Oral Mucositis In Cancer Care Is The End In Sight

Oral Mucositis in Cancer Care: Is The End in Sight? Peter B. Lockhart, DDS, FDS RCPS Chair, Department of Oral Medicine Carolinas Medical Center

Oral Mucositis
Mucositis vs. stomatitis
Inflammation vs. ulceration
Chemotherapy- vs. radiotherapy-induced
Complication vs. sequela
Is the end in sight? Terminology:

Absolutely Doubtful No way Possibly Never Perhaps Likely Yes Could be No

Oral Mucositis
“ collective consequence of a number of concurrent and sequential biological processes”
Can be the most debilitating of side effects
oral and GI
Ranges from mild inflammation to ulceration

Who Oral Mucositis Scale
Grade 0: No changes
Grade 1: Soreness/erythema ■ Grade 2: Ulceration/solid foods
Grade 3: Liquid diet ■ Grade 4: No alimentation

Oral Mucositis – Incidence
High dose chemo. + Stem cell therapy
Near 100% for any grade
30-50% Grade 3 & 4 without TBI
>60% Grade 3 & 4 with TBI
?

Mucositis Complications and Sequelae
Pain
Oral infection
Systemic infection?
Bacteremia/Sepsis
Oral bleeding
Xerostomia
Taste
Hydration/Nutrition
Fatigue
Interrupted cancer treatment

Mucositis - Impact
Drugs – antibiotics, pain medications
Additional clinic visits
Re-admissions to hospital
Increased hospitalization - up 74 days
Feeding tubes ~ 85-90%
Quality of life issues

Economic Impact
Non-transplant chemotherapy
With grade 3 or 4 oral mucositis:
35% require dose delays
60% require dose reduction
30% have cessation of chemotherapy
Cost: $5,565/cycle

Economic Impact
High dose chemo. and transplant
With oral ulceration:
required 5.8 additional days of narcotics
required 1.9 additional days of TPN
 systemic infection and fatigue
 intensive nursing care; medical and dental specialists
Cost: $42,749

Stomatotoxicity 1978 - 1988
Unpredictable incidence/severity
Duration variable
Mechanism?
Role of trauma, xerostomia, and oral flora?

Chemotherapy Stomatotoxicity 1978 - 1988 Direct Indirect Bleeding Decreased nutrition Mucosal infection Cell renewal Thinning Mucositis and ulceration Thrombocytopenia Neutropenia Xerostomia

Clinical Considerations
Oral Mucositis Risk Factors
Chemotherapy dose and protocol
Concomitant H&N RT or TBI
Trauma
Pre-chemotherapy oral status
Real vs. hypothetical vs. teleological

Trauma – Dentures

Concomitant Chemotherapy and RT

Trauma – Teeth and Restorations

Soft Tissue Necrosis
Traumatic vs. spontaneous
Intraoral source RT
Can occur late
Prolonged duration

Histologic Changes from Chemotherapy
120 necropsies from 30 patients
Death within 30 d. myelosuppresive chemo.
Multiple oral anatomical sites
“ Blinded” oral pathologist
Methods Lockhart P, Sonis ST. J Dermatol Surg Oncol 1981; 7(12):1019-1025

Histologic Changes
Collagen degeneration
Hyperplasia
Parakeratosis
Glandular degeneration
Atrophy
Dysplasia
15 15 11 10 7 7 (75%) (75%) (55%) (50%) (35%) (35%) (N=20) Lockhart P, Sonis ST, J Dematol Surg, 1981

Atrophy and Collagen Degeneration

Mucosal Sloughing

Pathobiology of Oral Mucositis
1970s – 1980s
• Defining the problems – incidence, nature and severity
• Clinical prevention and m anagement issues
• Focus on epithelium
1990s
• NIH consensus conference (1989)
• Focus on mucosal cells and mediators
• Pharmaceutical studies – clinical trials

Mucositis Study Group International Society for Oral Oncology (ISOO) 1985 Multinational Association of Supportive Care in Cancer (MASCC) 1995

Mucositis Pathobiology and Practice Guidelines - 2004 © MASCC 2004 Cancer Supplement May 1, 2004

DNA damage and apoptosis Reactive oxygen species (free radicals) Mucositis, damaged cells, blood vessels Mechanism – Current Thinking

Today’s Pathobiology Perspective: A Multiple Mechanism Model Healing Ulceration Signaling and Amplification Upregulation and Message Gen Initiation Keefe and Sonis – Cancer Supplement. 100:1995-2011, 2004.

Today’s Pathobiology Perspective: A Multiple Mechanism Model Healing Ulceration Signaling and Amplification Upregulation and Message Gen Initiation Apoptosis Tissue Injury IL-1  TNF-  IL-6 NF-  B Angiogenesis Clonogenic Cell Death ROS DNA Injury Fibronectin Breaks Up Activates Macrophages MMP Gene Upregulation Cell Membrane Epithelium Endothelium Connective Tissue Macrophages Sphingomyelinase Ceramide Pathway Ceramide Synthase Expression of Adhesion Molecules COX-2 CT RT

Feb. 2007

Basic Oral Care
Guidelines:
Dental assessment and care – pre-treatment, during treatment, follow-up
“ ...basic oral care including an ultra soft toothbrush with regular replacement of the toothbrush”
Bland rinses
Promote mucosal moisturization and protection
Check for fungal, bacterial or viral infections
Keefe DM, et al. Cancer, 109; 2007

Topical Anesthetics
No recommendations (lack of well designed trials)
Reasonable for mild/moderate and breakthrough pain management
Check that the patient eats

Prevention Anti-inflammatory Agents
Multiple small studies but results still conflicting
May be helpful for:
Rectal and pelvic cancer RT
Amifostine

Prevention – Alternative Therapies
Vitamins A, E, B12, Folate, and diet supplements
Glutamine (II C)
Aloe vera
PV701 – Milk-derived protein extract
No Guideline possible - Conflicting and insufficient evidence

Prevention - Cryotherapy
Recommended for:
Bolus 5 FU and Leucovorin/5FU (II A)
Suggested for:
Etidronate (IV B)
High dose Melphalan in HSCT (II A)
Keefe DM, et al. Cancer, 109; 2007 © MASCC 2004

Agents in Clinical Trials
IL-11
trials stopped early for excess toxicity
GM-CSF and G-CSF (II,C)
still no evidence for reduced oral mucositis
KGF-1 (palifermin)
Recommended for HDC and TBI with HSCT
KGF-2 (repifermin)
withdrawn by company
Prevention Keefe DM, et al. Cancer, 109; 2007

Antimicrobial Lozenges
Polymyxin tetracycline Amphotericin B (PTA)
Bacitracin Clotrimazole Gentamicin (BCoG)
H&N RT, adults, prevention
Results: Equal to placebo
Guideline : Recommend against use for prevention

Guidelines: Oral Mucositis
Pain Management
Recommended PCA with morphine for oral mucositis pain for stem cell transplant (I A)
Benzydamine
Recommended for prevention of RT induced mucositis in patients with H&N Ca receiving moderate dose RT
Note closure of North American trial

MASCC/ISOO SUMMARY
Mucosal alteration associated with chemo- and radiotherapy is multifactorial
Many clinical studies failed to meet current standards
Guidelines demonstrate few preventive and treatment options for mucositis
Further research necessary
pathophysiology
epidemiology
therapy

Role of Xerostomia in Mucositis
Mucositis - No prevention available
Xerostomia? - H&N RT data and 1 chemo. abstract
Pilocarpine stimulation of salivary glands
incidence
severity
duration
Lockhart PB et al Bone Marrow Transplantation35:713-720, 2005

Prospective, double-blind, randomized, placebo-controlled trial
40 stem cell transplant patients
5 mg pilocarpine vs. placebo every 4 hrs beginning day -1 (4 tabs/day)
Bedside evaluations on alternate days
Methods

No statistically significant differences in:
Overall incidence
Pilocarpine 16/20 (80%)
Placebo 15/16 (94%)
Severity
Duration
Results - Mucositis Lockhart PB et al Bone Marrow Transplantation35:713-720, 2005

No statistically significant differences in:
Mouth dryness
Nutritional intake
Hygiene
Eating
Speaking
Sleeping
Pain at rest or with swallowing
Systemic narcotic use
Results Lockhart PB et al Bone Marrow Transplantation35:713-720, 2005

Mucositis - Bacteremia and Sepsis
Mucosal barrier to pathogenic bacteria and fungi
Fever
Role in mucositis?

Alteration in the Profile of Oral Flora Following Cancer Chemotherapy
Aim:
Characterize oral bacterial flora before and after first cycle of intensive chemotherapy
Culture-independent molecular techniques.
Napenas, J et al Unpublished data

Gram-negative Bacteria and Oral Mucositis G (-) bacilli Lipopolysaccharide release Binding to epithelium Cytokine release: TNF, IL-6, IL-1 Increased inflammatory process

Study Design
Prospective cohort study
Outpatients
Inclusion criteria:
newly diagnosed breast cancer
Adriamycin 50 mg/m 2

Oral Examination and Sample Collection
Oral bacterial sampling (buccal swab) on Chemotherapy – Day 0 and Day 7-14
Mucositis score (World Health Organization)

Culture Independent Methodology Bacterial isolate PCR of 16S rRNA TOPO TA cloning kit E. Coli 16S rRNA library (24-25 clones) DNA sequencing Species identification

Results
9 female patients
41 bacterial species
9 species – pre and post-chemotherapy
7 species - pre-chemotherapy only
25 species - post-chemotherapy only

Pre- vs. Post Chemotherapy
Increased species diversity – 6
Decreased species diversity – 2
No changes in number of species - 1
Conclusion: Appears to be a shift to a more complex oral bacterial profile on the buccal mucosa of breast cancer patients undergoing chemotherapy

Few clinical histology studies
Mucositis demonstrates a wide variety of histologic changes:
collagen degeneration, epithelial hyperplasia, atrophy
variability likely due to the biologic complexity
Need further understanding of genetic regulations
Molecular Analysis of Mucosa with Chemotherapy–Induced Oral Mucositis Brennan MT et all Unpublished data

Methods
Five newly diagnosed AML patients
Buccal mucosa punch biopsy specimens (3 mm)
Immediately prior to induction chemotherapy and 2 days following
3 healthy controls (HC)
RNA extracted

Results
Microarray analysis completed for:
AML pre-chemotherapy (n=4)
AML post-chemotherapy (n=4)
Healthy controls (n=3)
3 main pair-wise comparisons in gene expression changes
HC vs. pre-chemo
HC vs. post-chemo
Pre-chemo vs. post-chemo

Results
26 genes found to be differentially expressed*
Half of the genes appear to be differentially expressed solely from chemotherapy
no statistical significance between HC and PreC group
significant shift when the PostC group is compared to both HC and PreC
* p<0.001, q<11.5%)

Results
Validated the following genes by real-time RT-PCR
ASS
PolH
LIV-1
TNFRSF10A
ASS is downregulated while the other genes were upregulated – all 2.5 fold

Conclusions:
Damage to the oral mucosa is significant and reflected by the differential expression of genes involved in nitric oxide metabolism, DNA repair, and wound repair
Identifiable genetic susceptibility polymorphisms could provide pharmacogenomics-based tailored prevention or management

Laser Capture Microdissection
Tissues are comprised of many different cell types
Each cell type expresses a different set of genes
Genes expressed, and the level of expression of each gene in a given cell type, provides insight into biological processes that are active in those cell types

Laser Capture Microdissection
Gene expression analysis from whole biological samples can obscure changes that occur in particular tissues or cell types
Laser Capture Microdissection allows relevant cell types to be purified from complex mixtures
Whole Tissue Targeted Cells Remaining Cells Captured Cells

Microarray analysis of mucosal necropsy samples
Basal cells isolated by laser-assisted microdissection from eight 25-year old mucosa samples
Control group – 3 oral mucosal biopsies from healthy controls
Full genome gene expression analysis using Affymetrix GeneChip Human X3P Arrays
Verification made prior to comparison between control group (n=6) and archival group (n=8)
Lockhart PB et al Unpublished data

Results
Significant upregulation observed for:
human Ribosomal Protein L11 (~15 times)
iNOS homologs (~20 times)
Both involved in nitric oxide and p53-mediated epithelial inflammation

CONCLUSIONS
Excellent RNA recovery and microarray data from 30-year old tissue samples
Results in concordance with those obtained from the AML study

Mucositis Accomplishments 1978 – 2008
Mechanism – progress made but much to be done
Prevention – disappointing
Pain control – essentially unchanged
Oral care – essentially unchanged
Pharmaceutical studies – slow progress after many approaches
Funding – largely pharmaceutical

The Future
Radiotherapy – tissue sparing (IMRT, IGRT)
Chemotherapy – more targeted therapies
Mechanism – basic science and animal data
Prevention – novel clinical studies
Pain control – billion dollar drug
Microbiology – further studies needed
Emergence of new challenges – Bisphosphonates...

Institute for Oral Medicine Carolinas Medical Center, Charlotte, NC
Farah Bahrani-Mougeot, PhD
Peter Lockhart, DDS
Michael Brennan, DDS
Jen-Luc Mougeot, PhD
Philip Fox, DDS
Louise Kent, RN
Jenene Noll, RN

Oral Mucositis In Cancer Care Is The End In Sight

by fondas vak on Feb 07, 2010

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