 2 · 60 mg/m2 d11–12 (A2 d53–54, A3 d102–103); VP16 60 mg/m2 d11–12 (A2 d53–54, A3
d102–103); MTX 12 mg i.th. d8 (A2 d50, A3 99). Cycle B1/B2/B3: rituximab 375 mg/m2 d28 (B2 d77, B3 d119); dexamethasone 10 mg/m2 p.o. d29–33 B2
78–82, B3 d120–124); vincristine 1 mg d29 (B2 d78, B3 d120); MTX 500 mg/m2 d29 (B2 d78, B3 d120); cyclophosphamide 200 mg/m2 d29–33 (B2 78–82,
B3 120–124); adriamycine 25 mg/m2 d32–33 (B2 d81–82, B3 123–124); MTX 12 mg i.th. d29 (B2 d78, B3 120).
A
WHO
grade oral
mucositis
IV
8
1 10
24
5
III
II
IV
III
7
9
6 7
9 3
block A1
-palifermin
98 7
10
6
7
3
1 4
5
2
8
1 4
6 10
I
B
WHO
grade oral
mucositis
II
8
2
5
6
10
1 34 9
I
5
3 2
block A2
+ palifermin
block B1
-palifermin
block B2
+ palifermin
Figure 2. (A) Maximum grade mucositis with and without palifermin in cycles A1 versus A2 (P < 0.05, Mann–Whitney–Wilcoxon test). Numbers in circles
refer to patients as given in Table 1. Patient 9 did not receive MTX during cycle A1. (B) Maximum grade mucositis with and without palifermin in cycles B1
versus B2 (P < 0.05, Mann–Whitney–Wilcoxon test). Numbers in circles refer to patients as given in Table 1. Patient 2 received palifermin in cycle B1.
effective in reducing the incidence of oral mucositis in patients
with metastatic colorectal cancer undergoing 5-fluorouracil/
calcium folinate chemotherapy [27]. In contrast to these data,
a recently published Cochrane review about ‘Interventions
for preventing oral mucositis for patients with cancer receiving
treatment’ by Worthington et al. [28] on the basis of three
randomized trials [17, 29, 30] shows that there is no statistically
significant difference between palifermin/repifermin and
Volume 19 | No. 9 | September 2008
placebo. It was concluded that recombinant KGF could not be
supported or refuted as more or less effective than placebo
due to insufficient evidence. However, HD-MTX-based
chemotherapy is well known to be associated with high
mucositis rates and MTX-based chemotherapy regimen was not
included in the Cochrane review [28]. This opens the possibility
that there might be a stronger mucositis-preventive effect
of palifermin in MTX-based chemotherapy.
doi:10.1093/annonc/mdn179 | 1647
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Annals of Oncology
A
Morphine
dose / mg
B
Morphine
dose / mg
9
5
7
500
3
8
500
7
7
1
1
2
6
10
54
4
10
9
7936
cycle A1 without
palifermin
6 310 4 21 5 8
cycle A2 with
palifermin
8
6 3 10 4 2 1 5 8 9
cycle B1 without
palifermin
cycle B2 with
palifermin
Figure 3. (A) Total amount of i.v. given morphine (in milligram) with and without palifermin in cycles A1 versus A2 (P < 0.05, Mann–Whitney–Wilcoxon
test). Numbers in diamonds refer to patients as given in Table 1. Patient 9 did not receive MTX during cycle A1. (B) Total amount of i.v. given morphine (in
milligram) with and without palifermin in cycles B1 versus B2 (P < 0.05, Mann–Whitney–Wilcoxon test). Numbers in diamonds refer to patients as given in
Table 1. Patient 2 received palifermin during cycle B1 and developed no higher grade mucositis.
Figure 4. (A) Grade IV mucositis at day 13 after cycle B1 without
palifermin support (patient 3, Table 1). (B) Grade I mucositis and
hyperkeratosis at day 13 after cycle B2 with palifermin support (patient 3,
Table 1). (C) Grade III mucositis at day 11 after cycle B1 without
palifermin support (patient 10, Table 1). (D) Grade I mucositis at day 12
after cycle B2 with palifermin support (patient 10, Table 1). (E) Grade IV
mucositis at day 11 after cycle B1 without palifermin support (patient 6,
Table 1). (F) Grade I mucositis at day 10 after cycle B2 with palifermin
support (patient 6, Table 1).
1648 | Schmidt et al.
The cases reported here receiving HD-MTX provide evidence
that palifermin might reduce the risk of oral mucositis and its
severe side-effects such as infections. Our data lead to the
suggestion that the effect is due to palifermin. In cycle A1, the
incidence of mucositis could be increased by the application of
the run-in therapy. Therefore, it cannot be completely excluded
that the decrease in mucositis rate is partly caused by the
absence of the run-in therapy in the subsequent cycles. This,
however, is not the case in cycles B1 and B2, where treatment is
identical. Furthermore, it seems theoretically possible that
single patients may tolerate subsequent cycles of chemotherapy
with a less severe mucositis than the first cycle. This, however, is
not in line with our experience treating patients in the time
before accessability of palifermin. With two exceptions (both
obtaining the run-in treatment in the first cycles), every patient
had a benefit with a reduction in mucositis grade and also
shown by the amount of opioid analgetics given during the
mucositis period. Having used palifermin for a while in our
department, patients started to actively ask for off-label use
of this specific drug for mucositis prevention and refused
HD-MTX-containing chemotherapy without. Furthermore,
our observations suggest the possibility of a dose reduction for
palifermin which should be further studied.
However, this is a report on a case series with retrospective
evaluation and cannot replace prospective, controlled studies
which should be carried out before the use of palifermin in
HD-MTX regimen can be recommended as standard of care for
mucositis prevention in HD-MTX chemotherapy.
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