PHENOLIZATION TREATMENT LUAY P. SUSAN, ROBERT
OF BLADDER
IN
OF MASSIVE INTRACTABLE HEMATURIA M.D.
J. MARSH,
From the Department St. Vincent Hospital,
M.D. of Urology, The Hess Urology Erie, Pennsylvania
Clinic,
ABSTRACT - intractable hemowhagic cystitis secondary to radiation or cyclophosphamide (Cytoxan) therapy could lead to serious complications; however, intravesical instillation of phenol has reduced the dilemma of this life-threatening problem. We present a case of intractable hemorrhagic cystitis secondary to cyclophosphamide therapy treated with 100 per cent phenol with no untoward side effects. Since fomnalin instillation into the bladder has been associated with severe complications, phenol appears to be safer and more effective in the treatment of intractable hematuria, and, therefwe, its clinical trial is recommended.
Hemorrhagic cyclophosphamide cystitis could occur months or years following treatment. Usually the bleeding is painless, profuse, and life threatening, and the patient requires multiple blood transfusions. The complication was first reported by Coggins, Raudin, and Elsman in 1959. l The management of massive bladder hemorrhage due to radiation or cyclophosphamide carries with it a perplexing problem. The various methods of therapy have been achieved with limited success. They include cauterization of the bleeding points with silver nitrate’ or fulguration with electrocautery.3 Local or systemic administration of aminocaproic acid, prednisone,4 phytonadione (Aqua Mephyton), vitamin substance E (Tocopherol), 5 and estrogenic (Premarin) have been used in an attempt to control the bleeding. The Helmstein hydrostatic pressure balloon has also been used as an alternate method to surgical intervention.6 Bilateral internal iliac artery ligation has been used in uncontrollable bleeding with various success. Urinary diversion with or without cystectomy is occasionally required in extreme bleeding. In the poor-risk patients when other conservative measures have failed, phenol instillation is a lifesaving procedure and a substitute for surgical treatment.
UROLOGY
i
JANUARY 1975 / VOLUME V, NUMBER 1
Case Report A sixteen-year-old white girl was in a state of remission from acute lymphoblastic leukemia which had been diagnosed ten years previously. At that time she underwent an induction regimen followed with a maintenance regimen. Seven years ago she had a relapse for which she was given cyclophosphamide, methotrexate, vincristine, and prednisone for three years. Since that time she has had no evidence of bone marrow relapse of her disease. Although the patient was taking methotrexate and prednisone, she has had no cyclophosphamide for the last four years. The patient was admitted in November, 1973, because of gross profuse hematuria. Following her admission the patient continued to bleed. Her hematocrit dropped to 15, and she required 8 units of blood to maintain a hematocrit between 29 and 30. Her platelet count, activated plasma thromboplastin time, and prothrombin time were within normal limits. She had a white blood count of 4,200, and blood urea nitrogen of 14 mg. per 100 ml. Excretory urogram was within normal limits (Fig. 1A). Cystogram revealed adequate bladder capacity. Cystoscopy revealed difise telangiectasia and suburothelial capillary oozing. Fulguration with a ball-tipped electrode was unsuccessful. 3 On three occasions the bladder
119
FIGURE 1. Intravenous pyelogram: (A) showing normal findings on admission; (B) six weeks postoperatively showing normal upper tracts and small bladder capacity; {C) six months postoperatively showing normal upper tracts and adequate bladder capacity.
required evacuation of clots through a panendoscope. Since the patient continued to bleed, she underwent suprapubic instillation of phenol in the urinary bladder under general anesthesia. During the procedure the incised edges of the bladder were grasped with Allis forceps and surrounded with packs to prevent spillage of phenol into surrounding tissues. A mixture of 30 cc. of 100 per cent phenol and 30 cc. glycerin was instilled into the bladder for exactly one minute. The mixture was then removed by suction and replaced with 60 cc. of90 per cent alcohol to neutralize the effect of the remaining phenol that was left in contact with the bladder urothelium. The alcohol was left in the bladder for exactly one minute and then aspirated. The bladder was then irrigated with profuse amounts of saline and closed leaving a 30 F Foley catheter, suprapubically, and the wound was drained. The patient’s urine was immediately clear postoperatively and remained so until her hospital discharge five days later. During that time she was placed on high-fluid intake, although no diuretic drugs were used. In February, 1974, six weeks postoperatively, the catheter was removed during which an intravenous pyelogram revealed good excretory function of both kidneys but a small bladder capacity (Fig. 1B). She had frequency of urination and nocturia which subsided gradually within four weeks. In August, 1974, the patient was completely asymptomatic; her urine
120
was clear, and an excretory urogram revealed normal upper tracts and an adequate bladder capacity (Fig. 1C). She could hold 300 cc. of urine with no difficulty. Comment Cyclophosphamide is an alkylating agent used in the treatment of leukemia, lymphomas, and selected solid tumors. It has been used as an immunosuppressive agent in organ transplantation, severe rheumatoid arthritis, and steroidresistant nephrosis in children. The toxic effect of cyclophosphamide produces symptoms of cystitis in the absence of infection. Its toxic metabolites on the other hand cause weakness in the vessel walls of the bladder and result in persistent hemorrhage. ’ Large doses of cyclophosphamide over a long period of time lead to fibrosis of the bladder musculature.’ Formaldehyde solution, commonly known as formalin, is a clear colorless liquid having a pungent irritating odor. It is miscible with alcohol and water. In 1969 Brown9 was the first to report the use of 10 per cent formalin instillation in the bladder for the treatment of hematuria. Since then formalin has been used in various concentrations. Phenol, also called phenic, phenylic, or carbonic acid, has a characteristic odor; and when undiluted it whitens and cauterizes skin and mucous membranes. It is highly soluble in alcohol and glycerin. Its instillation into the
UROLOGY
/ JANUARY
1975
i
VOLUMEV,
NCMRER
1
bladder of dogs results in destruction of the urothelium but does not extend into the muscular layer. lo Intravesical instillation of formalin has inherent dangers. The back diflirsion of formalin into the suburothelial capillaries and the open telangiectatic vessels leads to chemical cystitis, fixation of the bladder musculature, and results in a small contracted bladder. Formalin can also cause fixation of the intramural ureter leading to reflux or obstruction and subsequent hydronephrosis. When formalin has been used in concentrations of 4 per cent and 10 per cent for a thirty-minute contact time, destruction of the upper urinary tracts, papillary necrosis, l1 and bilateral ureterohydronephrosis have been reported. l2 Perforation of the bladder has also occurred after using formalin for fifteen minutes.13 Using the same concentration for ten minutes, marked reduction in bladder capacity and moderate amount of hydronephrosis has been reported in 3 of 4 patients. l4 It appears that the longer formalin is left in the bladder, the more chance of diffusion and occurrence of more fibrosis of the detrusor muscle exists. The recurrence of bleeding, on the other hand, is more apt to occur in using the diluted formalin than the concentrated form. This might require a second instillation of formalin;15,16 at times it has been used more than twice.11914’1’ Little attention has been paid to the use of phenol in the treatment of massive intractable hematuria. Vermooten, Peters, and JohnsonlO have used phenol in animal bladders successfully. The bladder capacity diminished temporarily and then returned to its normal size with complete epithelialization of the urothelium. There was no evidence of detrusor muscle destruction. It appears that the satisfactory laboratory results of phenol, absence of toxicity, and immediate effect in patients who are extremely ill and poor surgical risks are encouraging signs in using the acid. 232 West 25th Street Erie, Pennsylvania 16512 (DR. SUSAN)
UROLOGY / JANUARY1975 i
VOLUME V, NUMBER 1
References 1. COGGINS, P. R., FLUDIN, R. G., and ELSMAN, S. M.: Clinical pharmacology and preliminary evaluation of Cytoxan (cyclophosphamide), Cancer Chemother. Rep. 3: 9 (1959). 2. POOL, T. L.: Irradiation cystitis: diagnosis and treatment, Surg. Clin. North Am. 39: 947 (1959). 3. LAPIDER, J.: Treatment of delayed intractable
4.
5.
6.
7. 8.
9. 10.
11.
12.
13.
hemorrhagic cystitis following radiation or chemotherapy, J. Urol. 104: 707 (1970). PERSKY, L., and AUSTIN, G., JR.: ACTH in radiation cystitis, ibid. 70: 724 (1953). WOJEWSKI, A., and ROESSLER, R. : Treatment of postirradiation lesions of the urinary bladder, Bull. PoI. Med. Sci. Hist. 8: 100 (1965). HOLSTEIN, P., JACOBSON,K., PEDERSEN, J. F., and SORENSON, J. S. : Intravesical hydrostatic pressure treatment: new method for control of bleeding from the bladder mucosa, J. Urol. 109: 234 (1973). PHILIPS, F. S., etal.: Cyclophosphamide and urinary bladder toxicity, Cancer Res. 21: 1577 (1961). JOHANSON,W. W., and MEADOWS, D. C.: Urinary bladder fibrosis and telangiectasia associated with longterm cyclophosphamide therapy, N. Engl. J. Med. 284: 290 (1971). BROWN, R. B.: A method of management of inoperablecarcinomaofthe bladder, Med. J. Aust. 1: 23 (1969). VERMOOTEN,V., PETERS, P. C., and JOHNSON,D. E.: Treatment of papillomatosis of the bladder with phenol and glycerin: a clinical and laboratory study, J. Urol. 99: 588 (1968). KALISH, M., SILBER, S. J., and HERWIG, K. R.: Papillary necrosis result of intravesical instillation of formalin, Urology 2: 315 (1973). SPIRO, L. H., HECHT, H., HOROWI~, A., and ORKIN, . Formalin treatment for massive bladder hemor,Ldage, ibid. 2: 669 (1973). SCOTT, M. P., JR., MARSHALL, S., and LYON, R. P.: Bladder rupture following formalin therapy for hemorrhage secondary to cyclophosphamide therapy, ibid. 3: 364 (1974).
FAIR, W. R.: Formahn in the treatment of massive bladder hemorrhage: techniques, results, and complications, ibid. 3: 573 (1974). 15. FIRLIT, C. F.: Intractable hemorrhagic cystitis secondary to extensive carcinomatosis: management with formalin solution, J. Urol. 110: 57 (1973). 16. BARAKAT,H. A., JAVADPOUR,N., and BUSH, I. M.: Management of massive intractable hematuria, Urology 1: 351 (1973). 17. SHAH, B. C., and ALBERT, D. J.: Intravesical instillation of formalin for the management of intractable hematuria, J. Urol. 110: 519 (1973).
14.
121
OF BLADDER
IN
OF MASSIVE INTRACTABLE HEMATURIA M.D.
J. MARSH,
From the Department St. Vincent Hospital,
M.D. of Urology, The Hess Urology Erie, Pennsylvania
Clinic,
ABSTRACT - intractable hemowhagic cystitis secondary to radiation or cyclophosphamide (Cytoxan) therapy could lead to serious complications; however, intravesical instillation of phenol has reduced the dilemma of this life-threatening problem. We present a case of intractable hemorrhagic cystitis secondary to cyclophosphamide therapy treated with 100 per cent phenol with no untoward side effects. Since fomnalin instillation into the bladder has been associated with severe complications, phenol appears to be safer and more effective in the treatment of intractable hematuria, and, therefwe, its clinical trial is recommended.
Hemorrhagic cyclophosphamide cystitis could occur months or years following treatment. Usually the bleeding is painless, profuse, and life threatening, and the patient requires multiple blood transfusions. The complication was first reported by Coggins, Raudin, and Elsman in 1959. l The management of massive bladder hemorrhage due to radiation or cyclophosphamide carries with it a perplexing problem. The various methods of therapy have been achieved with limited success. They include cauterization of the bleeding points with silver nitrate’ or fulguration with electrocautery.3 Local or systemic administration of aminocaproic acid, prednisone,4 phytonadione (Aqua Mephyton), vitamin substance E (Tocopherol), 5 and estrogenic (Premarin) have been used in an attempt to control the bleeding. The Helmstein hydrostatic pressure balloon has also been used as an alternate method to surgical intervention.6 Bilateral internal iliac artery ligation has been used in uncontrollable bleeding with various success. Urinary diversion with or without cystectomy is occasionally required in extreme bleeding. In the poor-risk patients when other conservative measures have failed, phenol instillation is a lifesaving procedure and a substitute for surgical treatment.
UROLOGY
i
JANUARY 1975 / VOLUME V, NUMBER 1
Case Report A sixteen-year-old white girl was in a state of remission from acute lymphoblastic leukemia which had been diagnosed ten years previously. At that time she underwent an induction regimen followed with a maintenance regimen. Seven years ago she had a relapse for which she was given cyclophosphamide, methotrexate, vincristine, and prednisone for three years. Since that time she has had no evidence of bone marrow relapse of her disease. Although the patient was taking methotrexate and prednisone, she has had no cyclophosphamide for the last four years. The patient was admitted in November, 1973, because of gross profuse hematuria. Following her admission the patient continued to bleed. Her hematocrit dropped to 15, and she required 8 units of blood to maintain a hematocrit between 29 and 30. Her platelet count, activated plasma thromboplastin time, and prothrombin time were within normal limits. She had a white blood count of 4,200, and blood urea nitrogen of 14 mg. per 100 ml. Excretory urogram was within normal limits (Fig. 1A). Cystogram revealed adequate bladder capacity. Cystoscopy revealed difise telangiectasia and suburothelial capillary oozing. Fulguration with a ball-tipped electrode was unsuccessful. 3 On three occasions the bladder
119
FIGURE 1. Intravenous pyelogram: (A) showing normal findings on admission; (B) six weeks postoperatively showing normal upper tracts and small bladder capacity; {C) six months postoperatively showing normal upper tracts and adequate bladder capacity.
required evacuation of clots through a panendoscope. Since the patient continued to bleed, she underwent suprapubic instillation of phenol in the urinary bladder under general anesthesia. During the procedure the incised edges of the bladder were grasped with Allis forceps and surrounded with packs to prevent spillage of phenol into surrounding tissues. A mixture of 30 cc. of 100 per cent phenol and 30 cc. glycerin was instilled into the bladder for exactly one minute. The mixture was then removed by suction and replaced with 60 cc. of90 per cent alcohol to neutralize the effect of the remaining phenol that was left in contact with the bladder urothelium. The alcohol was left in the bladder for exactly one minute and then aspirated. The bladder was then irrigated with profuse amounts of saline and closed leaving a 30 F Foley catheter, suprapubically, and the wound was drained. The patient’s urine was immediately clear postoperatively and remained so until her hospital discharge five days later. During that time she was placed on high-fluid intake, although no diuretic drugs were used. In February, 1974, six weeks postoperatively, the catheter was removed during which an intravenous pyelogram revealed good excretory function of both kidneys but a small bladder capacity (Fig. 1B). She had frequency of urination and nocturia which subsided gradually within four weeks. In August, 1974, the patient was completely asymptomatic; her urine
120
was clear, and an excretory urogram revealed normal upper tracts and an adequate bladder capacity (Fig. 1C). She could hold 300 cc. of urine with no difficulty. Comment Cyclophosphamide is an alkylating agent used in the treatment of leukemia, lymphomas, and selected solid tumors. It has been used as an immunosuppressive agent in organ transplantation, severe rheumatoid arthritis, and steroidresistant nephrosis in children. The toxic effect of cyclophosphamide produces symptoms of cystitis in the absence of infection. Its toxic metabolites on the other hand cause weakness in the vessel walls of the bladder and result in persistent hemorrhage. ’ Large doses of cyclophosphamide over a long period of time lead to fibrosis of the bladder musculature.’ Formaldehyde solution, commonly known as formalin, is a clear colorless liquid having a pungent irritating odor. It is miscible with alcohol and water. In 1969 Brown9 was the first to report the use of 10 per cent formalin instillation in the bladder for the treatment of hematuria. Since then formalin has been used in various concentrations. Phenol, also called phenic, phenylic, or carbonic acid, has a characteristic odor; and when undiluted it whitens and cauterizes skin and mucous membranes. It is highly soluble in alcohol and glycerin. Its instillation into the
UROLOGY
/ JANUARY
1975
i
VOLUMEV,
NCMRER
1
bladder of dogs results in destruction of the urothelium but does not extend into the muscular layer. lo Intravesical instillation of formalin has inherent dangers. The back diflirsion of formalin into the suburothelial capillaries and the open telangiectatic vessels leads to chemical cystitis, fixation of the bladder musculature, and results in a small contracted bladder. Formalin can also cause fixation of the intramural ureter leading to reflux or obstruction and subsequent hydronephrosis. When formalin has been used in concentrations of 4 per cent and 10 per cent for a thirty-minute contact time, destruction of the upper urinary tracts, papillary necrosis, l1 and bilateral ureterohydronephrosis have been reported. l2 Perforation of the bladder has also occurred after using formalin for fifteen minutes.13 Using the same concentration for ten minutes, marked reduction in bladder capacity and moderate amount of hydronephrosis has been reported in 3 of 4 patients. l4 It appears that the longer formalin is left in the bladder, the more chance of diffusion and occurrence of more fibrosis of the detrusor muscle exists. The recurrence of bleeding, on the other hand, is more apt to occur in using the diluted formalin than the concentrated form. This might require a second instillation of formalin;15,16 at times it has been used more than twice.11914’1’ Little attention has been paid to the use of phenol in the treatment of massive intractable hematuria. Vermooten, Peters, and JohnsonlO have used phenol in animal bladders successfully. The bladder capacity diminished temporarily and then returned to its normal size with complete epithelialization of the urothelium. There was no evidence of detrusor muscle destruction. It appears that the satisfactory laboratory results of phenol, absence of toxicity, and immediate effect in patients who are extremely ill and poor surgical risks are encouraging signs in using the acid. 232 West 25th Street Erie, Pennsylvania 16512 (DR. SUSAN)
UROLOGY / JANUARY1975 i
VOLUME V, NUMBER 1
References 1. COGGINS, P. R., FLUDIN, R. G., and ELSMAN, S. M.: Clinical pharmacology and preliminary evaluation of Cytoxan (cyclophosphamide), Cancer Chemother. Rep. 3: 9 (1959). 2. POOL, T. L.: Irradiation cystitis: diagnosis and treatment, Surg. Clin. North Am. 39: 947 (1959). 3. LAPIDER, J.: Treatment of delayed intractable
4.
5.
6.
7. 8.
9. 10.
11.
12.
13.
hemorrhagic cystitis following radiation or chemotherapy, J. Urol. 104: 707 (1970). PERSKY, L., and AUSTIN, G., JR.: ACTH in radiation cystitis, ibid. 70: 724 (1953). WOJEWSKI, A., and ROESSLER, R. : Treatment of postirradiation lesions of the urinary bladder, Bull. PoI. Med. Sci. Hist. 8: 100 (1965). HOLSTEIN, P., JACOBSON,K., PEDERSEN, J. F., and SORENSON, J. S. : Intravesical hydrostatic pressure treatment: new method for control of bleeding from the bladder mucosa, J. Urol. 109: 234 (1973). PHILIPS, F. S., etal.: Cyclophosphamide and urinary bladder toxicity, Cancer Res. 21: 1577 (1961). JOHANSON,W. W., and MEADOWS, D. C.: Urinary bladder fibrosis and telangiectasia associated with longterm cyclophosphamide therapy, N. Engl. J. Med. 284: 290 (1971). BROWN, R. B.: A method of management of inoperablecarcinomaofthe bladder, Med. J. Aust. 1: 23 (1969). VERMOOTEN,V., PETERS, P. C., and JOHNSON,D. E.: Treatment of papillomatosis of the bladder with phenol and glycerin: a clinical and laboratory study, J. Urol. 99: 588 (1968). KALISH, M., SILBER, S. J., and HERWIG, K. R.: Papillary necrosis result of intravesical instillation of formalin, Urology 2: 315 (1973). SPIRO, L. H., HECHT, H., HOROWI~, A., and ORKIN, . Formalin treatment for massive bladder hemor,Ldage, ibid. 2: 669 (1973). SCOTT, M. P., JR., MARSHALL, S., and LYON, R. P.: Bladder rupture following formalin therapy for hemorrhage secondary to cyclophosphamide therapy, ibid. 3: 364 (1974).
FAIR, W. R.: Formahn in the treatment of massive bladder hemorrhage: techniques, results, and complications, ibid. 3: 573 (1974). 15. FIRLIT, C. F.: Intractable hemorrhagic cystitis secondary to extensive carcinomatosis: management with formalin solution, J. Urol. 110: 57 (1973). 16. BARAKAT,H. A., JAVADPOUR,N., and BUSH, I. M.: Management of massive intractable hematuria, Urology 1: 351 (1973). 17. SHAH, B. C., and ALBERT, D. J.: Intravesical instillation of formalin for the management of intractable hematuria, J. Urol. 110: 519 (1973).
14.
121
