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The Prospective Oral Mucositis Audit: relationship of severe oral mucositis with clinical and medical resource use outcomes in patients receiving high-dose melphalan or BEAM-conditioning chemotherapy and autologous SCT

Authors:
  • University of Basel / University of Zürich
  • University Hospital Würzurg, Germany

Abstract and Figures

The Prospective Oral Mucositis Audit was an observational study in 197 patients with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL) undergoing, respectively, high-dose melphalan or BEAM chemotherapy and autologous SCT at 25 European centres. We evaluated the relationship between severe oral mucositis (SOM; WHO Oral Toxicity Scale grade 3-4) and local and systemic clinical sequelae and medical resource use. SOM occurred in 44% of patients. The duration of SOM (mean 5.3 days) correlated with time to neutrophil engraftment. The following parameters increased gradiently with maximum grade of oral mucositis: duration of pain score >or=4, opioid use, dysphagia score >or=4, total parenteral nutrition (TPN) use, incidence and/or duration of fever and infection, and duration of antibiotic use. SOM increased the duration of TPN use by 2.7 days (P<0.001), opioids by 4.6 days (P<0.001), and antibiotics by 2.4 days (P=0.045). SOM prolonged hospital stay by 2.3 days (P=0.013) in MM patients, but not in NHL patients (who tended to have a longer hospital stay). In conclusion, this analysis of prospectively collected observational data provides important insight into the scope and impact of SOM in the European transplant setting.
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ORIGINAL ARTICLE
The Prospective Oral Mucositis Audit: relationship of severe oral mucositis
with clinical and medical resource use outcomes in patients receiving
high-dose melphalan or BEAM-conditioning chemotherapy and
autologous SCT
S McCann
1
, M Schwenkglenks
2
, P Bacon
3
, H Einsele
4
, A D’Addio
5
, J Maertens
6
, D Niederwieser
7
,
W Rabitsch
8
, A Roosaar
9
, T Ruutu
10
, H Schouten
11
, R Stone
12
, S Vorkurka
13
, B Quinn
14
and N Blijlevens
15
, on behalf of the EBMT Mucositis Advisory Group
1
Department of Haematology, St James’s Hospital, Dublin, Ireland;
2
European Center of Pharmaceutical Medicine, II Department
of Internal Medicine, Hematology/Oncology, University of Basel, Basel, Switzerland;
3
Amgen (Europe) GmbH, Zug, Switzerland;
4
Department of Internal Medicine II, Julius Maximilian’s University of Wu
¨rzburg, Wu
¨rzburg, Germany;
5
Institute of Haematology
and Medical Oncology ‘L. and A. Seragnoli’, Bologna, Italy;
6
Department of Haematology, Universitaire Ziekenhuizen Leuven,
Catholic University, Leuven, Belgium;
7
Department of Haematology and Oncology, University of Leipzig, Leipzig, Germany;
8
BMT
Unit, Medical University of Vienna, Vienna, Austria;
9
Karolinska Institutet, Institute of Odontology, Huddinge, Sweden;
10
Helsinki
University Central Hospital, Helsinki, Finland;
11
University Hospital Maastricht, Maastricht, The Netherlands;
12
Nottingham City
Hospital NHS Trust, Nottingham, UK;
13
University Hospital Alej Svobody 80, Plzen, Czech Republic;
14
St George’s Hospital,
London, UK and
15
Department of Haematology, University Medical Centre St Radboud, Nijmegen, The Netherlands
The Prospective Oral Mucositis Audit was an observa-
tional study in 197 patients with multiple myeloma (MM)
or non-Hodgkin’s lymphoma (NHL) undergoing, respec-
tively, high-dose melphalan or BEAM chemotherapy and
autologous SCT at 25 European centres. We evaluated
the relationship between severe oral mucositis (SOM;
WHO Oral Toxicity Scale grade 3–4) and local and
systemic clinical sequelae and medical resource use. SOM
occurred in 44% of patients. The duration of SOM (mean
5.3 days) correlated with time to neutrophil engraftment.
The following parameters increased gradiently with
maximum grade of oral mucositis: duration of pain score
X4, opioid use, dysphagia score X4, total parenteral
nutrition (TPN) use, incidence and/or duration of fever
and infection, and duration of antibiotic use. SOM
increased the duration of TPN use by 2.7 days
(Po0.001), opioids by 4.6 days (Po0.001), and anti-
biotics by 2.4 days (P¼0.045). SOM prolonged hospital
stay by 2.3 days (P¼0.013) in MM patients, but not in
NHL patients (who tended to have a longer hospital stay).
In conclusion, this analysis of prospectively collected
observational data provides important insight into the
scope and impact of SOM in the European transplant
setting.
Bone Marrow Transplantation (2009) 43, 141–147;
doi:10.1038/bmt.2008.299; published online 8 September 2008
Keywords: oral mucositis; multiple myeloma; non-
Hodgkin’s lymphoma; high-dose chemotherapy; medical
resource use
Introduction
Oral mucositis (OM) is a very common debilitating adverse
event in patients receiving high-dose chemotherapy and
SCT,
1
and results from damage to both epithelial and
submucosal tissues by the conditioning regimen.
2
Clinical
manifestations of OM include signs and symptoms of an
inflammatory process, ranging from mild erythema, oede-
ma and soreness to extreme pain and ulceration. Severe
OM interferes with daily activities such as speaking, eating
and swallowing and has a negative impact on quality of
life.
3,4
It can lead to dehydration, malnutrition and serious
infections
5–8
and has been linked to inferior overall survival
(P¼0.002) after SCT.
6
Several US-based analyses from various cancer settings
have demonstrated that severe OM increases healthcare
resource utilization by necessitating opioid analgesia, anti-
infective treatment, total parenteral nutrition (TPN) and
subsequently prolonging hospitalization.
3,5,8,9
However,
medical resource use in relation to OM has not been
systematically assessed in the European SCT setting,
although a recently published overview provided insights
in the management of OM in European transplantation
centres.
10
The Prospective Oral Mucositis Audit (POMA), con-
ducted by our group in 25 centres across 13 European
countries, was the first multi-country audit study with OM
Received 24 April 2008; revised 17 July 2008; accepted 19 July 2008;
published online 8 September 2008
Correspondence: Professor S McCann, Department of Haematology,
Durkan Building, Trinity Centre, St James’s Hospital, Dublin 8, Ireland.
E-mail: smccann@stjames.ie
Bone Marrow Transplantation (2009) 43, 141–147
&2009 Macmillan Publishers Limited All rights reserved 0268-3369/09 $32.00
www.nature.com/bmt
occurrence as the primary objective. The first part of the
analysis (described in our initial paper) revealed a high
incidence of severe (World Health Organization (WHO)
oral toxicity scale grade 3–4)
11
OM (44%) in patients with
multiple myeloma (MM) or non-Hodgkin’s lymphoma
(NHL) who underwent high-dose dose melphalan or
BEAM conditioning, respectively and autologous SCT.
1
Severe OM risk and/or duration were significantly asso-
ciated with higher chemotherapy dose per kg body weight
and poor performance status, but in contrast to some
previous reports they were not related to age.
The POMA study also aimed to evaluate the clinical
sequelae of OM, including pain, dysphagia, fever and
infection, and to examine its impact on the use of
healthcare resources, including TPN, opioids and anti-
biotics, and duration of hospitalization. We present here
the results of these analyses.
Patients and methods
Study design and patient population
The POMA design has been described previously.
1
In
brief, this prospective, observational audit recruited 197
adult patients with MM or NHL who received high-
dose melphalan (200 mg/m
2
; MM patients) or BEAM
(carmustine 300 mg/m
2
, etoposide 800 mg/m
2
, cytarabine
800–1600 mg/m
2
and melphalan 140 mg/m
2
; NHL patients)
conditioning chemotherapy followed by autologous SCT.
Exclusion criteria were previous SCT/BMT, palifermin
administration and presence of oral abnormalities at
baseline. Prophylaxis and treatment for OM and its clinical
sequelae were according to local clinical practice. Ethical
approval was obtained according to country-specific
requirements and all patients provided written informed
consent.
Patients were selected from European transplant units,
which had a history of reporting patients to the European
Society for Bone and Marrow Transplantation registry.
Centres were selected in which patients received autografts
as inpatients to monitor ‘mucositis’ accurately. Centres
were selected to represent a wide spectrum of European
countries and to allow training of nurses to be a practical
proposition.
Study assessments and data collection
Data collection included baseline demographic and medical
characteristics and type and dosage of conditioning
chemotherapy. OM assessments were conducted daily from
day 1 of conditioning chemotherapy until 30 days post
transplantation or hospital discharge (whichever occurred
first), using the five-point WHO oral toxicity scale (grade 1:
soreness and erythema, no further symptoms; grade 2:
ulcers present, but solid diet possible; grade 3: only liquids
can be swallowed; grade 4: oral alimentation impossible).
To achieve consistent high-quality OM assessment, on-site
nurse assessors and physicians underwent an intensive
training programme.
12
Ulcerative OM was defined as WHO
scale score 2–4 and severe OM as WHO scale score 3–4.
Specific 10-point scales were used to record local signs and
symptoms of severe OM (0 ¼no symptoms present;
10 ¼worst possible symptoms, as judged by patients).
Body temperature was recorded on the daily OM assess-
ment forms. Time to neutrophil engraftment (40.5 10
9
/l)
was retrieved from the European Society for Bone and
Marrow Transplantation Promise database. Information
on infections and use of medical resources, including
medications used for OM prophylaxis and treatment was
obtained from the study sites. Medication categories
included mouthwashes, opioid analgesics, antibiotics, anti-
fungals, antivirals and other medications. These categories
were not prospectively defined and were therefore open to
interpretation by site staff. However, drug names were
requested for verification purposes (except in the case of
mouthwashes, as local preparations were often used). No
on-site monitoring was performed for this study.
Statistical methodology
Clinical end points included in this analysis were: WHO
oral toxicity scale score; duration of pain score X4, and
dysphagia score X4; incidence and duration of fever
(X38.0 1C), incidence of infection (clinically defined or
microbiologically confirmed) and of microbiologically
confirmed bacterial infection before day 30 post transplant-
ation, and time to neutrophil engraftment. Medical
resource utilization end points were duration of TPN,
opioid analgesic and antibiotic use and duration of
hospitalization.
The WHO scoring system was chosen because most
European transplant centres were familiar with this
instrument based on a survey by the nurses’ group of the
European Society for Bone and Marrow Transplantation.
10
Missing WHO scale and pain score values during the
audit period were interpolated and missing values at
the beginning or end of the audit period extrapolated. For
the purpose of longitudinal assessments, a grade of 0 was
also imputed after patient discharge and fever and
dysphagia were assumed to be absent after patient
discharge. Temporal patterns were assessed by plotting
mean daily WHO scale-based OM scores and applicable
symptom-specific scores over the audit period. The propor-
tion of patients with fever was plotted in a similar way.
Using univariate analyses, associations of interest
were assessed using the w
2
test, the non-parametric
Mann–Whitney U-test or the Spearman’s correlation
coefficient and its P-value, as appropriate. Multivariate
Poisson regression was used to further assess the impact of
severe OM on the duration of hospitalization. Parameters
that were explored as potential determinants of length of
hospital stay included baseline characteristics (age, sex,
weight, height, body surface area, Eastern Cooperative
Oncology Group (ECOG) performance status, type and
dosage of chemotherapy), time to neutrophil engraftment,
as well as infection-related parameters (incidence and
duration of fever and incidence of infection and micro-
biologically confirmed bacterial infection before day 30
post transplantation—which would be difficult to interpret
in models of OM occurrence).
Random effects modelling was used to assess possible
distortions of the main study results by centre effects.
Oral mucositis: clinical and healthcare resource outcomes
S McCann et al
142
Bone Marrow Transplantation
Poisson regression used generalized estimation equations
(GEE)-based robust s.e. estimates to allow for clustering by
study centre. Statistical analyses were performed using the
STATA/SE version 9 statistical software package. Statis-
tical tests were two-sided at the 5% significance level. Two-
sided 95% confidence intervals are shown.
Results
Study population
Patient baseline characteristics and conditioning chemo-
therapy doses for the 197 evaluable patients enrolled into
POMA (109 patients (55. 3%) with MM and 88 (44.7%)
with NHL) are summarized in Table 1. Mean recruitment
per centre±s.d. was 7.9±4.8 patients (range, 1–18). In the
MM group, the mean age was higher and there were fewer
women, consistent with the epidemiology of this disease.
The audit period lasted (mean±s.d.) 19.8±4.5 days in the
MM group and 22.4±3.7 days in the NHL group. The time
from first chemotherapy administration to transplantation
was longer in the NHL group than in the MM group
(median 7 vs 3 days), as BEAM is typically administered
over 5 days and high-dose melphalan over 1–2 days.
Patients received various types of OM prophylaxis,
including mouthwashes (78% of patients), antibiotics
(36%), antifungals (54%) and antivirals (44%), according
to local practice. The most frequently used antifungal
substance was fluconazole, followed by itraconazole,
systemic or local amphotericin B, and nystatin. Antivirals
were aciclovir or valaciclovir.
Evolution of OM
A total of 87 (44.2%). of 197 patients experienced severe
OM (46% in patients with MM and 42% in patients with
NHL), with a mean duration of 5.3±3.2 days: there were
no relevant differences between MM and NHL patients
with regard to these end points. A significant amount of
variation between centres with respect to these end points
was noted but random effects modelling yielded no
indication of a related distortion of the overall results.
The temporal relationship of WHO scale score with pain
and dysphagia scores, fever and neutrophil engraftment is
shown in Figure 1. The median onset of ulcerative OM and
of severe OM was on days 11 and 12, respectively, after the
start of conditioning chemotherapy. This coincided with
median onset of fever, infection and microbiologically
confirmed bacterial infection, both in patients with and in
patients without severe OM. The peak level of discomfort
was experienced on days 12–13 and this coincided with the
beginning of neutrophil engraftment (Figure 1). The
relationship of maximum grade of OM and clinical and
healthcare resource outcomes is summarized in Table 2.
Pain and opioid use
Not surprisingly, the duration of pain score X4 increased
gradiently with the maximum WHO OM scale score
(Po0.001), reaching a mean duration of 6.5 days in
patients with WHO grade 4 OM. Opioid analgesic use also
increased across the OM grades (Po0.001), patients with
Table 1 Patient demographics, baseline medical characteristics and treatment regimens, mean±s.d. (range) except where indicated
Multiple myeloma Non-Hodgkin’s lymphoma
nObserved value nObserved value
Age (years) 109 56.8 (39–73) 88 50.0 (18–69)
Female sex, n(%) 109 40 (36.7) 88 44 (50.0)
BSA 108 1.9 (1.4–2.4) 88 1.8 (1.3–2.7)
ECOG status, n (%)
0 59 (55.1) 67 (76.1)
1 42 (39.3) 16 (18.2)
2 5 (4.7) 5 (5.7)
3 1 (0.9) 0 (0.0)
Melphalan dose, mg/m
2
BSA
a
105 196±11 (136–219) 85 137 (115–151)
Carmustine, mg/m
2
BSA
a,b
85 290±35 (0–322)
Etoposide, mg/m
2
BSA
a
84 835±201 (598–1615)
Cytarabine, mg/m
2
BSA
a
83 1388±330 (735–1720)
Observation time, median days (range) 109 19 (4–33) 88 22 (15–39)
Abbreviations: BSA ¼body surface area; ECOG ¼Eastern Cooperative Oncology Group.
a
Dose actually administered.
b
Carmustine was omitted from the conditioning regimen in one non-Hodgkin’s lymphoma patient.
0
010
Day of assessment
20 30 40
1
Mean WHO / pain /
dysphagia score
2
3
4
0
0.25
Proportion of pts. with fever
/
proportion of pts. engrafted
0.5
0.75
1
Figure 1 Evolution of mean WHO oral toxicity scale, pain and dysphagia
scores and proportions of patients with fever and neutrophil engraftment.
This assumes a standardized observation time of 39 days and zero score
values and proportions after the patients’ individual audit periods. Based
on n¼197 patients (193 with engraftment data).
Oral mucositis: clinical and healthcare resource outcomes
S McCann et al
143
Bone Marrow Transplantation
severe OM requiring an additional 4.6 days of opioid use
(Po0.001) compared with those without severe OM
(Table 2).
Dysphagia and TPN use
The duration of dysphagia score X4 increased with
increasing maximum WHO OM scale score (Po0.001),
reaching a mean duration of 8.4 days in patients with WHO
grade 4 OM. Duration of use of TPN (averaged across all
patients including those who did not receive TPN) also
increased across OM grades (Table 2), patients with severe
OM receiving an additional 2.7 days of TPN compared
with those without severe OM; (Po0.001). The incidence of
TPN use ranged from 19% in patients with no OM to 59%
in patients with WHO grade 4 OM. It was 35% across all
patients.
Fever and antibiotic use
Fever, infection and microbiologically confirmed infection,
increased with increasing grade of OM (Table 2). Compar-
ison of patients with and without severe OM showed that
patients with severe OM had a higher incidence of fever (68
vs 47% of patients; difference 21%; P¼0.004), infection
(42 vs 24%; P¼0.013) and microbiologically confirmed
bacterial infection (27 vs 12%; P¼0.013), and a longer
duration of fever (4.2 vs 3.0 days; P¼0.033). The duration
of severe OM (in patients who developed severe OM)
mostly showed the same associations, but it was not
significantly associated with the incidence of infection or of
microbiologically confirmed bacterial infection (data not
shown).
Combined duration of antibiotic use with prophylactic
and therapeutic intent also increased across OM grades
(Table 2), patients with severe OM receiving an additional
2.4 days of antibiotics (P¼0.045) compared with those
without severe OM.
Neutrophil engraftment
Time to neutrophil engraftment did not show any clear
correlation with the maximum grade of OM (Table 2) or
severe OM incidence, but it was positively correlated with
the duration of severe OM (Spearman’s correlation
coefficient 0.27; P¼0.012). This observation was confirmed
when time to neutrophil engraftment was tentatively
allowed as an additional covariate in the multivariate
analysis of severe OM duration (Po0.001), as noted in our
earlier analysis.
1
Length of hospital stay
Length of hospital stay increased with increasing severity of
OM in patients with MM, ranging from 17.0±5.4 days in
patients with no OM to 21.5±3.7 days in patients with
grade 4 OM, with severe OM prolonging hospital stay by
2.3 days (P¼0.013). However this trend was less clear in
patients with NHL, who tended to have a longer hospital
stay than patients with MM (Table 2).
Multivariate Poisson regression analysis showed that
higher age, higher baseline Eastern Cooperative Oncology
Group performance status, longer duration of severe OM,
longer time from start of conditioning to transplantation
and longer time from transplantation to neutrophil
engraftment were associated with significantly longer
hospitalization (Table 3). The impact of duration of severe
OM on duration of hospitalization was attenuated by both
time to transplantation and time to neutrophil engraftment
(Table 3) (indicating that the effect of duration of severe
OM on hospital stay is reduced if hospitalization is
prolonged anyway). When indicators of fever or infection
were added to the model, the effect of severe OM duration
Table 2 Relationship between maximum grade of OM and clinical and health resource outcomes
Outcome Maximum WHO scale score (no. of patients)
a
P
b
0(n¼26) 1 (n¼45) 2 (n¼39) 3 (n¼60) 4 (n¼27)
Clinical end points
c
Pain score X4, days 0.1±0.3 0.9±1.9 1.5±2.3 5.2±4.0 6.5±3.6 o0.001
Dysphagia score X4, days 1.1±2.5 1.1±2.5 2.4±3.3 6.4±3.8 8.4±3.8 o0.001
Fever X38 1C, no. of patients (%) 8 (30.8) 21 (46.7) 23 (59.0) 38 (63.3) 21 (77.7) o0.001
Fever X38 1C, days 0.8±1.8 1.5±2.3 1.7±2.0 2.5±3.2 3.6±3.5 o0.001
Infection, no. of patients (%)
d
7 (29.2) 10 (23.8) 7 (20.0) 21 (42.9) 7 (38.9) 0.075
Microbiologically confirmed infection,
no. of patients (%)
d
2 (8.3) 7 (16.7) 3 (8.6) 11 (22.4) 7 (38.9) 0.011
Time to neutrophil engraftment, days 13.3±4.7 12.6±1.5 12.8±1.9 13.8±7.9 13.9±3.4 0.206
Health resource end points (duration, days)
c
Opioid use 0.3±1.4 0.9±2.4 2.6±5.0 6.5±5.6 4.8±4.6 o0.001
TPN use 2.2±4.5 2.4±4.8 2.9±5.7 5.4±7.3 4.9±5.2 o0.001
Antibiotic use 4.8±6.4 5.5±7.7 8.7±8.4 9.1±9.5 8.3±7.2 o0.010
Length of hospital stay (MM) 17.0±5.4 19.8±3.9 19.7±4.7 21.5±4.5 21.5±3.7 0.008
Length of hospital stay (NHL) 21.1±3.0 23.1±4.1 24.1±5.2 22.2±3.5 23.8±3.3 0.086
Abbreviations: MM ¼multiple myeloma; NHL ¼non-Hodgkin’s lymphoma; TPN ¼total parenteral nutrition.
a
Patient numbers shown differ slightly for both the infection variables (n¼24, 42, 35, 49, 18); time to engraftment (n¼26, 43, 39, 60, 27); and antibiotic use
(n¼26, 45, 39, 59, 27), on account of missing data.
b
w
2
test for incidence trend across grade of OM or Spearman’s correlation coefficient between duration and maximum grade of OM.
c
Duration end points were calculated across all patients including those with 0 duration values.
d
Before 30 days post transplantation.
Oral mucositis: clinical and healthcare resource outcomes
S McCann et al
144
Bone Marrow Transplantation
was also attenuated. A similar pattern was seen using
incidence, instead of duration, of severe OM in the analysis.
Discussion
The initial analysis of the POMA findings provided the first
prospective, robust data on patterns and determinants of
severe OM in patients undergoing high-dose melphalan or
BEAM chemotherapy and autologous SCT.
1
This second
analysis of data from this pan-European audit provides
new insights into the clinical sequelae of severe OM and
associated medical resource use.
Consistent with other observations,
8,13
we found that
severe OM was closely related to development of fever,
with the incidence of fever being 21% higher and the
duration of fever 1.2 days longer, in those with severe OM.
Previous studies in the SCT setting have shown that the risk
of fever and/or febrile neutropenia (FN) increases with
increasing grade of OM.
8,9
Moreover, the recombinant
growth factor palifermin, which protects the oral mucosa
from damage induced by myelotoxic-conditioning treat-
ment, was able to reduce the risk of FN in patients
undergoing SCT.
14
The association of fever with oral mucositis has been
attributed to local and systemic infections, as disruption of
the mucosal barrier may provide an entry point for
pathogens.
2,13
However, infection frequently cannot be
documented in febrile patients. An alternative hypothesis is
that fever may be a manifestation of the inflammatory
process that is induced by conditioning chemotherapy
2,15–17
and driven by acute phase cytokines such as tumour
necrosis factor a(TNF-a) and interleukin 6 (IL-6).
17,18
Mucositis itself is also a potential source of local and
systemic cytokines. These cytokines can induce sepsis-like
signs and symptoms when administered exogenously to
humans. Indeed, one study found that blood levels of TNF-
aand IL-6 were significantly correlated with changes in
body temperature in cancer patients who were administered
TNF.
19
We found that severe OM duration was positively
correlated with time to neutrophil engraftment and that
engraftment coincided with peak OM scores (Figure 1).
This supports previous observations that healing of OM
coincides with neutrophil recovery.
20–23
Although some
investigators have failed to find a link between OM and
neutropenia,
5,24
Rapoport et al.
25
noted that duration of
neutropenia was a risk factor for OM and the severity of
OM has been linked to the degree of neutropenia.
26
Oral
neutrophil kinetic studies (using mouth rinses) in patients
recovering from profound neutropenia have demonstrated
that neutrophils are present in the tissues before peripheral
neutrophil counts recover,
21,27,28
consistent with their
important role in mucosal defence and repair. A study in
the BMT setting found that neutrophil levels in mouth
rinses decreased to undetectable levels during the neutro-
penic period, but recovered 1–2 and 3–9 days before
peripheral neutrophil counts reached 0.1 and 1.0 10
9
/l,
respectively, regardless of whether or not patients received
granulocyte-colony stimulating factor (G-CSF) support.
21
A study in paediatric SCT patients found that the return of
neutrophils to the oral cavity marked the beginning of the
mucosal recovery phase. Moreover, the time span between
oral and peripheral neutrophil recovery was inversely
related to the number of infection-related febrile episodes
occurring after peripheral engraftment.
27
Duration of severe OM was associated with the duration
of hospitalization, and development of severe OM pro-
longed the hospital stay by 2.3 days (P¼0.013) in MM
patients. However, fever and infection were cofactors in
prolonging hospitalization. Therefore, if severe OM is itself
a causative factor in fever and infection (Table 2), including
these covariates may lead to underestimation of the effect
of severe OM on duration of hospitalization, a major driver
of costs in this setting. Other factors influencing hospital
stay were age, baseline Eastern Cooperative Oncology
Table 3 Factors influencing duration of hospitalization (Poisson Model)
Duration of hospitalization
Coefficient (95% CI)
a
P
Age
b
0.004 (0.002 to 0.006) o0.001
Baseline ECOG status
c
0.052 (0.019 to 0.085) 0.002
Severe OM duration
d
0.058 (0.024 to 0.091) 0.001
Time to transplantation
e
0.058 (0.036 to 0.080) o0.001
Time to neutrophil engraftment
f
0.026 (0.014 to 0.038) o0.001
Interaction of time to transplantation and
severe OM duration
–0.005 (0.009 to –0.001) 0.015
Interaction of time to neutrophil engraftment
and severe OM duration
–0.002 (–0.004 to –0.000) 0.022
Constant 2.162 (1.869; 2.456) o0.001
a
Multiplying the coefficients of Poisson Models by 100 yields a value approximating to percentage changes of the expected values of the response variable.
N¼191 on account of missing covariate values. One patient who died around the time of transplantation was hospitalized for only 3 days and one patient
with an outlying time from transplantation to neutrophil engraftment of 65 days was also excluded.
b
Per additional year of age.
c
Per score increase by 1.
d
Per additional day.
e
Per additional day from start of conditioning to transplantation.
f
Per additional day from transplantation to neutrophil engraftment.
Oral mucositis: clinical and healthcare resource outcomes
S McCann et al
145
Bone Marrow Transplantation
Group status, time to transplantation and time to
neutrophil engraftment. Duration of use of TPN, opioids
and antibiotics also increased with increasing grade of OM,
patients with severe OM requiring an additional 2.7 days of
TPN, 4.6 days of opioids and 2.4 days of antibiotics. All
three associations are further supported by the very similar
temporal patterns of OM occurrence, pain, dysphagia and
fever (Figure 1).
Our findings are consistent with earlier data from the
United States. An earlier prospective, multicentre study in
blood or marrow transplant recipients (n¼92)
8
and a
retrospective chart review in SCT recipients (n¼281)
9
found that resource use and clinical outcomes, including
duration of hospitalization, were significantly correlated
with the severity of OM. A retrospective case–control study
in 24 patients who developed a-haemolytic streptococcal
bacteraemia following autologous BMT
13
found that OM
prolonged hospital stay both independently and as a
cofactor associated with bacteraemia.
Systemic drug exposure was a key determinant of severe
OM risk in our previous analysis,
1
in line with other
observations.
29,30
Indeed, a recent study by a German
group found that patients treated with a melphalan dose
X70 mg/m
2
had a 23-fold increased risk of developing
mucositis (Po0.001) compared with those receiving lower
doses.
30
Thus, we tentatively evaluated whether there was
an association between melphalan dose per kg body weight
and medical resource use, in MM patients only. No
relationship was found, indicating that the observed
associations of OM with medical resource use were not
directly on account of higher drug doses.
Changes in guidelines to prevent or treat OM have
recently been reviewed
31
and include the use of cryotherapy
(ice-water or chips) during the infusion of high-dose
melphalan; however, the authors also state: ‘However,
additional and sustained efforts will be required to gain a
fuller understanding of the pathobiology, impact on overall
patient status, optimal therapeutic strategies, and improved
educational programs for health professionals, patients, and
caregivers’.
In conclusion, our analysis of prospectively collected
observational data has provided important insights into the
scope and impact of severe OM in patients undergoing SCT
in routine clinical practice in Europe. The correlation of
severe OM with serious systemic sequelae such as infection
and increased use of healthcare resources, together with the
adverse impact on patient quality of life, underlines the
need for effective measures for preventing OM. It is hoped
that our findings will help to guide the use of novel
preventive treatments.
Acknowledgements
Roisin Cinne
´ide and Kim Champion were data manager and
study coordinator, respectively. The EBMT Oral Mucositis
Advisory Group wishes to thank Amgen (Europe) GmbH, Zug,
Switzerland, for supporting this work. Julia Balfour (Consultant
Medical Writer, Kilconquhar, Scotland) and Claire Foster
(Amgen (Europe) GmbH) assisted with the writing of the paper.
We also gratefully acknowledge the participation of the
investigators, staff and patients from the study centres.
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... 7 Typically, OM develops 10-14 days after initiation of chemotherapy and heals within 2-4 weeks, consistent with the clinical course of neutropenia. 8 Neutropenia has been reported to play a key role in the development of OM. Severity of OM is associated with the degree of neutropenia, and resolution coincides with granulocyte recovery. ...
... Severity of OM is associated with the degree of neutropenia, and resolution coincides with granulocyte recovery. 8 This is assumed to be a result of neutropenia leading to impaired mucosal defense and repair. 8 Management of OM is crucial as it provides a portal for potentially life-threatening infection. ...
... 8 This is assumed to be a result of neutropenia leading to impaired mucosal defense and repair. 8 Management of OM is crucial as it provides a portal for potentially life-threatening infection. 8 Previous studies have shown that the risk of infection increases with increasing grade of OM. 8 As most patients with OM develop neutropenic fever, broad-spectrum beta-lactam with combination of antifungal and antiviral agents is commonly used as a standard treatment to cover gram-negative bacteria, Coagulase-negative Streptococci, Streptococcus viridans, Candida albicans, and Herpes simplex. ...
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Severe oral mucositis as a complication of chemotherapy may lead to airway obstruction and require prolonged intubation. As its course is consistent with the course of neutropenia, airway management strategies should be determined individually. Severe oral mucositis as a complication of chemotherapy may lead to airway obstruction and require prolonged intubation. As its course is consistent with the course of neutropenia, airway management strategies should be determined individually.
... In the present study, in agreement with the literature, allogeneic HSCT patients exhibited more intensive mucositis than autologous recipients. 26 In fact, the more intense conditioning used for allogeneic HSCT is intentional due to the need to induce bone marrow aplasia and patient immunosuppression, prerequisites for the success of this treatment modality. This can be explained by the more intensive conditioning regimens in the allogeneic setting that use BuCy or cyclophosphamide + total body irradiation (TBI), or fludarabine + melphalan. ...
... 33 Although some investigators have failed to find a link between OM and neutropenia, Rapoport 34 noted that persistence of neutropenia was a risk factor for OM severity. Similarly, McCann et al. 26 observed that severe OM duration was positively correlated with time to neutrophil engraftment. Various studies have shown ambivalent neutrophil recovery using granulocyte colony-stimulating factor (G-CSF, filgrastim) or granulocyte-macrophage colony-stimulating factor (GM-CSF, molgramostim) administered systemically or orally for OM reduction. ...
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The aim of the present study was to analyze the relationship of OM with possible risk factors such as oral health condition, immunological status and IL-1β profile in patients submitted to hematopoietic stem cell transplantation (HSCT). Fifty-four individuals submitted to HSCT were included. All patients received previous dental treatment and photobiomodulation (PBM) as the institutional OM preventive protocol. OM scores, immune status, and IL-1β levels were determined during the conditioning period and at D+3 and D+8 after HSC infusion. IL-1β gene polymorphism was also analyzed during conditioning. Possible associations of OM with risk factors were analyzed using conditional Fisher's exact test. OM was observed in 34 patients (62.9%) classified as Grade 1 (13 patients/24.1%), Grade 2 (14 patients/25.9%), Grade 3 (3 patients/5.5%), and Grade 4 (4 patients/7.4%). Allogeneic HSCT individuals exhibited a higher OM grade than autologous subjects. Moreover, an association was observed between severe OM and severe gingivitis (p = 0.01), neutropenia (p = 0.03), and leukopenia (p = 0.04). A significant association between OM and lower IL-1β levels was detected at three time points, i.e., conditioning (p = 0.048), D+3 (p = 0.01), and D+8 (p = 0.005). The results showed that IL-1β gene polymorphism was not associated with OM. Our study provided important insights into the scope of OM risk factors in the setting of HSCT. Patients submitted to HSCT with severe gingivitis prior to chemotherapy and with severe neutropenia and leukopenia exhibited a higher OM grade. Further investigation will be necessary to better understand the exact role of IL-1β in the context of OM pathobiology and to validate cytokine analysis in larger cohorts.
... [1][2][3] Chemotherapy-induced malnutrition, dehydration and weight loss often necessitates parenteral nutrition and prolonged hospitalisation. [4][5][6] In addition, mucositis plays a key role in the induction of extra-intestinal systemic side effects. [7][8][9][10] The damaging effects to the GI mucosa may cause bacterial translocation with infections and systemic inflammation propagating organ toxicities (eg, liver toxicity). ...
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Introduction Cancer treatment with high-dose chemotherapy damages the mucosal barrier of the gastrointestinal (GI) tract and is associated with severe toxicity involving mucositis, severe inflammation and organ dysfunction. Currently, there is no effective prophylaxis against this. Glucagon-like peptide 1 (GLP-1), a well-known regulator of blood glucose, has been suggested in mouse studies to possess trophic effects on gut epithelial cells as well as anti-inflammatory properties. In line with this, endogenous GLP-1 levels have been shown to be inversely correlated with toxicities after haematopoietic stem cell transplantation (HSCT) and treatment with a GLP-1 receptor agonist (GLP-1RA) was shown to limit chemotherapy-induced mucositis in rodents. This present study investigates the effects of the GLP-1RA semaglutide on GI mucositis severity score in patients with lymphoma undergoing high-dose chemotherapy followed by autologous (auto) HSCT. Methods and analysis This is a randomised, double-blind, placebo-controlled, two-centre investigator-initiated clinical study. Forty adult patients with malignant lymphoma referred for auto-HSCT will be randomised in a 1:1 manner to receive either semaglutide or placebo once-weekly for 8 weeks. This includes a run-in period of 3–4 weeks with semaglutide 0.25 mg prior to high-dose chemotherapy treatment followed by a period of 4–5 weeks with semaglutide 0.5 mg including the 1 week of high-dose chemotherapy treatment. Clinical assessment of endpoint measurements and safety will be performed weekly during treatment and in a follow-up period of 10 weeks. The primary endpoint is GI mucositis severity (mean severity grade (0–II) during week 1–4 after auto-HSCT). Secondary endpoints include C-reactive protein increment, quality of life and safety. Fever, bacteraemia, antibiotic use, weight loss, morphine consumption, duration of hospitalisation, use of parenteral nutrition, change in muscle mass and clinical and laboratory evidence of organ toxicities will also be assessed. Ethics and dissemination The study complies with Danish and European Union legislation and is approved by the Danish Medicines Agency, the Danish National Medical Research Ethics Committee (EU CT #2022-502139-20-00) and the Danish Data Protection Agency. The study is monitored by the Capital Region of Denmark’s good clinical practice unit. All results, positive, negative and inconclusive, will be disseminated at national and international scientific meetings and in peer-reviewed scientific journals. Trial registration number NCT06449625
... To this must also be added the lack of freedom of movement by having to remain, throughout the admission, inside an isolation room without performing any exercise, which facilitates the appearance of edema. Likewise, it is observed that the prescription of parenteral nutrition (PN) is associated with episodes of mucositis in hospitalized patients, similar to what was seen in the work of Gonzalez-Barrera et al. [49]. Although the patients at home underwent greater weight loss, they did not report difficulties ingesting solid and liquid foods, which would have raised the need for NP in said group. ...
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... 7 These clinical problems that lead to nutritional problems can prompt the use of total parenteral nutrition, antibiotics and opioid analgesics, changes in the treatment plan, repeated hospitalizations, an increase in the cost of treatment, and deterioration in the quality of life. 2,8,9 Propolis, a complementary and alternative treatment product, is a natural substance produced by honeybees. Worker bees produce propolis by biochemically modifying the resins they collect from plants with the enzymes they secrete. ...
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... The conditioning with Treo/Flu preceding auto-HSCT seems to be feasible in elderly patients which will sustain less complications. Severe oral mucositis developing after auto-HSCT is associated with an increased risk of duration of pain score ≥4, opioid use, dysphagia score ≥4, total parenteral nutrition, incidence and/or duration of fever and infection as well as duration of antibiotic use [44]. Patients receiving Treo/Flu suffered significant less frequently from Grade III-IV mucositis and stomatitis (p < 0.0001) as well as infectious complications (p = 0.0105; all Fisher's exact test) if compared with patients after conditioning with TEAM, respectively. ...
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Chapter
Mucositis is a generalized term used to denote either oral or gastrointestinal mucositis as a consequence of cancer therapy. This chapter will describe the epidemiology of mucositis in relation to radiation therapy for head and neck cancers, chemotherapy, and hematopoietic stem cell transplantation. Clinical features, risk factors and pathogenesis of mucositis are covered in depth. In addition, the current consensus on mucositis management and economic consequences are reviewed in this chapter. Although considered to have a different pathogenesis, targeted therapy related oral mucosal adverse effects are often referred in the literature as mucositis or stomatitis. This entity is described in this chapter, too.
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Patients with idiopathic, cyclic, and congenital neutropenia have recurrent severe bacterial infections. One hundred twenty-three patients with recurrent infections and severe chronic neutropenia (absolute neutrophil count < 0.5 x 10(9)/L) due to these diseases were enrolled in this multicenter phase III trial. They were randomized to either immediately beginning recombinant human granulocyte colony- stimulating factor (filgrastim) (3.45 to 11.50 micrograms/kg/d, subcutaneously) or entering a 4-month observation period followed by filgrastim administration. Blood neutrophil counts, bone marrow (BM) cell histology, and incidence and duration of infection-related events were monitored. Of the 123 patients enrolled, 120 received filgrastim. On therapy, 108 patients had a median absolute neutrophil count of = or = 1.5 x 10(9)/L. Examination of BM aspirates showed increased proportions of maturing neutrophils. Infection-related events were significantly decreased (P < .05) with approximately 50% reduction in the incidence and duration of infection-related events and almost 70% reduction in duration of antibiotic use. Asymptomatic splenic enlargement occurred frequently; adverse events frequently reported were bone pain, headache, and rash, which were generally mild and easily manageable. These data indicate that treatment of patients with severe chronic neutropenia with filgrastim results in a stimulation of BM production and maturation of neutrophils, an increase in circulating neutrophils, and a reduction in infection-related events.
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Mucositis is an inevitable side-effect of the conditioning regimens used for haematopoietic stem cell transplantation. The condition is better referred to as mucosal barrier injury (MBI) since it is primarily the result of toxicity and is a complex and dynamic pathobiological process manifested not only in the mouth but also throughout the entire digestive tract. A model has been proposed for oral MBI and consists of four phases, namely inflammatory, epithelial, ulcerative and healing phases. A variety of factors are involved in causing and modulating MBI including the nature of the conditioning regimen, the elaboration of pro-inflammatory and other cytokines, translocation of the resident microflora and their products, for example, endotoxins across the mucosal barrier, exposure to antimicrobial agents and whether or not the haematopoietic stem cell graft is from a donor. Neutropenic typhlitis is the most severe gastrointestinal manifestation of MBI, but it also influences the occurrence of other major transplant-related complications including acute GVHD, veno-occlusive disease and systemic infections. The pathobiology, clinical counterparts and the means of measuring MBI are discussed together with potential approaches for prevention, amelioration and, perhaps, even cure. Bone Marrow Transplantation (2000) 25, 1269-1278.
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• It has been suggested that the monokine tumor necrosis factor (TNF) (cachectin) is responsible for metabolic abnormalities frequently accompanying malignant neoplasms. The acute metabolic effects of TNF in patients with cancer were studied. Subcutaneous administration of recombinant human TNF led to a rise in the C-reactive protein level (4.4±1.2 mg/dL vs 11.6±1.8 mg/dL) and a reduction in the serum zinc level (12.9±0.8 μmol/L vs 7.3±0.8 μmol/L [79± 5 mg/dL vs 48±5 mg/dL]) (values are the mean±SEM). Forearm efflux of total amino acids more than doubled after intravenous TNF injection, principally because of increases in release of the gluconeogenic amino acids alanine and glutamine. Concomitantly, the arterial levels of alanine, glutamine, and total amino acids fell, indicating that TNF also stimulated the uptake of amino acids by other tissues. The observed amino acid pattern cannot be explained solely on the basis of measured changes in cortisol, glucagon, or insulin levels. These findings are discussed in relation to known alterations of amino acid metabolism in cancer-associated cachexia. (Arch Surg 1987;122:1396-1400)
Article
Melphalan is associated with severe side effects such as mucositis, diarrhea, and myelosuppression. We investigated how much the individual severity of these side effects is predicted by pharmacokinetics. In addition, we studied glutathione S-transferase GSTM1, GSTT1, and GSTP1 polymorphisms in relation to adverse events. A high interindividual pharmacokinetic variability was observed in 84 patients. There was a linear correlation between creatinine and melphalan clearance (P=0.0004). Patients treated with a dose 70 mg/m2 had a 23-fold increased risk to develop mucositis (P<0.001) and a 12-fold increased risk to develop diarrhea (P<0.001) compared with lower doses. The GSTP1 codon 105 polymorphism may be relevant for development of mucositis and the GSTT1 deletion may predict diarrhea, but these findings require confirmation. Melphalan-induced side effects were significantly dependent only on dose. Therapeutic drug monitoring or genotyping for GST does not appear to be very helpful in optimizing therapy with melphalan.
Article
Antibacterial prophylaxis with quinolone antibiotics has resulted in an increase in streptococcal infections among bone marrow transplantation (BMT) recipients with myelosuppression. Oral ulceration (mucositis), which frequently occurs as a consequence of chemotherapy, has been implicated as a significant portal of entry for streptococci. The objectives of this study were to confirm the correlation between mucositis and streptococcal bacteremia, determine the risk associated with this correlation, and evaluate the impact of mucositis and streptococcal bacteremia on hospital course and costs associated with autologous BMT.
Article
Background: Few longitudinal studies have investigated the onset, duration, and resolution of ulcerative mucositis in bone marrow transplant recipients. This study prospectively followed a group of such patients on a daily basis to obtain data on the incidence of ulcerative mucositis, location and duration of lesions, severity with different conditioning regimens, and the relationship of such mucositis to the absolute neutrophil count. Methods: Fifty-nine bone marrow transplant recipients on prophylactic acyclovir were examined daily for 26 days after marrow infusion, and all oral ulcerative lesions were recorded. Results: Oral ulcers occurred in 76.3% of patients, began at a mean of 5 days after marrow infusion (day + 5), and lasted for a median of 6 days. More than 90% of patients showed complete resolution of ulcers on or before day + 15, and all showed resolution when the absolute neutrophil count was > 500 cells/ml. Persistence of ulcers was noticed in patients who had oral graft-versus-host disease and in some patients who initially developed more severe ulcerations. Ninety-six percent of ulcers were located on nonkeratinized mucosa. Conclusions: Ulcerative mucositis occurs in about 75% of bone marrow transplant recipients in the absence of herpes simplex virus infection. Most lesions occur on nonkeratinized mucosae which are vulnerable to trauma, especially if such mucosae are rendered atrophic by conditioning regimens. Oral ulcers may persist beyond day + 15 and after recovery of the neutrophil count in patients who initially develop more severe ulcerations or in patients who develop graft-versus-host disease.
Article
Considerable progress in research and clinical application has been made since the original guidelines for managing mucositis in cancer patients were published in 2004, and the first active drug for the prevention and treatment of this condition has been approved by the United States Food and Drug Administration and other regulatory agencies in Europe and Australia. These changes necessitate an updated review of the literature and guidelines. Panel members reviewed the biomedical literature on mucositis published in English between January 2002 and May 2005 and reached a consensus based on the criteria of the American Society of Clinical Oncology. Changes in the guidelines included recommendations for the use of palifermin for oral mucositis associated with stem cell transplantation, amifostine for radiation proctitis, and cryotherapy for mucositis associated with high-dose melphalan. Recommendations against specific practices were introduced: Systemic glutamine was not recommended for the prevention of gastrointestinal mucositis, and sucralfate and antimicrobial lozenges were not recommended for radiation-induced oral mucositis. Furthermore, new guidelines suggested that granulocyte–macrophage-colony stimulating factor mouthwashes not be used for oral mucositis prevention in the transplantation population. Advances in mucositis treatment and research have been complemented by an increased rate of publication on mucosal injury in cancer. However, additional and sustained efforts will be required to gain a fuller understanding of the pathobiology, impact on overall patient status, optimal therapeutic strategies, and improved educational programs for health professionals, patients, and caregivers. These efforts are likely to have significant clinical and economic impact on the treatment of cancer patients. Cancer 2007;109:820–31. © 2007 American Cancer Society.
Article
Patients undergoing cancer chemotherapy often suffer from oral complications as a result of their disease and its treatment. The effects of the chemotherapy on the bone marrow and oral mucosa, coupled with the patient's immunosuppressed state and altered oral microbial flora, predispose these patients to oral mucositis, infection, and hemorrhage. The oral mucosa appears to mirror the effects of the chemotherapy on the bone marrow, as there appears to be a direct relationship between the changing peripheral blood counts and the status of the oral mucosa.
Article
Patients are at risk of mucositis and infections in the oral cavity during the neutropenic period after chemotherapy, which are significant causes of morbidity. In phase I/II studies with the haemopoietic growth factor granulocyte colony stimulating factor (G-CSF), a reduction in post-chemotherapy mucositis has been observed in addition to haematologic effects. To understand this phenomenon better in patients receiving G-CSF following high-dose chemotherapy with autologous bone marrow transplantation (ABMT), we studied the effects of G-CSF on levels of neutrophils recoverable from the oral cavity using a quantitative mouthrinse assay. In normal subjects, mouthrinses contained 472 +/- 329 x 10(3) neutrophils/mouthrinse. After chemotherapy followed by ABMT, mouthrinse neutrophil levels decreased to undetectable levels during the neutropenic period, but recovered 1-2 and 3-9 d before circulating neutrophil levels reached 0.1 and 1 x 10(9)/l respectively, whether or not patients received G-CSF. In patients who received G-CSF, the mean cumulative mucositis score was reduced from 35 +/- 9 to 21 +/- 12 (P < 0.05), and the maximum mean daily mucositis score was reduced from 2.8 +/- 0.5 to 1.7 +/- 0.9 (P < 0.01), compared to patients who did not receive G-CSF after ABMT. These studies provide in vivo evidence that neutrophils produced during G-CSF therapy are available to leave the circulation and enter tissues where their function is required for host defence. Since the usual temporal relationship between oral and peripheral blood neutrophil recovery was preserved during G-CSF administration after ABMT, these data support the hypothesis that the reduction in post-ABMT mucositis observed with G-CSF therapy may reflect a beneficial effect of G-CSF on the kinetics of oral mucosal neutrophil recovery in addition to the effect of G-CSF to accelerate peripheral blood neutrophil recovery.