VA Class:AN200

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• mitoMYcin

Mitomycin is an antineoplastic antibiotic produced by Streptomyces caespitosus .

Adenocarcinoma of the Stomach and Pancreas

Mitomycin is used as a component of combination chemotherapeutic regimens for the treatment of disseminated adenocarcinoma of the stomach or pancreas and as palliative treatment of these tumors when other treatment modalities are ineffective.100,121 Mitomycin does not replace appropriate surgery and/or radiation therapy, and the drug is not recommended for use as single-agent, primary therapy.100

To date, use of mitomycin, alone or in combination with other antineoplastic agents, has been limited to the treatment of advanced metastatic disease in patients who have become resistant to other antineoplastic agents. Response rates have generally been low and of short duration, and the drug is highly toxic. Precise evaluation of mitomycin's effectiveness is difficult because of the refractory nature and advanced stage of the neoplasms treated, the impracticability of including control patients in studies, and variation in criteria used for assessment of response. Response rates (as measured by a 25% or greater decrease in tumor size for at least 2 weeks) to mitomycin therapy vary with tumor type. About 10-17% of patients with advanced GI or pancreatic adenocarcinoma have responded to mitomycin therapy. In the treatment of disseminated adenocarcinoma of the stomach or pancreas, mitomycin is often used in combination with doxorubicin and fluorouracil.

Bladder Cancer

Mitomycin is used intravesically for the treatment of residual tumor and/or as adjuvant therapy for prophylaxis of superficial bladder cancer†.113,115,120,121,130,131,138

Intravesical therapy with chemotherapeutic agents is used as adjuvant treatment in patients with superficial bladder cancer.113,114,115,121 Compared with surgery alone, surgery plus intravesical chemotherapy has been shown to cause regression of existing papillary tumor and reduce the rate of short-term tumor recurrence; however, no effect on disease progression or overall survival has been demonstrated.119,123,124,129,139 In patients with superficial bladder cancer who have high risk of disease progression and/or recurrence following transurethral resection with fulguration, BCG live is an agent of choice for adjuvant intravesical therapy.113,114,115,119,121,122,140,141,142 (See Uses: Immunotherapy for Bladder Cancer in BCG Vaccine 80:12 for an overview of therapy for superficial bladder cancer.) Selected chemotherapeutic agents, such as mitomycin, have been shown to have comparable efficacy and less toxicity than BCG live for adjuvant intravesical therapy.126,127,139,143 In patients receiving intravesical mitomycin, overall complete response rates of approximately 40 and 58% have been reported for the treatment of papillary tumors and carcinoma in situ, respectively.115,116,130

In a large randomized study, the rate of recurrence was lower in patients receiving single or multiple instillations of mitomycin versus transurethral resection alone for the prophylaxis of superficial bladder cancer at low, medium, or high risk of recurrence.120 In patients with superficial bladder cancer who have a low or intermediate risk of recurrence, intravesical mitomycin has been shown to be equally effective in preventing tumor recurrence and less toxic than intravesical BCG live.117,126,127 In one comparative study, patients with low- or intermediate-grade papillary tumors (stage Ta or T1, grade 1 or 2) receiving intravesical mitomycin had reduced incidence and rate of tumor recurrence but more local toxicity (e.g., hematuria, strangury) than those receiving intravesical interferon alfa-2b.113,118 Chemical cystitis is observed in approximately 15% of patients treated with intravesical mitomycin, and allergic reactions occur in about 10% of patients.115

The mechanism of action of cytotoxic agents administered intravesically in the treatment of superficial bladder cancer has not been fully determined.114 Both a direct toxic effect on bladder tumor cells and a nonspecific inflammatory action are believed to contribute to the therapeutic effect of intravesical chemotherapy.114

In general, intravesical therapy with a cytotoxic agent should be administered as soon as possible following transurethral resection (TUR) for superficial bladder cancer.117,128 For patients treated within 6-24 hours following TUR, a 6-month course of therapy generally is sufficient; however, for patients in whom intravesical therapy is instituted 24 hours or more following surgery, a 12-month course usually is recommended.117,128 Studies to date have not shown additional benefit for continued maintenance therapy with intravesical instillation of chemotherapeutic agents (e.g., mitomycin, doxorubicin, epirubicin).120,128,131,144,145 The most common adverse reaction associated with intravesical chemotherapy is local irritation (i.e., cystitis); local toxicity tends to increase with the number and frequency of instillations and with the dose administered.115

The usual dose of mitomycin administered intravesically is 20-60 mg,115,116,118,120,125,126,127,128 and a typical treatment schedule consists of administration once a week for 8 weeks.116,118 No benefit of maintenance therapy with mitomycin has been demonstrated.115,116,120,124,128,131

Cervical Cancer

Mitomycin has been shown to have some activity against squamous cell carcinoma of the cervix†121,136 and has been used in cisplatin-containing combination chemotherapy regimens (e.g., bleomycin, cisplatin, mitomycin, and vincristine) for the treatment of metastatic or recurrent cervical cancer.132,135 However, the benefit of combination cisplatin-based chemotherapy regimens versus cisplatin alone has not been fully established,133,134,135 and agents other than mitomycin generally are preferred for the treatment of advanced cervical cancer.136,137 (See Uses: Cervical Cancer in Cisplatin 10:00 for an overview of treatment for cervical cancer.)

Non-small Cell Lung Cancer

Mitomycin and cisplatin used in combination with vinblastine (MVP)146,149 or ifosfamide with mesna (MIC)150 are alternative regimens for the treatment of non-small cell lung cancer†.121 Currently preferred regimens for the treatment of advanced non-small cell lung cancer include the combination of cisplatin with another agent, such as paclitaxel, vinorelbine, or gemcitabine.121,146 (See Uses: Non-small Cell Lung Cancer in Cisplatin 10:00.)

Anal Cancer

Mitomycin is used in combination with fluorouracil for the treatment of anal cancer†.121 Randomized trials have shown that concurrent chemotherapy (mitomycin and fluorouracil) and radiation therapy is superior to radiation therapy alone in controlling local disease in patients with anal cancer.152,153 Mitomycin in combination with fluorouracil is a preferred regimen for the primary treatment of anal cancer.121 In a randomized trial, a higher rate of disease-free survival and a lower rate of colostomy was observed in patients receiving radiation therapy and combination therapy with mitomycin/fluorouracil than in those receiving radiation therapy and fluorouracil for anal cancer.154 In another randomized trial, 5-year disease-free survival rates were similar but the colostomy rate was lower in patients receiving mitomycin and fluorouracil with radiation therapy than in those receiving cisplatin and fluorouracil with radiation therapy as primary therapy for anal cancer.155

Other Uses

Mitomycin has been used in the treatment of malignant mesothelioma†.121

Mitomycin has been used as an adjunct to radiation therapy in the treatment of squamous cell carcinoma of the head and neck†.147 Mitomycin also has shown activity in the treatment of metastatic breast cancer†.148

Reconstitution and Administration

Mitomycin is administered IV via a functioning IV catheter. Care should be taken to avoid extravasation of the drug , and some clinicians recommend that the reconstituted solution be administered through the tubing of an IV infusion. If extravasation occurs, cellulitis, ulceration, and tissue sloughing may result.

Mitomycin powder for injection is reconstituted by adding 10, 40, or 80 mL of sterile water for injection to a vial labeled as containing 5, 20, or 40 mg of mitomycin, respectively, to provide a solution containing approximately 0.5 mg/mL. The vial should be shaken to enhance dissolution; if the powder for injection does not dissolve immediately, allow the vial to stand at room temperature until complete dissolution occurs.

Dosage

Dosage of mitomycin must be based on the clinical and hematologic response and tolerance of the patient and whether other myelosuppressive therapy is also being used to obtain optimum therapeutic results with minimum adverse effects. Clinicians should consult published protocols for the dosage of mitomycin and other chemotherapeutic agents and the method and sequence of administration.

Adenocarcinoma of the Stomach and Pancreas

For the treatment of disseminated adenocarcinoma of the the stomach or pancreas, the manufacturer recommends that mitomycin be given (after complete hematologic recovery from any previous chemotherapy) as a single IV dose every 6-8 weeks, with an initial dose of 20 mg/m².100 Doses greater than 20 mg/m² increase the risk of toxicity and have not been shown to be more effective than lower doses.100 Because of cumulative myelosuppression, patients should be fully reevaluated after each course of mitomycin therapy.100 Dosage of mitomycin subsequent to the initial dose should be adjusted according to the hematologic response of the patient to the previous dose administered.100 An additional course of therapy should be given only after the leukocyte count has returned to 4000/mm³ and the platelet count has returned to 100,000/mm³.100 Dosage of mitomycin subsequent to the initial dose may be adjusted according to the following suggested schedule100 :

When disease continues to progress after 2 courses of mitomycin therapy, the drug should be discontinued since the likelihood of response is minimal.100

Hematologic Effects

The most serious and frequent toxic effect of mitomycin is myelosuppression, which is cumulative and is manifested by thrombocytopenia and/or leukopenia. Anemia occurs infrequently. Myelosuppression occurs more frequently when the drug is administered daily for 6 or more days followed by alternate-day therapy than when it is given daily for 2-5 days followed by once- or twice-weekly doses. There appears to be no correlation between total dose administered and bone marrow toxicity. Thrombocytopenia and/or leukopenia may develop up to 8 weeks after initiation of therapy. Parameters of bone marrow function usually return to pretreatment values within about 3 months following discontinuance of therapy; however, in approximately one-fourth of the patients treated, low counts did not return to normal. Hematologic disorders, particularly thrombocytopenia and leukopenia, occur more frequently and tend to be more prolonged when additional courses of therapy are given.

Thrombocytopenia (platelet count less than 100,000/mm³) has occurred in almost 40% of patients receiving mitomycin; in some of these patients, the degree of platelet depression has been severe (50,000/mm³ or less). Thrombocytopenia usually appears within 2-4 weeks following initiation of mitomycin therapy. Temporary apparent recovery may then occur, followed by further platelet depression to a nadir in the fourth to sixth week. A few patients have experienced bleeding episodes secondary to thrombocytopenia. Platelet transfusions may be required to treat severe thrombocytopenia with purpura.

Leukopenia (leukocyte count less than 4000/mm³) has occurred in approximately one-half of patients receiving mitomycin; in some of these patients the degree of leukocyte depression has been severe (2000/mm³ or less). Leukopenia occurs within 2-4 weeks, and the nadir is reached in the sixth week. A few patients have developed infections secondary to leukopenia; rarely, the secondary infection has resulted in death.

Acute Adverse Effects

Within 1-2 hours following IV administration of mitomycin, nausea and vomiting may occur. Nausea may continue for 2-3 days, although vomiting usually subsides rapidly. Fever and anorexia may also occur. Prolonged malaise has frequently occurred in patients receiving mitomycin and has been associated with weakness and weight loss, even in patients whose tumors are responding to therapy.

Mucocutaneous Effects

Mucocutaneous toxicity, consisting of mouth ulcers, alopecia, desquamation, and pruritus, has occurred in about 4% of patients receiving mitomycin and appears to be related to the total dose given. Mitomycin is extremely irritating; it may cause pain on injection, induration, thrombophlebitis, and paresthesia. Delayed erythema and/or ulceration at or distant from the injection site have occurred weeks to months after administration of the drug despite the lack of apparent evidence of extravasation at the time of administration. Extravasation may occur with or without an accompanying stinging or burning sensation and even if there is adequate blood return on aspiration with direct IV injection of the drug.100 If extravasation occurs, necrosis of surrounding tissue and sloughing are likely. In some cases, skin grafts have been necessary. Cellulitis at the injection site has occurred and is occasionally severe.

Renal Effects

Renal toxicity (evidenced by a rise in BUN and/or serum creatinine concentration) has occurred in about 2% of patients receiving mitomycin. Although not clearly established,100 the risk of mitomycin-induced renal toxicity may be related to the total dose administered, the risk being low at cumulative doses less than 50 mg/m² but increasing substantially at higher cumulative doses.101,108 Renal failure may occur as a component of a hemolytic uremic syndrome in patients receiving mitomycin. (See Cautions: Hemolytic Uremic Syndrome.)100,101,102,103,104,105,106,107,108

Respiratory Effects

Mitomycin-induced pulmonary toxicity with hemoptysis, dyspnea, coughing, and pneumonia has developed infrequently, but can be severe. Dyspnea with a nonproductive cough and radiographic evidence of pulmonary infiltrates may indicate pulmonary toxicity induced by the drug. Corticosteroids have been used for the treatment of mitomycin-induced pulmonary toxicity, but their therapeutic value has not been determined.

Acute shortness of breath and severe bronchospasm has occurred a few minutes to several hours after administration of a vinca alkaloid (e.g., vinblastine) in some patients who were previously or concomitantly treated with mitomycin.100 Symptomatic treatment with bronchodilators, corticosteroids, and/or oxygen has been used to provide relief.100

Adult respiratory distress syndrome has been reported in at least a few patients receiving mitomycin (in combination with other chemotherapeutic agents) who were maintained at fraction of inspired oxygen (FIO₂) concentrations exceeding 50% perioperatively.100 Careful adjustment of oxygen therapy and fluid balance is advised in patients receiving mitomycin.100 (See Cautions: Precautions and Contraindications.)

Hemolytic Uremic Syndrome

A severe and often fatal syndrome of microangiopathic hemolytic anemia, thrombocytopenia, renal failure, and hypertension (hemolytic uremic syndrome) has occurred in some patients receiving mitomycin;100,101,102,103,104,105,106,107,108 pulmonary edema may also be a component of the syndrome and appears to be a particularly grave prognostic factor.104 The syndrome has occurred principally in patients receiving long-term therapy (6-12 months) with the drug in combination with fluorouracil; however, the syndrome has occurred in patients treated for less than 6 months or in those receiving mitomycin in combination with other drugs.100,101,102,103,104,105,106,107,108 Hemolytic uremic syndrome also has been reported in patients receiving mitomycin as a single agent.100

The syndrome can vary from a chronic course with mild anemia and slowly progressive renal impairment to a fulminant course with severe anemia, rapid deterioration of renal function, and death.101,102,103,104,105,106,107,108 The optimum management of mitomycin-associated hemolytic uremic syndrome has not been established, but the use of systemic corticosteroids, plasma exchange, plasmapheresis, and/or IV vincristine has been beneficial in some patients and early treatment may be preferred.103,104,105,106,107,108

Other Adverse Effects

Asymptomatic ulcers at the site of tumor resection have been observed occasionally in patients with resected carcinoma of the bladder who have received intravesical instillation of mitomycin.109,110,111 Although these ulcers appear to be associated with delayed healing of the operative site,109,111 biopsy of persistent lesions to exclude the possibility of recurrent bladder cancer has been recommended.109,110,111 Calcification of the bladder wall has been reported in at least one patient with bladder carcinoma receiving intravesical instillation of mitomycin.112 Bladder fibrosis/contraction, which in rare cases has required cystectomy, also has been reported in patients receiving the drug by intravesical instillation.100

Asthenia100 and malaise100 have been reported in patients receiving mitomycin. Other reported adverse effects of mitomycin therapy which are not necessarily attributed to the drug itself include headache, blurred vision, confusion, edema, drowsiness, syncope, fatigue, hematemesis, and diarrhea.

Precautions and Contraindications

Mitomycin is a highly toxic drug with a low therapeutic index. The drug should be used only under constant supervision by physicians experienced in cancer chemotherapy, and it should be administered only to hospitalized patients who receive frequent determinations of hematopoietic, renal, and pulmonary function. Patients receiving mitomycin should be informed of the drug's potential toxicity, particularly bone marrow suppression; deaths secondary to mitomycin-induced leukopenia and subsequent septicemia have been reported.

Since thrombocytopenia and/or leukopenia may occur up to 8 weeks after mitomycin therapy is initiated, repeated hematologic studies (platelet count, leukocyte count, differential, prothrombin time, bleeding time, and hemoglobin determinations) are necessary during mitomycin therapy and for at least 7 weeks following discontinuance of the drug. When the leukocyte count decreases to less than 4000/mm³ or the platelet count decreases to less than 100,000/mm³, or a progressive decline in either occurs, mitomycin therapy should be discontinued until hematologic recovery occurs.100 Patients receiving mitomycin should also be observed for evidence of renal or pulmonary toxicity. If other etiologies can be excluded in patients who develop pulmonary toxicity during mitomycin therapy, the drug should be discontinued.

Caution is advised when administering oxygen therapy to patients receiving mitomycin.100 Adult respiratory distress syndrome has been reported in at least a few patients receiving mitomycin (in combination with other chemotherapeutic agents) who were on oxygen therapy.100 (See Cautions: Respiratory Effects.) The concentration of oxygen should be adjusted to use only enough to provide adequate arterial saturation because oxygen therapy itself can have a toxic effect on the lungs.100 Careful attention to fluid balance also is advised, and overhydration should be avoided.100

Mitomycin is contraindicated in patients with platelet counts of less than 100,000/mm³, leukocyte counts of less than 4000/mm³, or serum creatinine concentration greater than 1.7 mg/dL.100 Mitomycin is also contraindicated in patients who have substantial prolongation of prothrombin time or bleeding time, coagulation disorders, increased bleeding from other causes, or potentially serious infections, and in patients who are hypersensitive to the drug.

Pediatric Precautions

Safety and efficacy of mitomycin in children have not been established.100

Carcinogenicity

Mitomycin has been shown to be carcinogenic in mice and rats when administered in doses approximating usual therapeutic amounts.

Pregnancy, Fertility, and Lactation

Pregnancy

Mitomycin has produced teratogenic effects in animals. Safe use of mitomycin in pregnant women has not been established.

Fertility

The effect of mitomycin on fertility is not known.

Lactation

It is not known whether mitomycin is distributed in milk.100 Because of the potential for serious adverse reactions to mitomycin in nursing infants, nursing should be discontinued during mitomycin therapy.100

Acute pulmonary reactions have been reported following the administration of vinca alkaloids (e.g., vinblastine, vincristine, vinorelbine) in patients with previous or concomitant use of mitomycin.100 (See Cautions: Respiratory Effects.)

Adult respiratory distress syndrome has been reported in at least a few patients receiving mitomycin in combination with other chemotherapeutic agents who were on oxygen therapy.100 (See Cautions: Respiratory Effects.)

Pharmacology

Mitomycin is an antineoplastic antibiotic. The drug is active against gram-positive bacteria and some viruses, but its cytotoxicity precludes its use as an anti-infective agent.

Mitomycin's mechanism of antineoplastic activity is similar to that of the alkylating agents. It has been postulated that enzymatic reduction of mitomycin within susceptible cells is necessary for its antineoplastic activity. Activated mitomycin appears to cause cross-linking of DNA. In high concentrations, the drug may also inhibit RNA and protein synthesis.

Pharmacokinetics

Absorption

Immediately following IV administration of 30, 20, 10, or 2 mg of mitomycin, average maximum blood concentrations of 2.4, 1.7, 0.52, and 0.27 mcg/mL, respectively, have been recorded. Blood mitomycin concentrations decrease rapidly. In one study, blood concentrations were reduced by 50% at 17, 10, 9, and 6 minutes following IV doses of 30, 20, 10, and 2 mg, respectively. The rapid decrease in blood concentrations has been attributed to distribution in tissues and enzymatic inactivation of the activated drug rather than to excretion.

Distribution

In animals, highest mitomycin concentrations are found in the kidneys, followed by muscles, eyes, lungs, intestines, and stomach. The drug is not detectable in the liver, spleen, or brain which rapidly inactivate mitomycin. Higher concentrations of the drug are generally present in cancer tissues than in normal tissues.

Elimination

Mitomycin is rapidly inactivated in the microsomal fraction of the liver and also in the kidneys, spleen, brain, and heart which contain high concentrations of enzymes capable of metabolizing the drug. There appears to be an inverse relationship between the rate of drug inactivation by certain neoplasms and its efficacy against these tumors. Homogenates of carcinomas against which mitomycin is ineffective inactivate the drug as rapidly as do normal liver tissues; homogenates of carcinomas against which the drug is active, however, inactivate mitomycin only slightly.

In adults, less than 10% of an IV dose is excreted in urine as active drug. Mitomycin is also excreted to a small extent in bile.

Chemistry and Stability

Chemistry

Mitomycin is an antineoplastic antibiotic produced by Streptomyces caespitosus. The drug is also referred to as mitomycin-C to differentiate it from mitomycins A and B which, under certain conditions, are also produced by S. caespitosus. Mitomycin occurs as a blue-violet, crystalline powder and is soluble in water. The potency of mitomycin is assayed microbiologically.

Stability

Mitomycin powder for injection should be protected from light and preferably stored at 15-30°C; temperatures greater than 40°C should be avoided. In the dry state, commercially available mitomycin powder is stable for at least 4 years at room temperature.

Following reconstitution of the powder for injection with sterile water for injection, mitomycin solutions containing 0.5 mg/mL have a pH of 6-8 and are stable for 1 week at room temperature and for 2 weeks when refrigerated at 2-8°C. Solutions of mitomycin diluted to a concentration of 20-40 mcg/mL are stable at room temperature for 3 hours in 5% dextrose injection, 12 hours in 0.9% sodium chloride, and 24 hours in sodium lactate injection. The combination of mitomycin 5-15 mg and heparin 1000 to 10,000 units in 30 mL of 0.9% sodium chloride injection is stable for 48 hours at room temperature.

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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