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Mitomycin


Mitomycin

Article Author:
Hadeer Sinawe
Article Editor:
Damian Casadesus
Updated:
9/3/2020 10:03:33 AM
For CME on this topic:
Mitomycin CME
PubMed Link:
Mitomycin

Indications

Mitomycin is an antibiotic medication approved by the Food and Drug Administration (FDA) for use in the systemic therapy of metastatic adenocarcinoma of the stomach or pancreas in combination with other drugs.[1] Mitomycin is also indicated for the treatment of bladder cancer, with maintenance doses of mitomycin proving effective for decreasing the tumor recurrence rate of low and intermediate-risk tumors.[2]

This medication is also indicated as a potential palliative treatment, especially when other treatments have failed. It also has approval for use as an adjunct to ab externo glaucoma surgery.[3] Due to raised intraocular pressure in the development of glaucoma, mitomycin is used during surgery to reduce postoperative scarring following a trabeculectomy or glaucoma drainage surgery.[4][3] However, its use in hepatic artery chemoembolization is yet to be approved by the FDA.

Mechanism of Action

Mitomycin is an antibiotic that is isolated from the broth of Streptomyces caespitosus. This drug has demonstrated antitumor activity.[5][6] Mitomycin belongs to a group of alkylating agents that work by cross-linking the complementary strands found in DNA with absolute specificity and high efficiency for the CpG sequence.[3] 

Once activated by a reduction cascade, a series of spontaneous transformations cause mitomycin to attack DNA twice, resulting in cross-linking of strands of DNA double helix, thereby inhibiting DNA synthesis. Mitomycin is non-specific for a particular cell cycle phase but can exert its maximum effect in both the late G as well as the early S-phases.[6]

At higher concentrations, it also suppresses RNA and protein synthesis, hence being useful against some bacteria, spirochetes, and viruses. Lending to its toxic profile, mitomycin has a limited role as an antibiotic.[6] Mitomycin also causes chromosomal breaks, thus leading to shortened strands of DNA, which eventually leads to chromosomal damage; this property renders mitomycin as a potent carcinogen and teratogen.[3]

In glaucoma surgery, the antifibrotic property of mitomycin prevents tissue scarring when surgeons create a surgical ocular flap to relieve excess fluid buildup.[4]

Administration

Mitomycin administration is via the intravenous and intravesical routes. Subcutaneous or intramuscular administration is not advised or recommended. Close monitoring during intravenous infusions is advised, due to the high likelihood of extravasation. Signs of extravasation include poor blood return, pain, and swelling.[7]

Extreme caution is necessary to prevent extravasation as the drug is known to cause irritation, skin ulceration, and cellulitis. Given the cytotoxic nature of mitomycin, precautions, and procedures for handling, reconstitution, and disposal require strict adherence. It can be diluted up to a concentration of 40 micrograms per milliliter at room temperature in 5% dextrose, 0.9% sodium chloride, or sodium lactate injection. These solutions are stable and are to be used within 4 hours, 48 hours, or 24 hours, respectively.

In ophthalmology, topical administration is the only established route of administration.[3][4]

Adverse Effects

Bone marrow toxicity is the most commonly reported adverse effect, occurring in most of the patients treated with mitomycin in one study. It produces cumulative myelosuppression. Thrombocytopenia and possibly leukopenia may occur anytime within the first two months after beginning therapy, with an average duration of one month [8]. The recovery time after the termination of therapy was about ten weeks. About 25% of the leukopenic or thrombocytopenic episodes were permanent and did not return to baseline levels. As these patients are already immunocompromised, extreme caution is necessary to ensure further bone marrow suppression does not contribute to overwhelming subsequent infections.

Hemolytic uremic syndrome (HUS) has been observed in patients receiving systemic medication, with an incidence of <15% [1]. Patients presented with microangiopathic hemolytic anemia with fragmented red blood cells on peripheral blood smears. Patients with HUS also suffer the common and well-known side effects of the syndrome, including thrombocytopenia (≤100,000/mm) and renal failure (serum creatinine ≥1.6 mg/dL), which is irreversible. The use of blood product transfusions has correlated with exacerbation of the HUS symptoms. There is a high mortality rate of 52% associated with this syndrome.[9]

In another study, nausea, fever, vomiting, and anorexia occurred in up to 14% of people taking mitomycin. Alopecia and stomatitis occurred in up to 4% of individuals. Roughly 2% of the patients showed a statistically significant rise in creatinine. However, there was no correlation between the dose given or duration of therapy with the degree of renal impairment.[10]

Pulmonary toxicity has been infrequently reported, with patients presenting with dyspnea, nonproductive cough, and pulmonary infiltrates on radiologic imaging.[11] Vinca alkaloids, a common class of chemotherapeutic agents, also showed severe or life-threatening dyspnea and bronchospasm within minutes to hours of mitomycin administration.[10] Adult respiratory distress syndrome has also occurred in patients receiving mitomycin with other medications.[12] 

The most frequent adverse events with ocular administration of mitomycin occur locally and include blebitis, hypotony maculopathy, hypotony, endophthalmitis, cataract development, vascular reactions, and corneal reactions.[4]

Contraindications

Mitomycin is generally avoided and somewhat contraindicated in patients with a history of reactions to the drug, whether a hypersensitivity reaction or an idiosyncratic reaction. Its use is not recommended for patients with a high serum creatinine >1.7 mg/dL or creatinine clearance <30 mL/min. Other contraindications include coagulopathy, thrombocytopenia, or any bleeding diathesis.[8] Mitomycin should be avoided in patients with severe immunosuppression due to bone marrow suppression, including leukopenia and thrombocytopenia.

Monitoring

Patients receiving treatment with this medication should be observed during and after therapy. HUS may occur at any point during therapy, with signs such as anemia, thrombocytopenia, and renal failure, especially when they are receiving doses exceeding 60mg. Fragmented red blood cells may also be present on peripheral smear.[1][8]

The use of mitomycin in pregnant women remains unestablished; therefore, it is not recommended from a safety standpoint. Parenterally-administered mitomycin can cause fetal issues if given during pregnancy; it is classified into category D by the FDA. Breastfeeding is not recommended and is to be discontinued when receiving mitomycin therapy.[13]

Toxicity

Pulmonary toxicity is a rare, but well documented adverse effect of mitomycin C. In one trial at the Mayo Clinic, despite pre-medication with the use of corticosteroids, pulmonary toxicity occurred, with changes in diffusing lung capacity of 9 and PaO2 of 49 mm Hg. For patients who had bronchoscopies, a significant number had changes noted on pulmonary histology consistent with lung injury.

Despite initial responses to corticosteroids, 40% of patients still experienced progressive pulmonary insufficiency despite very high corticosteroid doses. Attention must focus on the chronic and progressive phase of lung toxicity associated with mitomycin C, as this event is a largely underestimated complication of the treatment regimen.[12]

Enhancing Healthcare Team Outcomes

Mitomycin use requires a specialized care setting. Management of therapy and potential adverse effects is only possible with adequate facilities and healthcare professionals. Myelosuppression may prove severe and can necessitate dose reductions. Therefore, mitomycin requires an experienced healthcare professional who is knowledgeable in the discipline of chemotherapy. It also requires close cooperation between primary care physicians, oncologists, hematologists, and pharmacists to enhance patient care, improve outcomes, and quality of life. 

Any practitioner who must give an intravesical treatment requires appropriate training and assessment. They should be able to demonstrate a focused understanding of underlying malignancy, associated health care concerns, and matters of safety in the handling of these drugs as well as demonstrating clinical competence related to the drug.

Both patients and the practitioner must be educated about mitomycin, its administration, and adverse effects.


References

[1] Verweij J,Pinedo HM, Mitomycin C: mechanism of action, usefulness and limitations. Anti-cancer drugs. 1990 Oct;     [PubMed PMID: 2131038]
[2] Volpe A,Racioppi M,D'Agostino D,Cappa E,Filianoti A,Bassi PF, Mitomycin C for the treatment of bladder cancer. Minerva urologica e nefrologica = The Italian journal of urology and nephrology. 2010 Jun;     [PubMed PMID: 20562793]
[3] Teus MA,de Benito-Llopis L,Alió JL, Mitomycin C in corneal refractive surgery. Survey of ophthalmology. 2009 Jul-Aug;     [PubMed PMID: 19539836]
[4] Cabourne E,Clarke JC,Schlottmann PG,Evans JR, Mitomycin C versus 5-Fluorouracil for wound healing in glaucoma surgery. The Cochrane database of systematic reviews. 2015 Nov 6;     [PubMed PMID: 26545176]
[5] Charpentier X,Kay E,Schneider D,Shuman HA, Antibiotics and UV radiation induce competence for natural transformation in Legionella pneumophila. Journal of bacteriology. 2011 Mar;     [PubMed PMID: 21169481]
[6] Tomasz M, Mitomycin C: small, fast and deadly (but very selective). Chemistry     [PubMed PMID: 9383461]
[7] Veeratterapillay R,Heer R,Johnson MI,Persad R,Bach C, High-Risk Non-Muscle-Invasive Bladder Cancer-Therapy Options During Intravesical BCG Shortage. Current urology reports. 2016 Sep;     [PubMed PMID: 27492610]
[8] Sturm JB,Hess M,Weibel S,Chen NG,Yu YA,Zhang Q,Donat U,Reiss C,Gambaryan S,Krohne G,Stritzker J,Szalay AA, Functional hyper-IL-6 from vaccinia virus-colonized tumors triggers platelet formation and helps to alleviate toxicity of mitomycin C enhanced virus therapy. Journal of translational medicine. 2012 Jan 11;     [PubMed PMID: 22236378]
[9] Salvadori M,Bertoni E, Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations. World journal of nephrology. 2013 Aug 6;     [PubMed PMID: 24255888]
[10] Levine EA,Votanopoulos KI,Shen P,Russell G,Fenstermaker J,Mansfield P,Bartlett D,Stewart JH, A Multicenter Randomized Trial to Evaluate Hematologic Toxicities after Hyperthermic Intraperitoneal Chemotherapy with Oxaliplatin or Mitomycin in Patients with Appendiceal Tumors. Journal of the American College of Surgeons. 2018 Apr;     [PubMed PMID: 29331663]
[11] Abel ML,Kokosis G,Blazer DG, Pulmonary toxicity after intraperitoneal mitomycin C: a case report of a rare complication of HIPEC. World journal of surgical oncology. 2017 Feb 20;     [PubMed PMID: 28219391]
[12] Okuno SH,Frytak S, Mitomycin lung toxicity. Acute and chronic phases. American journal of clinical oncology. 1997 Jun;     [PubMed PMID: 9167754]
[13] Sato N,Haga J,Anazawa T,Kenjo A,Kimura T,Wada I,Mori T,Marubashi S,Gotoh M, Ex vivo Pretreatment of Islets with Mitomycin C: Reduction in Immunogenic Potential of Islets by Suppressing Secretion of Multiple Chemotactic Factors. Cell transplantation. 2017 Aug;     [PubMed PMID: 28901184]