Oral Mucositis

Michael Schmitt, MD PhDHead

Clinical Stem Cell Transplantation and ImmunotherapyDepartment of Internal Medicine III

University of RostockGermany

Oral Toxicity Timeline

Baseline

Acute Toxicity

Treatment Duration

Late (Long-Term) Toxicity

Acute Toxicity Chronic Toxicity

Injury Starts on Day 1 of Cancer Therapy

TIME

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 cytokines1

• Phase 2 (up regulation and messenger generation)1

– Multiple destructive processes occur simultaneously1

– 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):1995–2025ROS, 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’ impact1

• Phase 4 (ulceration and inflammation)1

– Combined effects of stages 1–3 lead to ulceration1

– Bacterial infection may occur leading to 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

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.

% Mucositis

% No mucositis40%

Chemotherapy1

Bone Marrow Transplant1

Radiation Therapy to Head and Neck2

97%

70%

Adapted from Köstler WJ, et al.1

Adapted from Köstler WJ, et al.1

Adapted from Sonis ST. 2

Common Toxicities of Radiotherapy for Head and Neck Cancer1-4

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.

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%

Stem Cell Transplantation and Oral Mucositis: Factors Associated With Increased Incidence and Toxicity

Autologous AllogeneicAmount of chemotherapy administered Pre transplant body mass index >25 kg/m2

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

Stiff P. Bone Marrow Transplant. 2001;27;(suppl 2):S3-S11.TBI = total body irradiation; NHL = non-Hodgkin lymphoma

Mucotoxic Regimens in Hematologic Malignancies

Niscola P. Haematologica. 2007;92:222-231.

Regimen Components

CHOP Cyclophosphamide, doxorubicin, vincristine, prednisone

MACOP-BIntermediate-dose methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin

ABVD Doxorubicin, bleomycin, vinblastine, dacarbazine

FLAG and Ida-FLAG Fludarabine, cytarabine,G-CSF with or without idarubicin

AIDA ATRA, idarubicin

“Hi7 +3” Daunorubicin, cytosine arabinoside

D-AC High-dose cytosine arabinoside

ESHAP, DHAP, ICE, ASHAP CAV, hyper CVAD Multiple drug combinations and permutations noted above

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.

1. Papas AS et al. Bone Marrow Transplant. 2003;31:705-712.

Days of Mucositis (mean) N

umbe

r of D

ays

0

1

2

Control Caphosol

3

4

5

6

7

87.2

3.7 p<0.001

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.

Percent of Patients With Oral Mucositis ≤Grade 1*%

of P

atie

nts

0%

10%

20%

Control Caphosol

30%

40%

50%

60%

70%

80%

19%

40%

90%

Adapted from Papas AS et al.1

100%

1. Papas AS et al. Bone Marrow Transplant. 2003;31:705-712.* Pain was assessed by patients using a 0-100 visual analog scale where 100 equals the most pain imaginable.

Days of Pain (mean)*N

umbe

r of D

ays

0

1

2

Control Caphosol

3

4

5

6

7

8 7.7

2.9

p<0.0001

Adapted from Papas AS et al.1

1. Papas AS et al. Bone Marrow Transplant. 2003;31:705-712.

Days of Morphine (mean)N

umbe

r of D

ays

0

1

2

Control Caphosol

3

4

5

4.0

1.3

p<0.001

Adapted from Papas AS et al.1

1. Papas AS et al. Bone Marrow Transplant. 2003;31:705-712.

Total Morphine Use (mean)To

tal m

g of

Mor

phin

e

0

20

60

Control Caphosol

80

120

140122.8

34.5

p<0.0001

40

100

Adapted from Papas AS et al.1

An advanced electrolyte solution

Supersaturated aqueous solution of calcium and phosphate

Designed to replace ionic and pH balance in oral cavity

Caphosol® : Formulation

Caphosol Instructions for use

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

Hypothesised Mechanism of Action

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