What is the mechanism of action, recommended dosing, indications, safety monitoring, and contraindications for Mitomycin C in cancer treatment?

Mitomycin C in Cancer Treatment

Mechanism of Action

Mitomycin C functions as a hypoxia-activated bioreductive alkylating agent that preferentially targets tumor cells with low oxygen content through DNA cross-linking. 1, 2

• Under hypoxic conditions, mitomycin C undergoes enzymatic reduction (primarily via NADPH-cytochrome c reductase) to generate reactive intermediates that form bifunctional DNA cross-links, blocking DNA replication and cell division 2, 3
• The drug demonstrates preferential cytotoxicity to hypoxic tumor cells compared to well-oxygenated cells, making it particularly effective against solid tumors where oxygen-poor regions limit conventional therapy 2
• The mechanism involves inhibition of DNA synthesis through these cross-links, ultimately leading to cell death 1

Primary Indication: Non-Muscle Invasive Bladder Cancer (NMIBC)

Intravesical mitomycin C is a standard treatment for non-muscle invasive bladder cancer, particularly for intermediate-risk disease and as adjuvant therapy following transurethral resection. 1

Single Immediate Postoperative Instillation

• A single postoperative instillation of 40 mg mitomycin C in 40 mL water administered immediately after TURBT (transurethral resection of bladder tumor) reduces recurrence risk by 17% (95% CI: 8-28%) 1
• This single-dose approach is most effective when given within 24 hours post-resection and is recommended for all eligible patients 1

Induction and Maintenance Therapy

• For intermediate-risk NMIBC, mitomycin C induction followed by maintenance therapy provides 2-year recurrence-free survival rates of 75-76% with 40 mg dosing 4
• Mitomycin C with maintenance was superior to BCG induction without maintenance in meta-analysis of 1,066 patients 1
• However, BCG with maintenance appears superior to mitomycin C only when maintenance BCG is administered 1

Alternative to BCG

• Mitomycin C serves as an alternative for patients unable to tolerate BCG immunotherapy 1
• For BCG-refractory disease, switching to mitomycin C is an option before considering cystectomy 1

Dosing Regimens

Intravesical Administration for Bladder Cancer

Standard dosing: 40 mg mitomycin C in 40 mL water is more effective than 30 mg dosing for preventing recurrence 1, 4

• Single immediate postoperative dose: 40 mg in 40 mL water instilled within 24 hours of TURBT 1
• Induction regimen: Weekly instillations for 6-8 weeks 1
• Maintenance regimen: Monthly instillations for at least 1 year, though optimal duration remains uncertain 1, 4
• Intensive short-term schedule (investigational): Three times per week for 2 weeks has shown 61.7% complete response rates in selected low-to-intermediate risk recurrent cases 5

Systemic Administration (Historical)

• Intermittent high-dose schedule: 20 mg/m² IV every 6-8 weeks was the standard for systemic disease, though this indication has largely been replaced by newer agents 3, 6

Safety Monitoring and Toxicities

Local (Intravesical) Toxicity

• Local bladder irritation symptoms (dysuria, frequency, urgency) are common but typically resolve with symptomatic treatment 5
• Chemical cystitis occurs but rarely requires treatment discontinuation 5
• Critical precaution: Avoid instillation if bladder perforation is suspected or recent traumatic catheterization occurred, as systemic absorption can cause severe toxicity 1

Systemic Toxicity (with IV administration)

• Cumulative myelosuppression, particularly thrombocytopenia, is the dose-limiting toxicity 3
• Pulmonary toxicity (interstitial pneumonitis) can occur with cumulative doses 3
• Renal toxicity and occasional cardiac toxicity have been reported 3
• Hemolytic uremic syndrome is a rare but serious complication 3
• Mild acute nausea, vomiting, and anorexia are common but tolerable 3

Monitoring Parameters

• For intravesical therapy: Monitor for signs of bladder irritation, hematuria, and systemic absorption symptoms 5
• For systemic therapy: Complete blood counts (especially platelets), renal function, pulmonary function tests with cumulative dosing 3

Contraindications

Absolute Contraindications for Intravesical Use

• Bladder perforation or suspected perforation 1
• Recent traumatic catheterization (wait 1-2 weeks) 1
• Active urinary tract infection 1
• Gross hematuria 1

Relative Contraindications

• Severely reduced bladder capacity 1
• Known hypersensitivity to mitomycin C 3

Systemic Use Contraindications

• Severe bone marrow suppression (thrombocytopenia, leukopenia) 3
• Coagulation disorders 3
• Increased bleeding tendency from other causes 3

Important Clinical Considerations

Comparative Effectiveness

• No single intravesical chemotherapy agent has proven superior to others when comparing induction courses without maintenance 1
• The 40 mg dose appears more effective than 30 mg for preventing recurrence (76% vs 66% 2-year RFS) 4
• Maintenance duration beyond 1 year has not shown additional benefit in available studies 4

Non-Bladder Cancer Applications

• Mitomycin C has limited current role in breast, gastric, pancreatic, and colorectal cancers as newer agents have largely replaced it 6
• Topical ophthalmic use (0.02% solution for 12-120 seconds) is employed to prevent corneal scarring after keratectomy, though this is off-label and requires careful attention to exposure time and copious irrigation 1

Key Clinical Pitfall

The most important alopecia consideration: Unlike many chemotherapy agents, mitomycin C does not cause hair loss, making it favorable for patients concerned about this side effect 7