Oral Toxicity Timeline

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Myrtle Marshall
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1 Oral Mucositis Michael Schmitt, MD PhD Head Clinical Stem Cell Transplantation and Immunotherapy Department of Internal Medicine III University of Rostock Germany

2 Oral Toxicity Timeline Injury Starts on Day 1 of Cancer Therapy Baseline Acute Toxicity Chronic Toxicity Treatment Duration Acute Toxicity Late (Long-Term) Toxicity TIME

destructive processes occur simultaneously 1 ROS cause tissue and DNA damage, activation of transcription factors

3 Stages of OM: the initial steps Phase 1 (Initiation) 1 CT and RT lead to DNA damage and activation of destructive processes, including generation of ROS and cytokines 1 Phase 2 (up regulation and messenger generation) 1 Multiple destructive processes occur simultaneously 1 ROS cause tissue and DNA damage, activation of transcription factors and enzyme activation may also occur 1. Sonis S et al. Cancer 2004;100:(9 Suppl): ROS, reactive oxygen species

Stages of OM: the problem worsens Phase 3 (signalling and amplification) 1 Initial CT and RT damage plus messenger generation forms positive feedback loops intensifying each others impact 1 Phase 4

4 Stages of OM: the problem worsens Phase 3 (signalling and amplification) 1 Initial CT and RT damage plus messenger generation forms positive feedback loops intensifying each others impact 1 Phase 4 (ulceration and inflammation) 1 Combined effects of stages 1 3 lead to ulceration 1 Bacterial infection may occur leading to further tissue damage 1 Sepsis can also occur Patient may experience: Pain Difficulty swallowing Dry mouth Vocal changes Life-threatening sepsis 1. Sonis S et al. Cancer 2004;100:(9 Suppl):

5 Rates of Oral Mucositis Chemotherapy 1 40% % Mucositis % No mucositis Radiation Therapy to Head and Neck 2 97% Adapted from Köstler WJ, et al. 1 Bone Marrow Transplant 1 Adapted from Sonis ST. 2 70% Adapted from Köstler WJ, et al Köstler WJ, et al. CA Cancer J Clin. 2001;51: Sonis ST. J Support Oncol. 2004;2(suppl 3):3-8.

6 Common Toxicities of Radiotherapy for Head and Neck Cancer 1-4 Toxicity Proportion of Patients Xerostomia 57% to 95% Dysgeusia 90% Anorexia/weight loss/malnutrition 55% to 85% Chewing/eating difficulties 60% to 70% Mucositis/stomatitis 40% to 97% Dysphagia 65% to 100% Radiation necrosis/osteoradionecrosis 5% to 15% Pain 75% to 85% 1. Brizel DM et al. J Clin Oncol. 2000;18: Epstein JB et al. Head Neck. 2001;23: Gal TJ et al. Arch Otolaryngol Head Neck Surg. 2003;129: Sonis ST. J Support Oncol. 2004;2(suppl 3):3-8.

7 Stem Cell Transplantation and Oral Mucositis: Factors Associated With Increased Incidence and Toxicity Autologous Allogeneic Amount of chemotherapy administered Pre transplant body mass index >25 kg/m 2 Previous exposure to anthracyclines, vinca alkyloids, cyclophosphamide, fludarabine, platinum analogues, methotrexate Use of TBI as conditioning regimen Female gender 6-Mercaptopurine Type of disease (eg, NHL) Etoposide inclusion Melphalan inclusion Busulfan inclusion TBI = total body irradiation; NHL = non-hodgkin lymphoma Stiff P. Bone Marrow Transplant. 2001;27;(suppl 2):S3-S11.

8 Mucotoxic Regimens in Hematologic Malignancies Regimen CHOP MACOP-B ABVD FLAG and Ida-FLAG AIDA Hi7 +3 D-AC ESHAP, DHAP, ICE, ASHAP CAV, hyper CVAD Components Cyclophosphamide, doxorubicin, vincristine, prednisone Intermediate-dose methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin Doxorubicin, bleomycin, vinblastine, dacarbazine Fludarabine, cytarabine,g-csf with or without idarubicin ATRA, idarubicin Daunorubicin, cytosine arabinoside High-dose cytosine arabinoside Multiple drug combinations and permutations noted above Niscola P. Haematologica. 2007;92:

9 Palliative Agents for Oral Mucositis Topical agents Mixture of agents (e.g. Magic or Miracle Mouthwash), including lidocaine, benzocaine, kaolin, pectin, and chlorhexidine 1 Gelclair 2 Systemic agents Patient-controlled analgesia with morphine for stem cell transplant recipients Transdermal fentanyl 1. Rubenstein EB, et al. Cancer. 2004;100: Gelclair Bioadherent Oral Gel [package insert], Lugano, Switzerland: Helsinn Healthcare SA; 2006.

10 Caphosol for Oral Mucositis in Patients Receiving Bone Marrow Transplant Prospective, randomized, controlled, double-blind study of Caphosol in conjunction with standard oral care for the treatment of oral mucositis in bone marrow transplant recipients High-risk population: stem cell transplant recipients (N=95) Stratified by type of transplant: autologous or allogeneic Patients instructed to rinse a minimum of 4x daily from the start of cancer therapy Allowed to increase to a maximum of 10x per day as needed Papas AS et al. Bone Marrow Transplantation. 2003;31:

11 Days of Mucositis (mean) Number of Days p< Adapted from Papas AS et al. 1 Control Caphosol 1. Papas AS et al. Bone Marrow Transplant. 2003;31:

12 Percent of Patients With Oral Mucositis Grade 1* 100% 90% 80% 70% 60% % of Patients 50% 40% 30% 20% 19% 40% 10% 0% Control Caphosol Adapted from Papas AS et al. 1 *Mucositis scored using National Institute of Dental and Craniofacial Research (NIDCR) scale. 1. Papas AS et al. Bone Marrow Transplant. 2003;31:

13 Days of Pain (mean)* Number of Days p< Adapted from Papas AS et al. 1 Control Caphosol * Pain was assessed by patients using a visual analog scale where 100 equals the most pain imaginable. 1. Papas AS et al. Bone Marrow Transplant. 2003;31:

14 Days of Morphine (mean) Number of Days p< Adapted from Papas AS et al. 1 Control Caphosol 1. Papas AS et al. Bone Marrow Transplant. 2003;31:

15 Total Morphine Use (mean) Total mg of Morphine p< Control Caphosol Adapted from Papas AS et al Papas AS et al. Bone Marrow Transplant. 2003;31:

16 Caphosol : Formulation An advanced electrolyte solution Supersaturated aqueous solution of calcium and phosphate Designed to replace ionic and ph balance in oral cavity Caphosol Instructions for use

17 Hypothesised Mechanism of Action Caphosol : helps maintain integrity of the oral cavity Caphosol : relatively high concentrations of calcium and phosphate ions Calcium and phosphate ions diffuse into intracellular spaces in the epithelium and permeate the mucosal lesion Calcium ions: play a role in inflammatory process, blood clotting cascade, and tissue repair Phosphate ions: may be a supplemental source of phosphates for damaged mucosal surfaces Papas AS, Clark RE, et al. Bone Marrow Transplantation. 2003;31:

18 Summary and Conclusions Oral toxicity both acute and chronic is a frequent consequence of current cancer treatment regimens that results in significant morbidity As a result of increasing intensity of regimens, increasing survival, and altered patient expectations, maintenance of oral health during cancer treatment is of mounting significance Oral mucositis begins when radiation or chemotherapy begins 1 1. Sonis ST. J Support Oncol. 2004;2(suppl 3):3-8.

19 Summary Caphosol is a supersaturated solution of calcium and phosphate that is indicated for use: As an adjunct to standard oral care in preventing and treating oral mucositis caused by radiation or high-dose chemotherapy For treatment of xerostomia (regardless of cause) 1 Among treatment options, Caphosol used from day 1 of cancer therapy has shown improvement of oral mucositis In bone marrow transplant recipients, Caphosol has been proven to reduce the frequency, duration, and severity of oral mucositis when initiated at the start of cancer therapy 2 Caphosol demonstrated low levels of oral mucositis, dysphagia, and pain in chemotherapy, radiation, and chemotherapy/radiation patients with a high level of patient and physician satisfaction 3 1. Caphosol [package insert]. Princeton, NJ: EUSA Pharrma (USA); Papas AS et al. Bone Marrow Transplant. 2003;31: COMFORT Registry, data on file.

20 Hui, Xun, Xinchao, Jiju, Yvonne, Michael, Anita, Ely, Leila

Summary of Evidence-based Clinical Practice Guidelines for Care of Patients with Oral and Gastrointestinal Mucositis (2005 Update) ORAL MUCOSITIS

Summary of Evidence-based Clinical Practice Guidelines for Care of Patients with Oral and Gastrointestinal Mucositis (2005 Update) ORAL MUCOSITIS FOUNDATIONS OF CARE The panel suggests that oral care protocols