- Email: [email protected]
Side Effects Associated with Intravesical Mitomycin C
0022-5347 /81/1265-0596$02.00/0 Vol. 126, November Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1981 by The Williams & Wilkins Co.
SIDE EFFECTS ASSOCIATED WITH INTRAVESICAL MITOMYCIN C I. NISSENKORN, H. HERROD
AND
M. S. SOLOWAY
From the Departments of Urology and Pediatrics, University of Tennessee Center for Health Sciences and Memphis Veterans Administration Medical Center, Memphis, Tennessee
ABSTRACT
The nature and severity of side effects accompanying intravesical chemotherapy with mitomycin C were studied in 29 patients. No patient experienced systemic toxicity. Local side effects developed in 7 patients (24 per cent), and consisted of moderate cystitis in 3 and drug-related palmar desquamation, with or without generalized rash, in 4. Based on skin tests 3 of these patients were believed to have a contact dermatitis. The fourth patient had a generalized rash, in addition to palmar desquamation, that appeared after subsequent instillations of mitomycin C and the drug had to be discontinued. Careful cleansing of the hands and perineum on the day of treatment can prevent most skin reactions. Since Semple used intravesical podophyllin to treat bladder papillomas in 19481 a variety of compounds have been evaluated for their effectiveness in eradicating bladder tumors. 2 • 3 One of these drugs, mitomycin C, has achieved excellent response rates in the initial trials. 4 • 5 A major advantage is the relatively low incidence of systemic toxicity. We report our experience with side effects in 29 patients treated with intravesical mitomycin C for definitive therapy of superficial bladder cancer. MATERIALS AND METHODS
The 19 men and 10 women studied ranged in age from 49 to 87 years. All patients had biopsy proved stage O or A transitional cell carcinoma. They received mitomycin C as definitive therapy for a variety of reasons, for example multiple prior tumors, medical problems that obviated anesthesia and multifocal urothelial abnormalities. Through an indwelling catheter 30 (6 patients) or 40 mg. mitomycin C in 30 to 40 ml. sterile distilled water (100 µg./ml.) were instilled into the bladder and left for 2 hours. The procedure was done weekly for 8 weeks and then monthly for 1 year. Cystoscopic examinations were done before treatment, 3 months after treatment was started and at 3-month intervals. Tumor biopsy (initially) and 3 to 4 random mucosa! biopsies were obtained during each cystoscopic examination. The hematocrit level, and the differential blood and platelet counts were examined before each treatment. Patients were asked to report any side effects. Skin tests were done in patients with a skin rash, including a scratch test, patch test and intradermal test. The scratch and patch tests were done with a solution of approximately 10 µg./ ml. mitomycin C. For the intradermal test 1 µg. mitomycin C was injected in a volume of 0.1 cc. The same skin tests were done on 4 patients who had no signs of drug toxicity and were treated by the same reginien of mitomycin C. All patients were examined at 20 minutes, and 24 and 48 hours after application of the skin tests. RESULTS
The over-all response rate to mitomycin was 86 per cent. A complete response was observed in 43 per cent of the 29 patients and a partial response was noted (>50 per cent reduction in tumor size) in 43 per cent. Side effects. No patient experienced systemic toxicity. There were no alterations in the hematocrit level, or differential white or platelet counts. Local side effects during the induction regimen occurred only in men. These reactions included moderate Accepted for publication January 9, 1981. 596
cystitis in 3 patients and drug-related desquamation of the palmar skin, with or without rashes in other parts of the body, in 4. In the latter 4 patients symptoms started between 3 and 6 weeks of the weekly Initomycin instillations. In 2 patients desquamation of the palmar skin was mild and subsided after treatment with hydrocortisone cream, while in the remaining 2 it was severe on both hands and accompanied by a macular rash in the perineal region and penile edema. In 1 of the latter 2 patients symptoms cleared after topical treatment with hydrocortisone cream and oral diphenhydramine hydrochloride. The weekly treatment schedule had to be interrupted only once. This patient was instructed to wash the hands and genitalia after the first few voidings following the mitomycin instillation. New symptoms and rashes did not appear after this regimen was started. The other patient had a generalized rash in addition to the palmar skin desquamation. Treatment with hydrocortisone cream and diphenhydramine hydrochloride provided symptomatic relief but the rash reappeared after subsequent instillations of mitomycin C. After efforts to overcome the symptoms by preventive steroid treatment and strict hygiene failed bladder instillations ofmitomycin C were discontinued. This patient had a local recurrence of transitional cell carcinoma at the dome of the bladder 5 months later. Skin tests. The results of the skin tests are depicted in the table. Of the 4 patients with apparent drug-related skin rashes none had a positive scratch test and 3 had positive intradermal skin tests. These reactions were evident in 12 to 18 hours of the test, became vesiculated and required treatment with systeinic hydrocortisone. Three of the 4 patients had positive patch tests characterized by erythema and vesiculation extending beyond the area of the patch test. These reactions were present after 48 hours of the patch testing. There were no positive skin tests in patients treated with mitomycin C with no side effects. DISCUSSION
The use of mitomycin C for intravesical chemotherapy of superficial bladder cancer was described originally by Shida and associates. 6 Mishina and associates demonstrated its impressive activity when they reported a 44 per cent complete and a 32 per cent partial response rate in 50 patients. 4 Bracken and Johnson reported an 81 per cent response rate in a series of 32 patients, with complete response noted in 50 per cent. 5 They were unable to detect the presence of mitomycin in the serum after bladder instillation. White blood cell and platelet counts, and liver and renal function tests remained unchanged during therapy. The only reported local side effect consisted of frequency and sometimes painful urination. Topical therapy was completed in all cases.
SIDE EFFECTS ASSOCIATED WITH INTRAVESICAL MITOMYCIN C
Skin test responses in patients treated with mitomycin C Pt. l 2 3 4
5-8
Clinical Findings Pa!mar desquamation Palmar desquamation Palmar desquamation and generalized rash Palmar desquamation and generalized rash No rash
Scratch
Intra dermal
Patch
Neg. Neg.
Neg. Pos.
Neg. Pos.
Neg.
Pos.
Pos.
Neg.
Pos.
Pos.
Neg.
Neg.
Neg.
597
sensitivity reaction since they arose rapidly and were more violent than most delayed types of hypersensitivity reactions. Whether there also might be an element of irritant dermatitis involved is difficult to judge since some substances can be irritants and allergens. It does appear that among our rrnr.up,1m.'-' careful cleansing of the hands and perineum can prevent most reactions. REFERENCES
The over-all response rate in our series is similar to previous reports. Irritation of the lower urinary tract, consisting of freand urgency, occurred in 3 of 29 patients and resolved with temporary cessation of the drug or with appropriate treatment of a urinary tract infection. A skin rash that was related temporally to instillation of mitomycin C was noted in 4 of 29 patients. In 3 of these patients the positive patch test suggests that the rash was owing to contact dermatitis. Therefore, all patients were requested to wash the hands and genitalia thoroughly on the of therapy. 1 patient continued to have these cutaneous reactions this precaution. Mi.tomycin C is one of the anti.tumor antibiotics. It is an alkylating agent that affects cells by inhibiting deoxyribonucleic acid synthesis. 7 Consequently, rapidly dividing cells, such as those in the skin, gastrointestinal tract and bone marrow, are to be susceptible to the effects of mitomycin C. Although some alkylating agents as well as antitumor antibiotics have been reported to cause mucocutaneous lesions, intravesical instillation of mitomycin C generally has been believed to have minimal cutaneous effects. 3- 6 A recent report by Bracken and associates8 indicated that 2 of 43 patients had a palmar desquamation similar to that observed in Olli' patients. Based on our skin test results it appears that the rash observed in these is likely caused a contact dermatitis. The positive a~·cum= tests were not typical of a delayed type of hyper-
1. Semple, J. E.: Papillomata of bladder treated with podophyllin.
Preliminary report. Brit. Med. J., 1: 1235, 1948. 2. Veenema, R. J., Dean, A. L., Jr., Roberts, M., Fingerhut, B., Chowhury, B. K. and Tarassoly, H.: Bladder carcinoma treated by direct instillation of thio-TEPA. J. Urol., 88: 60, 1962. 3. Esquivel, E. L., Jr., Mackenzie, A. R. and Whitmore, W. F., Treatment of bladder tumors by instillation of thio-TEPA, actinomycin D, or 5-fluorouracil. Invest. Urol., 2: 381, 1965. 4. Mishina, T., Oda, K., Murata, S., Ooe, H., Mori, Y. and Takahashi, T.: Mitomycin C bladder instillation therapy for bladder tumorEs. J. Urol., 114: 217, 1975. 5. Bracken, R. B. and Johnson, D. E.: Treatment of cial tumors of the urinary bladder with intravesical m,,mnurrn In: Mitomycin C: Current Status and New Developments. by S. K. Carter and S. T. Crooke. New York: Academic Press, Inc., p. 205, 1979. 6. Shida, K., Doguchi, T., Sasazaki, T., Sato, H., Takahashi, U., Tatani, M., Kato, N., Drano, E., Oogoshi, M., Tazaki, H., Ozeka, Z., Matsunaga, S., Yajima, H., Nakagami, Y. and Nakamura, Y: Treatment of the bladder cancer with instillations of mitomyu::in C (first report). Jap. J. Clin. Urol., 21: 1057, 1967. 7. Lown, J. W.: The molecular mechanism of antitumor action of the mitomycins. In: Mitomycin C: Current Status and New Devel opments. Edited by S. K. Carter and S. T. Crooke. New Academic Press, Inc., p. 5, 1979. 8. Bracken, R. B., Johnson, D. E., von Eschenbach, A. C., Swanson, D. A., De Furia, D. and Crooke, S. T.: Role of intravesicai. mitomycin C in management of superficial bladder tumors. Urology, 16: 11, 1980.
THE JOURNAL OF UROLOGY
Copyright © 1981 by The Williams & Wilkins Co.
SIDE EFFECTS ASSOCIATED WITH INTRAVESICAL MITOMYCIN C I. NISSENKORN, H. HERROD
AND
M. S. SOLOWAY
From the Departments of Urology and Pediatrics, University of Tennessee Center for Health Sciences and Memphis Veterans Administration Medical Center, Memphis, Tennessee
ABSTRACT
The nature and severity of side effects accompanying intravesical chemotherapy with mitomycin C were studied in 29 patients. No patient experienced systemic toxicity. Local side effects developed in 7 patients (24 per cent), and consisted of moderate cystitis in 3 and drug-related palmar desquamation, with or without generalized rash, in 4. Based on skin tests 3 of these patients were believed to have a contact dermatitis. The fourth patient had a generalized rash, in addition to palmar desquamation, that appeared after subsequent instillations of mitomycin C and the drug had to be discontinued. Careful cleansing of the hands and perineum on the day of treatment can prevent most skin reactions. Since Semple used intravesical podophyllin to treat bladder papillomas in 19481 a variety of compounds have been evaluated for their effectiveness in eradicating bladder tumors. 2 • 3 One of these drugs, mitomycin C, has achieved excellent response rates in the initial trials. 4 • 5 A major advantage is the relatively low incidence of systemic toxicity. We report our experience with side effects in 29 patients treated with intravesical mitomycin C for definitive therapy of superficial bladder cancer. MATERIALS AND METHODS
The 19 men and 10 women studied ranged in age from 49 to 87 years. All patients had biopsy proved stage O or A transitional cell carcinoma. They received mitomycin C as definitive therapy for a variety of reasons, for example multiple prior tumors, medical problems that obviated anesthesia and multifocal urothelial abnormalities. Through an indwelling catheter 30 (6 patients) or 40 mg. mitomycin C in 30 to 40 ml. sterile distilled water (100 µg./ml.) were instilled into the bladder and left for 2 hours. The procedure was done weekly for 8 weeks and then monthly for 1 year. Cystoscopic examinations were done before treatment, 3 months after treatment was started and at 3-month intervals. Tumor biopsy (initially) and 3 to 4 random mucosa! biopsies were obtained during each cystoscopic examination. The hematocrit level, and the differential blood and platelet counts were examined before each treatment. Patients were asked to report any side effects. Skin tests were done in patients with a skin rash, including a scratch test, patch test and intradermal test. The scratch and patch tests were done with a solution of approximately 10 µg./ ml. mitomycin C. For the intradermal test 1 µg. mitomycin C was injected in a volume of 0.1 cc. The same skin tests were done on 4 patients who had no signs of drug toxicity and were treated by the same reginien of mitomycin C. All patients were examined at 20 minutes, and 24 and 48 hours after application of the skin tests. RESULTS
The over-all response rate to mitomycin was 86 per cent. A complete response was observed in 43 per cent of the 29 patients and a partial response was noted (>50 per cent reduction in tumor size) in 43 per cent. Side effects. No patient experienced systemic toxicity. There were no alterations in the hematocrit level, or differential white or platelet counts. Local side effects during the induction regimen occurred only in men. These reactions included moderate Accepted for publication January 9, 1981. 596
cystitis in 3 patients and drug-related desquamation of the palmar skin, with or without rashes in other parts of the body, in 4. In the latter 4 patients symptoms started between 3 and 6 weeks of the weekly Initomycin instillations. In 2 patients desquamation of the palmar skin was mild and subsided after treatment with hydrocortisone cream, while in the remaining 2 it was severe on both hands and accompanied by a macular rash in the perineal region and penile edema. In 1 of the latter 2 patients symptoms cleared after topical treatment with hydrocortisone cream and oral diphenhydramine hydrochloride. The weekly treatment schedule had to be interrupted only once. This patient was instructed to wash the hands and genitalia after the first few voidings following the mitomycin instillation. New symptoms and rashes did not appear after this regimen was started. The other patient had a generalized rash in addition to the palmar skin desquamation. Treatment with hydrocortisone cream and diphenhydramine hydrochloride provided symptomatic relief but the rash reappeared after subsequent instillations of mitomycin C. After efforts to overcome the symptoms by preventive steroid treatment and strict hygiene failed bladder instillations ofmitomycin C were discontinued. This patient had a local recurrence of transitional cell carcinoma at the dome of the bladder 5 months later. Skin tests. The results of the skin tests are depicted in the table. Of the 4 patients with apparent drug-related skin rashes none had a positive scratch test and 3 had positive intradermal skin tests. These reactions were evident in 12 to 18 hours of the test, became vesiculated and required treatment with systeinic hydrocortisone. Three of the 4 patients had positive patch tests characterized by erythema and vesiculation extending beyond the area of the patch test. These reactions were present after 48 hours of the patch testing. There were no positive skin tests in patients treated with mitomycin C with no side effects. DISCUSSION
The use of mitomycin C for intravesical chemotherapy of superficial bladder cancer was described originally by Shida and associates. 6 Mishina and associates demonstrated its impressive activity when they reported a 44 per cent complete and a 32 per cent partial response rate in 50 patients. 4 Bracken and Johnson reported an 81 per cent response rate in a series of 32 patients, with complete response noted in 50 per cent. 5 They were unable to detect the presence of mitomycin in the serum after bladder instillation. White blood cell and platelet counts, and liver and renal function tests remained unchanged during therapy. The only reported local side effect consisted of frequency and sometimes painful urination. Topical therapy was completed in all cases.
SIDE EFFECTS ASSOCIATED WITH INTRAVESICAL MITOMYCIN C
Skin test responses in patients treated with mitomycin C Pt. l 2 3 4
5-8
Clinical Findings Pa!mar desquamation Palmar desquamation Palmar desquamation and generalized rash Palmar desquamation and generalized rash No rash
Scratch
Intra dermal
Patch
Neg. Neg.
Neg. Pos.
Neg. Pos.
Neg.
Pos.
Pos.
Neg.
Pos.
Pos.
Neg.
Neg.
Neg.
597
sensitivity reaction since they arose rapidly and were more violent than most delayed types of hypersensitivity reactions. Whether there also might be an element of irritant dermatitis involved is difficult to judge since some substances can be irritants and allergens. It does appear that among our rrnr.up,1m.'-' careful cleansing of the hands and perineum can prevent most reactions. REFERENCES
The over-all response rate in our series is similar to previous reports. Irritation of the lower urinary tract, consisting of freand urgency, occurred in 3 of 29 patients and resolved with temporary cessation of the drug or with appropriate treatment of a urinary tract infection. A skin rash that was related temporally to instillation of mitomycin C was noted in 4 of 29 patients. In 3 of these patients the positive patch test suggests that the rash was owing to contact dermatitis. Therefore, all patients were requested to wash the hands and genitalia thoroughly on the of therapy. 1 patient continued to have these cutaneous reactions this precaution. Mi.tomycin C is one of the anti.tumor antibiotics. It is an alkylating agent that affects cells by inhibiting deoxyribonucleic acid synthesis. 7 Consequently, rapidly dividing cells, such as those in the skin, gastrointestinal tract and bone marrow, are to be susceptible to the effects of mitomycin C. Although some alkylating agents as well as antitumor antibiotics have been reported to cause mucocutaneous lesions, intravesical instillation of mitomycin C generally has been believed to have minimal cutaneous effects. 3- 6 A recent report by Bracken and associates8 indicated that 2 of 43 patients had a palmar desquamation similar to that observed in Olli' patients. Based on our skin test results it appears that the rash observed in these is likely caused a contact dermatitis. The positive a~·cum= tests were not typical of a delayed type of hyper-
1. Semple, J. E.: Papillomata of bladder treated with podophyllin.
Preliminary report. Brit. Med. J., 1: 1235, 1948. 2. Veenema, R. J., Dean, A. L., Jr., Roberts, M., Fingerhut, B., Chowhury, B. K. and Tarassoly, H.: Bladder carcinoma treated by direct instillation of thio-TEPA. J. Urol., 88: 60, 1962. 3. Esquivel, E. L., Jr., Mackenzie, A. R. and Whitmore, W. F., Treatment of bladder tumors by instillation of thio-TEPA, actinomycin D, or 5-fluorouracil. Invest. Urol., 2: 381, 1965. 4. Mishina, T., Oda, K., Murata, S., Ooe, H., Mori, Y. and Takahashi, T.: Mitomycin C bladder instillation therapy for bladder tumorEs. J. Urol., 114: 217, 1975. 5. Bracken, R. B. and Johnson, D. E.: Treatment of cial tumors of the urinary bladder with intravesical m,,mnurrn In: Mitomycin C: Current Status and New Developments. by S. K. Carter and S. T. Crooke. New York: Academic Press, Inc., p. 205, 1979. 6. Shida, K., Doguchi, T., Sasazaki, T., Sato, H., Takahashi, U., Tatani, M., Kato, N., Drano, E., Oogoshi, M., Tazaki, H., Ozeka, Z., Matsunaga, S., Yajima, H., Nakagami, Y. and Nakamura, Y: Treatment of the bladder cancer with instillations of mitomyu::in C (first report). Jap. J. Clin. Urol., 21: 1057, 1967. 7. Lown, J. W.: The molecular mechanism of antitumor action of the mitomycins. In: Mitomycin C: Current Status and New Devel opments. Edited by S. K. Carter and S. T. Crooke. New Academic Press, Inc., p. 5, 1979. 8. Bracken, R. B., Johnson, D. E., von Eschenbach, A. C., Swanson, D. A., De Furia, D. and Crooke, S. T.: Role of intravesicai. mitomycin C in management of superficial bladder tumors. Urology, 16: 11, 1980.