What is the etiology of diarrhea in patients with prostate cancer?

Etiology of Diarrhea in Prostate Cancer Patients

Diarrhea in prostate cancer patients is primarily caused by cancer treatments including hormonal therapy, radiation therapy, targeted therapies, immunotherapy, and chemotherapy, with each having distinct pathophysiological mechanisms. 1

Treatment-Related Causes

Hormonal Therapy-Induced Diarrhea

• Older hormonal agents (gonadotropin-releasing hormone agonists, antiandrogens, antioestrogens) are associated with low and variable incidence of diarrhea, often without clinical relevance 1
• Newer hormonal agents used in prostate cancer often cause mild intensity diarrhea 1
• Underlying mechanisms include:
  • Bile salt malabsorption 1
  • Pancreatic insufficiency 1

Radiation Therapy-Induced Diarrhea

• Approximately 60% of patients experience temporary mild diarrhea during pelvic radiation treatment 1
• Pathophysiology includes:
  • Direct radiation damage to intestinal tissue 1
  • Release of free radicals from interaction of radiation with cellular water 1
  • Damage to stem cells within intestinal crypts causing reduction of mucosal integrity 1
  • Flattening of intestinal villi 1
  • Modification of intestinal microflora 1
  • Deterioration of enzymatic activities 1
• Risk factors include:
  • Patient-related: low BMI, comorbidities (diabetes, hypertension, IBD), smoking history 1
  • Treatment-related: volume of small bowel in radiation field, radiation dose, fractionation, technique 1
  • Acute effects occur at doses as low as 10 Gy, with curative doses typically ranging from 50-75 Gy 1

Targeted Therapy-Induced Diarrhea

• Multiple targeted agents used in advanced prostate cancer can cause diarrhea 1
• Mechanisms vary by drug class:
  • Tyrosine kinase inhibitors (TKIs) have significantly higher risk of causing both all-grade and high-grade diarrhea compared to conventional regimens 1
  • mTOR inhibitors cause diarrhea through microflora disequilibrium and malabsorption 1
  • CDK4/6 and PARP inhibitors can cause diarrhea, though underlying mechanisms are not well understood 1

Immunotherapy-Induced Diarrhea

• Immune checkpoint inhibitors can cause immune-mediated adverse events including diarrhea 1
• Particularly common with anti-CTLA-4 therapy 1
• Shares characteristics with inflammatory bowel disease 1
• May present with or without colitis 1

Chemotherapy-Induced Diarrhea

• Common side effect of chemotherapy regimens used in advanced prostate cancer 2
• Can cause depletion of fluids and electrolytes, malnutrition, dehydration, and hospitalization 3
• Dosimetric factors in radiation therapy correlate with diarrhea risk, particularly intestinal cavity volumes receiving 15 Gy (IC-V15) 4

Infectious Causes

• C. difficile infection is an important consideration in cancer patients with diarrhea 5
  • Occurs in 7-50% of cases following antibiotic administration 5
  • Risk factors include recent antibiotic use, hospitalization, and immunosuppression from cancer treatment 5
• Other infectious causes to consider:
  • Bacterial pathogens (Salmonella, Shigella, Campylobacter, Yersinia) 5
  • Viral causes (adenovirus, astrovirus, CMV, norovirus, rotavirus) 5
  • Parasitic infections 5

Other Mechanisms

• Chemotherapy-associated lactose intolerance 5
• Rare associations such as celiac disease triggered or unmasked by immunotherapy 6
• Flavopiridol (cyclin-dependent kinase inhibitor) commonly causes diarrhea in prostate cancer patients 7

Clinical Approach to Diagnosis

• Evaluate diarrhea severity, duration, and associated symptoms (fever, abdominal pain, blood in stool) 5
• Assess for warning signs: fever, neutropenia, dehydration, severe cramping 5
• Laboratory testing should include:
  • C. difficile testing using two-step approach with enzyme immunoassays or nucleic acid amplification tests 5
  • Complete blood count, electrolytes, creatinine, and BUN 5
  • Blood cultures if fever is present 5
• Extended workup for persistent symptoms should include testing for other enteric pathogens 5

Important Considerations

• Always rule out infectious causes before attributing diarrhea to treatment toxicity 5
• Neutropenic patients may not develop typical pseudomembranes on endoscopy 5
• Multiple etiologies may coexist in prostate cancer patients 1
• Accurate assessment of all possible causes is essential for appropriate management 1