Oral Mucositis In Cancer Care
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  • 45 min Morning talk

Oral Mucositis In Cancer Care Presentation Transcript

  • 1. Oral Mucositis in Cancer Care: Is The End in Sight? Peter B. Lockhart, DDS, FDS RCPS Chair, Department of Oral Medicine Carolinas Medical Center
  • 2. Oral Mucositis
    • Mucositis vs. stomatitis
    • Inflammation vs. ulceration
    • Chemotherapy- vs. radiotherapy-induced
    • Complication vs. sequela
    Is the end in sight? Terminology:
  • 3. Absolutely Doubtful No way Possibly Never Perhaps Likely Yes Could be No
  • 4. 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
  • 5. 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
  • 6. 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
    ?
  • 7. Mucositis Complications and Sequelae
    • Pain
    • Oral infection
    • Systemic infection?
    • Bacteremia/Sepsis
    • Oral bleeding
    • Xerostomia
    • Taste
    • Hydration/Nutrition
    • Fatigue
    • Interrupted cancer treatment
  • 8. 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
  • 9. 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
  • 10. 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
  • 11. Stomatotoxicity 1978 - 1988
    • Unpredictable incidence/severity
    • Duration variable
    • Mechanism?
    • Role of trauma, xerostomia, and oral flora?
  • 12. Chemotherapy Stomatotoxicity 1978 - 1988 Direct Indirect Bleeding Decreased nutrition Mucosal infection Cell renewal Thinning Mucositis and ulceration Thrombocytopenia Neutropenia Xerostomia
  • 13. 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
  • 14. Trauma – Dentures
  • 15. Concomitant Chemotherapy and RT
  • 16. Trauma – Teeth and Restorations
  • 17. Soft Tissue Necrosis
    • Traumatic vs. spontaneous
    • Intraoral source RT
    • Can occur late
    • Prolonged duration
  • 18. 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
  • 19. 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
  • 20. Atrophy and Collagen Degeneration
  • 21. Mucosal Sloughing
  • 22. 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
  • 23. Mucositis Study Group International Society for Oral Oncology (ISOO) 1985 Multinational Association of Supportive Care in Cancer (MASCC) 1995
  • 24. Mucositis Pathobiology and Practice Guidelines - 2004 © MASCC 2004 Cancer Supplement May 1, 2004
  • 25. DNA damage and apoptosis Reactive oxygen species (free radicals) Mucositis, damaged cells, blood vessels Mechanism – Current Thinking
  • 26. 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.
  • 27. 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
  • 28. Feb. 2007
  • 29. 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
  • 30. Topical Anesthetics
    • No recommendations (lack of well designed trials)
    • Reasonable for mild/moderate and breakthrough pain management
    • Check that the patient eats
    Keefe DM, et al. Cancer, 109; 2007
  • 31. Prevention Anti-inflammatory Agents
      • Multiple small studies but results still conflicting
      • May be helpful for:
      • Rectal and pelvic cancer RT
      • Amifostine
    Keefe DM, et al. Cancer, 109; 2007
  • 32. 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
    Keefe DM, et al. Cancer, 109; 2007
  • 33. 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
  • 34.
    • 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
  • 35. 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
    Keefe DM, et al. Cancer, 109; 2007
  • 36. 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
    Keefe DM, et al. Cancer, 109; 2007
  • 37. 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
    Keefe DM, et al. Cancer, 109; 2007
  • 38. 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
  • 39.
    • 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
  • 40.
    • 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
  • 41.  
  • 42.
    • 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
  • 43. Mucositis - Bacteremia and Sepsis
    • Mucosal barrier to pathogenic bacteria and fungi
    • Fever
    • Role in mucositis?
  • 44. 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
  • 45. Gram-negative Bacteria and Oral Mucositis G (-) bacilli Lipopolysaccharide release Binding to epithelium Cytokine release: TNF, IL-6, IL-1 Increased inflammatory process
  • 46. Study Design
    • Prospective cohort study
    • Outpatients
    • Inclusion criteria:
      • newly diagnosed breast cancer
      • Adriamycin 50 mg/m 2
  • 47. Oral Examination and Sample Collection
    • Oral bacterial sampling (buccal swab) on Chemotherapy – Day 0 and Day 7-14
    • Mucositis score (World Health Organization)
  • 48. 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
  • 49. Results
    • 9 female patients
    • 41 bacterial species
      • 9 species – pre and post-chemotherapy
      • 7 species - pre-chemotherapy only
      • 25 species - post-chemotherapy only
  • 50. 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
  • 51.
    • 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
  • 52. 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
  • 53. 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
  • 54. 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%)
  • 55. 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
  • 56.
    • 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
  • 57. 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
  • 58. 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
  • 59. 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
  • 60. 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
  • 61. CONCLUSIONS
    • Excellent RNA recovery and microarray data from 30-year old tissue samples
    • Results in concordance with those obtained from the AML study
  • 62. 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
  • 63. 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...
  • 64. 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