Lecture 11 Mucositis in Cancer Care Ladha

BACKGROUND:

• Common complication of chemotherapy

o Inpatient or outpatient

• Begins 5-10 days after starting therapy

o Can last 7-14 days

• Erythema, edema, atrophy, ulcerations

o Pain (narcotic analgesia)

o Restricted oral intake (TPN)

IMPACT OF OM:

• Most studies for OM look at data from inpatients, but data is

similar in outpatients

• Underreported in studies where OM is one of the endpoints

o Can occur throughout the GIT

o Focus mostly on oral cavity, oropharynx, hypopharynx

• Has now emerged as the MOST significant ADR of

chemotherapy that patients report

o Occurs in 20-40% of patients receiving chemo

o Up to 80% incidence in high-dose chemo

• Leads to additional morbidity and possible mortality

o Site for local infection

o Oral flora port of entry (sepsis)

o Indirectly increases LOS in hospital

▪ 2-fold increase for ER visits

▪ 7 days hospitalization per chemo cycle

▪ 22% pts with grade 3/4 OM require TPN

(refeeding risk)

o Chemo dose-reduction

▪ 23% of regimens (clinically significant)

▪ 28% of regimens (grade 3/4 mucositis)

• Radiation-induced OM

o Rarely results in dose reductions

o Skin breakdown, local pain

o Hospitalization for airway maintenance

RISK ASSESSMENT:

• Initial ID of risk factors may help start txt more timely

• Consider BOTH therapy and patient-related factors

PATIENT-RELATED RISK FACTORS:

NON-MODIFIABLE:

Age • High cell turn over (very young)

• Slow healing time (very old)

• Assumed, but inconsistent results from studies

• Really not predictive

Gender • Controversial (suggested higher in women)

• Longer duration/severity in women

Ethnicity • Suggested African Americans have less mucositis with 5-FU than Caucasians

Nutrition Status & Weight

• Surrogate of other co-morbidities

• BMI > 25 (increased ratio of adipose tissue: lean body mass)

Chronic Conditions

• Diabetes, thyroid dysfunction, resp disease

• Hepatic or renal impairment o Altered chemo drug metabolism

MODIFIABLE:

Oral health • Poor dental hygiene, dentition & oral fxn

• Periodontal plaque bacteria bacterial invasion of ulcerative mucositis lesions

• Retained root tips = nidus for infections

• Constant physical trauma from ill-fitting dental appliances, fractured/sharp teeth

• Non-keratinized oral mucosa surfaces

Salivary gland

• Hypofunction = loss of surface lubrication increased trauma & irritation

• Microbial colonization

• Mucosal surface dehydration

Lifestyle • Alcohol, tobacco, drugs

RISK CLASSIFICATION:

Low • No prior OM

• Receiving treatment known to cause moderate/severe OM

Moderate • Previous hx of grade 2 OM

• Receiving treatment known to cause OM o Capecitabine, 5-FU, docetaxel, cyclophosphamide,

anthracyclines, targeted treatments (ex// EGFR-inhibitors)

• Palliative radiation to head/neck

• Pharmacological treatments or co-morbidities predisposing patient to xerostomia

• Very young or elderly

High • Previous hx of grade 3/4 OM and/or resistant grade 2 OM

• Surgery to oral cavity or head/neck region (ex// tumor removal)

• High-dose chemo txt prior to autologous HSCT or allogenic HSCT (with or without total-body irradiation)

• Radical radiotherapy to head/neck (± chemo txt)

PATHOPHYSIOLOGY:

CHEMOTHERAPY:

RADIATION:

GRADING SCALE OF OM: (Grade 4 = mucositis to extent that alimentation not possible)

1 2 3

SCALE Soreness ± erythema

Erythema, ulcers Ulcers with extensive erythema

VOICE Normal Deep, raspy Difficulty speaking

SWALLOW Normal Some pain Unable to swallow

LIPS Smooth, pink, moist

Dry or cracked Ulcerated or bleeding

TONGUE Pink, moist Coated & shiny ± red Blistered or cracked

SALIVA Watery Thick Absent

MUCOUS MEMBRANE

Pink, moist Red & coated (w/o ulcers)

Ulcers

GINGIVA Pink, firm Edematous ± redness Spontaneous or pressure-induced bleeding

TEETH Clean, no debris

Plaque & localized debris

Generalized plaque & debris

Lecture 11 Mucositis in Cancer Care Ladha

PREVENTION STRATEGIES:

Effective oral hygiene • BID brushing (soft-bristle toothbrush)

• Daily flossing

• Frequent rinsing with bland oral rinses (NaCl, bicarbonate, water)

• Oral moisturizers

Topical therapy • Only cryotherapy has supportive conclusive data (melphalan-induced OM)

• Weak data supporting disinfectant mouthwashes, antibiotic rinses, pastilles or lozenges o AVOID: chlorhexidine, sucralfate, antibiotic lozenges or rinses, G-CSF moutwah

Palifermin • ONLY drug approved by FDA and HC (based on phase 3 RCT, extrapolated approval to include any myelotoxic chemo and HSCT) o Phase 3 RCT: suggests palifermin reduces grade 3 or 4 OM; reduces use of opioids & TPN

▪ AEs: transient skin rash, mucosal changes, altered taste sensation, thickened tongue

• Guidelines: only use for autologous HSCT o Evidence in other types of cancer? Two RCTs for head/neck patients

1. Reduced severity of grade 2 or higher OM; but thickened tongue & altered taste 2. Grade 4 OM lower in treatment; some NSS events (grade 4 OM delayed; median duration shortened;

xerostomia lowered)

• Avoid in pediatrics (no efficacy or safety evidence)

• For prevention of grade 3+ OM when anticipate: o Lesions increase risk of systemic infection o Clinically significant pain (ex// use of opioids) o Oral hemorrhage risk o Airway compromise requiring endotracheal intubation

• Total of 6 doses (60 mcg/kg/dose IV): day -3, -2, -1 (pre-HSCT) day 0 (day of transplant) day 1, 2

• MOA: human recombinant keratinocyte growth factor-1 (KGF) o Increases thickness of mucosal epithelium o Upregulates genes for scavenging enzymes that target reactive oxygen species (ROS) o Stimulate IL-12 reduces tumor TNF-alpha o Reduces angiogenesis and apoptosis

Amifostine • Organic thiophosphate; free radical scavenger radioprotectant

• Administer 30 mins prior to each treatment

• Approved indications: o Reduce incidence of moderate-severe xerostomia in post-op radiation treatment of H/N cancers (radiation field

includes majority of parotid glands) o Nephrotoxicity prophylaxis (platinum-based chemo)

• Controversy: vs. improved radiation techniques?

Other growth factors & anti-inflammatories

• No clear evidence for benefit: betamethasone, pentoxifylline, G-CSF, benzadyamine (an NSAID)

TREATMENT STRATEGY: TREATMENT GOAL = PALLIATION

MAGIC MOUTHWASH:

• Choosing ingredients

o Established commercial products

o Injectibles, powders, crushed/dissolved tablets, powder

from caps

o Sugar & alcohol-free vehicles

• Most common ingredients:

Antiinflammatory Diphenhydramine

Anesthetic Viscous lidocaine

Coating agents Al-OH and Mg-OH suspension (Maalox)

• Other ingredients:

Steroids HC, triamcinolone, prednisone

Antimicrobials Nystatin, tetracycline

Mucoprotection Misoprostol

Coating agents Sucralfate susp, carboxymethylcellulose

Vehicle Water, sugar-free suspending vehicles, existing vehicle in commercial products

PAIN MANAGEMENT:

FUTURE DIRECTION:

• TNF-alpha inhibitors

• COX-2 inhibitors

• Free radical scavengers/antioxidants

o Ex// NAC oral rinse

• Growth factors

o Ex// velafermin

• Pharmacogenetics

Lecture 11 Mucositis in Cancer Care Ladha

TARGETED THERAPIES (mTOR INHIBITORS):

• New anti-cancer therapies for GI, lung, pancreas, breast, renal

• Mammalian target of rapamycin (mTOR): sirolimus (rapamycin); temsirolumus; everolimus

• Distinct oral toxicities (not classic OM) dermatological

o 35-53% incidence

o Discrete, ovoid ulcers

o Characteristic erythematous halo

o Clinically look like aphthous ulcers

▪ Non-keratinized

▪ Quicker onset (within 24 hours of starting)

• Suggested pathophysiology

1. Direct epithelial injury

2. Proinflammatory cytokine release

3. Innate immune response activation

► Influx inflammatory cells

• Suggested treatment:

o Same management as aphthous ulcers

o High-potency corticosteroids