Phase I-II evaluation of intravesical novantrone (mitoxantrone) in superficial bladder cancer

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Abstract
The objective of this study was to determine the safety and efficacy of intravesical novantrone in refractory superficial bladder cancer. The eligibility criteria included proven carcinoma in situ or superficial transitional cell carcinoma of the bladder at stage Ta or T1 that was proven refractory to or in relapse after the use of at least one other standard anti-cancer agent. The patient was to have received no prior radiotherapy or intravesical therapy for at least 4 weeks prior to entry. Patients also did not suffer significant cardiac dysfunction, such as angina, congestive, heart failure, or uncompensated cardiomyopathy. All patients were given 4–6 doses of intravesical novantrone at the same dose level at weekly dosing interval. Patients were required to retain the drugs in the bladder for 2 h. Baseline study included history/physical, hematology, blood chemistry, cystoscopy, bladder barbotage, urine cytology, cystometrogram to assess the bladder capacity, and finally, chest X-ray, EKG, and MUGA scan, if indicated. Weekly assessment involved toxicity notation, blood chemistry, hematology and urinalysis. Monthly assessment included physical examination, toxicity notation, hematology, urinalysis and blood chemistry. Within 4 weeks of completion of the last dose, patients underwent repeat cystoscopy to assess disease status. Patients who responded to the 4–6 week induction phase were entered in a monthly dose regimen for up to 5 months. A total of 23 patients were enrolled: 22 males and 1 female. One patient dropped out before receiving medication because of a protocol violation for entry criteria. Twenty-two patients were eligible for assessment of safety and 20 were eligible for assessment of efficacy. Prior therapy for treatment. Twelve patients had papillary carcinoma, stage T1-Ta and grade I-II, and eight had carcinoma in situ. Twenty-two patients received an escalating weekly dose ranging from 5 to 13.5 mg. Patients could be entered more than once. Four patients received monthly maintenance doses for up to 5 months. The results indicate that the drug dose level up to 10.5 mg weekly dose was tolerated without major side effects on the bladder. At doses of 12 and 13.5 mg the patients developed mild to severe bladder irritative symptoms, with significant reduction in bladder capacity. Two patients were dropped from the study because of the severe bladder symptoms. Both were receiving 13.5 mg weekly doses at the second and third week of treatment.The average time to tumor recurrence for five responders with TIS and 12 responders in stage Ta-T1 and grade I-II, was similar and slightly longer in patients who failed previous treatment with BCG. Intravesical novantrone appeared to hold promise as a therapy for superficial bladder cancer. Further randomized comparative study is needed.

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