Download Finding/Complication

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28 June, 2011
MULTICENTER STUDY ON
THE BURDEN OF ILLNESS OF ORAL SIDE EFFECTS FROM
CONDITIONING THERAPY BEFORE CONDITIONING THERAPY (CHEMOAND RADIOTHERAPY) BEFORE STEM CELL TRANSPLANTATION IN
PATIENTS DIAGNOSED WITH HEMATOLOGIC DISEASES
- ORA-STEM STUDY Numerous oral complications have been associated with cancer therapies. In
order to establish recommendations for pre-, interim-, and post-cancer therapy
management of oral problems in patients with hematological malignancies receiving
high dose conditioning regimen and stem cell transplantation (autologous or
allogeneic), an understanding of the scope of oral complications from cancer therapy
must be established and be related to time after treatment and treatment regimen.
The lack of clarity in this field is reflected in a lack of comprehensive and effective
oral management regimens in the clinical arena. With a deeper understanding of oral
complications, oral care regimens to minimize such complications can be
appropriately formulated and evaluated. There is thus a pressing need to establish the
nature, incidence and temporal relationship of oral complications related to
conditioning therapies, as well as other types of cancer therapies.
The literature reports a wide range of oral complications with varying incidences.
Mucositis, or inflammation of the mucosal surfaces, sometimes also called mucosal barrier
injury (MBI), is a major dose-limiting side effect of cancer therapy. Severe mucositis has
been associated with pain, infection, poor nutrition, increased hospitalization and a major
impact on quality of life and economic outcomes. Other reported complications are
bleeding, dysphagia (difficulty swallowing), dysgeusia (altered sensation of taste),
infection (bacterial, viral, and fungal), pain, trismus, osteonecrosis, osteoradionecrosis,
xerostomia/salivary gland dysfunction, caries, periodontal disease, dental growth and
developmental disturbances in children and graft-versus-host-disease (GVHD).(1) Recent
systematic reviews of these oral complications have confirmed the limitations in
knowledge of the incidence and severity of the various additive oral complications.
Furthermore, how these common oral complications further complicate clinical and
economic outcomes and affect quality of life (QoL) is poorly understood.
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Overall aim
The overall aim of the current prospective international observational multicenter
study in stem cell transplant patients is to establish the nature, incidence and temporal
relationship of oral complications related to conditioning regimen (chemotherapy with or
without total body irradiation-TBI), stem cell transplantation and immunologic reactions
(mainly GVHD) and to determine what objective and subjective oral complications related
to treatment can predict negative clinical and economic outcomes and reduced QoL.
Specific Aims
To address the gaps in the knowledge of oral complications associated with
hematological malignancies receiving high dose conditioning regimen and stem cell
transplantation (autologous or allogeneic) the following specific aims will be evaluated.
Primary aim
1. What is the incidence, severity and temporal relationship of oral complications
related to type of conditioning regimen and how do they develop:
1.1. subjective oral complications
1.1.1. oral pain
1.1.2. xerostomia (dry mouth)
1.1.3. dysgeusia (taste changes)
1.1.4. dysphagia (swallowing difficulties)
1.2. objective oral complications
1.2.1. oral mucositis
1.2.2. oral infections (viral, fungal, bacterial)
1.2.3. submucosal hemorrhage
1.2.4. dental and periodontal diseases and complications
1.2.5. osteonecrosis
1.2.6. GVHD
1.2.7. hyposalivation
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Secondary aims
2. Are there signs to predict oral complications.
2.1. Are there early clinical signs which can be used to predict mucositis and GVHD?
2.2. Does genetic polymorphisms in candidate genes demonstrate an increased risk for
the development of severe mucositis and GVHD?
3. How are oral complications related to other confounding variables.
3.1. Demographics (age, sex, race)
3.2. Cancer diagnosis
3.3. Cancer therapy
3.4. Autologous or allogeneic stem cell transplantation
3.5. Antimicrobial prophylaxis or Keratinocyte Growth Factor (KGF) medication
3.6. Ongoing immunosuppression for GVHD
3.7. Recommendations for local special oral care program
3.8. Non-oral signs/symptoms
3.8.1. Nausea/Vomiting
3.8.2. Diarrhea
3.8.3. Fever
3.8.4. Weight
3.8.5. Blood values
4. How do subjective and objective oral complications related to treatment, impact on
poor general clinical and economic outcomes.
4.1. Are oral complications identified as a cause of additional hospital visits, prolonged
hospital stays or death?
4.2. Can oral complications/infections be related to systemic infection?
4.3. Are oral complications identified as a cause for increased medication/treatment
(e.g. antibiotics, morphine)?
4.4. Are oral complications (e.g. xerostomia, taste etc.) possible to relate to poor
nutrition/parental nutrition?
5. How is patients’ QoL affected by treatment-related oral complications in the short and
long time, specifically
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5.1. subjective oral complications:
5.1.1. oral pain
5.1.2. xerostomia (dry mouth)
5.1.3. dysgeusia (taste changes)
5.1.4. dysphagia (swallowing difficulties).
Patient Population
Inclusion criteria
Patients receiving conditioning regimen (full intensity conditioning, FIC, or reduced
intensity conditioning, RIC), followed by stem cell transplantation (autologous or
allogeneic) in adults from Gothenburg Sweden, Stockholm Sweden and additional centers.
Diagnoses:

acute leukemia

myelodysplastic syndrome (MDS)

aplastic anemia

lymphoma including chronic lymphoid leukemia

chronic myeloid leukemia

myelofibrosis

multiple myeloma

lymphoma including chronic lymphoid leukemia

testis cancer

others, such as autoimmune diseases (scleroderma; systemic sclerosis)
Exclusion criteria

Patients unable to give consent.

Children younger than 18 years.
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Publication strategy
The Publications Committee (Drs I. v. Bültzingslöwen, M. Brennan, M. Jontell and J-E.
Johansson) will decide on publications originated from the Ora-Stem Study.
Authors of publication may be
I. Project organizers Mike Brennan North Carolina USA, Inger v. Bültzingslöwen, Mats
Jontell Gothenburg, Sweden
II. Hematologist Jan-Erik Johansson Gothenburg Sweden
III. Principal investigator (PI) from each participating centers,
i. Karin Garming-Legert, Karolinska Institute, Stockholm Sweden
ii. Bengt Hasseus, Peter Johansson, Sahlgrenska Academy, Gothenburg
Sweden
iii. PI from additional participating centers (to be decided later)
Background and Significance
The annual incidence of cancer is 11 million cases worldwide.(2) Earlier cancer
detection and advances in cancer therapies have provided important management advances
to improve survival and quality of life. Common cancer treatment strategies include
surgical resection, chemotherapy (CT), radiotherapy (RT), and hematopoietic stem cell
transplantations (HSCT). The goal of such treatments is to eliminate all cancer cells.
However, side effects from these therapies can limit the effectiveness of treatment and have
a marked impact on the patient’s QoL. The oral cavity is a common site of complications
related to cancer therapies. The Surgeon General’s report on Oral Health in America
estimates that more than 400,000 patients in the U.S. undergoing cancer treatment will
develop oral complications annually.(3)
To fully understand which oral complications from cancer therapies are important
targets for prevention and better management, it is important to understand the burden of
illness from cancer and from cancer therapies. Numerous studies have identified, and
report a wide range of incidence and severity for different oral complications from cancer
therapies. In 1989, the National Institutes of Health Development Consensus Conference
on the Oral Complications of Cancer Therapies provided recommendations for oral
assessment and oral/dental management prior, during and following cancer therapy.(4)
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These recommendations served to summarize our understanding of the subject at the time.
Since the Consensus Conference, there has been a gradual increase in interest in these
problems. During this time, there was a movement towards developing preventive and
management strategies. The conference brought together leading experts in the field and
clearly catalyzed and legitimized the development of a formal specialty discipline of oral
oncology.
Documentation of the burden of illness has been more successful regarding some
oral complications than others. Mucositis, or inflammation of the oral and gastrointestinal
mucous membranes, is a painful and dose-limiting side effect of CT and RT. Severe
mucositis can: result in delay in the delivery of cancer therapy and/or dose reduction of
cancer therapy; prolong hospitalization; require IV narcotics for pain control; and interfere
with or prevent oral nutrition, limit oral hygiene and speaking for prolonged periods of
time, and increase the risk of systemic infection.(5) The Mucositis Study Section of the
Multinational Association of Supportive Care in Cancer (MASCC) and the International
Society of Oral Oncology (ISOO) held two Consensus Conferences regarding the impact
and treatment of cancer-related oral mucositis. Participants reviewed the available literature
on mucositis for quality, and devised recommendations based on the strength of the
literature. The main areas of review included the epidemiology of mucositis by cancer
regimen, pathophysiology, and clinical research of treatment regimens. Two manuscripts
presented the findings of the first consensus conference.(5;6) In 2005, an update of the
mucositis literature was completed to include the same areas of review. Over 3000 articles
were reviewed for the three year period of the 2005 consensus conference. Compared to the
initial review from 1966 to 2001, this amount of articles in a short time period, represents a
sharp increase in the interest of research in the field of mucositis, with recent therapies
becoming available which appear to have a significant impact in the moderation of this
common oral complication.(7)
The clinical and economic impact of oral and gastrointestinal mucositis has been
shown to exceed $40,000 for HSCT patients who develop oral ulcerations.(8) Increased
costs were related to additional days of hospitalization, total parenteral nutrition, and
intravenous narcotic therapy. In a retrospective analysis of the economic burden from
chemotherapy-induced mucositis in patients treated for solid tumors, the presence of grade
3 or 4 alimentary mucositis resulted in an incremental cost of $3500 per chemotherapy
cycle.(9) Limited data on the economic impact from non-mucositis oral complications is
available. An economic analysis of amifostine compared to placebo in patients with
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advanced head and neck cancer, demonstrated improvement in xerostomia and mucositis in
the amifostine group. Supportive care costs from management of oral complications from
radiation therapy were $4,401 for the amifostine group and $5,873 for the control
group.(10)
In patients who experience more severe oral mucositis (i.e. WHO grade 3-4),
approximately 35% will have a delay in chemotherapy, 60% will have a reduced dose of
chemotherapy, and 30% will have the regimen discontinued.(5) Additionally, the
development of severe mucositis will necessitate a feeding tube to maintain nutrition in
70% of patients, result in fever in 60% of patients, and necessitate hospitalization in 62% of
patients.(5) Additionally, at a WHO grade 3 or 4 mucositis, 70% of patients receiving
standard dose chemotherapy, and 87% receiving high-dose chemotherapy with a stem cell
transplant (SCT), will require feeding tubes to maintain adequate nutrition.(5) Mucositis
associated with autologous bone marrow transplants can extend a hospital stay by 6 days
with a cost estimated at $27,000 per patient.(11) In another study, human stem cell
transplant recipients with oral ulceration had increased costs of $42,749 per patient.(8)
Risk factors for the development of mucositis have been identified and include low
body mass and certain chemotherapeutic agents (e.g. paclitaxel, doxorubicin, etoposide, 5fluorouracil, and irinotecan).(5;12) Increased risk from specific chemotherapeutic agents is
likely the result of direct cytotoxic effects from these agents. Other proposed factors
include diagnosis of acute myelogenous leukemia, acute lymphocytic leukemia, or
myelodysplastic syndrome; prolonged neutrophil recovery; young age; and conditioning
regimen for bone marrow transplantation.(13) However, the pathogenesis of mucositis is
poorly understood,(14) and it is unclear why patients of the same age, with the same
malignancy and chemotherapy regimens develop mucositis with different frequency and
severity. Mucositis demonstrates a wide variety of histologic changes ranging from
degeneration of collagen to epithelial hypoplasia (15) the variability of which is likely due
to the biologic complexity of mucositis.
Recent evidence indicates that genetic predisposition has a role in RT and CT
associated alimentary mucositis.(16;17) Differences in radiation-associated ulceration have
been demonstrated in dissimilar mouse strains. In this investigation of two different animal
models of radiation-associated mucositis, the observed mucosal ulceration was dependent
on mouse strain, and not dependent on radiation dosage.(16) In another study, individual
genetic differences accounted for variations in CT associated mucositis from a specific CT
regimen. Patients undergoing bone marrow transplantation who demonstrated certain
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genetic polymorphisms of a folate-metabolizing enzyme had more severe mucosal toxicity
from methotrexate.(17) The identification of gene products consistently over- or underexpressed might identify therapeutic targets for interventions that would decrease the
incidence and duration of cancer treatment-related mucositis. Identifying genetic
polymorphisms in such patients could be used to screen for mucositis-prone patients.
Microarray analysis of oral mucosa tissue samples before and following chemotherapy will
allow us to identify candidate genes which may be important in the pathophysiology of
mucositis or as predictors of the development of chemotherapy-associated mucositis. Such
genes may form the basis for future screening tests to predict the likelihood of mucositis
following treatment with specific CT protocols and identify patients who would benefit
from targeted preventative therapy.
Numerous preventive care protocols have been proposed to minimize oral
complications from cancer therapies. Unfortunately, these protocols are rarely evidencebased and often rely on “expert opinion” or anecdotes. The lack of well-controlled,
prospective studies is the primary reason for the limitation in preventive and management
protocols. The Institute of Medicine (IOM) report determined that insufficient systematic
research is available to assess the prevention and management of the oral problems
associated with head and neck cancer, leukemia, and lymphoma.
The Surgeon General’s report Oral Health in America calls for both the building of
the science and evidence base, and the application of science effectively to improve oral
health. This recommendation development process aims to effectively transfer research
findings in the field of oncology, including oral complications seen with cancer therapies,
and oral management prior to the start of cancer therapy, to the public and health
professionals. Well developed, evidence–based management recommendations have the
potential to enhance the appropriateness of clinical practice, improve the quality of oral
health care, lead to better patient outcomes, improve cost-effectiveness, and identify areas
of further research needs. In order to effectively change perceptions of the burden of illness
of oral complications from cancer therapies, a complete understanding of the impact of
these complications is vital. Concern for underestimating the impact of oral complications
may result in avoidance or delay in appropriate care for cancer patients.
Considering our limited understanding of the burden of illness in the oral cavity
from various cancer therapies, it is difficult to produce evidence-based, preventive and
management protocols. Therefore, a prospective multi-center study is necessary to collect
data on the burden of illness from various cancer regimens.
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Preliminary Pilot Studies
Registration of oral complications using MedView software program
The search for new knowledge in oral medicine should be facilitated by prospective
use of formalized information gathered in multicenter studies. The Institute of Odontology,
Göteborg University, and Department of Computing Science, Chalmers University of
Technology, have developed MedView, a prototype for the collection and analysis of large
amounts of clinical data. MedView is a computer program that is based on formalized input
and registration of all clinical information. MedView provides a suite of tools for
formalizing, gathering, and analyzing data. The output applications are focused on
visualization and statistical analysis. MedView is aimed at clinical research and is well
suited for multicenter studies.(18)
MedView program is accessible on the Internet. Each participating center/dentist
needs a unique pass word. All clinical information is entered using electronic protocols,
where case history and data from the clinical examinations are defined by formalized
parameters. The patients can be registered and identified with a code, which is known only
to the treating surgeon. The reason is to permit transfer of information within the network
without compromising the identity of the patient, and the procedure has been approved by
the Swedish Data Inspection Board.
During the clinical interview and examination, the operator enters the correct
parameter, which is then inserted adjacent to the corresponding question. Clinical
information regarding results from biopsies, laboratory tests and other invasive or noninvasive investigations are included, as are diagnoses, treatment modalities and clinical
outcomes of performed therapies. The protocols are flexible and can be changed by the user
to meet new or altered demands. This is accomplished by MedRecords Creator. These
applications enable the addition of new values or parameters on a continuous basis. They
can also be used to create entirely new protocols for specific topics or scientific
evaluations. The protocols can therefore be created in any language. MedRecords contains
a function, which permits the user to simultaneously observe a summary of registered
information develop, as values are inserted in the protocol. When the examination is
completed, the obtained summary can be copied and pasted into a document or template
and printed out. The clinical appearances of mucosal lesions are registered with digital
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images. All images in the entire database are saved in a single picture file. The images are
given an identity by the program, and no renaming procedures are required. By a “clickand-drag” procedure, an attachment is made between the individual image and the input
protocol. Technically, all images should be taken with 3 CCD cameras in order to ensure a
high quality of colour balance. Images from other sources may be included. If the
pathologist provides digital images from the histopathological examination, these images
can also be attached to the MedRecords file, and the same is possible for x-ray images.
Medview generates a database based on formalized and harmonized criteria, where
information can be retrieved, visualized and analyzed. The database is placed at the Oral
Medicine Department, Institute of Odontology, Sahlgrenska Academy, Göteborg
University, Sweden.(19)
The Oral Medicine Department, Public Dental Health and Sahlgrenska Academy in
Göteborg, has documented oral complications in MedView after peripheral stem cell
transplantation (PSCT) for 246 patients from 2005 to 2008 in a pilot study.
The aim was to test if the MedView system can be used for this patient group. Oral
mucositis, oral pain, eating/drinking problems and taste changes retrieved from this pilot
study are reported here.
Oral mucositis was documented by the World Health Organization (WHO)
mucositis grading scale. The prevalence of grade III or IV mucositis was 65 percent (153 of
236 patients) during the PSCT period. The level of oral pain was registered on a visual
analogue scale (VAS). The WHO score correlated well with the self-reported VAS score
(Table 1). It can be noted that even when the objective clinical signs of mucositis were mild
to moderate (grade I-II), the subjective problems were still considerable for some patients.
The maximum WHO score was registered at day +8 after transplantation.
Difficulty eating solid foods at one or more occasions during the transplant therapy
was registered on a four grade scale. Out of the 246 patients, 159 reported difficulties. The
inability to ingest solid foods was most common between days 4 through 13 after
treatment. As much as 90 of 246 patients reported inability to drink or ingest liquid foods at
some point during the transplant period; the highest concentration of reports being around
day 8 after transplantation.
Registrations regarding taste changes were made at four, and sometimes eight,
months post-transplant check-up in 96 patients. No registration of grade of severity or time
of onset was made. Out of the 96 patients, 37 experienced taste changes after
transplantation. Of these, 16 had recovered at the time of questioning.
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In conclusion, this pilot study shows that the MedView system can be used in this
patient group. The clinical issues that were included seemed relevant; however validated
scales should be used whenever possible and further issues be included. It should be
pointed out, that the way data was reported changed during the years, leaving room for
error. This was probably most obvious regarding why the patients were unable to ingest
solid or liquid foods. Our clinical experience is that the most common cause for this is
dysgeusia (do not want to eat) or discomfort from the throat or gut instead of oral
mucositis. The instrument (MedView) should be calibrated by all participants in a
multicenter study to reduce the risk of these kinds of errors.
Table 1. The table shows how patients with different grades of oral mucositis, according to
the WHO Mucositis grading scale, graded their level of pain on a VAS scale 1-10.
Patients
Proportion of patients,
Proportion of patients, for
with WHO
for each WHO grade,
each WHO grade, who
mucositis
who graded their level of
graded their level of pain as
scale, grade
pain as being ≥ 5.0 on
being
≥ 8.0 on VAS
I-IV
VAS
22%
3%
I
35%
8%
II
75%
23%
III
87%
54%
IV
Review of oral complications associated with cancer therapies
To determine the most common oral complications associated with cancer therapies
reported in the literature, members of the Oral Care Study Section of MASCC/ISOO under the leadership of one of the project organizers - completed a literature search and
data collection (Table 2). These preliminary results were presented at a planning meeting of
the Oral Care Study Section prior to the annual MASCC/ISOO meeting in Geneva,
Switzerland in June, 2005.
Two separate searches were completed for RT and CT. The search strategy was
adapted from “highly sensitive search strategies for identifying reports of randomized
controlled trials in MEDLINE” in the Cochrane Reviewer’s Handbook.(20) Searches were
completed with MEDLINE, Cochrane, and ACP Journal Club (Best Evidence) citations. A
total of 528 articles were identified by the search strategy. Abstracts were reviewed and
articles were chosen based on the presence of original data on oral complications related to
a cancer therapy. Narrative reviews were excluded, while systematic reviews were accepted
for review. A well-done systematic review has recently been completed for mucositis by
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the Mucositis Study Section of MASCC/ISOO,(5;6) therefore, this oral complication was
not included in the search strategy, and articles that reported only mucositis were excluded
for further review by evaluators.
A total of 176 articles that reported oral complications were selected for review by
nine oral health experts. Of these 176 articles, 48 evaluated oral complications associated
with CT, while 128 evaluated complications of RT with or without CT. Only 13% of these
articles were randomized controlled trials, and 73% of all studies were prospective. The
five most commonly reported oral complications in order of incidence included xerostomia,
dysphagia, fungal infection, osteoradionecrosis, and dysgeusia (Table 2). A wide incidence
range was apparent for all oral complications.
Table 2: Oral complications (except mucositis) incidence (of any grade) for all cancer
therapies.
Oral Complication
# Studies
Mean
(%)
Incidence
Range
(%)
Xerostomia
67
63.4
7.7 – 100
Dysphagia
25
54.1
5 – 100
12
41.9
9.5 – 100
Hemorrhages
5
32.1
4 – 72
Fungal Infection
21
26.8
3 – 91.7
Viral Infection
4
23.2
9.9 – 35.7
Oral Pain
7
18.3
7 – 55
(difficulties
swallowing)
Dysgeusia
(taste disturbances)
The results of the preliminary review provide important baseline data to understand
the scope of oral complications from cancer therapy literature. These findings are vital in
the planning of a prospective study to identify the burden of illness of oral complications
from cancer therapies. Furthermore, bacterial infections, mucositis, osteonecrosis and
GVHD may also cause considerable harm and are of interest to evaluate in the prospective
study. The preliminary review has been followed by systematic reviews of the current
scientific literature on oral side effects from cancer treatment.(21-32)
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Analysis of gene expression to elucidate genetic predisposition for mucositis
Preliminary research studies conducted by the Department of Oral Medicine at Carolinas
Medical Center have successfully identified gene changes in the oral mucosa resulting from
chemotherapy in patients with acute myeloid leukemia (AML). Microarray analysis was
completed for a total of 11 tissue samples from patients and control subjects with RNA
isolated from the buccal mucosal biopsies and gene expression analysis with Affymetrix
Human Genome U133 Plus 2.0 microarray. In addition to pre- (n=4) and postchemotherapy (n=4) buccal mucosa tissue collected from patients with AML, buccal
mucosa samples were collected from three healthy controls (n=3). Comparisons included
the following: pre-chemotherapy AML (PreC) vs. healthy control (HC); post-chemotherapy
AML (PostC) vs. HC; and PreC vs. PostC. Sufficient RNA was obtained in all 11 samples
processed in the preliminary analysis. Thirty-two genes were identified to be differentially
expressed. These genes might be involved in the onset and / or control of chemotherapyinduced mucositis as well. These preliminary results suggest that chemotherapy has a
significant effect on differential gene expression in oral tissues from AML patients.
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Experimental Design
Methodology
Patients who meet the enrolment criteria will be approached and consent will be
reviewed and obtained. The MedView computer software will be used for registration of
data. Each patient is coded with a letter depending on treating center (A=Gothenburg,
B=Stockholm, C=XXX, and so on) and a number (e.g. A/053).
A pre-treatment assessment (Phase I) will be completed to include the following:
medical conditions, current cancer diagnosis, planned cancer regimen, medications,
allergies, social history, patient report of oral problems, dental history, subjective oral
complaints, objective measures of oral disease, current laboratory values, dental treatment
recommended and untreated dental disease. This pre-treatment assessment will occur 1
week to 8 weeks prior to stem cell transplantation.
Before or upon admission to the hospital for conditioning for stem cell
transplantation, an assessment (Phase II) of medical condition, medications, subjective and
objective oral findings, quality of life measures and laboratory values will be completed.
The admission evaluation will occur at day -7 to -1 days.
A similar bedside assessment (Phase III) as the admission evaluation will be
completed 3 days/week (Monday, Wednesday and Friday) starting day 0, +1, +2 or +3
(depending on day of the week for transplantation) until resolution of neutropenia (i.e.
absolute granulocyte count > 0.5 x 109). For patients with continued mucositis or other oral
problems requiring hospitalization after resolution of neutropenia, an oral examination will
be completed for up to 6 weeks duration after transplant.
Additional visits for urgent care for acute oral problems will be documented
regarding the nature of the oral problem and treatment provided (Phase IV). This will be
documented for up to 6 months for the autologous stem cell transplantation patients and 12
months for the allogeneic transplant patients. Patients will be followed-up (Phase V) in an
outpatient setting at 100 days for those treated with an autologous stem cell transplantation.
These patients will also receive a questionnaire at 1 year post-transplantation to identify
any long-term side effects, thereafter yearly until resolution of side effects. Those treated
with allogeneic transplantation will be followed up at 100 days, 6, 9 and 12 months.
Thereafter, yearly follow-ups will be performed until resolution of side-effects. The
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assessment will include cancer response to therapy, current medical conditions,
medications, subjective and objective oral findings, QoL measures and laboratory values.
Study outline of the standardized examination process, see Fig 1. The different
Phases correspond to the different sections in the MedView computer software program
form.
Of the variables that will be measured, the following need detailed description.
GVHD
GVHD may occur in allogeneic stem cell transplant patients. Graft lymphocytes
react on patient antigens. Acute GVHD (aGVHD) occurs within 100 days after
transplantation. aGVHD is graded as none (0), mild (I), moderate (II), severe (III) and life
threatening (IV) and involves skin, liver and/or GI tract. Symptoms of GVHD 100 days or
more post-transplant are diagnosed as chronic GVHD (cGVHD), whether proceeded by
aGVHD or not. cGVHD may be limited (skin and/or liver engagement) or extensive
(involves skin, nails, hair, mouth, eyes, genitals, liver, lungs, GI-tract, fascia, muscles,
skeleton/joints, serous organs, blood, immune system). Oral symptoms are by definition
signs of cGVHD, although there are reports on early clinical oral symptoms. This may be
of interest to evaluate. Oral signs of GVHD are oral dryness, burning sensation, gingival
reactions, mucositis, erythema, lichen, etc.
Periodontology measures
At Phase II, clinical oral assessment of the percentage of teeth with plaque and
supragingival calculus should be documented whilst other periodontal parameters, such as
subgingival calculus, bleeding on probing and periodontal pockets can be captured earlier,
for example in phase I. If periodontal treatment was done after these measured, it should be
documented.
Oral hygiene, measured at Phase II
Baseline oral hygiene will be measured by the number of teeth with plaque present. Plaque
visible with the eye (yes/no) will be registered for each tooth:

<20% of teeth with plaque will be graded as good oral hygiene

20-50% is intermediate and

>50% of teeth with plaque is considered poor oral hygiene.
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Calculus
Calculus is essential to measure since it will facilitate accumulation of plaque. It will be
measured as
Supragingival calculus measured in Phase II

<20% of teeth with calculus

20-50% of teeth with calculus
>50% of teeth with calculus
Subgingival calculus measured in Phase I

<20% of teeth with calculus

20-50% of teeth with calculus

>50% of teeth with calculus
Pocket depth, measured in Phase I and in Phase II ( if possible)
Full pocket depth index will be registered on four surfaces on each tooth at the dental
clinic: 1-3 mm (shallow pockets), 4-6 mm (medium deep pockets), >6 mm (deep pockets):

<20% of teeth with a least one deep pockets, moderate severity

20-50% of teeth with deep pockets, intermediate severity

>50% of teeth with deep pockets, high severity
Bleeding on Probing (BoP), measured in Phase I and in Phase II (if possible)
Bleeding will be noted (Y/N) with each tooth.
The percentage of teeth with the presence of BoP

<20% of teeth with BoP

20-50% of teeth with BoP

>50% of teeth with BoP
Saliva samples to measure salivation
The amount of unstimulated whole saliva will be measured by collecting saliva for
5 min. The amount of stimulated whole saliva will be measured during 5 min of chewing
paraffin. To be collected at Phase I and at Phase V/+100 days in both autologous and
allogeneic transplant patients, in allogeneic transplant patients also at Phase V/1 year.
Xerostomia (subjective feeling of dry mouth) is evaluated in all Phases. A question
about xerostomia is also to be included in the 1 year-questionnaire to autologous transplant
patient.
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Saliva samples for polymorphism study
We will obtain saliva DNA samples from cancer patients prior to a conditioning
regimen of chemotherapy for autologous or allogeneic stem cell transplantation. These
patients will be followed prospectively to document the incidence and severity of
mucositis. We will evaluate if genetic polymorphisms in the candidate genes identified in
mucositis studies completed by the Department of Oral Medicine, Carolinas Medical
Center will demonstrate an increased risk for the development of severe mucositis (WHO
grade 3 or 4).
A saliva sample will be obtained prior to the start of cancer therapy and sent to
Carolinas Medical Center for storage. Saliva for polymorphism study should be taken after
the samples to measure salivation. To keep collection of DNA as simple as possible, we
will use the Oragene DNA™ system (DNA Genotek Inc.,Ottawa, Ontario, Canada). All that this requires
is for the patients to rinse their mouth with water to clear any food debris before spiting 2
ml of saliva into the Oragene™ container. Once the container is closed, the contained
reagents release the DNA from buccal epithelial cells in the saliva and stabilize it for long
term storage. Samples can be kept at room temperature for several years without
deterioration. The container is designed, approved, and comes with packaging for mailing.
The median yield from a 2 ml saliva sample is 110 µg of DNA. This is higher than for most
other oral epithelial cell sampling systems and more than adequate for future genetic
epidemiological studies. Following collection, the sample could be stored locally at room
temperature before mailing to the Carolinas Medical Center for storage at -20ºC before
further processing and analysis.
Approximately 15 candidate genes identified in previous mucositis studies
completed by the Department of Oral Medicine at Carolinas Medical Center will be
evaluated for polymorphisms that increase the risk for the development of severe oral
mucositis. The flow of the study will include the following:
1. Identify candidate genes based on results of prior studies from the Department of Oral
Medicine at Carolinas Medical Center
2. Compile single nucleotide polymorphisms (SNPs) within candidate genes.
3. Select SNP panel. The idea is to use the fewest number of SNPs that are feasible.
Typically this is done by using two approaches: 1) identifying “tag” SNPs that exist in a
haplotype with other SNPs so that only one of the SNPs needs to be assayed to get
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18
information on both, and 2) remove SNPs that have low minor allele frequencies (e.g.
<5%), since it is unlikely that such alleles provide much information to association studies.
4. Determine the appropriate platform to assay the selected SNPs. This will depend largely
upon the number of SNPs comprising the panel, the number of samples (patients) that are
to be evaluated, the number of samples that can be batched together for efficiency, and the
turnaround time necessary for the work.
5. Develop assays if necessary. For example, with Taqman many of the assays may already
be developed, whereas for Sequenom multiplexed panels we always have to develop novel
assays because even if we’ve assayed the variant before, each multiplex behaves a little
different.
6. Run the samples.
Some pilot studies have to be made and a power analysis to determine the sample size. We
also have to consider the question of race: there are differences in the genome between
races which clearly can influence interpretation of the results. The polymorphism study can
justify that we register race.
When the number of SNPs grows beyond a half dozen or so, then the Sequenom
platform is often more cost effective. However, this is only the case when a large number
of samples are analyzed.
The sample would be linked to data from the present study such as sex, race, ethnic
background, cancer diagnosis and therapy and oral complications. The sample will be
coded by the enrolment site/patient sequential number (e.g. A/053). None of the data
collected with the questionnaires will contain personal health identifiers, therefore only
researchers at the enrolment site will have a key to determine the donor’s identity. This
key will not be provided to other researchers. The samples will be stored for possible future
genetic studies that are outside the remit of the current grant proposal. We anticipate
seeking separate funding and ethical approval in the future for additional analysis of this
material.
Appropriate consent will be obtained for this polymorphism study and possible
future genetic studies.
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19
NCI CTCAE v.3
Whenever possible, adverse events will be measured by validated scales (see
Variables below). For assessment of several adverse events, the US National Cancer
Institute Common Terminology Criteria for adverse events (NCI CTCAE) version 3 (33)
will be used. The NCI CTCAE v.3 displays grades 1 through 5 with clinical descriptions of
severity for each adverse event (Table 3). Quality of life will be measured by the Oral
Mucositis Daily Questionnaire (OMDQ).
Table 3. NCI CTCAE v. 3 grading scale, based on the following general guideline
GRADE
SEVERITY
1
Mild
2
Moderate
3
Severe
4
life-threatening or disabling
5
death related to adverse event(s)
Variables
Whenever possible, validated instruments to measure symptoms will be used.
Oral Findings (Complications) to be included in the study
Subjective Oral Findings/Complications:
Finding/Complication
Method
for
Instrument
data
Timing
(Phase)
collection
Oral pain
(Severity and Location)
Validated
Scales
- NCI CTCAE v.3
III
(34)
-.WHO pain ladder
(35), adapted (40)
Xerostomia
(Dryness vs. Viscosity)
Scale (one or
more)
- NCI CTCAE v.3
Taste Changes
(Dysgeusia) (Abnormal
vs. Decreased)
Dysphagia (Difficulty to
eat, speak and swallow)
Scale
- J. Epstein scales (36)
III
Scale
- NCI CTCAE v.3
III
I, III, V
- VAS scale
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20
Objective Oral Findings/Complications:
Finding/Complication
Method for
data
collection
Scales
Instrument
Timing
(Phase)
- WHO (II, III, IV, V)
(37)
- Oral Mucositis
Assessment Scale OMAS (III, IV) (8)
II, III, IV,
V
-clinical
judgement
-culture when
necessary
-clinical
judgement
Clinical examination
and description
II, III, IV,
V
Clinical examination
and description
II, III, IV,
V
Existing dental and
periodontal disease
-clinical
judgement
/diagnosis
I, II
Dental and periodontal
complications during
cancer therapy
-clinical
judgement
/diagnosis
Osteonecrosis
-clinical
judgement
/diagnosis
-clinical
judgement
/diagnosis
Salivary probe
Clin. and radiographic
examination of:
number of remaining
teeth/implants, caries,
rootcanal treated teeth,
chronic apical
periodontitis, partially
erupted wisdom teeth,
plaque, calculus,
marginal periodontitis
Clin. and radiographic
examination of:
pulpitis, abscesses,
pericoronitis, gingival
bleeding and so on.
Clin. and radiographic
examination
Clinical examination
and description
III, IV, V
5 minutes
(mL/minutes)
I, V
Camera
I-V when
indicated
Oral Mucositis
Oral infections: viral,
fungal or bacterial
Submucosal
hemorrhages
GVHD
Stimulated Salivary
Flow (paraffin chewing)
Others
Photo documentation
III, IV, V
V
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21
Signs to predict oral complications.
Finding/Complication
Salivary sample (2 mL
from stimulated saliva)
for the genetic
polymorphism study
Method for
data
collection
Instrument
Timing
(Phase)
Salivary
probe
Gene expression
analysis
I
Timing
(Phase)
Confounding variables
Finding/Complication
Method
for
data collection
Instrument
Demographics
Patient records,
Interviewing
age, gender, race
I
(White, Black, Hispanic,
Asian, Other)
Cancer Diagnosis
Patient records
Diagnosis Name
I
Cancer Therapy
Patient records
I, II
Type of transplant
Antimicrobial
prophylaxis
Pat records
Patient records
Previous CT, RT and
investigational
therapies;
CT for current HSCT
Auto or allo
Type, dose, duration
KGF medication
Patient records
Type, dose, duration
III
Immunosuppr. for
GVHD
Patient records
Type, dose, duration
III, IV, V
Recommendations for
Patient records
local special oral care
programs+individualized
patient recommendations
Nausea
Scale
Type, dose, duration
III
NCI-CTCAE v.3
III
Vomit
Scale
NCI CTCAE v.3
III
Diarrhea
Scale
III, V
Fever
Patient records
Number of episodes
during last 24 hours
(OMDQ questionnaire)
Celsius
Weight
Patient records
Kg or Pound
II, III, IV,
V
II, III
Blood values
Patient records
WBC, PTL
II,III,IV,V
II
II, III
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22
Outcome Measures
General Clinical Outcomes as a result from Oral Findings/Complications
Finding/Complication
Method
for
Instrument
Timing
data collection
(Phase)
Systemic infection
Patient records
Type of infection,
symptoms, duration,
CRP, temperature
(type, dose, duration)
II, III, IV, V
Add. antibiotic therapy
Patient records
Narcotic analgesics
Patient records
Oral or i.v.
Type, dose, duration
(type, dose, duration)
III, IV, V
Other add. medication
Patient records
Nutrition
Patient records
III
Patient records
Total Parenteral
Nutrition; Enteral
Nutrition (Feeding
Tube); solid, liquid,
enteral vs. parenteral
Kg
Weight
Survival
Patient records
Y/N, days
VI
III, IV, V
III, IV, V
III, , V
Economic Outcomes as a result from Oral Findings/Complications
Finding/Complication
Method for
data collection
Instrument
Timing
(Phase)
Days of Hospitalization
Patient records
Days
III, IV
Emergency Department
or Additional Hospital
Visits
Patient records
Emergency Dental
Consultations
Clinical
examinations or
patient history
Number of Visits,
III, IV
Location of Visits,
Timing (Days after
Tx)
Number of Visits,
III, IV, V
Location of Visits,
Timing (Days following
transplantation)
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23
Quality of Life (QoL)
QoL variables potentially affected by oral complications
Finding/
Method for
Instrument
Complication
data
collection
Quality of Life issues
Questionnaire
Oral Mucositis Daily
related to symptoms from once a week for
Questionnaire
the oral cavity
in-patients.
(OMDQ) (38)
Follow-up after
1 year.
For allogeneic
once a year
thereafter
Global questions on
Questionnaire
Study specific Oraeffects of oral cavity on
Once/week for
Stem questions
general well-being
in-patients.
Follow-up after
1 year. For
allogeneic
once/year
thereafter
Timing
(Phase)
III, V
III, V
See MedView for a full version of the study form.
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24
Statistic analyses and Sample size
Analyses will be primarily descriptive in nature. Continuous variables will be assessed by Student’s t-test or Wilcoxon Rank-Sum test, and dichotomous variables by chisquare or Fisher exact test, with a critical value of 0.05. For multivariate analyses, variables
thought to have prognostic value will first be analyzed by univariate analysis and appropriate variables (p<0.1) will be entered into a multivariable logistic regression analysis. Odds
ratios will be calculated to represent the relative risk of the predictor variables. Analyses
will be performed with the SAS statistical program (SAS Institute Inc., Cary, North Carolina, USA).
Primary Aim – Sample Size
The overall aim of the current prospective international observational multicenter
study is to establish the nature, incidence and temporal relationship of oral complications
related to conditioning regimen
Estimated risk of patient-reported oral complications among subjects undergoing HSCT
Sample sizes were selected (conservatively) to provide acceptable precision for
estimates of risk for oral complications. The source of the expected incidences is included
in Table 4. These samples sizes were determined with α = 0.05 and differing levels of
acceptable absolute precision.
Table 4. Expected incidence of oral complications after HSCT and estimated sample size to
reach a statistically significance level of 95%.
Oral Complication
Estimate source
Expected
Incidence
Sample Size
Precision
Mucositis
Preliminary study
65%
Xerostomia
(31)
40%
Oral Pain
(29)
45%
Dysphagia
Preliminary
literature review
54%
237
133
83
244
140
86
251
148
91
252
+/- 6%
+/- 8%
+/- 10%
+/- 6%
+/- 8%
+/- 10%
+/- 6%
+/- 8%
+/- 10%
+/- 6%
139
93
+/- 8%
+/- 10%
24
25
GVHD*
(39)
7-54%
62-252
Dysgeusia
Preliminary study
38%
Oral Viral
(25)
43%
Oral Fungal
(24)
38%
246
133
88
254
148
93
252
142
91
+/- 6%
+/- 8%
+/- 10%
+/- 6%
+/- 8%
+/- 10%
+/- 6%
+/- 8%
+/- 10%
+/- 6%
+/- 8%
+/- 10%
* Dependent on donor matching with acute GVHD 20-48% for matched related-donor and
up to 90% for an unrelated donor. 35%-60% of patients with acute GVHD will have oral
manifestations.
Using the most conservative estimate, a total of 254 patients will need to be enrolled to
obtain 6% precision for the main oral complications listed in Table 4.
Ethical approval / Informed consent
A separate ethical application will have to be done for each country involved. In the
US, there are 18 specified identifiers that are not allowed, decided by US Government (see
Appendix 1). Of most significance, birth dates or dates of the examinations can not be
included, so will need to code as day -4 to day +20 etc…, depending when the stem cells
are given. Some national adjustments may have to be done.
Study Timeline
Start of study 2011.
25
26
Fig 1.
Allogeneic
Check-up
At 100 days
Check-up
At 6 months
Check-up
At 9 months
Check-up
At 12 months
Tx
(day 0)
Oral exam Check-up
6-8 weeks 1-2 days
before
before
Bedside examinations
from day 0 (or +1 day),
mon, wed, fri until
resolution of
neutropoenia or, if
patient continues
to have mucositis until
discharge
Check-up
At 100 days
Questionnaire
at 12 months
Autologous
PHASE I
PHASE II
PHASE III
PHASE IV
PHASE V
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Contact List
Name
E-mail
Skype
Mike Brennan
+1 704-355-5774
[email protected]
mike.brennan01
Inger v. Bültzingslöwen
+46 (0)703-922072
[email protected]
Katjavb
Karin Garming-Legert
+46 (0)705-488326
[email protected]
karingl1
Bengt Hasseus
+46 (0)730-882425
[email protected]
Peter Johansson
+46 (0)762-645902
[email protected]
Jan Erik Johansson
[email protected]
Mats Jontell
+46 (0)702-268105
[email protected]
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