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Bone Marrow Suppression after Intravesical Mitomycin C Treatment
0022-534 7/86/1362-0459$02.00/0
THE
JOURNAL OF UROLOGY
Vol. 136, August
Copyright © 1986 by The Williams & Wilkins Co.
Printed in U.S.A.
BONE MARROW SUPPRESSION AFTER INTRAVESICAL MITOMYCIN C TREATMENT TAWFIK A. ZEIN, NEAL FRIEDBERG
AND
HONG KIM
From the Departments of Urology and Hematology, Brookdale Hospital Medical Center, Brooklyn, New York
ABSTRACT
Intravesical chemotherapy has been established as a modality for the treatment and prevention of superficial bladder tumors. However, the optimal time for instillation of chemotherapy following transurethral resection is still not clear. We report on a patient with a superficial bladder tumor treated immediately after transurethral resection with relatively high dose mitomycin C. Bone marrow failure developed within 2 weeks. A possible relationship is suggested. In 1948 Semple introduced intravesical chemotherapy treatment for superficial bladder cancer. 1 lntravesical therapy is now established for treatment and prevention of recurrence of superficial tumors. Recently, mitomycin C was reported to induce a 45 per cent complete response rate in superficial transitional cell cancer. 2 · 4 Mitomycin C also seems to provide control in tumors that may not respond to thiotepa. 5 The major toxicity is local. Systemic side effects are not observed, although absorption into the circulation has been measured. 6-B We report a case in which aplastic anemia occurred as a systemic side effect. CASE REPORT
A 79-year-old white woman presented to the hospital with symptoms of poor appetite and hematuria. Medical history was negative for systemic diseases, including malignancies. She had no known allergies and took no medications. Laboratory studies showed normal liver and renal function. Hemoglobin was 14.8 gm./dl., hematocrit 44.4 per cent and white blood count 6.6 X 103 / µl., with an adequate platelet count. The urine sediment showed numerous red blood cells. Urine cytology was negative. An excretory urogram revealed normal upper tracts. Cystoscopy demonstrated mild bladder trabeculations, patent ureteral orifices and generalized mucosal congestion. A large (3 X 3 cm.) papillary tumor involving the right lateral wall and base was noted. Transurethral resection of the tumor was performed, followed immediately by instillation of 80 mg. mitomycin C into the bladder through a Foley catheter that was clamped for 2 hours. The urine became clear and the Foley catheter was removed 4 days after resection. Discharge from the hospital was delayed because of chest pain that required evaluation by a cardiologist. On day 10 after the intravesical instillation the white blood count and platelet count decreased to 700 and 13,000/µl., respectively. Hematocrit was 29 per cent. Flurazepam hydrochloride, hydroxyzine hydrochloride and diazepam, which had been administered while the patient was in the hospital, were discontinued immediately. Bone marrow aspirate showed no evidence of malignant cells, no hematopoietic elements and empty spicules. The patient was afebrile. Blood, urine and sputum cultures were negative. She received platelet concentrate transfusion and began intravenous antibiotics. Sixteen days after the resection and in travesical instillation a chest radiograph showed a right pleural effusion and bilateral infiltrates. The patient had a cardiac arrest 5 days later and could not be resuscitated. DISCUSSION
About 70 to 80 per cent of bladder tumors at presentation are confined to the mucosa (cTa and Tis) or lamina propria Accepted for publication March 7, 1986.
(cTl). Despite surgical resection 50 to 70 per cent will recur within the first year. 9 Random biopsies from apparently normal bladder mucosa adjacent to superficial tumors show a 10 per cent incidence of carcinoma in situ. 10 Thus, early treatment is indicated. lntravesical chemotherapy is convenient, since it bathes the entire urothelium, the patient retains a functioning bladder, the side effects are minimal and, above all, its treatment or prevention of recurrence has been proved. There have been an increasing number of reports on the side effects with mitomycin C therapy. In 1975 Mishina and associates reported urinary frequency in 3 of 50 patients treated with 20 mg. mitomycin C 3 times a week for 24 doses, and no evidence of bone marrow depression was found. 3 In a series of 29 patients Nissenkorn and associates described 7 with side effects, including 4 with palmar desquamation and 3 with moderate chemical cystitis. None of the patients had systemic toxicity.11 Recently, decreased bladder capacity in some patients receiving intravesical mitomycin C has been observed. One patient had a severely contracted bladder that required supravesical urinary diversion. The histological sections showed severe inflammatory reaction and extensive fibrosis replacing the muscularis. 12 Although mitomycin C has a high molecular weight of approximately 300, it has been shown independently by many observers that it is absorbed into the circulation in minimal amounts during intravesical instillation. 2·6-8 De Wall and associates developed an assay that detected mitomycin C in the blood of all patients who received intravesical instillations. 8 The level in the blood was proportional to the dose given intravesically but it was not high enough to cause systemic toxicity. However, they did not exceed an intravesical dose of 60 mg. and did not mention the time relationship between the transurethral resection and the instillation of chemotherapy. With the recommended therapeutic intravenous dose (IO to 20 mg./m. 2) of mitomycin C the peak serum level is 0.52 to 2.4 mg./ml. and myelosuppression occurs in 85 to 90 per cent of the patients within 2 to 6 weeks, with occasional fatal outcomes. Pulmonary toxicity consists of interstitial infiltrates and pleural effusions. The systemic absorption of mitomycin C after intravesical instillation has been measured in previous studies, although the time of instillation with respect to the transurethral resection was either delayed or not recorded. Our patient had a 3 x 3 cm. bladder tumor resected. The remaining bladder mucosa was congested and hyperemic. The dose of mitomycin C (80 mg.) was higher than recommended and was given at the completion of resection. The combination of surgical trauma and concurrent inflammation with dilated and excessively permeable blood vessels makes it likely that mitomycin C was absorbed in high concentration, resulting in the fatal complication of aplastic anemia. The bone marrow and pulmonary toxicities were similar to that seen with intra-
460
ZEIN AND ASSOCIATES
venous mitomycin C. The outcome of this case leads to the recommendations that mitomycin C administration should be deferred until the urine is no longer grossly bloody and that a maximum dose of 40 mg. be instilled.
7.
REFERENCES 1. Semple, J.E.: Papillomata of the bladder treated with podophyllin. Preliminary report. Brit. Med. J., 1: 1235, 1948. 2. Bracken, R. B. and Johnson, D. E.: Treatment of multiple superficial tumors of the urinary bladder with intravesical mitomycin C. In: Mitomycin C: Current Status and New Developments, 1st ed. Edited by S. K. Carter and S. T. Crooke. New York: Academic Press, chapt. 33, p. 205, 1979. 3. Mishina, T., Oda, K., Murata, S., Ooe, H., Mori, Y. and Takahashi, T.: Mitomycin C bladder instillation therapy for bladder tumors. J. Urol., 114: 217, 1975. 4. Soloway, M. S. and Ford, K. S.: Subsequent tumor analysis of 36 patients who have received intravesical mitomycin C for superficial bladder cancer. J. Urol., 130: 74, 1983. 5. Soloway, M. S.: lntravesical and systemic chemotherapy in management of superficial bladder cancer. Urol. Clin. N. Amer., 11: 623, 1984. 6. Fliichter, S. H., Harzmann, R. and Bichler, K.-H.: Local mitomycin C therapy of transitional cell carcinoma of the bladder-serum
8.
9. 10.
11. 12.
resorption study and clinical results. In: Mitomycin C: Current Impact on Cancer Chemotherapy. Edited by M. Ogawa, M. Rozencweig and M. J. Staquet. Amsterdam: Excerpta Medica, pp. 143-152, 1982. Wajsman, Z., Dhafir, R. A., Pfeffer, M., MacDonald, S., Block, A., Dragone, N. and Pontes, J.E.: Studies ofmitomycin C absorption after intravesical treatment of superficial bladder tumors. J. Urol., 132: 30, 1984. De Wall, J. G., Kurth, K. H., van Oosterom, A. T., de Laat, R. and de Jong, E. A. J. M.: Plasma levels of mitomycin-C during its intravesical instillation. J. Urol., part 2, 131: 139A, abstract 141, 1984. National Bladder Cancer Collaborative Group A (NBCCGA): Development of a strategy for a longitudinal study of patients with bladder cancer. Cancer Res., 37: 2898, 1977. Zein, T., Wajsman, Z., Englander, L. S., Gamarra, M., Lopez, C., Ruben, R. P. and Pontes, J. E.: Evaluation of bladder washings and urine cytology in the diagnosis of bladder cancer and its correlation with selected biopsies of the bladder mucosa. J. Urol., 132: 670, 1984. Nissenkorn, I., Herrod, H. and Soloway, M. S.: Side effects associated with intravesical mitomycin C. J. Urol., 126: 596, 1981. Wajsman, Z., McGill, W., Englander, L., Ruben, R. P. and Pontes, J. E.: Severely contracted bladder following intravesical mitomycin C therapy. J. Urol., 130: 340, 1983.
THE
JOURNAL OF UROLOGY
Vol. 136, August
Copyright © 1986 by The Williams & Wilkins Co.
Printed in U.S.A.
BONE MARROW SUPPRESSION AFTER INTRAVESICAL MITOMYCIN C TREATMENT TAWFIK A. ZEIN, NEAL FRIEDBERG
AND
HONG KIM
From the Departments of Urology and Hematology, Brookdale Hospital Medical Center, Brooklyn, New York
ABSTRACT
Intravesical chemotherapy has been established as a modality for the treatment and prevention of superficial bladder tumors. However, the optimal time for instillation of chemotherapy following transurethral resection is still not clear. We report on a patient with a superficial bladder tumor treated immediately after transurethral resection with relatively high dose mitomycin C. Bone marrow failure developed within 2 weeks. A possible relationship is suggested. In 1948 Semple introduced intravesical chemotherapy treatment for superficial bladder cancer. 1 lntravesical therapy is now established for treatment and prevention of recurrence of superficial tumors. Recently, mitomycin C was reported to induce a 45 per cent complete response rate in superficial transitional cell cancer. 2 · 4 Mitomycin C also seems to provide control in tumors that may not respond to thiotepa. 5 The major toxicity is local. Systemic side effects are not observed, although absorption into the circulation has been measured. 6-B We report a case in which aplastic anemia occurred as a systemic side effect. CASE REPORT
A 79-year-old white woman presented to the hospital with symptoms of poor appetite and hematuria. Medical history was negative for systemic diseases, including malignancies. She had no known allergies and took no medications. Laboratory studies showed normal liver and renal function. Hemoglobin was 14.8 gm./dl., hematocrit 44.4 per cent and white blood count 6.6 X 103 / µl., with an adequate platelet count. The urine sediment showed numerous red blood cells. Urine cytology was negative. An excretory urogram revealed normal upper tracts. Cystoscopy demonstrated mild bladder trabeculations, patent ureteral orifices and generalized mucosal congestion. A large (3 X 3 cm.) papillary tumor involving the right lateral wall and base was noted. Transurethral resection of the tumor was performed, followed immediately by instillation of 80 mg. mitomycin C into the bladder through a Foley catheter that was clamped for 2 hours. The urine became clear and the Foley catheter was removed 4 days after resection. Discharge from the hospital was delayed because of chest pain that required evaluation by a cardiologist. On day 10 after the intravesical instillation the white blood count and platelet count decreased to 700 and 13,000/µl., respectively. Hematocrit was 29 per cent. Flurazepam hydrochloride, hydroxyzine hydrochloride and diazepam, which had been administered while the patient was in the hospital, were discontinued immediately. Bone marrow aspirate showed no evidence of malignant cells, no hematopoietic elements and empty spicules. The patient was afebrile. Blood, urine and sputum cultures were negative. She received platelet concentrate transfusion and began intravenous antibiotics. Sixteen days after the resection and in travesical instillation a chest radiograph showed a right pleural effusion and bilateral infiltrates. The patient had a cardiac arrest 5 days later and could not be resuscitated. DISCUSSION
About 70 to 80 per cent of bladder tumors at presentation are confined to the mucosa (cTa and Tis) or lamina propria Accepted for publication March 7, 1986.
(cTl). Despite surgical resection 50 to 70 per cent will recur within the first year. 9 Random biopsies from apparently normal bladder mucosa adjacent to superficial tumors show a 10 per cent incidence of carcinoma in situ. 10 Thus, early treatment is indicated. lntravesical chemotherapy is convenient, since it bathes the entire urothelium, the patient retains a functioning bladder, the side effects are minimal and, above all, its treatment or prevention of recurrence has been proved. There have been an increasing number of reports on the side effects with mitomycin C therapy. In 1975 Mishina and associates reported urinary frequency in 3 of 50 patients treated with 20 mg. mitomycin C 3 times a week for 24 doses, and no evidence of bone marrow depression was found. 3 In a series of 29 patients Nissenkorn and associates described 7 with side effects, including 4 with palmar desquamation and 3 with moderate chemical cystitis. None of the patients had systemic toxicity.11 Recently, decreased bladder capacity in some patients receiving intravesical mitomycin C has been observed. One patient had a severely contracted bladder that required supravesical urinary diversion. The histological sections showed severe inflammatory reaction and extensive fibrosis replacing the muscularis. 12 Although mitomycin C has a high molecular weight of approximately 300, it has been shown independently by many observers that it is absorbed into the circulation in minimal amounts during intravesical instillation. 2·6-8 De Wall and associates developed an assay that detected mitomycin C in the blood of all patients who received intravesical instillations. 8 The level in the blood was proportional to the dose given intravesically but it was not high enough to cause systemic toxicity. However, they did not exceed an intravesical dose of 60 mg. and did not mention the time relationship between the transurethral resection and the instillation of chemotherapy. With the recommended therapeutic intravenous dose (IO to 20 mg./m. 2) of mitomycin C the peak serum level is 0.52 to 2.4 mg./ml. and myelosuppression occurs in 85 to 90 per cent of the patients within 2 to 6 weeks, with occasional fatal outcomes. Pulmonary toxicity consists of interstitial infiltrates and pleural effusions. The systemic absorption of mitomycin C after intravesical instillation has been measured in previous studies, although the time of instillation with respect to the transurethral resection was either delayed or not recorded. Our patient had a 3 x 3 cm. bladder tumor resected. The remaining bladder mucosa was congested and hyperemic. The dose of mitomycin C (80 mg.) was higher than recommended and was given at the completion of resection. The combination of surgical trauma and concurrent inflammation with dilated and excessively permeable blood vessels makes it likely that mitomycin C was absorbed in high concentration, resulting in the fatal complication of aplastic anemia. The bone marrow and pulmonary toxicities were similar to that seen with intra-
460
ZEIN AND ASSOCIATES
venous mitomycin C. The outcome of this case leads to the recommendations that mitomycin C administration should be deferred until the urine is no longer grossly bloody and that a maximum dose of 40 mg. be instilled.
7.
REFERENCES 1. Semple, J.E.: Papillomata of the bladder treated with podophyllin. Preliminary report. Brit. Med. J., 1: 1235, 1948. 2. Bracken, R. B. and Johnson, D. E.: Treatment of multiple superficial tumors of the urinary bladder with intravesical mitomycin C. In: Mitomycin C: Current Status and New Developments, 1st ed. Edited by S. K. Carter and S. T. Crooke. New York: Academic Press, chapt. 33, p. 205, 1979. 3. Mishina, T., Oda, K., Murata, S., Ooe, H., Mori, Y. and Takahashi, T.: Mitomycin C bladder instillation therapy for bladder tumors. J. Urol., 114: 217, 1975. 4. Soloway, M. S. and Ford, K. S.: Subsequent tumor analysis of 36 patients who have received intravesical mitomycin C for superficial bladder cancer. J. Urol., 130: 74, 1983. 5. Soloway, M. S.: lntravesical and systemic chemotherapy in management of superficial bladder cancer. Urol. Clin. N. Amer., 11: 623, 1984. 6. Fliichter, S. H., Harzmann, R. and Bichler, K.-H.: Local mitomycin C therapy of transitional cell carcinoma of the bladder-serum
8.
9. 10.
11. 12.
resorption study and clinical results. In: Mitomycin C: Current Impact on Cancer Chemotherapy. Edited by M. Ogawa, M. Rozencweig and M. J. Staquet. Amsterdam: Excerpta Medica, pp. 143-152, 1982. Wajsman, Z., Dhafir, R. A., Pfeffer, M., MacDonald, S., Block, A., Dragone, N. and Pontes, J.E.: Studies ofmitomycin C absorption after intravesical treatment of superficial bladder tumors. J. Urol., 132: 30, 1984. De Wall, J. G., Kurth, K. H., van Oosterom, A. T., de Laat, R. and de Jong, E. A. J. M.: Plasma levels of mitomycin-C during its intravesical instillation. J. Urol., part 2, 131: 139A, abstract 141, 1984. National Bladder Cancer Collaborative Group A (NBCCGA): Development of a strategy for a longitudinal study of patients with bladder cancer. Cancer Res., 37: 2898, 1977. Zein, T., Wajsman, Z., Englander, L. S., Gamarra, M., Lopez, C., Ruben, R. P. and Pontes, J. E.: Evaluation of bladder washings and urine cytology in the diagnosis of bladder cancer and its correlation with selected biopsies of the bladder mucosa. J. Urol., 132: 670, 1984. Nissenkorn, I., Herrod, H. and Soloway, M. S.: Side effects associated with intravesical mitomycin C. J. Urol., 126: 596, 1981. Wajsman, Z., McGill, W., Englander, L., Ruben, R. P. and Pontes, J. E.: Severely contracted bladder following intravesical mitomycin C therapy. J. Urol., 130: 340, 1983.