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Topical Application of Thio-Tepa* to Penile and Urethral Tumors
THE JOURNAL
O}P
Vol. 94, Sept. Printed in U.S.A.
UROLOGY
Copyright © 1965 by The Williams & Wilkins Co.
TOPICAL APPLICATION OF THIO-TEPA* TO PE="J"ILE AND URETHRAL TUMORS SHU F. CHEN Gt
AND
RALPH J. VEENEMA
From the Department of Urology, Francis Delafielcl Hospital, Colwnbia-Presb,tterian Medical Center, New York, New York
The conventional therapy of penile and urethral neoplasms is surgical removal including local excision or fulguration for the benign tumors and extensive, radical extirpation for malignant lesions. Recurrence after local excision 01' fulguration of penile condyloma accuminata or 1:apillomata is not uncommon. TABLE
1. Resiilts of topical thio-TEPA treatment in 6 patients !
Patient
Ag e
may occur with irn.proper use and the drng must be applied topically to each individual lesion. Since intravesical instillation of thio-TEP A has been effective in destroying some multiple, superficial, well-differentiated bladder tumors' we were encouraged to observe the effect of the drug topically on 11enile and urethral lesions.
Pathology
Location i
I
No. of
Result
Treatments
Followup
Side Effects
---
1. J.B.,
55
14572
Penis
Squamous cell ca., grade 3 Posterior Squamous cell ca., grade 3 Fossa na- Condylomata VlCUaccuminata laris
2. M. M., 16907
53
3. N. R., 16863
25
4. L. J., 18353
40
5. H. L., 18352
21
Penis
6. H. R., 17503
19
Penis
""""'I
Penis
I Condylomata accuminata
I
I
Partial penectomy; no recurrence 1 yr. Invasive tumor, died 1 yr. after pelvic perfusion No recurrence for 1 yr.
22
Destruction Occasional of surface local pain I tumor Part destruc- Local pain 17 tion superficially Mild anterior 8 I Completely urethritis, 1 destroyed wk. after last therapy 21 Almost com- Moderate skin plete dereaction struction
Condylomata accuminata
13
Partial destruction
Mild skin reaction
Condylomata accuminata
11
Partial destruction & necrosis
Moderate skin reaction
Circumcision and fulguration of tiny residual lesions. No recurrence for 2 mos. Unchanged since last treatment (2 mos.). Circumcision and of fulguration residual small lesions. No recurrence for 1 mo. '
Podo]Jhyllin resin is used topically with good results but erosion of the adjacent normal tissue Accepted for publication December 30, 1964. Read at annual prize essay contest, New York Section, American Urological Association, Inc., New York, New York, April 17-18, 1964. * Thio-TEP A: Triethylene thiophosphoramide, manufactured by Lederle Laboratories, Pearl River, New Yori~. t Present address. Edward J. Meyer Memorial Hospital, Buffalo, New York. 259
METHOD OF THERAPY
For penile tumors, the penis was bathed 1 or 2 times daily in thio-TEP A, 60 mg. dissolved in 60 cc of distilled water diluent contained in a cylindrical paper cup. All tumors were soaked in 1 Veenema, R. J., Dean, A. L., Jr., Roberts, NI., Fingerhut, B., Chowhury, B. K. and Tarassoly, H.: Bladder carcinoma treated by direct instillation of thio-TEPA. J. Urol., 88: 60-63, 1962.
260
CHENG AND VEENEMA
F:w. 1. J.B. No. 14572. Diagnosis: squamous cell carcinoma of penis. A, before treatment. B, after treat-
ment.
Fm. 2. L. J. No. 18353. Diagnosis: condylomata accuminata of penis. A, before treatment. B, after treatment. the solution for 2 hours. Spilling of the solution was avoided and the anterior scrotal skin was protected by vaseline gauze. White blood cells (WBC) and platelets were checked 3 times a week during treatment and for 2 weeks following therapy. The total dose given was empirically determined by observing the response of the lesion, the local reaction of the skin and the presence of leukopenia (below 3000
per cu. mm.) or thrombocytopenia (below 100,000 per cu. mm.). For urethral tumors, thio-TEPA suppositories (15 mg. each) were inserted into the urethra once daily. The patient was instructed not to void for 2 hours. If skin reaction occurred as a result of the treatment 1 per cent thio-TEPA solution was injected directly into the tumor once daily
APPLICATION OF THIO-TEPA TO PENILE AND URETHRAL TUMORS
t
261
FIG. 3. L. J. No. 18353. Diagnosis: condylomata accuminata of penis, biopsy, microscopic section. A, before treatment. B, after treatment. rather than bathing the entire penis. The amount of thio-TEPA solution used for injection depended upon the size of the tumor. Injections were made at multiple sites in the tumor and in the base.
RESULTS
Six patients with penile and urethral tumors were treated (table 1). There were 2 patients with squamous cell carcinoma, one located on the penis, the other in the posterior urethra. Both
262
CHENG AND VEENEMA
patients refused surgical intervention and were given a trial of topical thio-TEP A. In both cases there was superficial destruction of carcinoma but no effect on the invasive tumor tissue (fig. 1). The diagnosis in the remaining 4 patients was condylomata accuminata. N. R. had multiple small papillomatous growths located in the fossa navicularis of urethra which were completely destroyed after 8 suppositories. No recurrence has been noted for a year. L. J. had multiple condylomata at the prepuce and coronal sulcus. These lesions responded dramatically to 21 soaking treatments (figs. 2 and 3). Subsequently a biopsy showed acanthotic changes of skin. Histologic study revealed acanthotic, parakeratotic and necrotic changes and a decrease of the cellular layer of the lesion (fig. 3, B). The nuclei of the epithelial cells showed swelling which was considered to be due to the chemotherapeutic effect. H. L. had condylomata at the ventral and H. R., dorsal aspects of the glans penis. Both patients showed flattening and decrease of the size of the lesion after 10 treatments which greatly facilitated subsequent circumcision and excision of the residual lesions. LOCAL REACTION AND GENERAL TOXICITY
Of the 6 patients studied, four had moderate local skin or mucosal reaction with resultant pain, burning, redness and swelling of the prepuce and adjacent skin. The treatment had to be discontinued in 2 patients (cases 4 and 6) because of the swelling of the prepuce to the extent that a dorsal slit had to be done. Local reaction usually subsided 7 to 10 days after treatment was stopped. There was no evidence of systemic toxicity in these 6 patients but there was mild depression of the "\VBC count.
DISCUSSION
Topical application of thio-TEPA to penile and urethral neoplasms yielded notable results. The tumors became flattened and decreased in size and sonie small condylomata and papillomata (1 to 2 mm. in diameter) disappeared. The invasive carcinomas of the penis and the urethra did not respond well to topical chemotherapy alone although the exophytic portion of the tumor was destroyed. In extensive multiple condylomata, the number and size were sufficiently reduced to permit re1noval of the remaining lesion by excision or fulguration. The wound healing was not impaired. 2 • 3 Histologic study revealed acanthotic, parakerototic and necrotic changes and a decrease of the cellular layer of the epithelium. The nuclei of the epithelial cells showed swelling which was considered to be due to the chemotherapeutic effect. Observation thus far would indicate that a program of 60 mg. thio-TEP A in 60 cc distilled water once daily for penile soaking and 15 mg. thio-TEP A for urethral suppository for 2 hours daily is safe. Local skin or mucosa] reaction usually does not occur before 10 treatments. In general, patients tolerated the therapy well. SUMMARY
The effects of topical thio-TEPA were observed in 6 patients with penile and urethral tumors. Following treatment, all tumors showed flattening and a decrease in size; small lesions (1 to 2 mm. in diameter) were completely destroyed. 2 Rath, H. and Enquist, I. F.: The effect of thioTEPA on wound healing. AMA Arch. Surg., 79: 812-814, 1959. 3 Conn, J. H., Leb, S. M. and Hardy, J. P.: Effect of nitrogen mustard and thio-TEPA on wound healing. Surg. Forum, 8: 80, 1957.
O}P
Vol. 94, Sept. Printed in U.S.A.
UROLOGY
Copyright © 1965 by The Williams & Wilkins Co.
TOPICAL APPLICATION OF THIO-TEPA* TO PE="J"ILE AND URETHRAL TUMORS SHU F. CHEN Gt
AND
RALPH J. VEENEMA
From the Department of Urology, Francis Delafielcl Hospital, Colwnbia-Presb,tterian Medical Center, New York, New York
The conventional therapy of penile and urethral neoplasms is surgical removal including local excision or fulguration for the benign tumors and extensive, radical extirpation for malignant lesions. Recurrence after local excision 01' fulguration of penile condyloma accuminata or 1:apillomata is not uncommon. TABLE
1. Resiilts of topical thio-TEPA treatment in 6 patients !
Patient
Ag e
may occur with irn.proper use and the drng must be applied topically to each individual lesion. Since intravesical instillation of thio-TEP A has been effective in destroying some multiple, superficial, well-differentiated bladder tumors' we were encouraged to observe the effect of the drug topically on 11enile and urethral lesions.
Pathology
Location i
I
No. of
Result
Treatments
Followup
Side Effects
---
1. J.B.,
55
14572
Penis
Squamous cell ca., grade 3 Posterior Squamous cell ca., grade 3 Fossa na- Condylomata VlCUaccuminata laris
2. M. M., 16907
53
3. N. R., 16863
25
4. L. J., 18353
40
5. H. L., 18352
21
Penis
6. H. R., 17503
19
Penis
""""'I
Penis
I Condylomata accuminata
I
I
Partial penectomy; no recurrence 1 yr. Invasive tumor, died 1 yr. after pelvic perfusion No recurrence for 1 yr.
22
Destruction Occasional of surface local pain I tumor Part destruc- Local pain 17 tion superficially Mild anterior 8 I Completely urethritis, 1 destroyed wk. after last therapy 21 Almost com- Moderate skin plete dereaction struction
Condylomata accuminata
13
Partial destruction
Mild skin reaction
Condylomata accuminata
11
Partial destruction & necrosis
Moderate skin reaction
Circumcision and fulguration of tiny residual lesions. No recurrence for 2 mos. Unchanged since last treatment (2 mos.). Circumcision and of fulguration residual small lesions. No recurrence for 1 mo. '
Podo]Jhyllin resin is used topically with good results but erosion of the adjacent normal tissue Accepted for publication December 30, 1964. Read at annual prize essay contest, New York Section, American Urological Association, Inc., New York, New York, April 17-18, 1964. * Thio-TEP A: Triethylene thiophosphoramide, manufactured by Lederle Laboratories, Pearl River, New Yori~. t Present address. Edward J. Meyer Memorial Hospital, Buffalo, New York. 259
METHOD OF THERAPY
For penile tumors, the penis was bathed 1 or 2 times daily in thio-TEP A, 60 mg. dissolved in 60 cc of distilled water diluent contained in a cylindrical paper cup. All tumors were soaked in 1 Veenema, R. J., Dean, A. L., Jr., Roberts, NI., Fingerhut, B., Chowhury, B. K. and Tarassoly, H.: Bladder carcinoma treated by direct instillation of thio-TEPA. J. Urol., 88: 60-63, 1962.
260
CHENG AND VEENEMA
F:w. 1. J.B. No. 14572. Diagnosis: squamous cell carcinoma of penis. A, before treatment. B, after treat-
ment.
Fm. 2. L. J. No. 18353. Diagnosis: condylomata accuminata of penis. A, before treatment. B, after treatment. the solution for 2 hours. Spilling of the solution was avoided and the anterior scrotal skin was protected by vaseline gauze. White blood cells (WBC) and platelets were checked 3 times a week during treatment and for 2 weeks following therapy. The total dose given was empirically determined by observing the response of the lesion, the local reaction of the skin and the presence of leukopenia (below 3000
per cu. mm.) or thrombocytopenia (below 100,000 per cu. mm.). For urethral tumors, thio-TEPA suppositories (15 mg. each) were inserted into the urethra once daily. The patient was instructed not to void for 2 hours. If skin reaction occurred as a result of the treatment 1 per cent thio-TEPA solution was injected directly into the tumor once daily
APPLICATION OF THIO-TEPA TO PENILE AND URETHRAL TUMORS
t
261
FIG. 3. L. J. No. 18353. Diagnosis: condylomata accuminata of penis, biopsy, microscopic section. A, before treatment. B, after treatment. rather than bathing the entire penis. The amount of thio-TEPA solution used for injection depended upon the size of the tumor. Injections were made at multiple sites in the tumor and in the base.
RESULTS
Six patients with penile and urethral tumors were treated (table 1). There were 2 patients with squamous cell carcinoma, one located on the penis, the other in the posterior urethra. Both
262
CHENG AND VEENEMA
patients refused surgical intervention and were given a trial of topical thio-TEP A. In both cases there was superficial destruction of carcinoma but no effect on the invasive tumor tissue (fig. 1). The diagnosis in the remaining 4 patients was condylomata accuminata. N. R. had multiple small papillomatous growths located in the fossa navicularis of urethra which were completely destroyed after 8 suppositories. No recurrence has been noted for a year. L. J. had multiple condylomata at the prepuce and coronal sulcus. These lesions responded dramatically to 21 soaking treatments (figs. 2 and 3). Subsequently a biopsy showed acanthotic changes of skin. Histologic study revealed acanthotic, parakeratotic and necrotic changes and a decrease of the cellular layer of the lesion (fig. 3, B). The nuclei of the epithelial cells showed swelling which was considered to be due to the chemotherapeutic effect. H. L. had condylomata at the ventral and H. R., dorsal aspects of the glans penis. Both patients showed flattening and decrease of the size of the lesion after 10 treatments which greatly facilitated subsequent circumcision and excision of the residual lesions. LOCAL REACTION AND GENERAL TOXICITY
Of the 6 patients studied, four had moderate local skin or mucosal reaction with resultant pain, burning, redness and swelling of the prepuce and adjacent skin. The treatment had to be discontinued in 2 patients (cases 4 and 6) because of the swelling of the prepuce to the extent that a dorsal slit had to be done. Local reaction usually subsided 7 to 10 days after treatment was stopped. There was no evidence of systemic toxicity in these 6 patients but there was mild depression of the "\VBC count.
DISCUSSION
Topical application of thio-TEPA to penile and urethral neoplasms yielded notable results. The tumors became flattened and decreased in size and sonie small condylomata and papillomata (1 to 2 mm. in diameter) disappeared. The invasive carcinomas of the penis and the urethra did not respond well to topical chemotherapy alone although the exophytic portion of the tumor was destroyed. In extensive multiple condylomata, the number and size were sufficiently reduced to permit re1noval of the remaining lesion by excision or fulguration. The wound healing was not impaired. 2 • 3 Histologic study revealed acanthotic, parakerototic and necrotic changes and a decrease of the cellular layer of the epithelium. The nuclei of the epithelial cells showed swelling which was considered to be due to the chemotherapeutic effect. Observation thus far would indicate that a program of 60 mg. thio-TEP A in 60 cc distilled water once daily for penile soaking and 15 mg. thio-TEP A for urethral suppository for 2 hours daily is safe. Local skin or mucosa] reaction usually does not occur before 10 treatments. In general, patients tolerated the therapy well. SUMMARY
The effects of topical thio-TEPA were observed in 6 patients with penile and urethral tumors. Following treatment, all tumors showed flattening and a decrease in size; small lesions (1 to 2 mm. in diameter) were completely destroyed. 2 Rath, H. and Enquist, I. F.: The effect of thioTEPA on wound healing. AMA Arch. Surg., 79: 812-814, 1959. 3 Conn, J. H., Leb, S. M. and Hardy, J. P.: Effect of nitrogen mustard and thio-TEPA on wound healing. Surg. Forum, 8: 80, 1957.