| Cycle length: 6.5 weeks (chemoradiotherapy). |
| Drug | Dose and route | Administration | Given on days |
| Mitomycin | 10 mg/m2 (maximum 15 mg*) IV | Infuse as slow IV push (over 5 to 10 minutes). | Day 1¶ |
| CapecitabineΔ | 825 mg/m2 per dose by mouth | Twice daily (total dose 1650 mg/m2 per day) on radiation days; swallow whole with water within 30 minutes after a meal, with each dose as close to 12 hours apart as possible. Do not cut or crush tablets.◊ | Days 1 through completion of radiotherapy (do not give with boost fractions) |
| Radiotherapy§ | 59.4 Gy primary tumor; elective 45 to 49.5 Gy to pelvic and inguinal lymph nodes | Three dimensional CF-RT: 25 fractions (45 Gy) followed by three weeks rest then 8 to 11 additional fractions (1.8 Gy per boost) based on clinical/radiographic assessment (week 5). IMRT: 33 fractions (59.4 Gy) followed by a boost of three fractions (1.8 Gy each), if needed, based on clinical/radiographic assessment (week 5). | Five days per week beginning week 1 and continuing through at least week 6 |
| Pretreatment considerations: |
| Emesis risk | - Mitomycin: LOW.
- Capecitabine: LOW.
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults and radiotherapy-induced nausea and vomiting: Prophylaxis and treatment.
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| Infection prophylaxis | - Primary prophylaxis with G-CSF is not indicated. G-CSF should be used with caution, if at all, with chemoradiotherapy.
- Refer to UpToDate topics on prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults.
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| Vesicant/irritant properties | - Mitomycin is a potent vesicant and can cause ulceration, necrosis, cellulitis, and tissue sloughing; avoid extravasation.[2]
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
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| Dose adjustment for baseline renal dysfunction | - Lower initial doses of mitomycin may be needed in patients with renal insufficiency. A lower starting dose of capecitabine may be needed for patients with moderate renal impairment.[3]
- Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency, conventional cytotoxic agents.
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| Monitoring parameters: |
- Assess CBC with differential and platelet count prior to treatment and weekly for at least eight weeks after starting treatment. Thrombocytopenia with or without neutropenia may occur anytime within eight weeks, with an average time of four weeks.[2] Recovery occurs within 10 weeks; however, myelosuppression is cumulative and counts may not recover in about 25% of cases.
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- Assess basic metabolic panel (including serum creatinine) and liver function tests prior to starting treatment then weekly during chemoradiotherapy.
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- Monitor for signs and symptoms of localized dermatological toxicity and for changes in urinary and bowel habits during and after radiation therapy.
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- More frequent anticoagulant response (INR or prothrombin time) monitoring is necessary for patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy.
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- Monitor for diarrhea, stomatitis, and cutaneous toxicity (palmar-plantar erythrodysesthesias) during treatment.
- NOTE: Severe diarrhea, mucositis, and myelosuppression after capecitabine should prompt evaluation for dihydropyrimidine dehydrogenase deficiency.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents and cutaneous side effects of conventional chemotherapy agents.
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- Monitor for signs and symptoms of mitomycin-associated acute lung injury.
- Refer to UpToDate topics on mitomycin-C pulmonary toxicity.
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- 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. TMA is usually associated with cumulative doses ≥50 mg/m2. Discontinue mitomycin immediately and permanently.
- Refer to UpToDate topics on drug-induced thrombotic microangiopathy.
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- Cardiotoxicity observed with capecitabine includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease.
- Refer to UpToDate topics on cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - This regimen should not be initiated unless white blood cells are ≥4000/microL, neutrophils are ≥1500/microL, and platelets are ≥100,000/microL.[2,3] At some institutions, the mitomycin dose is repeated on day 29, as was used in RTOG 98-11.[4] The day 29 mitomycin dose should be reduced to 7.5 mg/m2 if the nadir WBC is <2400/microL but >1000/microL, or if the nadir platelet count is >50,000/microL but <85,000/microL. If the nadir WBC is <1000/microL or the nadir platelet count is <50,000/microL, the day 29 dose of mitomycin is reduced to 5 mg/m2. If the day 28 WBC is <2400/microL or platelet count <85,000/microL, we delay the start of the second cycle of therapy by one week. Reduce subsequent mitomycin doses if leukocyte nadir is <3000/microL or platelet nadir is <75,000/microL. The authors of this study do not state specific chemotherapy dose adjustment parameters for toxicity observed; however, other studies of capecitabine chemoradiotherapy[5,6], and the United States Prescribing Information[3], suggest withholding capecitabine for grade 3 or 4 hematologic toxicity, and that capecitabine be restarted after at least seven days or when recovered to ≤grade 1.
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| Nonhematologic toxicity (including hepatotoxicity) | - The authors of this study do not specify chemotherapy dose adjustments for nonhematologic toxicity; however, other studies of capecitabine-based chemoradiotherapy[5,6] recommend interrupting capecitabine for ≥grade 2 nonhematologic toxicity (except alopecia) that is likely related to capecitabine until it decreases to ≤grade 1 for the first incidence.[5,6] Decrease subsequent capecitabine dose by 25% for ≥grade 3 nonhematologic toxicity or recurrent grade 2 toxicity (except alopecia).[5,6]
- The United States Prescribing Information for capecitabine provides the following guidelines for capecitabine dose modification:[3]
- Grade 2: For the first, second, and third occurrence, hold capecitabine therapy. After resolution to grade 1 or less, resume treatment (first occurrence, no dosage adjustment; second occurrence, 75% of the starting dose; third occurrence, 50% of the starting dose).[3] For the fourth occurrence of a grade 2 toxicity, discontinue capecitabine therapy.
- Grade 3: For the first and second occurrence, hold capecitabine therapy. After resolution to grade 1 or less, resume treatment at a reduced dose (first occurrence, 75% of the starting dose; second occurrence, 50% of the starting dose). For the third occurrence of a grade 3 toxicity, discontinue capecitabine therapy.
- Grade 4: Discontinue capecitabine therapy. Alternatively, hold capecitabine therapy, and begin next treatment at 50% of the starting dose when toxicity resolves to grade 1 or less; discontinue treatment for first recurrence of grade 4 toxicity.
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| Pulmonary toxicity | - Mitomycin should be discontinued for any signs or symptoms of acute lung injury.[2]
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| Thrombotic microangiopathy | - TMA, also sometimes called thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS) has been associated with mitomycin. 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.
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| Omitted capecitabine doses for toxicity are not replaced or restored. |
| If there is a change in body weight of at least 10%, doses should be recalculated. |
