Mucositis, Constipation & Diarrhea in Cancer Pts

mucositis

inflammation of oral & gastrointestinal mucous membranes

caused by damage from radiation or cytotoxic chemo

accompanied by mucosal & submucosal changes

can be ulcerative

mucositis: risk factors relate to

cancer treatment regimen & patient regimen: chemo vs. radiation vs. chemo-radiation
• 20-40% pts receiving conventional chemotherapy
• ~100% pts receiving head & neck radiation therapy

pt: neutropenia, nutritional status, salivary fxn (dry mouth - NOT produce enough saliva)

mucositis: impact

dose limiting & can lead to delay or cessation of cancer therapy

impact on quality of life
• restrict oral intake
• painful → lack of oral hygiene
• 2ndary infection of ulcerations → systemic complications

mucositis: pathophysiology

results from damage in rapidly dividing basal epithelial “stem” cells and cells & tissues of submucosa

complex process involving
• chemo agent &/or radiation
• reactive oxygen species
• 2ndary messengers
• proinflammatory cytokines
• metabolic byproducts of colonizing microorganisms

mucositis pathobiology: 5 stage model

initiation

primary damage response

signal amplification

ulceration

healing → delay in cancer pts

mucositis: clinical characteristics

depend on severity (grade) → 1-5 (5=death)

can be at any site along GI tract
• oral (stomatitis)
• gastrointestinal mucositis NOT including oral cavity - esophagitis & proctitis (rectum)

mucositis: management

depends on severity & includes 1 or more
• pain control
• nutritional support
• oral hygiene - very important!
• cryotherapy
• laser therapy
• growth factors - IV, 1 specific
• anti-inflammatory agents
• antioxidants

MASCC/ISOO clinical practice guidelines for oral mucositis: prevention

1a. 30 min of oral cryotherapy to prevent oral mucositis in pts receiving bolus 5-fluorouracil chemotherapy
1b. oral cryotherapy in pts undergoing autologous hematopoietic stem cell transplant (HSCT) when conditioning includes high-dose melphalan

2a. low-level laser therapy in adults receiving radiation therapy (RT) or radiation-chemotherapy (RT-CT) to head & neck (H&N)
2b. low-level laser therapy in pts receiving HSCT conditioned with high-dose chemotherapy, w/ or without total body irradiation (TBI)

3. benzydamine mouthwash in pts w/ H&N cancer who receive RT-CT or moderate dose RT

4. honey in pts w/ H&N cancer who receive treatment with either RT or RT-CT

5. KGF-1 (keratinocyte growth factor-1, palifermin) IV in pts w/ hematologic cancer undergoing autologous HSCT w/ conditioning regimen that includes high-dose CT & TBI

MASCC/ISOO clinical practice guidelines for oral mucositis: treatment

topical morphine 0.2% mouthwash for treatment of pain in pts w/ H&N cancer who receive RT-CT

*guideline recommends against using sucralfate & chlorhexidine for prevention/treatment of oral mucositis

MASCC/ISOO clinical practice guidelines for oral mucositis: recommends against ___ for prevention/treatment of oral mucositis

using sucralfate & chlorhexidine

MASCC/ISOO clinical practice guidelines for gastrointestinal mucositis (not including oral cavity): recommendations

probiotics containing Lactobacillus spp. may be beneficial for prevention of RT-induced or RT-CT-induced diarrhea in pts w/ pelvic malignancy

hyperbaric oxygen to treat RT-induced proctitis in pts w/ pelvic malignancy

IV amifostine to prevent radiation proctitis in pts receiving radiation therapy

octreotide to treat diarrhea induced by standard- or high dose chemotherapy associated with HSCT, if loperamide ineffective

mucositis management: nutritional support

depending on severity, pt may require
• dietary consultation
• liquid dietary supplements
• gastrostomy tube placement
• TPN

mucositis management: cryotherapy

placement of ice chips in mouth during chemo administration
• should work for any drug w/ short t_½
• reduces drug delivery to oral mucosa by causing vasoconstriction

mucositis management: laser therapy

low level laser can reduce severity of chemotherapy & radiation induced oral mucositis

diarrhea

can result from
• tumor - colon cancer
• chemotherapy regimen
• abdominal or pelvic radiation therapy
• graft versus host disease (GVHD) in allogeneic transplantation

affects quality of life

can be fatal

diarrhea frequency & severity w/ frequently used combinations of chemotherapy agents

capecitabine/irinotecan (CapeIRI) - 47%

fluorouracil/leucovorin/oxaliplatin/irinotecan (FOLFOXIRI) - 20%

irinotecan/bolus fluorouracil (mIFL) - 19%

bolus fluorouracil w/ folinic acid - 16%

irinotecan w/ fluorouracil & folinic acid - 15%

docetaxel w/ capecitabine - 14%

fluorouracil/leucovorin/irinotecan (FOLFIRI) - 14%

bolus fluorouracil/leucovorin/oxaliplatin (FLOX) - 10%

diarrhea: pathophysiology

can be
• osmotic - excessive intake OR diminished absorption of water soluble solutes
• secretory - overstimulation of intestinal tract secretory capacity
• exudative - disruption of intestinal epithelium
• motility disturbances

chemotherapy-induced believed to result from toxicity to rapidly dividing crypt cells of intestinal epithelium
• will focus on 5-FU & irinotecan-induced diarrhea

diarrhea pathophysiology: 5-fluorouracil-induced

disruption of integrity of gut lining → enteric organisms into bloodstream → sepsis
*diarrhea is exudative type

variable severity - can be severe & at times life-threatening

most commonly observed when 5-FU co-administered w/ leucovorin (LV)
• slightly more common w/ bolus > continuous administration of 5-FU/LV

pts w/ dihydropyrimidine dehydrogenase (DPD) deficiency can have life-threatening complications to 5-FU

tests available

diarrhea pathophysiology: irinotecan-induced

acute - due to cholinergic properties of irinotecan
• accompanied by other cholinergic symptoms
• dose dependent
• respond to/can be prevented by atropine

delayed
• median time to onset: 6-14 days
• occurs at all dose levels
• pts w/ UGT1A1*28 at higher risk for developing severe toxicities

diarrhea: management

medical hx including exposure to possible causative
• antineoplastic agent
• ABX
• infective agent

physical examination

uncomplicated, grade 1-2 → additional risk factors &/or not responding to initial treatment →
OR complicated, grade 3-4 or grade 1-2 w/ additional symptoms →
CBC w/ differential, electrolytes, creatinine, CRP, total serum protein & albumin test →

in case of abdominal pain: US or CT
in case of fever: blood cultures
in case of prior & prolonged hospitalizations, ABX use, advanced age, use of feeding tubes & use of PPIs
• test for Clostridium difficile
• consider testing for Shigella, Salmonella, Campylobacter, STEC 0157:H7 strains, Giardia, Cryptosporidium & Entamoeba histolytica

diarrhea: ambulatory/outpatient setting

uncomplicated diarrhea →
• oral hydration
• dietary modification - lactose-containing
• loperamide 4 mg initially, 2 mg after every loose stool to max 16 mg/day
• avoid skin irritation
• notify treating physician

diarrhea: inpatient setting

complicated diarrhea (fluid depletion, vomiting, fever) →

1) administer loperamide 4 mg initially, 2 mg after every loose stool to max 16 mg/day; IV fluids & electrolytes AND daily evaluation of CBC, electrolytes, urinary output
2) consider octreotide SC 100-150 mcg TID or IV 25-50 mcg TID; escalation up to 500 mcg TID
3) consider ABX: fluoroquinolones, metronidazole, broad spectrum
4) stool evaluation: blood & stool microbiology testing

consider Clostridium difficile

constipation

disorder characterized by irregular & infrequent OR difficult evacuation of bowels

functional vs. secondary (know the cause - opioids) according to Rome Foundation

opioid-induced constipation (OIC)

type of 2ndary constipation

primarily peripheral mu-opioid receptor mediated

common in pts w/ cancer pain

chronic SE of opioids

NOT believed to be dependent on opioid dose

functional constipation: Rome IV criteria

for at least last 3 months
1) must include ≥2 of
• straining during defecation
• lumpy/hard stools
• sensation of incomplete evacuation
• sensation of anorectal obstruction/blockage
• manual maneuvers to facilitate defecation
• <3 spontaneous bowel movements/week
• loose stools rarely present without use of laxatives
2) insufficient criteria for IBS → rule out

opioid-induced constipation (OIC): Rome IV criteria

new or worsening symptoms constipation with opioid use

must include ≥2 of
• straining during defecation
• lumpy/hard stools
• sensation of incomplete evacuation
• sensation of anorectal obstruction/blockage
• manual maneuvers to facilitate defecation
• <3 spontaneous bowel movements/week
• loose stools rarely present without use of laxatives

constipation: clinical features

pts show symptoms resulting from
• constipation - abdominal discomfort, gas
• complications of constipation
➢ local - GI obstruction/perforation
➢ upper GI - halitosis (bad breath), anorexia, early satiety
➢ systemic - death from fecal impaction
➢ psychological - anxiety, depression

constipation management: MASCC recommendations in pts w/ advanced cancer

regularly assess constipation in pts w/ advanced cancer

individualize constipation management

provide adequate privacy & equipment (foot stool)

treat reversible causes + minimize aggravating factors

use conventional laxatives 1st line in both functional & 2ndary constipation
• if 1st line fail, consider adding OR switching to another conventional laxative or specialist med

use peripherally-acting mu-opioid receptor antagonist (PAMORAs) 1st line in OIC
• if PAMORAs fail in OIC, reassess & consider adding or switching to conventional laxative or specialist med

co-prescribe laxatives (or PAMORA) in pts prescribed opioids

use suppositories/enemas ONLY when pts have evidence of stool in rectum or descending colon & have failed other interventions

refer “resistant” cases to specialist for further investigation/management

constipation: treatment

laxatives (bulk-forming, osmotic, softening, stimulant)
• methylcellulose, polyethylene glycol, docusate, senna

PAMORAs = peripherally acting mu opioid receptor antagonists for OIC
• methylnaltrexone (Relistor) SQ
• naloxegol (Movantik) PO
• naldemedine (Symproic) PO

specialist meds
• chloride-channel agonist - lubiprostone (Amitiza)
• selective 5-HT4 receptor agonist - prucalopride (Motegrity)
• guanylate cyclase-C (GC-C) agonist - linaclotide (Linzess)