On April 15, 2020, mitomycin gel was approved for the treatment of adult patients with low-grade upper tract urothelial cancer.^1,2 Mitomycin gel is for pyelocalyceal use alone and not for intravenous, topical, or oral administration.

Supporting Efficacy Data

Approval was based on findings in the ongoing multicenter OLYMPUS trial (ClinicalTrials.gov identifier NCT02793128).² In the trial, 71 patients with treatment-naive or recurrent noninvasive low-grade upper tract urothelial cancer with at least one measurable papillary tumor located above the ureteropelvic junction. Patients who had larger tumors could have had prior tumor debulking. Patients received mitomycin weekly at 4-mg/mL instillations via ureteral catheter or nephrostomy tube for 6 weeks. For patients with a complete response at 3 months, instillations were to be administered monthly, for a maximum of 11 additional instillations.

The median patient age was 71 years (range = 42–87 years); 68% were male, 87% were white, and 90% had an Eastern Cooperative Oncology Group performance status of 0 or 1. The median number of papillary lesions subsequent to debulking and/or biopsy and prior to treatment was one (range = 1–5); 37% of patients underwent tumor debulking during the 6 weeks preceding enrollment, and 48% had tumors located in regions not amenable to endoscopic resection. General anesthesia was used in 37% of patients for at least one instillation during the treatment period and for 61% of patients for at least one instillation during the follow-up period.

The major efficacy outcome measures were complete response and durability of complete response. Complete response was defined as complete absence of tumor lesions 3 months after mitomycin initiation as assessed by urine cytology and ureteroscopy (biopsy was performed if warranted).

A total of 41 patients (58%, 95% confidence interval = 45%–69%) achieved a complete response at 3 months following treatment initiation and were included in follow-up. Following initial treatment, 29 patients received at least one dose of maintenance therapy (median = 6 doses). The median duration of response was not reached (range = 0–18.8+ months). Seven patients had documented recurrences, and 19 responders remained in complete response at 12 months.

How It Works

Mitomycin inhibits the synthesis of DNA. The guanine and cytosine content correlate with the degree of mitomycin-induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed.

How It Is Used

The dose of mitomycin to be instilled is 4 mg/mL via ureteral catheter or a nephrostomy tube, with the total instillation volume based on volumetric measurements using pyelography not to exceed 15 mL (60 mg of mitomycin). The drug is instilled once weekly for 6 weeks. For patients with a complete response 3 months after mitomycin initiation, instillations may be administered once a month for a maximum of 11 additional instillations.

Patients must be instructed to take oral sodium bicarbonate in three 1.3-g doses, one dose each the evening prior to, the morning of, and 30 minutes prior to the instillation procedure. General anesthesia, local anesthesia, sedation, prophylactic antibiotics, and/or antihistamines may be used at the discretion of the treating urologist. Patients to be anesthetized should not take sodium bicarbonate within 30 minutes prior to the treatment. Withholding of diuretics 1 day prior to instillation until 4 hours after instillation should be considered. Treatment should be avoided in patients with a glomerular filtration rate (GFR) of < 30 mL/min.

Safety Profile

Among the 71 patients receiving mitomycin, the most common adverse events of any grade (≥ 20%) were ureteric obstruction (58%), flank pain (39%), urinary tract infection (34%), hematuria (32%), renal dysfunction (25%), fatigue (24%), nausea (24%), abdominal pain (23%), dysuria (21%), and vomiting (20%). Among the patients with ureteric obstruction, 88% required ureteral stent placement. The most common grade ≥ 3 adverse events included ureteric obstruction (17%), urinary tract infection (4%), and vomiting (4%). The most common grade 3 or 4 laboratory abnormalities were hyperuricemia (16%) and estimated GFR abnormalities.

Serious adverse events occurred in 37% of patients, with those occurring in more than 3% consisting of ureteric obstruction (including ureteric stenosis and hydronephrosis), flank pain, and urosepsis. Adverse events led to dosage interruption in 34% of patients, more than 3% of whom experienced renal dysfunction, ureteric obstruction, urinary tract infection, and flank pain. Adverse events led to permanent discontinuation of treatment in 16 patients (23%), including 11 during the treatment phase and 5 during the maintenance phase. Adverse events leading to permanent discontinuation in more than 3% of patients included ureteric obstruction. Two deaths occurred due to cerebrovascular accident and failure to thrive.

Mitomycin has warnings/precautions for ureteric obstruction, bone marrow suppression, and embryofetal toxicity. Patients should be monitored for signs and symptoms of ureteric obstruction; transient or long-term ureteral stents or alternative procedures may be required. Blood cell counts should be monitored for thrombocytopenia and neutropenia. Mitomycin is contraindicated in patients with perforation of the bladder or upper urinary tract. Patients should be advised not to breastfeed while receiving mitomycin.

REFERENCES

1. U.S. Food and Drug Administration: FDA approves mitomycin for low-grade upper tract urothelial cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-mitomycin-low-grade-upper-tract-urothelial-cancer. Accessed April 22, 2020.

2. U.S. Food and Drug Administration: Highlights of prescribing information for Jelmyto (mitomycin) for pyelocalyceal solution. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211728s000lbl.pdf. Accessed April 22, 2020.