Methods to Improve Efficacy of Intravesical Mitomycin C: Results of a Randomized Phase III

Jessie L.-S. Au, Robert A. Badalament, M. Guillaume Wientjes, Donn C. Young, Jill A. Warner, David L. Pollifrone, Ohio State University, Columbus; Pieter L. Venema, Leyenburg Teaching Hospital, The Hague, Netherlands; Jeffrey D. Harbrecht, Riverside Methodist Hospital, Columbus Ohio; Joseph L. Chin, University of Western Ontario, London, Canada; Seth P. Lerner, Brian J. Miles, Baylor College of Medicine, Houston Texas [Journal of the National Cancer Institute 2001;93:597-604] For the International Mitomycin C Consortium

Researchers have found a relatively simple way to dramatically improve the cancer-killing capacity of a drug often used to treat superficial bladder cancer. The changes nearly doubled the number of people who were cancer-free after five years, compared to those receiving the standard therapy, and lengthened the time before tumors recurred in these patients.

The finding is the result of a five-year, international study involving 14 acedemic and research centers, published in the April 18 issue of the Journal of the National Cancer Institute.

The study looked at ways to improve the use of mitomycin C (MMC) following surgical removal of the tumor. In both the standard and the experimental therapy, MMC is placed in the bladder where it is held by the patient for about two hours.

The new therapy, however, took special measures to maintain a high drug concentration in the bladder.

“We compared the usual way of giving the drug to a new approach, said Jessie L-S Au, distinguished university professor and Dorothy M. Davis Chair in Cancer Research at the College of Pharmacy at Ohio State University.

Patients receiving the experimental treatment went an average of 29.1 months before their cancer recurred, while those receiving the standard treatment had recurrence in 11.3 months.

There was also a statistically significant difference in the number of patients who were recurrence-free after five years: 42.6 percent in the modified treatment versus 23.5 receiving standard treatment.

“We have found a way to make this treatment more effective in a highly significant way,” said Au, a researcher with Ohio State’s Comprehensive Cancer Center. “We nearly doubled the percentage of patients who were disease-free after five years.”

The study, done by Au and a team of researchers, involved 230 patients with confirmed superficial bladder cancer who were at high risk of recurrence. Of these, 111 patients received standard treatment and 119 received the experimental therapy.

“We set out to find out why there was such variability and found two main reasons – the inability to deliver the drug in the highest possible concentration to the tumor site, and the biology of the tumor that makes it less sensitive to the drug. We can’t change the second one, but we found out that the problem with the delivery of the drug was quite simple,” says Au.

For the standardized therapy;

*Urine was drained from the bladder using a catheter.
*A 20-mg dose of MMC was placed in the bladder, where it was held for two hours.
* No special steps were taken to reduce the remaining volume or to reduce urine acidity.

The experimental therapy

*Increased the dose to 40 mg.
*Reduced the amount of fluid in which the drug is dissolved.
prohibited fluid intake before and during the treatment, to reduce excess urine in the bladder.
*Further reduced urine in the bladder with a catheter immediately prior to treatment.
*Reduced the acidity of the urine with oral doses of sodium bicarbonate before treatment, because mitomycin C is unstable in acidic urine.

Au says that by using a computer model to determine what effect incremental changes would have, the researchers hypothesized that changing all variables at once would give a 20% to 40% benefit. “So we deviated from the norm of traditional clinical trials, but we think the benefit is great,” she says.

Next, Au will also try to improve the efficacy of MMC further by using an additional drug to make the tumor more sensitive to the drug. Au’s study was sponsored by the National Cancer Institute and was done in conjunction with The Ohio State University Comprehensive Cancer Center.

In an accompanying editorial James E. Montie, MD, writes that the authors’ choice to “go for the home run” produced enough change to provide a detectable effect given the small number of patients in the trial.

Though optimized mitomycin C therapy may give clinicians another option in treating this disease, according to Au, the data presented in the study should not be extrapolated to higher-grade, more aggressive forms of the disease, Montie writes in his editorial. The study is based on good research and it would be reasonable to integrate the optimized therapy for treatment of low grade disease, he says.

Study of Anti-Cancer Drug Has Important Implications For African Americans

The Ohio State study on MMC had an unexpected finding that has important implications for African Americans with superficial bladder cancer, and possibly other cancers.

The five-year, multi-institutional study, led by Jessie L-S Au, distinguished university professor and Dorothy M. Davis Chair in Cancer Research at the College of Pharmacy at Ohio State University, demonstrated a way to significantly improve the effectiveness of the drug.

Of the 230 people involved in the research, six were African Americans. Three of these patients were randomly selected to receive the standard therapy and three the modified therapy.

Regardless of treatment, however, all six people experienced a recurrence of their disease in less than one year. The difference between the African-American and the Caucasian data was highly statistically significant, said Au, but because the number of African-American patients was so low, no firm conclusions can be drawn from the outcome.

Based on this outcome, however, “mitomycin C doesn’t seem like a good drug for African Americans, and an alternative drug should be tried,” said Au. “I can’t say which drug, though, because no one looks at race as a risk factor in clinical trials.”

Au’s finding indicates that should change. “This data is strong evidence that we should study race as a risk factor,” she said. “Perhaps the difference is genetic. African Americans may lack the two enzymes in the body that make this drug work.” Au plans to study archived tissues from African-American patients for presence of the enzymes.

Journal of the National Cancer Institute
Ohio State University

American Cancer Society

back to intravesical chemotherapy
back to superficial bladder cancer

Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial.

Au JL, Badalament RA, Wientjes MG, Young DC, Warner JA, Venema PL, Pollifrone DL, Harbrecht JD, Chin JL, Lerner SP, Miles BJ; International Mitomycin C Consortium.

Ohio State University, 496 W. 12th Ave., Columbus, OH 43210, USA.

BACKGROUND: Intravesical chemotherapy (i.e., placement of the drug directly in the bladder) with mitomycin C is beneficial for patients with superficial bladder cancer who are at high risk of recurrence, but standard therapy is empirically based and patient response rates have been variable, in part because of inadequate drug delivery. We carried out a prospective, two-arm, randomized, multi-institutional phase III trial to test whether enhancing the drug’s concentration in urine would improve its efficacy.

METHODS: Patients with histologically proven transitional cell carcinoma and at high risk for recurrence were eligible for the trial. Patients in the optimized-treatment arm (n = 119) received a 40-mg dose of mitomycin C, pharmacokinetic manipulations to increase drug concentration by decreasing urine volume, and urine alkalinization to stabilize the drug. Patients in the standard-treatment arm (n = 111) received a 20-mg dose without pharmacokinetic manipulations or urine alkalinization. Both treatments were given weekly for 6 weeks. Primary endpoints were recurrence and time to recurrence. Treatment outcome was examined by use of Kaplan-Meier analysis with log-rank tests. Statistical tests were two-sided.

RESULTS: Patients in the two arms did not differ in demographics or history of intravesical therapy. Dysuria occurred more frequently in the optimized arm but did not lead to more frequent treatment termination. In an intent-to-treat analysis, patients in the optimized arm showed a longer median time to recurrence (29.1 months; 95% confidence interval [CI] = 14.0 to 44.2 months) and a greater recurrence-free fraction (41.0%; 95% CI = 30.9% to 51.1%) at 5 years than patients in the standard arm (11.8 months; 95% CI = 7.2 to 16.4 months) and 24.6% (95% CI = 14.9% to 34.3%) (P =.005, log-rank test for time to recurrence). Improvements were found in all risk groups defined by tumor stage, grade, focality, and recurrence. CONCLUSIONS: This study identified a pharmacologically optimized intravesical mitomycin C treatment with statistically significantly enhanced efficacy.

PMID: 11309436 [PubMed – indexed for MEDLINE]

J Natl Cancer Inst. 2001 Apr 18;93(8):572-3