Oral Mucositis Michael Schmitt, MD PhD Head Clinical Stem Cell Transplantation and Immunotherapy Department of Internal Medicine III University of Rostock Germany 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 Stages of OM: the initial steps • Phase 1 (Initiation)1 • Phase 2 (up regulation and – CT and RT lead to DNA damage and messenger generation)1 activation of destructive processes, – Multiple destructive processes occur including generation of ROS and simultaneously1 1 cytokines – 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):1995–2025 ROS, reactive oxygen species Stages of OM: the problem worsens • Phase 3 (signalling and amplification)1 • Phase 4 (ulceration and inflammation)1 – Initial CT and RT damage plus – Combined effects of stages 1–3 lead to messenger generation forms ‘positive ulceration1 feedback’ loops intensifying each – Bacterial infection may occur leading to 1 others’ impact further tissue damage1 • 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):1995–2025 Rates of Oral Mucositis Radiation Therapy to Chemotherapy1 Head and Neck2 % Mucositis 40% % No mucositis 97% 2 Adapted from Köstler WJ, et al.1 Adapted from Sonis ST. Bone Marrow Transplant1 70% Adapted from Köstler WJ, et al.1 1. Köstler WJ, et al. CA Cancer J Clin. 2001;51:290-315. 2. Sonis ST. J Support Oncol. 2004;2(suppl 3):3-8. Common Toxicities of Radiotherapy for Head and Neck Cancer1-4 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;18:3339-3345. 2. Epstein JB et al. Head Neck. 2001;23:389-398. 3. Gal TJ et al. Arch Otolaryngol Head Neck Surg. 2003;129:72-76. 4. Sonis ST. J Support Oncol. 2004;2(suppl 3):3-8. 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/m2 Previous exposure to anthracyclines, vinca alkyloids, cyclophosphamide, fludarabine, platinum Use of TBI as conditioning regimen analogues, methotrexate 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. Mucotoxic Regimens in Hematologic Malignancies Regimen Components Cyclophosphamide, doxorubicin, vincristine, CHOP prednisone Intermediate-dose methotrexate, doxorubicin, MACOP-B cyclophosphamide, vincristine, prednisone, bleomycin Doxorubicin, bleomycin, vinblastine, ABVD dacarbazine Fludarabine, cytarabine,G-CSF with or FLAG and Ida-FLAG without idarubicin AIDA ATRA, idarubicin “Hi7 +3” Daunorubicin, cytosine arabinoside D-AC High-dose cytosine arabinoside Multiple drug combinations and permutations ESHAP, DHAP, ICE, ASHAP CAV, hyper CVAD noted above Niscola P. Haematologica. 2007;92:222-231. Palliative Agents for Oral Mucositis • Topical agents – Mixture of agents (e.g. Magic or Miracle Mouthwash), including lidocaine, benzocaine, kaolin, pectin, and chlorhexidine1 – Gelclair®2 • Systemic agents – Patient-controlled analgesia with morphine for stem cell transplant recipients – Transdermal fentanyl 1. Rubenstein EB, et al. Cancer. 2004;100:2026-2046. 2. Gelclair Bioadherent Oral Gel [package insert], Lugano, Switzerland: Helsinn Healthcare SA; 2006. 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;31:705-712. Days of Mucositis (mean) 8 7.2 7 6 5 p<0.001 4 3.7 3 Number of Days 2 1 0 Control Caphosol Adapted from Papas AS et al.1 1. Papas AS et al. Bone Marrow Transplant. 2003;31:705-712. Percent of Patients With Oral Mucositis ≤Grade 1* 100% 90% 80% 70% 60% 50% 40% 40% % of Patients 30% 19% 20% 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;31:705-712. Days of Pain (mean)* 8 7.7 7 6 5 p<0.0001 4 2.9 3 Number of Days 2 1 0 Control Caphosol Adapted from Papas AS et al.1 * Pain was assessed by patients using a 0-100 visual analog scale where 100 equals the most pain imaginable. 1. Papas AS et al. Bone Marrow Transplant. 2003;31:705-712. Days of Morphine (mean) 5 4.0 4 3 p<0.001 2 Number of Days 1.3 1 0 Control Caphosol Adapted from Papas AS et al.1 1. Papas AS et al. Bone Marrow Transplant. 2003;31:705-712. Total Morphine Use (mean) 140 122.8 120 100 80 p<0.0001 60 Total mg of Morphine 40 34.5 20 0 Control Caphosol Adapted from Papas AS et al.1 1. Papas AS et al. Bone Marrow Transplant. 2003;31:705-712. 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 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;31:705-712. 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 begins1 1. Sonis ST. J Support Oncol. 2004;2(suppl 3):3-8. 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 therapy2 – 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 satisfaction3 1. Caphosol [package insert]. Princeton, NJ: EUSA Pharrma (USA); 2008. 2. Papas AS et al. Bone Marrow Transplant. 2003;31:705-712. 3. COMFORT Registry, data on file. Hui, Xun, Xinchao, Jiju, Yvonne, Michael, Anita, Ely, Leila .