Cycle length: Chemotherapy 28 days.
Duration of therapy: Chemotherapy for two cycles (cycle 2 starts on day 29) and radiotherapy for one cycle. |
| Drug | Dose and route | Administration | Given on days |
| Mitomycin | 10 mg/m2 IV (maximum 20 mg per dose) | Infuse as slow IV push or slow infusion in NS¶ (over 15 to 30 minutes).[3] | Days 1 and 29Δ |
| Fluorouracil (FU) | 1000 mg/m2 per day IV (maximum daily dose 2000 mg) | Dilute in 500 to 1000 mL D5W¶ and administer as continuous infusion over 24 hours per day for four days (96 hours). | Days 1 through 4, and days 29 through 32 |
| Radiotherapy (45 to 50.4 Gy) | 1.8 Gy daily, five days per week | Begin within 24 hours of the administration of chemotherapy. | Start on day 1 (total of five weeks) |
| Pretreatment considerations: |
| Emesis risk | - LOW on all days.
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults and radiotherapy-induced nausea and vomiting.
|
| Prophylaxis for infusion reactions | - Routine prophylaxis is not indicated.
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
|
| Vesicant/irritant properties | - Mitomycin is a potent vesicant and can cause ulceration, necrosis, cellulitis, and tissue sloughing; avoid extravasation.[3] FU is an irritant but can cause significant tissue damage with a large volume, concentrated extravasation; avoid extravasation.[4]
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
|
| Infection prophylaxis | - Primary prophylaxis with G-CSF not indicated; use of G-CSF should be avoided in patients receiving concomitant chemoradiotherapy.
- Refer to UpToDate topics on use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation.
|
| Dose adjustment for baseline liver or renal dysfunction | - Lower initial doses of mitomycin may be needed in patients with renal insufficiency. Do not use mitomycin if serum creatinine >1.7 mg/dL.[3] A lower starting dose of FU may be needed for patients with liver impairment.
- Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency, conventional cytotoxic agents; and chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents; and chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents.
|
| Monitoring parameters: |
- CBC with differential weekly during treatment.
|
- Assess electrolytes and liver and renal function prior to each new chemotherapy cycle.
|
- Monitor for signs and symptoms of drug-induced TMA, which usually involves microangiopathic hemolytic anemia, thrombocytopenia, and irreversible renal failure. Other symptoms such as pulmonary edema, neurologic deficits, and hypertension may be present. Usually associated with cumulative doses ≥50 mg/m2. Discontinue mitomycin immediately and permanently.
- Refer to UpToDate topics on drug-induced thrombotic microangiopathy.
|
- Assess change in neurologic function prior to each new chemotherapy cycle
|
- Monitor for diarrhea, stomatitis, and cutaneous toxicity (palmar-plantar erythrodysesthesias)
|
- Monitor for signs and symptoms of mitomycin C-associated acute lung injury.
- Refer to UpToDate topics on mitomycin-C pulmonary toxicity.
|
| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Thrombocytopenia with or without neutropenia may occur anytime within eight weeks, with an average time of four weeks. Management of the day 29 doses of chemotherapy is variable. In one study, if the nadir WBC count was <2400/microL but >1000/microL or nadir platelet count was >50,000/microL but <85,000/microL, the day 29 dose of mitomycin was reduced to 7.5 mg/m2.[1] If the nadir WBC count was <1000/microL or the nadir platelet count <50,000/microL, the day 29 dose of mitomycin C was reduced to 5 mg/m2. If on day 28, the WBC count was <2400/microL and/or the platelet count <85,000/microL, cycle 2 of both chemotherapy and RT was delayed one week. Others administer the day 29 dose of mitomycin to everyone regardless of interval hematologic toxicity, but reduce doses of day 29 cisplatin and FU by 50% for interval grade 4 neutropenia or febrile neutropenia.[2] Still, other clinicians delete the day 29 mitomycin dose depending on the degree of myelosuppression.
|
| Local skin reaction | - The original protocol permitted a treatment interruption up to 10 days if severe local skin reaction developed.[1] However, treatment interruptions should be minimized, and overall treatment time and total dose maintained as much as possible.
|
| Diarrhea, stomatitis | - Reduce week 5 dose of FU by 20% for grade 3 or 4 diarrhea or stomatitis.
- NOTE: Severe diarrhea, mucositis, and myelosuppression after FU should prompt evaluation for DPD deficiency.[4]
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
|
| Thrombotic microangiopathy | - TMA (also sometimes called thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic syndrome [HUS]) has been associated with mitomycin.[3] Consider the possibility of TMA if the patient develops Coombs-negative hemolysis, thrombocytopenia, renal failure, and/or neurologic findings. Management consists of drug discontinuation and supportive care, without plasma exchange, as long as there is high confidence in a drug-induced etiology rather than TTP.
- Refer to UpToDate topics on drug-induced thrombotic microangiopathy.
|
| Pulmonary toxicity | - Mitomycin should be discontinued for any signs or symptoms of acute lung injury.[3]
|
| Cardiotoxicity | - Cardiotoxicity observed with FU includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, ECG changes, and cardiomyopathy. There is no recommended dose for resumption of FU administration following development of cardiac toxicity, and the drug should be discontinued.[4]
- Refer to UpToDate topics on fluoropyrimidine-associated cardiotoxicity.
|
| Neurologic toxicity | - There is no recommended dose for resumption of FU administration following development of hyperammonemic encephalopathy, acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances; the drug should be permanently discontinued.[4]
|
| If there is a change in body weight of at least 10%, doses should be recalculated. |
