The Effects of Topical Thiotepa on the Recurrence Rate of Superficial Bladder Cancers

Vol. 99, .Tune Printed in U.S.A.

THE JOURNAL OF UROLOGY

Copyright © 1D68 by The Williams & Wilkins Co.

THE EFFECTS OF TOPICAL THIOTEPA ON THE REGURRENCE RATE OF SUPERFICIAL BLADDER CANCERS J. EDWIN DREW

AND

VICTOR F. MARSHALL

From the Department of Surgery (Urology), James Buchanan Bracly Foundation, New York Hospilal and the Department of Surgery (Urology), Cornell University Medical College, New York, New York

Following the advent of chemotherapy for cancer, numerous reports appeared in the literature on the effectiveness of thiotepa (n,n', n" -triethylenethiophosphoramide) administered systemically or topically for cancer of the bladder.1-4 Since one of us (JED) had had some unconvincing therapeutic results with the topical application of this agent to existing bladder tumors, we decided to use it, prophylactically, in patients ,vith already demonstrated proneness to recurrence of this disease. A prospective study was designed to determine the effectiveness of this chemical in altering the rnsceptibility of bladder urothelium to carcinogenic influences. Up to initiation of this study (1962) we had no knowledge of this medication being used prophylactic:ally. Accordingly, patients with proven bladder cancer already surgically treated, who were free of tumor at the initiation of this attempt, were selected for chemo-prophylaxis. Contraindication~ for treatment included a white count of less than 4,000, a platelet count of less than 100,000 and/or bladder irritability. The protocol for application of thiotepa included: 1) white and differential and platelet counts, 2) bladder emptied by small catheter, 3) "'fJ•o'c1111t,11~ obtained for routine urinalysis and Papanicolaou cytology, 4) 60 mg. thiotepa in 30 Accepted for publication June 27, 1967. Read at :111nual meeting of American Urological Association, Inc., New York, New York, JVIay 29-June l, 1967. Supported in part by grant from JVIr. Ronald Lee. 1 Jones, H. C. and Swinney, J.: Thio-TEPA in the treatment of tmnonrs of the bladder. Lancet, 2: 615-618, 1961. 2 Bateman, J.C.: Chemotherapy of solid tumors with triethylene thiophosphoramicle. N cw Engl. J. Med., 252: 879-887, 195."5. 3 Oravisto, K. J.: Topical nse of thio-TEPA for Iumours of the bladder. Urol. Internat., 20: 23-28, 196.~. 4 Veenema, IL J., Dean, A. L., Jr., Roberts, M., Fingerhut, B., Chowhury, B. K. and Tarassoly, H.: Bladder car~inoma treated by direct instillation of thio-TEPA. J. Urol., 88: 60-63, 1962.

cc water diluent introduced into bladder and catheter removed, 5) bladder contents voided in 15 to 60 minutes and 6) procedure repeated every 1 to 4 weeks. The over-all goal was to evaluate the prophylactic effectiveness of thiotepa by comparing the post-treatment rate of bladder tumor recurrence with the known pre-treatment rate of recurrence. To this encl, the patient would in effect serve as his own control. Therefore, only patients with a history of having had on three separate occasions in an 18-month period, biopsyproven superficial low grade and low stage bladder cancer 5 would be included in this study. Hopefully this would eliminate from evaluation those patients who might ha,'e a single casual tumor and ordinarily not demonstiate recurrence regardless of prophylactic treatment. The experiment was limited to low grade and low stage tumors since they were more likely to have been surgically cured. 6 Therefore, a group of cases more apt to be free of tumor was provided on which to conduct the study. These selected patients, then, would be subjected to periodic bladder instillations of standard amounts of thiotepa in known concentration and volmne and for ~pecific periods for each exposure and at pre-determined intervals under reasonably satisfactory protective precautions. During the time that the prophylactic measures were being used, the patient would be under the care of his original referring urologist who would be carrying on concurrently whatever program. of over-all treatment he would ordinarily use and which he had already used in the pre-prophylactic phase. His pC'riotlic check-up cy,;toscopies and findings would be a partial basis for 5 J\Iarshall, V. F.: The relation of the preoperative estimate to the pathologic demonstration of the extent of vesirnl neoplasms. J. Urol., 68: 714, 19.52. 6 Jewett, H.J. and Strong, G. H.: Infiltrating carcinoma of the bladder: Relation of depth of penetration of the bladder wall to incidence of local extension and metastases. J. Urol., 55: 366, 1946.

740

TOPICAL THIOTEPA FOR BLADDER CANCER

our cum:lusions as to the effectiveness of the medication and, since he was doing the examination, whatever degree of bias the authors could bring to such an evaluation was eliminated. \n additional index of effectiveness of the medication was provided by obtaining a urine specimen for cytological classification by the Papanicolaou technique at each patient visit.7 Finding urine with a classifaation of more than 3 wao considered to be au indication that. tumor recurrence control had not becm effected. Awarene% of the potential toxicity of this ehemieal to the hemopoietic system possible from bladder mucosa required a white blood count and differena.~ well a, a platelet count at each visit The possibility of increased absorption from a non-intact mucosa dictated the suspension of the thiotepa in.,tillation, for a period orcli-narily cunsiderecl adequate for healing followan~ at whir:h either biopsy or fulgurntion had taken place. Ordinarily, the symptoms of bladder irritability and/or the routine urinaly~is ,rnre relied on to suggest the clurnJ.ion of such suspension of thiotepa instillation. (This """n,op,(j about l month's dein t·csumption of treatment.) Initially treatment ,n1s canied out 011 a oncefeeling that the urothelium, the exact rate of' regeneration of which was unknown, wonk! be exposed to the agent at least once during irs normal life Subsequent cxperie11ce that the effects of topical thiotepa. were longer lasting than originally thought and, the routine rate oI instillatiorn was decreased to l time every 2 weeks. This rate coincided 1.-ith what hematologists suggested was tlie regeneration time for 11latelets so that platelet depression was the cause of clela.y in reinstitution of treatment, then the 2-week inte1Yal would be a more witable time for periodic in~iillations. The frequency of instillatiorn was al.,o influenced by the apparent response to the therapy so that a.s long;rr periods of tumorfrer ancl insignificant Papanicola.ou urine reports cleveloprcl, the interYal between treatments was ru11;;v,,Acu to 1 per month. This scheme ha., 110\Y !JC e11 1tsr:cl sufiiciently long; 1o permit a partial re,·icw with the thonght 0

S. · St.udiccs on the chemotherapy of nrinary bladder. Studies on exfoliaof ca.ucer of the uriuary bladder. , 53: 108-L'"il, 1962. ,

of evaluating the result so far and perhaps pro· viding guidelines for the future development of the program. For this purpose, the first 25 casl,s in th is pro,;pect.i1·e study were selected and reviewed, nnd of that number, 6 have beeu considered suitable fm analysis and pre;;e11tation. In the 19 ca,es tha1 ,vere unsuitable for determination of the effectiveness of this program, a variety of causes for rejection were found: 8 cases were due to error iu the initial diaguosis--i.e. the and sta.ge of the tumor presumed to be presen( a.t the time of the initial treatment were irnwcurate, being later demonstrated to be of highnr grade and stage; 4 pa.tieuts were lost i-o 2 patients had such frequent or continuous depression of the white or platelet counts that .~uf ficient numbers of instillations were not eomplished; l patient failed to comply with the prngram, again resulting in an number of instillations being 4 patirn1ts had not been in the program long enough for the full 18 months of post-treatment period of obs('.tYation. Certain problems which interfered v,ith trninterruptecl treatment arose--the earliest looked for and only rarely noted wa.s lilaclcler "irritability". This invariably proved and as indicated usually responded t,o simple delay of the next instillation or ,dwricning the period of retention of the instillate. Another factor was white count or depression, and again clelay in reinstitution of the thiotepa allowed the blood to n'sume normal levels. Of 2 patients who lrnve }iad suflicicutly pro tracted blood picture abnormalities to re~ult in exdusio11 of the patient from one ul(,ima.tely died with extensive metastases marrow as well as other organs, and the other continues to ha,-e marrow but borw marrov1· smea.rn have failed to reveal evidence of meta.stasis. From a review of the (-\ pai ieuts treated table), one might point out, a. number of fn.r'lc which seem significant. KYH :'\o. Case l--V. man who had three prr-proph)·iac:tic: proven tumors that we could attest to in an !fl-month period hilt who had a history of numc,rntis previous tumors treated elsewhere, had a total uf 32 instillations in 202 weeks. He has been c:ystoscopieally tumor-free for 138 weeks and ha,

742

No. recurrences before treatment No. treatments Time-span of treatments (wks.) Time tumor-free cystoscopically (wks.) No. weeks insignificant Papanicolaou No. weeks since last treatment No. cystoscopies post-treatment Classification* Currently tumor-free

DRE1V AND MARSHALL Case 1

Case 2

Case 3

Case 4

Case 5

Case 6

3 32 202 138 145 88 11 A Yes

6 30 79 108 49 53 9 A No

6 24 69 92 92 25 4 A Yes

11 57 207 153 0 7 15

4 67 142 190 0

6 6 11 154 204 11 10 A Yes

B No

16

5 B Yes

* Classification: A-no recurrence of demonstrable tumor cystoscopically and no Papanicolaou higher than class 3 for at least 18 months. B-either demonstrable tumor cystoscopically or Papanicolaou smear higher than class 3 during similar period. C-provable recurrences less in number than during pre-treatment evaluation period. D-recurrence rate apparently not affected. had insignificant Papanicolaou determinations for 145 weeks. He is, at present, urologically asymptomatic and free of tumor. Case 2-S. M., NYH No. 921427 and case 4R. L., NYH No. 874956, are linked because they both had recurrences in the urethra, rather than in the bladder. Since the instillation was intravesical and not intraurethral, it may indicate that the treated area was protected and the non-treated area was not protected against recurrence. S. M., who had had 6 recurrences in the bladder prior to treatment with thiotepa, was given 30 instillations in 79 weeks. He had no recurrence in the bladder for 108 weeks, insignificant Papanicolaou determinations for 49 weeks and then a urethral tumor developed. R. L., known to have had 11 recurrences prior to treatment with thiotepa, received 57 instillations in 207 weeks. He was free of bladder tumor for 153 weeks but has since developed two urethral papillomas. The last lesion developed 16 weeks ago, despite the fact that after the first urethral lesion was found, attempts have been made to include the urethra in the instillation technique. Case 5-J. L., NYH No. 943001, a 65-yearold man with 4 recurrences prior to treatment with thiotepa was given 67 instillations in 142 weeks. He is now free of tumor on cystoscopy for a period of 190 weeks but the Papanicolaou smear has been consistently significant. Cystoscopy, within the past month, revealed two patches of erythema, both biopsied and reported as chronic cystitis only. Recent excretory urography does not suggest a urothelial tumor in the collecting system of either side of the upper tracts.

Case 6-S. T., NYH No. 555074, a 56-yearold woman with 6 recurrences prior to treatment with thiotepa, remained free of tumor for 154 weeks after 6 thiotepa instillations given during an 11-week period. Ten negative cystoscopies were carried out during the subsequent period, but she did not have recurrence of tumor until 154 weeks after her last thiotepa instillation. Case 3-N. G., NYH No. 749637, a 69-yearold man with 3 recurrences prior to treatment with thiotepa, received 24 instillations in 69 weeks. He was free of tumor or significant Papanicolaou finding 92 weeks after the institution of his treatment and 25 weeks after the last treatment. Two other cases, not included here because they fall short by 1 and 2 months of the 18month post-treatment time period but who had cystoscopies conducted within the past 3 months, remain tumor-free. One of these, G. F. (NYH No. 482751), a 65-year-old woman, had such rapidly recurring and numerous tumors that she was advised that cystectomy would probably be her best chance of cure. The patient fortunately fell into the hands of another urologist with sufficient time and patience to do numerous transurethral resections which finally left her grossly tumor-free, at which point she entered the program.. She received 12 treatments in 64 weeks and at cystoscopy recently was grossly tumor-free and has not had a significant Papanicolaou smear in 17 weeks. The other, G. J\'L (NYH No. 979621), a man with 4 pre-treatment recurrences, has had 30 instillations in a 72-week span and has been tumor-free for 62 weeks, and it is 18 weeks since his last significant Papanicolaou smear.

TOPICAL THIOTEPA FOR BLADDER CANCER DISCUSSION

Obviously the total group of cases evaluated is small and the suitable ones selected from the group are statistically less than significant. Dut, within these limitations, the results in the selected group do suggest that in fact the application of thiotepa in the manner described does apparently influence the recurrence rate of superficial bladder cancers. The study may further suggest that the effects of the topical application of thiotepa may be longer lasting than one might anticipate from. the IJreslm1ed regeneration rate of bladder urothelium. It further suggests that, after a timelap8e without treatment recurrence may be anticipated. An interesting and perhaps corroborative implication may be drawn from the 2 cases in which after a satisfactory period of apparent protection afforded the treated bladder urothelium, both patients had tumors in the untreated urethra mucosa. One of these had a second recurrence in the urethral mucosa even after attempts had been made to include this region in the treated area urethral instillation of the same water-based thiotepa solution. Perhaps a more viscous diluent would remain in contact with the urethral mu-cosa for a longer period and provide better protection. The exact significance of the continuing higher class Papanicolaou smears in case 5, in the face of no demonstrable frank tumor in the bladder urethra, or upper urinary tracts is not clear'. Perhaps in the areas of "chronic cystitis" as indicated by cystoscopic biopsy frank tumor would have developed later had they not been cystoscopically fulguratecl. If this modality of prophylaxis is to prove

743

effectual, then its modification should be directed to developing a technique calculated to use a. minimum of the drug for the briefest period of time of exposure and applied as infrequently as necessary to provide maximum protection against recurrence. If patient dehydration to insure minimal dilution of the intravesical instillate, or if alkalinization of the urine to enhance its effectiveness, or the use of DJVISO (dimethylsulfoxide) to promote absorption can enhance the over-all usefulness of thiotepa prophylaxis without nificantly increasing toxic side effects, then such modifications may ultimately become part of the method, but they have not been utilized. From the limited information already at hand, we feel that an expanded program of the type described is justified. One of the goals, as mentioned, should be determination of the minimal effective dosage schedule. From our ;,;tudy, we have not reached any firm recommendation. A further goal of an expanded program should be more careful screening of the patients admitted to the study to eliminate higher grade and stage tumors which, having a lower probability of surgical cure, would be less likely to provide a tumor-free bladder. CONCLUSIO~

Results of a prospective study of the effectiveness of thiotepa applied topically to bladder mucosa in altering the recurrence rate of superficial low-grade bladder tumors in a small group of patients with demonstrated susceptibility to that disease would suggest that this modality of prophylaxis may be useful and that a larger study directed to the determination of the minimal effective dose is indicated.