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Radical Cystectomy without Radiation Therapy for Carcinoma of the Bladder
0022-5347/84/1313-04 77$02.00/0 Vol. 131, March
THE Jou&NAL OF UROLOGY
Copyright © 1984 by The Williams & Wilkins Co.
Printed in U.S.A.
RADICAL CYSTECTOMY WITHOUT RADIATION THERAPY FOR CARCINOMA OF THE BLADDER JAMES E. MONTIE,* RALPH A. STRAFFON
AND
BRUCE H. STEWARTt
From the Department of Uro/,ogy, Cleveland Clinic Foundation, Cleveland, Ohio
ABSTRACT
A review of a 20-year experience of radical cystectomy identified 99 patients who had not undergone preoperative radiation therapy. The 5-year survival rate of patients with clinical high stage lesions (T3, T4a) was 40 per cent. Life-table analyses showed that survival rate in this group was comparable with that reported for other groups receiving preoperative radiation therapy. The pelvic recurrence rate was 9 per cent and was frequently related to either urethral or nodal disease. Unquantifiable patient selection factors may well limit the reliability of these results. Radical cystectomy is now an accepted means of extirpating bladder cancer that cannot be controlled by endoscopic resection. Although there is little disagreement on this rather general indication, the timing of the application of cystectomy may vary widely and there is also considerable debate relative to the value of preoperative radiation therapy or regional lymphadenectomy. Comparative analysis of data from studies in the literature is hazardous because of differences in data analysis, patient selection and, more importantly, actual therapeutic benefit of various protocols. However, the most controversial issue is preoperative radiation therapy, although by the late 1970s some form was being used in most major centers. A survey of 150 practicing urologists attending a Cleveland Clinic postgraduate course in 1981 disclosed that 80 per cent were using some form of preoperative radiotherapy. However, several urologists at the Cleveland Clinic do not use preoperative radiation therapy routinely and, thus, a relatively unusual, contemporary series of patients treated by radical cystectomy alone can be studied. The survival, operative mortality and pelvic recurrence rate have been examined. MATERIALS AND METHODS
Between 1960 and 1979, 117 of 157 radical cystectomies (removal of the bladder and prostate with the plane of dissection along the pelvic sidewalls) were performed by 4 of 11 different urologists. Preoperative radiation therapy and intraoperative lymphadenectomy were left to the discretion of the operating surgeons and no systematic protocol was used. All patients were followed for at least 18 months. Survival data were analyzed by the Cutler-Ederer life-table method unless otherwise noted. 1 The histologic grade of the tumor was noted but it was not discussed because of inconsistent grading criteria during the years and lack of specific review of the pathologic material. A review of other potentially significant variables, such as endothelial space invasion or growth pattern of the tumor (that is sessile versus papillary) was not feasible and this limitation is acknowledged. 2 PATIENT POPULATION
The various radiation therapy groups are listed in table 1. The 90 patients who received no radiation therapy to the pelvis at any time form the basis of this report. In some analyses the 9 patients with postoperative radiation therapy were included Accepted for publication September 16, 1983. *Requests for reprints: Department of Urology, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, Ohio 44106. tDeceased 1983.
in the group who received no radiation therapy to minimize selection bias introduced when patients with poor pathologic characteristics were chosen for postoperative radiation therapy. Inclusion of these patients did not alter the results significantly. Clinical stage was obtained by a review of preoperative biopsies, endoscopic findings and bimanual examination under anesthesia. Histologic proof of muscle invasion, available in almost all instances, enabled the assignment of a high clinical stage. In a few cases high grade sessile lesions with a palpable mass were classified as high stage even without histologic proof of muscle invasion. The clinical stage, defined by the tumor, node and metastasis system, was examined within each group to ascertain any bias (table 2). 3 Although the planned preoperative radiation therapy group had been treated primarily by 1 surgeon, data from this group also showed a tendency for higher stage lesions (36 per cent T3a, T3b, T4a without radiation therapy versus 56 per cent T3a, T3b, T4a in planned preoperative radiation therapy). However, the relative frequency of T2 to T4a lesions in both groups is similar. SURVIVAL STAGE AND TREATMENT
Relapse rates and survival times have been analyzed in several different groups to allow comparisons with previously reported series. Until 1975 approximately 4 cystectomies were performed each year. From 1975 through 1979 approximately 20 cystectomies were undertaken yearly. Thus, if the total (157 cystectomies) is analyzed the results are skewed toward those with a shorter followup period. For this reason separate analyses were prepared on patients operated on before 1976. The over-all survival of the various radiation therapy groups is shown in figure 1. The relative frequency of low and high, clinical and pathological stages in the group without irradiation and the definitive irradiation groups is similar. In the planned preoperative radiation therapy group interpretation of the results is limited by the different regimens used, the slightly higher percentage of high stage lesions and the inordinate operative morbidity-contributed largely by a group of 8 patients who received a high preoperative dose regimen (2,400 rad in 3 days to the entire pelvis)-and was not possible. A lifetable analysis of the survival of 90 patients without radiation therapy and 9 with postoperative radiation therapy relative to clinical stage is shown in figure 2 and table 3. The estimated 5-year survival rate of patients with high stage (T2, T3, T4a) lesions is approximately 60 per cent. A life-table analysis relative to pathologic stage also is shown in table 3. The most reliable data are those accumulated from the patients followed for ~5 years, that is patients undergoing cystectomy between 1960 and 1975. Among the 24 patients with T3a, T3b, T4a disease who received no radiation therapy or had postoperative radiation therapy the cumulative proportion sur-
477
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MONTIE, STRAFFON AND STEW ART
TABLE
1. Treatment groups and radiation therapy, 1960 to 1979 No. Pts.
No pelvic radiation therapy at any time Postop. radiation therapy Previous definitive radiation therapy (salvage cystectomy) Planned preop. radiation therapy Total
90 9
34 23 156*
* In 1 patient radiation therapy status is unknown. TABLE 2.
Relative frequency of clinical stage of radiation therapy groups Radiation Therapy Previous Definitive No.(%)
None No.(%) Total No. pts. Clinical stage:* Ta, Tl, TIS T2, T3, T4a T3, T4a
Planned Preop. No.(%)
Postop. No.(%)
90
34
23
9
34 (38) 55 (62) 32 (36)
12 (36) 21 (64) 14 (42)
7 (30) 16 (70) 13 (56)
1 (11) 8 (89) 7 (78)
viving 60 months after surgery is 0.40. Of the 14 deaths during this period 11 were due to bladder cancer. Of the 23 patients who had histologic stage P3a, P3b, P4a, Nx or No lesions without radiation therapy or with postoperative radiation therapy the cumulative proportion surviving 60 months is 0.57 (fig. 3). Of the 10 deaths in this group 8 were due to bladder cancer. Life-table analyses of the survival rate of clinical high stage lesions (T3a, T3b, T4a) comparing 1960 to 1975 with 1976 to 1979 are shown in figure 4. A later analysis to determine if the apparent improved survival rate persists will be necessary when longer followup of the more recent group is available. The operative mortality in the group from 1960 to 1975 receiving no radiation therapy was 9 per cent (4 of 46) and from 1976 to 1979 it was 5 per cent. In 1980 to 1981 the operative mortality for all cystectomies was 1 in 63 cases. This decrease in operative mortality and, undoubtedly, morbidity may contribute to the improved survival figures. PELVIC LYMPHADENECTOMY AND PELVIC RECURRENCES
* Ta-papillary noninvasive carcinoma. Tl-microscopic invasion of lamina propria. TIS-carcinoma in situ. T2-microscopic invasion of superficial muscle. T3a-microscopic invasion of deep muscle and induration palpable. T3b-invasion in perivesical fat and induration or mass palpable. T4a-invasion of substance of prostate (microscopically proved), uterus or vagina. 3
Pelvic lymphadenectomy was defined as a formal dissection with the following margins: superior limit was the bifurcation of the common iliac artery, lateral limit was the genitofemoral nerve, inferior limit was the inguinal ligament and medial limit was the perivesical fat; obturator nodes were included in this 1.0 C)
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Life-table analysis relative to clinical and pathological stages of 90 patients without radiation therapy and 9 patients with postoperative radiation therapy between 1960 and 1979
Clinical Stage Death of any cause: No. pts. Death No. censored(%)* Death of bladder Ca: No. pts. Death No. censored(%)* Pathologic Stage Death of any cause: No. pts. Death No. censored(%)* Death of bladder Ca: No. pts. Death No. censored(%)*
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dissection. Of the 157 ,,~"'~""U pelvic performed in 61 (39 per including 8 per nodes. Of the 90 pwv,-,,vu without radiation 37 per cent) underwent node dissection and 14 per cent of these had positive nodes. No effect on survival or could be identified from the presence or absence of node dissection. were included with the no radiation Of these 99 1--·wv,v,,vu per experienced pelvic recurrences (2 of 9 with postoperative radiation therapy and 7 of 90 without radiation therapy). Of these recurrences 4 were likely ""''-v,,wu to urethral recurrences and 2 of 9 patients did not have a node u""'"'u,,uu. Of the 34 patients undergoing a salvage cystectomy 9 (26 per cent) had a pelvic recurrence. DISCUSSION
A historical perspective on radical cystectomy as the primary mode of therapy of advanced bladder cancer is important in evaluating the data presented herein. The feasibility of widespread application of a radical cystectomy began with the development of the ileal conduit by Bricker in 1950 as a satisfactory means of urinary diversion. Previously, this operation often was performed in several stages and was associated
rw,,c.- ,~n,,c, of 15 to 40 per {'.Srlto At that time Leadbetter and Cooper estimated that 50 pe:r cent of patients who survived these operations later died of bladder cancer. 4 In the 1950s Leadbetter and Cooper; and Whitmore and l\farshall 5 included a regional lymph node dissection in an attempt to impr-ove local control and, more importantly, overall survival. Unfortunately, this logical approach did not result in fewer cancer deaths. However, the operative mortality was consistently reduced to approximately 15 per cent. In 1959 Whitmore introduced a preoperative radiation therapy regimen consisting of 4,000 rad in 4 weeks followed by cystectomy and lymph node dissection approximately 6 weeks later. Subsequent analyses of the groups with and without radiation therapy demonstrated a decrease in pelvic recurrences (37 per cent without versus 24 per cent with preoperative radiation therapy) and an increase in the 5-year survivaLrate in patients with P3 lesions from 20 per cent without to 38 per cent with preoperative radiation therapy. 6 In 1966 the preoperative regimen was reduced to 2,000 rad in 5 days through limited portals with immediate cystectomy. This change was introduced primarily to provide increased convenience for the patient, with a presumed similar biologic effect. In 1971 the same radiation dose was maintained but treatment portals were enlarged to include the entire pelvis. The results of these last 2 protocols showed a gradual decrease in the pelvic recurrence rate (20 per cent 2,000 rad small field versus 17 per cent 2,000 rad large field) and similar 5-year survival figures for P3 lesions (58 per cent 2,000 rad small field versus 43 cent 2,000 rad large field). 6 During the same 2 randomized trials were performed, comparing definitive radiation therapy versus a long course of preoperative radiation therapy. The M. D. Anderson trial from 1964 to 1970 evaluated the 5,000 rad preoperative regimen for patients with clinical stage T3 disease and found a projected 5year survival rate of 51 per cent for the preoperative gToup versus 13 per cent for definitive radiation therapy alone. 7 A British study sponsored by the Institute of Urology in London from 1966 to 1975 evaluated 4,000 rad preoperative radiation therapy versus 6,000 rad definitive radiation therapy in patients with clinical stage T3 cancer. The 5-year survival rate for the preoperative radiation therapy and cystectomy group was 44 per cent compared to 24 per cent for those who received 8 radiation These 3 series the main evidence establishing preoperative radiation as standard treatment for high stage bladder cancer. Preoperative radiation therapy and cystectomy are better than the earlier series of cystectomy alone at Iv!:emorial Sloan-Kettering Cancer Center and are better than definitive radiation ,.h,,,..,r"' The series in recent years using preoperative radiation cystectomy have confirmed 5-year survival rates of 35 to 50 cent in ;,u.a,~uo~ with T2, T3 iesions. 9 - 17 A nro;:,no:m:s cases downstaged to Po has been a and. consistent feature in these studies. A trial nrns,c.,~D"M"= rmPrn"'!P1">!tme> 1"h,>r9,nu versus cystectomy alone ~·"~'~W to obtain. Prout organized a national, randomized tria.1 from 1964 to comparing 4,000 rad preoperative radiation therapy to cystectomy alone. 18 The difficulties encountered in performing this study are evident the observation that of 246 patients randomized to receive preoperative radiation therapy and cystectomy 123 (50 per cent) actually completed the protocol. Similarly, of 229 patients randomized to receive cystectomy alone only 133 (58 per cent) completed the treatment. Nevertheless, of 244 evaluable patients with clinical stage T2, T3 lesions the 5-year survival rate without radiation therapy was 31 per cent versus 37 per cent for the preoperative radiation therapy group. Although a survival advantage was evident for patients with Po lesions (obtained by either transurethral resection or preoperative radiation therapy), no over-all significant improvement was seen for the preoperative radiation therapy group as a whole. 9
480
MONTIE, STRAFFON AND STEW ART
Our study represents 1 of the largest contemporary series of patients with bladder cancer treated at a single institution by radical cystectomy without any preoperative radiation therapy. These data neither confirm nor deny the value of preoperative radiation therapy. However, they can underscore the questionable validity of using data from the 1950s as a control group for cystectomy without radiation. Before specifically comparing these data with published series, the problem of patient selection as a major unquantified variable also must be addressed. In the early years of the study (1960 to 1975) planned preoperative radiation therapy was used in only 6 patients and, thus, no effect is likely to be detected. At no time was definitive radiation therapy recommended as primary therapy unless extenuating circumstances were present. However, it is impossible to determine in a retrospective analysis such as this the number of patients who may have been deemed inoperable on the basis of a clinical examination only, without a laparotomy, and who thus never had a cystectomy. If, indeed, such a conservative approach was used widely patients with larger lesions may not have undergone an operation. The relatively low percentage of high stage (T3a, T3b, T4a) lesions (36 per cent) could support this interpretation, although no conscious bias in this direction was acknowledged by the involved surgeons. An alternative explanation for the low percentage of high stage lesions was the conscious effort to perform cystectomy at an earlier date in those patients who were believed to be at high risk for lethal tumors (that is high grade lesions). This could also skew the results to some degree. The 14 per cent incidence of positive nodes in patients undergoing a formal pelvic lymphadenectomy is lower than that reported in recent series and may support some element of patient selection. 19• 20 This figure could also just as simply reflect the diligence of the pathologist in sampling the nodes. Multiple methods of data management in various published series hamper comparative studies. The raw data from this review have been studied in several different ways to allow comparisons. The M. D. Anderson experience includes a regimen of 5,000 rad preoperative radiation therapy to relatively small pelvic portals followed by total cystectomy without lymphadenectomy. Chan and Johnson examined the time to relapse in clinical stage T3 lesions (including Bl, B2 and C lesions) and their data are shown in figure 5. 21 In a more recent analysis the survival rate of patients with T2 and T3 lesions was examined and found comparable to the present data in figure 6. 22 No appreciable difference can be detected between survival or time to relapse in these series. While the use of a long course of preoperative radiation therapy may permit segregation into low and high risk groups on the basis of the presence or absence of residual carcinoma in the specimen, this seems an inordinate price to pay if no real improvement in over-all survival is demonstrated over cystectomy without radiation therapy. In the Memorial Sloan-Kettering Cancer Center experience from 1971 to 1974 Smith and associates evaluated 2,000 rad to a large pelvic field in 5 days before cystectomy with lymphadenectomy.6 The 5-year survival rate for clinical high stage lesions (T3a, T3b) was 40 per cent (52 patients). The result for our series without preoperative radiation therapy was 41 per cent (24 patients). It is important to note that the internal comparison done by the Memorial Sloan-Kettering Cancer Center shows that from 1949 to 1959, 48 per cent of patients with cystectomy alone died of bladder cancer, whereas 46 per cent of patients treated with 2,000 rad preoperatively to a large pelvic field died of bladder cancer from 1971 to 1974. The hospital mortality was 14 per cent in the early group and only 2 per cent in the latter group. This does not imply any fundamental improvement in the over-all control of the disease but it does indicate a definite improvement in the delivery of the treatment. Contributing to the confusion regarding the value of preop-
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erative radiation therapy is the small number of studies from a concurrent period that evaluate cystectomy without radiation therapy. Pearse and associates reviewed data on 52 patients with T2 to T4 lesions who underwent radical cystectomy between 1953 and 1963. 23 With an operative mortality of 19 per cent, the 5-year survival rate was 38 per cent. Kutscher and associates reported an estimated 5-year survival of approximately 40 per cent for 23 patients with stage P2, P3 lesions but
of these ua.,c,eJ" '" received preopel'a24 Pr,. recent :report IV'IathnI' and asso-tive radiation ciates on 20 µacuv,,,;,;,e- stage P3 lesions showed survival rate of 50 cent. 25 Duke Medical Center "'"'""'''"y'""' Bredael and associates recorded a total of 100 between 1964 and 1973 who received no radiation before or after cystectomy. 26 The 5--year survival rate of 34 patients with pathologic P3 lesions was 29 per cent, compared to 44 per cent for 74 patients with P3 lesions who received 4 different types of preoperative or postoperative radiation therapy regimens. However, this comparison may not be valid because no discussion of selection criteria for either regimen is presented and the number of patients who may have been given planned preoperative radiation therapy but who later did not receive cystectomy because of metastases, medical contraindications, patient refusal or change in policy is not discussed. In the large series by Wallace and Bloom of planned long course (4,000 rad) preoperative radiation therapy 21 per cent of the patients randomized to receive this treatment never underwent cystectomy and elimination of these patients from analyses of results constitutes a strong selection bias. 27 Our study conflicts with an earlier report from this same institution that claimed a higher complication rate in patients receiving preoperative radiation therapy or node dissection. 28 A review of a larger number of patients with more precise stratification of the type of preoperative radiation therapy, clinical and pathologic stage, and type of lymph node dissection has not confirmed the original observations. The rationale of preoperative radiation th,,r"n" is based on 2 principles. First, cells expressed into the circulation during the operative procedure may be less viable and, as a result, there may be less distant metastases. However, clinical data do not support this finding. Approximately 50 per cent of the patients die of distant disease, a figure similar to that reported in the 1950s, although pelvic recurrences have actually decreased. Second, macroextensions or microextensions of the cancer that may not be encompassed in the surgical specimens can be controlled by preoperative radiation therapy. Support for this contention is based on data showing an expected pelvic recurrence rate with cystectomy alone of 30 to 40 per cent and a recurrence rate of 5 to 20 per cent with preoperative radiation th1°;rnrm 4 •6 • 18 • 19 Our data revealed that relapse in the pelvis was evident in 9 per cent. Prout and associates described 127 cases without preoperative radiation therapy from 1967 to 1975 and identified a pelvic recurrence rate of 7 cent. 2 Undoubtautopsy information on all n
2. Prout, Go R., Jr. Griffin) P. P. and Shipley, VV. U.: Bl2.dde:r '"'"''''"c disease. 43:, 2532, 1979. 3. Beahrs, 0. H. for Staging of Cancer. ~,,,p••w-vvCO,, pp, 171-173, 1982. 4. Leadbetter, J. F.: Regional gland dissection for carcinoma of the bladder: a technique for one-stage .0m,tc>,,tnnrn gland dissection and bilaterai uretero-enterostomy. 242, 1950. 5. Whitmore, W. F., Jr. and Marshail, V. F.: Radical surgery for carcinoma of the bladder. Cancer, 9: 596, 1956. 6. Smith, J. A., Jr., Batata, Grabstald, H., Sogani, P. C., Herr, H. and Whitmore, W. F., Jr.: Preoperative irradiation and cystectomy for bladder cancer. Cancer, 49: 869, 1982. 7. Miller, L. S. and Johnson, D. E.: Megavoltage irradiation for bladder cancer: alone, postope:rative, or preoperative? Proc. Natl. Cancer Conf., 7: '7'71, 1973. 8. Bloom, H.J. G.: Pre-operative intermediate-dose radiotherapy and cystectomy for deeply invasive carcinoma of the bladdei·: rationale and results. In: Bladder Cancer: Principles of Combination Therapy. Edited by R. T. D. Oliver, W. F. Hendry and H.J. G. Bloom. Boston: Butterworths Inc., chapt. 17, p. 151, 1981. 9, DeWeerd, J. l-I. and Colby, M. Y., Jr.: Bladder carcinoma treated by irradiation and surgery: interval report. J. UroL, 109: 409, 1973. 10. van der Werf-Messing, B. H.P.: Carcinoma of the bladder T 3 N,M0 treated by preoperative irradiation followed by cystectomy. Cancer, 36: 718, 1975. 11. Reid, E. C., Oliver, J. A. and Fishman, L J.: Preoperative irradiation and cystectomy in 135 cases of bladder cancer. Urology, 8: 247, 1976. 12. Reddy, E. K., Hartman, G. V. and Mansfield, C. M.: Carcinoma of the urinary bladder: rnle of radiation therapy. Int. J" Rad. OncoL Biol. Phys., 4: 963, 1978. 13. Ellingwood, K. K, Dryiie, D. M., DeTure, F. A. and Million, R. R.: Postdiversion '"°'".,"'Qt,,~1-,,,rnu inadiation for cancer of the bladder. Cancer, 14. Sagerman, R.H., T. and Emmanuel, G,: Integrated preoperative irradiation and radical cystectomy. Int. J. Rad, Oneal. Biol. Phys., 6: 607, 1980. 15. Skinner, D. G.: Current perspective in the management of highgrade invasive bladder cancer. Cancer, 45: 1866, 1980. 16. Hall, R. R. and Heath, A. B.: Radiotherapy a,,d cystectomy for T3 bladder carcinoma. Brit. J. UroL, 53: 598, 1981. 17. l\1ohiuddin, M. and Kramer, S.: Preoperative radiotherapy for bladder cancer: a n<>1·snP.-,trnP Urolog,;, 17: 515, 1981. 18. Prout, G. R., Jr.: surgical management of bladder carcinoma. Urol. Clin, N, Amer., 3: 149, 1976. J,.: Regional lymph node 19. Smith, J. A., Jr. and Whitmore, W. metastasis from bladder cancer. J. 126: 591, 1981. 20. Skinner, D. G., Tift, J. P. and Kaufman, J. J.: High short course prnoperative radiation and immediate stage radical ev,,tea,,tnrri with dissection in the managern.ent of U:roL, 1.27: 1982. 21. and Johnson, D, E.: 1n1;egrat;ed for invasive carcinon1a: experience vvith 108 patients, 12~, 549, 1978. 22. IVL Johnson D, E., Chat1 R. C. and Gonzales) tvL 0.: carcin.on1a: results with preoperative :radiation therapy and radical ""''t",,tnm 16: 1980. ~3. H. D., · Radical cystectomy cancer: 10-year J. Urol., Hl9: 623, 1973. 24. Kutscher, H. A., Leadbetter, G. W., Jr. and Vinson, R. K: Sur,ival after radical cystectomy for invasive transitional cell carcinoma of bladder. Urology, 17: 231, 1981. 25. Mathur, V. K., Krahn, H.P. and Ramsey, E.W.: Total cystectomy for bladder cancer. J. Urol., 125: 784, 1981. 26. Bredael, J. J,, Croker, B. P. and Glenn, J. F.: The curability of invasive bladder cancer treated by radical cystectomy. Eur. Urol., 6: 206, 1980. 27. Wallace, D. M. and Bloom, H.J. G.: The management of deeply infiltrating (T 3) bladder carcinoma: controlled trial of radical radiotherapy versus preoperative radiotherapy and radical cystectomy (first report). Brit. J. Urol., 48: 587, 1976. 28. Daughtry, J. D., Susan, L. P., Stewart, B. H. and Straffon, R. A.: Ilea! conduit and cystectomy: a 10-year retrospective study of ilea! conduits performed in conjunction with cystectomy and with a minimum 5-year followup. J. Urol., 118: 556, 1977. 29. Whitmore, W. F., Jr.: Integrated radiation and cystectomy for 1
1
No in any of the ther-e is a definite decrease in ity. The decision a urologist to abandon ;;:;uuv"'"''f·"" ment and to ~'"''"""',., with M,e+o,o+-~ may be made that the procedure is safer. This, itself, leads to earlier referral to a major cancer center for operative treatment. Our presents data suggesting that the result with cystectomy alone may be comparable with that of cystectomy with preoperative radiation therapy. Patient selection is a major obstacle in evaluating the reliability of these data. Indeed, our results may have been improved if preoperative radiation therapy were administered. Only a well designed clinical trial will resolve this issue. REFERENCES 1. Cutler, S. J. and Ederer, F.: Maximum utilization of the life table
method in analyzing survival. J. Chron. Dis., 8: 699, 1958.
1
482
MONTIE, STRAFFON AND STEWART bladder cancer. In: Carcinoma of the Bladder. Edited by J. G. Connolly. New York: Raven Press, p. 235, 1981. EDITORAL COMMENTS
These authors report a contemporary series of patients who have undergone cystectomy for muscle-invasive bladder cancer and the results appear to be comparable to those presented in other studies in which preoperative radiation had been part of the over-all treatment regimen. Although the majority of cases presented is recent and final survival rates will require continued analysis, the suggestion in these estimates of survival is that preoperative radiation therapy may add to the therapeutic efficacy in the management of bladder cancer only in a small, select group of patients. It should be noted that a substantial number of patients in this study had stage T2 disease and that bladder cancer deaths were substantially lower in this group than they were in the more advanced stages (T3 and T4). The success of surgical treatment in this group may have reflected in part the intrinsic behavior of the cancer with the greater likelihood that it was confined within the bladder. 1•2 Similar suggestions have been made in analyzing the hypothetical therapeutic benefits of radiation in patients whose tumors were found either to be papillary or to have penetrated only the superficial layers of muscle (reference 18 in article). 3 Figures presented for pelvic recurrence in these series also may reflect these suggestions. Clearly, our failure in the management of this disease is related to the development of distant metastases and the absence of any predictably effective systemic treatment in such situations. Results in this and previous studies suggest that the metastatic event probably has occurred already by the time patients with muscle invasive disease initially present. The tasks are, therefore, to identify patients at potential risk and to obtain effective systemic treatment. Accomplishment of these goals will then assure a quantum improvement in our ability to control these cancers whether or not radiation has been used. Michael J. Droller Department of Urology The Johns Hopkins Hospital Baltimore, Maryland This report emphasizes the contention of Radwin that contemporary
protocols using planned preoperative radiation therapy and radical cystectomy compared to historic surgery only do not prove to be of any benefit or advantage to the group of patients receiving combination therapy. 4 Rather, improved surgical technique, better preoperative and postoperative care resulting in lowered operative morbidity and mortality, the possible addition of a pelvic node dissection and, perhaps more importantly, patient selection have produced substantially better 5-year survival rates than reported historically. Figure 4 emphasizes this fact, yet the projected 5-year survival rate of nearly 80 per cent in the contemporary surgical group with clinical stages T3a, T3b and T4a disease is too good to be realistic, implying short followup. Nonetheless, their report and unpublished personal data suggest that preoperative radiation therapy adds little, if anything, to a meticulous properly performed radical cystectomy with pelvic lymphadenectomy. The low pelvic recurrence rate reported (9 per cent) supports the probability that patient selection and an earlier appropriate operation in patients with high grade invasive bladder cancer are more important factors to )mproved survival than any combination of planned irradiation precedmg surgery. These data, in addition to personal experience to be reported soon, make 1t hard to generate enthusiasm for initiation of another prospective randomized study designed to determine the possible benefit of preoperative radiation therapy. Instead, we must look to systemic therapy to reduce the nearly 50 per cent death rate from disseminated metastases following cystectomy in patients presenting with advanced yet apparently localized disease. Donald G. Skinner Division of Urology University of Southern California Medical Center Los Angeles, California 1. Droller, M. J.: Bladder cancer. Curr. Prob. Surg., 18: 205, 1981. 2. Soto, E. A., Friedell, G. H. and Tiltman, A. J.: Bladder cancer as seen in giant histologic sections. Cancer, 39: 447, 1977. 3. Pryor, J. P.: Factors influencing the survival of patients with transitional cell tumours of the urinary bladder. Brit. J. Urol., 45: 586, 1973. 4. Radwin, H. M.: Radiotherapy and bladder cancer: a critical review. J. Urol., 124: 43, 1980.
THE Jou&NAL OF UROLOGY
Copyright © 1984 by The Williams & Wilkins Co.
Printed in U.S.A.
RADICAL CYSTECTOMY WITHOUT RADIATION THERAPY FOR CARCINOMA OF THE BLADDER JAMES E. MONTIE,* RALPH A. STRAFFON
AND
BRUCE H. STEWARTt
From the Department of Uro/,ogy, Cleveland Clinic Foundation, Cleveland, Ohio
ABSTRACT
A review of a 20-year experience of radical cystectomy identified 99 patients who had not undergone preoperative radiation therapy. The 5-year survival rate of patients with clinical high stage lesions (T3, T4a) was 40 per cent. Life-table analyses showed that survival rate in this group was comparable with that reported for other groups receiving preoperative radiation therapy. The pelvic recurrence rate was 9 per cent and was frequently related to either urethral or nodal disease. Unquantifiable patient selection factors may well limit the reliability of these results. Radical cystectomy is now an accepted means of extirpating bladder cancer that cannot be controlled by endoscopic resection. Although there is little disagreement on this rather general indication, the timing of the application of cystectomy may vary widely and there is also considerable debate relative to the value of preoperative radiation therapy or regional lymphadenectomy. Comparative analysis of data from studies in the literature is hazardous because of differences in data analysis, patient selection and, more importantly, actual therapeutic benefit of various protocols. However, the most controversial issue is preoperative radiation therapy, although by the late 1970s some form was being used in most major centers. A survey of 150 practicing urologists attending a Cleveland Clinic postgraduate course in 1981 disclosed that 80 per cent were using some form of preoperative radiotherapy. However, several urologists at the Cleveland Clinic do not use preoperative radiation therapy routinely and, thus, a relatively unusual, contemporary series of patients treated by radical cystectomy alone can be studied. The survival, operative mortality and pelvic recurrence rate have been examined. MATERIALS AND METHODS
Between 1960 and 1979, 117 of 157 radical cystectomies (removal of the bladder and prostate with the plane of dissection along the pelvic sidewalls) were performed by 4 of 11 different urologists. Preoperative radiation therapy and intraoperative lymphadenectomy were left to the discretion of the operating surgeons and no systematic protocol was used. All patients were followed for at least 18 months. Survival data were analyzed by the Cutler-Ederer life-table method unless otherwise noted. 1 The histologic grade of the tumor was noted but it was not discussed because of inconsistent grading criteria during the years and lack of specific review of the pathologic material. A review of other potentially significant variables, such as endothelial space invasion or growth pattern of the tumor (that is sessile versus papillary) was not feasible and this limitation is acknowledged. 2 PATIENT POPULATION
The various radiation therapy groups are listed in table 1. The 90 patients who received no radiation therapy to the pelvis at any time form the basis of this report. In some analyses the 9 patients with postoperative radiation therapy were included Accepted for publication September 16, 1983. *Requests for reprints: Department of Urology, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, Ohio 44106. tDeceased 1983.
in the group who received no radiation therapy to minimize selection bias introduced when patients with poor pathologic characteristics were chosen for postoperative radiation therapy. Inclusion of these patients did not alter the results significantly. Clinical stage was obtained by a review of preoperative biopsies, endoscopic findings and bimanual examination under anesthesia. Histologic proof of muscle invasion, available in almost all instances, enabled the assignment of a high clinical stage. In a few cases high grade sessile lesions with a palpable mass were classified as high stage even without histologic proof of muscle invasion. The clinical stage, defined by the tumor, node and metastasis system, was examined within each group to ascertain any bias (table 2). 3 Although the planned preoperative radiation therapy group had been treated primarily by 1 surgeon, data from this group also showed a tendency for higher stage lesions (36 per cent T3a, T3b, T4a without radiation therapy versus 56 per cent T3a, T3b, T4a in planned preoperative radiation therapy). However, the relative frequency of T2 to T4a lesions in both groups is similar. SURVIVAL STAGE AND TREATMENT
Relapse rates and survival times have been analyzed in several different groups to allow comparisons with previously reported series. Until 1975 approximately 4 cystectomies were performed each year. From 1975 through 1979 approximately 20 cystectomies were undertaken yearly. Thus, if the total (157 cystectomies) is analyzed the results are skewed toward those with a shorter followup period. For this reason separate analyses were prepared on patients operated on before 1976. The over-all survival of the various radiation therapy groups is shown in figure 1. The relative frequency of low and high, clinical and pathological stages in the group without irradiation and the definitive irradiation groups is similar. In the planned preoperative radiation therapy group interpretation of the results is limited by the different regimens used, the slightly higher percentage of high stage lesions and the inordinate operative morbidity-contributed largely by a group of 8 patients who received a high preoperative dose regimen (2,400 rad in 3 days to the entire pelvis)-and was not possible. A lifetable analysis of the survival of 90 patients without radiation therapy and 9 with postoperative radiation therapy relative to clinical stage is shown in figure 2 and table 3. The estimated 5-year survival rate of patients with high stage (T2, T3, T4a) lesions is approximately 60 per cent. A life-table analysis relative to pathologic stage also is shown in table 3. The most reliable data are those accumulated from the patients followed for ~5 years, that is patients undergoing cystectomy between 1960 and 1975. Among the 24 patients with T3a, T3b, T4a disease who received no radiation therapy or had postoperative radiation therapy the cumulative proportion sur-
477
478
MONTIE, STRAFFON AND STEW ART
TABLE
1. Treatment groups and radiation therapy, 1960 to 1979 No. Pts.
No pelvic radiation therapy at any time Postop. radiation therapy Previous definitive radiation therapy (salvage cystectomy) Planned preop. radiation therapy Total
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* In 1 patient radiation therapy status is unknown. TABLE 2.
Relative frequency of clinical stage of radiation therapy groups Radiation Therapy Previous Definitive No.(%)
None No.(%) Total No. pts. Clinical stage:* Ta, Tl, TIS T2, T3, T4a T3, T4a
Planned Preop. No.(%)
Postop. No.(%)
90
34
23
9
34 (38) 55 (62) 32 (36)
12 (36) 21 (64) 14 (42)
7 (30) 16 (70) 13 (56)
1 (11) 8 (89) 7 (78)
viving 60 months after surgery is 0.40. Of the 14 deaths during this period 11 were due to bladder cancer. Of the 23 patients who had histologic stage P3a, P3b, P4a, Nx or No lesions without radiation therapy or with postoperative radiation therapy the cumulative proportion surviving 60 months is 0.57 (fig. 3). Of the 10 deaths in this group 8 were due to bladder cancer. Life-table analyses of the survival rate of clinical high stage lesions (T3a, T3b, T4a) comparing 1960 to 1975 with 1976 to 1979 are shown in figure 4. A later analysis to determine if the apparent improved survival rate persists will be necessary when longer followup of the more recent group is available. The operative mortality in the group from 1960 to 1975 receiving no radiation therapy was 9 per cent (4 of 46) and from 1976 to 1979 it was 5 per cent. In 1980 to 1981 the operative mortality for all cystectomies was 1 in 63 cases. This decrease in operative mortality and, undoubtedly, morbidity may contribute to the improved survival figures. PELVIC LYMPHADENECTOMY AND PELVIC RECURRENCES
* Ta-papillary noninvasive carcinoma. Tl-microscopic invasion of lamina propria. TIS-carcinoma in situ. T2-microscopic invasion of superficial muscle. T3a-microscopic invasion of deep muscle and induration palpable. T3b-invasion in perivesical fat and induration or mass palpable. T4a-invasion of substance of prostate (microscopically proved), uterus or vagina. 3
Pelvic lymphadenectomy was defined as a formal dissection with the following margins: superior limit was the bifurcation of the common iliac artery, lateral limit was the genitofemoral nerve, inferior limit was the inguinal ligament and medial limit was the perivesical fat; obturator nodes were included in this 1.0 C)
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Life-table analysis relative to clinical and pathological stages of 90 patients without radiation therapy and 9 patients with postoperative radiation therapy between 1960 and 1979
Clinical Stage Death of any cause: No. pts. Death No. censored(%)* Death of bladder Ca: No. pts. Death No. censored(%)* Pathologic Stage Death of any cause: No. pts. Death No. censored(%)* Death of bladder Ca: No. pts. Death No. censored(%)*
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dissection. Of the 157 ,,~"'~""U pelvic performed in 61 (39 per including 8 per nodes. Of the 90 pwv,-,,vu without radiation 37 per cent) underwent node dissection and 14 per cent of these had positive nodes. No effect on survival or could be identified from the presence or absence of node dissection. were included with the no radiation Of these 99 1--·wv,v,,vu per experienced pelvic recurrences (2 of 9 with postoperative radiation therapy and 7 of 90 without radiation therapy). Of these recurrences 4 were likely ""''-v,,wu to urethral recurrences and 2 of 9 patients did not have a node u""'"'u,,uu. Of the 34 patients undergoing a salvage cystectomy 9 (26 per cent) had a pelvic recurrence. DISCUSSION
A historical perspective on radical cystectomy as the primary mode of therapy of advanced bladder cancer is important in evaluating the data presented herein. The feasibility of widespread application of a radical cystectomy began with the development of the ileal conduit by Bricker in 1950 as a satisfactory means of urinary diversion. Previously, this operation often was performed in several stages and was associated
rw,,c.- ,~n,,c, of 15 to 40 per {'.Srlto At that time Leadbetter and Cooper estimated that 50 pe:r cent of patients who survived these operations later died of bladder cancer. 4 In the 1950s Leadbetter and Cooper; and Whitmore and l\farshall 5 included a regional lymph node dissection in an attempt to impr-ove local control and, more importantly, overall survival. Unfortunately, this logical approach did not result in fewer cancer deaths. However, the operative mortality was consistently reduced to approximately 15 per cent. In 1959 Whitmore introduced a preoperative radiation therapy regimen consisting of 4,000 rad in 4 weeks followed by cystectomy and lymph node dissection approximately 6 weeks later. Subsequent analyses of the groups with and without radiation therapy demonstrated a decrease in pelvic recurrences (37 per cent without versus 24 per cent with preoperative radiation therapy) and an increase in the 5-year survivaLrate in patients with P3 lesions from 20 per cent without to 38 per cent with preoperative radiation therapy. 6 In 1966 the preoperative regimen was reduced to 2,000 rad in 5 days through limited portals with immediate cystectomy. This change was introduced primarily to provide increased convenience for the patient, with a presumed similar biologic effect. In 1971 the same radiation dose was maintained but treatment portals were enlarged to include the entire pelvis. The results of these last 2 protocols showed a gradual decrease in the pelvic recurrence rate (20 per cent 2,000 rad small field versus 17 per cent 2,000 rad large field) and similar 5-year survival figures for P3 lesions (58 per cent 2,000 rad small field versus 43 cent 2,000 rad large field). 6 During the same 2 randomized trials were performed, comparing definitive radiation therapy versus a long course of preoperative radiation therapy. The M. D. Anderson trial from 1964 to 1970 evaluated the 5,000 rad preoperative regimen for patients with clinical stage T3 disease and found a projected 5year survival rate of 51 per cent for the preoperative gToup versus 13 per cent for definitive radiation therapy alone. 7 A British study sponsored by the Institute of Urology in London from 1966 to 1975 evaluated 4,000 rad preoperative radiation therapy versus 6,000 rad definitive radiation therapy in patients with clinical stage T3 cancer. The 5-year survival rate for the preoperative radiation therapy and cystectomy group was 44 per cent compared to 24 per cent for those who received 8 radiation These 3 series the main evidence establishing preoperative radiation as standard treatment for high stage bladder cancer. Preoperative radiation therapy and cystectomy are better than the earlier series of cystectomy alone at Iv!:emorial Sloan-Kettering Cancer Center and are better than definitive radiation ,.h,,,..,r"' The series in recent years using preoperative radiation cystectomy have confirmed 5-year survival rates of 35 to 50 cent in ;,u.a,~uo~ with T2, T3 iesions. 9 - 17 A nro;:,no:m:s cases downstaged to Po has been a and. consistent feature in these studies. A trial nrns,c.,~D"M"= rmPrn"'!P1">!tme> 1"h,>r9,nu versus cystectomy alone ~·"~'~W to obtain. Prout organized a national, randomized tria.1 from 1964 to comparing 4,000 rad preoperative radiation therapy to cystectomy alone. 18 The difficulties encountered in performing this study are evident the observation that of 246 patients randomized to receive preoperative radiation therapy and cystectomy 123 (50 per cent) actually completed the protocol. Similarly, of 229 patients randomized to receive cystectomy alone only 133 (58 per cent) completed the treatment. Nevertheless, of 244 evaluable patients with clinical stage T2, T3 lesions the 5-year survival rate without radiation therapy was 31 per cent versus 37 per cent for the preoperative radiation therapy group. Although a survival advantage was evident for patients with Po lesions (obtained by either transurethral resection or preoperative radiation therapy), no over-all significant improvement was seen for the preoperative radiation therapy group as a whole. 9
480
MONTIE, STRAFFON AND STEW ART
Our study represents 1 of the largest contemporary series of patients with bladder cancer treated at a single institution by radical cystectomy without any preoperative radiation therapy. These data neither confirm nor deny the value of preoperative radiation therapy. However, they can underscore the questionable validity of using data from the 1950s as a control group for cystectomy without radiation. Before specifically comparing these data with published series, the problem of patient selection as a major unquantified variable also must be addressed. In the early years of the study (1960 to 1975) planned preoperative radiation therapy was used in only 6 patients and, thus, no effect is likely to be detected. At no time was definitive radiation therapy recommended as primary therapy unless extenuating circumstances were present. However, it is impossible to determine in a retrospective analysis such as this the number of patients who may have been deemed inoperable on the basis of a clinical examination only, without a laparotomy, and who thus never had a cystectomy. If, indeed, such a conservative approach was used widely patients with larger lesions may not have undergone an operation. The relatively low percentage of high stage (T3a, T3b, T4a) lesions (36 per cent) could support this interpretation, although no conscious bias in this direction was acknowledged by the involved surgeons. An alternative explanation for the low percentage of high stage lesions was the conscious effort to perform cystectomy at an earlier date in those patients who were believed to be at high risk for lethal tumors (that is high grade lesions). This could also skew the results to some degree. The 14 per cent incidence of positive nodes in patients undergoing a formal pelvic lymphadenectomy is lower than that reported in recent series and may support some element of patient selection. 19• 20 This figure could also just as simply reflect the diligence of the pathologist in sampling the nodes. Multiple methods of data management in various published series hamper comparative studies. The raw data from this review have been studied in several different ways to allow comparisons. The M. D. Anderson experience includes a regimen of 5,000 rad preoperative radiation therapy to relatively small pelvic portals followed by total cystectomy without lymphadenectomy. Chan and Johnson examined the time to relapse in clinical stage T3 lesions (including Bl, B2 and C lesions) and their data are shown in figure 5. 21 In a more recent analysis the survival rate of patients with T2 and T3 lesions was examined and found comparable to the present data in figure 6. 22 No appreciable difference can be detected between survival or time to relapse in these series. While the use of a long course of preoperative radiation therapy may permit segregation into low and high risk groups on the basis of the presence or absence of residual carcinoma in the specimen, this seems an inordinate price to pay if no real improvement in over-all survival is demonstrated over cystectomy without radiation therapy. In the Memorial Sloan-Kettering Cancer Center experience from 1971 to 1974 Smith and associates evaluated 2,000 rad to a large pelvic field in 5 days before cystectomy with lymphadenectomy.6 The 5-year survival rate for clinical high stage lesions (T3a, T3b) was 40 per cent (52 patients). The result for our series without preoperative radiation therapy was 41 per cent (24 patients). It is important to note that the internal comparison done by the Memorial Sloan-Kettering Cancer Center shows that from 1949 to 1959, 48 per cent of patients with cystectomy alone died of bladder cancer, whereas 46 per cent of patients treated with 2,000 rad preoperatively to a large pelvic field died of bladder cancer from 1971 to 1974. The hospital mortality was 14 per cent in the early group and only 2 per cent in the latter group. This does not imply any fundamental improvement in the over-all control of the disease but it does indicate a definite improvement in the delivery of the treatment. Contributing to the confusion regarding the value of preop-
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erative radiation therapy is the small number of studies from a concurrent period that evaluate cystectomy without radiation therapy. Pearse and associates reviewed data on 52 patients with T2 to T4 lesions who underwent radical cystectomy between 1953 and 1963. 23 With an operative mortality of 19 per cent, the 5-year survival rate was 38 per cent. Kutscher and associates reported an estimated 5-year survival of approximately 40 per cent for 23 patients with stage P2, P3 lesions but
of these ua.,c,eJ" '" received preopel'a24 Pr,. recent :report IV'IathnI' and asso-tive radiation ciates on 20 µacuv,,,;,;,e- stage P3 lesions showed survival rate of 50 cent. 25 Duke Medical Center "'"'""'''"y'""' Bredael and associates recorded a total of 100 between 1964 and 1973 who received no radiation before or after cystectomy. 26 The 5--year survival rate of 34 patients with pathologic P3 lesions was 29 per cent, compared to 44 per cent for 74 patients with P3 lesions who received 4 different types of preoperative or postoperative radiation therapy regimens. However, this comparison may not be valid because no discussion of selection criteria for either regimen is presented and the number of patients who may have been given planned preoperative radiation therapy but who later did not receive cystectomy because of metastases, medical contraindications, patient refusal or change in policy is not discussed. In the large series by Wallace and Bloom of planned long course (4,000 rad) preoperative radiation therapy 21 per cent of the patients randomized to receive this treatment never underwent cystectomy and elimination of these patients from analyses of results constitutes a strong selection bias. 27 Our study conflicts with an earlier report from this same institution that claimed a higher complication rate in patients receiving preoperative radiation therapy or node dissection. 28 A review of a larger number of patients with more precise stratification of the type of preoperative radiation therapy, clinical and pathologic stage, and type of lymph node dissection has not confirmed the original observations. The rationale of preoperative radiation th,,r"n" is based on 2 principles. First, cells expressed into the circulation during the operative procedure may be less viable and, as a result, there may be less distant metastases. However, clinical data do not support this finding. Approximately 50 per cent of the patients die of distant disease, a figure similar to that reported in the 1950s, although pelvic recurrences have actually decreased. Second, macroextensions or microextensions of the cancer that may not be encompassed in the surgical specimens can be controlled by preoperative radiation therapy. Support for this contention is based on data showing an expected pelvic recurrence rate with cystectomy alone of 30 to 40 per cent and a recurrence rate of 5 to 20 per cent with preoperative radiation th1°;rnrm 4 •6 • 18 • 19 Our data revealed that relapse in the pelvis was evident in 9 per cent. Prout and associates described 127 cases without preoperative radiation therapy from 1967 to 1975 and identified a pelvic recurrence rate of 7 cent. 2 Undoubtautopsy information on all n
2. Prout, Go R., Jr. Griffin) P. P. and Shipley, VV. U.: Bl2.dde:r '"'"''''"c disease. 43:, 2532, 1979. 3. Beahrs, 0. H. for Staging of Cancer. ~,,,p••w-vvCO,, pp, 171-173, 1982. 4. Leadbetter, J. F.: Regional gland dissection for carcinoma of the bladder: a technique for one-stage .0m,tc>,,tnnrn gland dissection and bilaterai uretero-enterostomy. 242, 1950. 5. Whitmore, W. F., Jr. and Marshail, V. F.: Radical surgery for carcinoma of the bladder. Cancer, 9: 596, 1956. 6. Smith, J. A., Jr., Batata, Grabstald, H., Sogani, P. C., Herr, H. and Whitmore, W. F., Jr.: Preoperative irradiation and cystectomy for bladder cancer. Cancer, 49: 869, 1982. 7. Miller, L. S. and Johnson, D. E.: Megavoltage irradiation for bladder cancer: alone, postope:rative, or preoperative? Proc. Natl. Cancer Conf., 7: '7'71, 1973. 8. Bloom, H.J. G.: Pre-operative intermediate-dose radiotherapy and cystectomy for deeply invasive carcinoma of the bladdei·: rationale and results. In: Bladder Cancer: Principles of Combination Therapy. Edited by R. T. D. Oliver, W. F. Hendry and H.J. G. Bloom. Boston: Butterworths Inc., chapt. 17, p. 151, 1981. 9, DeWeerd, J. l-I. and Colby, M. Y., Jr.: Bladder carcinoma treated by irradiation and surgery: interval report. J. UroL, 109: 409, 1973. 10. van der Werf-Messing, B. H.P.: Carcinoma of the bladder T 3 N,M0 treated by preoperative irradiation followed by cystectomy. Cancer, 36: 718, 1975. 11. Reid, E. C., Oliver, J. A. and Fishman, L J.: Preoperative irradiation and cystectomy in 135 cases of bladder cancer. Urology, 8: 247, 1976. 12. Reddy, E. K., Hartman, G. V. and Mansfield, C. M.: Carcinoma of the urinary bladder: rnle of radiation therapy. Int. J" Rad. OncoL Biol. Phys., 4: 963, 1978. 13. Ellingwood, K. K, Dryiie, D. M., DeTure, F. A. and Million, R. R.: Postdiversion '"°'".,"'Qt,,~1-,,,rnu inadiation for cancer of the bladder. Cancer, 14. Sagerman, R.H., T. and Emmanuel, G,: Integrated preoperative irradiation and radical cystectomy. Int. J. Rad, Oneal. Biol. Phys., 6: 607, 1980. 15. Skinner, D. G.: Current perspective in the management of highgrade invasive bladder cancer. Cancer, 45: 1866, 1980. 16. Hall, R. R. and Heath, A. B.: Radiotherapy a,,d cystectomy for T3 bladder carcinoma. Brit. J. UroL, 53: 598, 1981. 17. l\1ohiuddin, M. and Kramer, S.: Preoperative radiotherapy for bladder cancer: a n<>1·snP.-,trnP Urolog,;, 17: 515, 1981. 18. Prout, G. R., Jr.: surgical management of bladder carcinoma. Urol. Clin, N, Amer., 3: 149, 1976. J,.: Regional lymph node 19. Smith, J. A., Jr. and Whitmore, W. metastasis from bladder cancer. J. 126: 591, 1981. 20. Skinner, D. G., Tift, J. P. and Kaufman, J. J.: High short course prnoperative radiation and immediate stage radical ev,,tea,,tnrri with dissection in the managern.ent of U:roL, 1.27: 1982. 21. and Johnson, D, E.: 1n1;egrat;ed for invasive carcinon1a: experience vvith 108 patients, 12~, 549, 1978. 22. IVL Johnson D, E., Chat1 R. C. and Gonzales) tvL 0.: carcin.on1a: results with preoperative :radiation therapy and radical ""''t",,tnm 16: 1980. ~3. H. D., · Radical cystectomy cancer: 10-year J. Urol., Hl9: 623, 1973. 24. Kutscher, H. A., Leadbetter, G. W., Jr. and Vinson, R. K: Sur,ival after radical cystectomy for invasive transitional cell carcinoma of bladder. Urology, 17: 231, 1981. 25. Mathur, V. K., Krahn, H.P. and Ramsey, E.W.: Total cystectomy for bladder cancer. J. Urol., 125: 784, 1981. 26. Bredael, J. J,, Croker, B. P. and Glenn, J. F.: The curability of invasive bladder cancer treated by radical cystectomy. Eur. Urol., 6: 206, 1980. 27. Wallace, D. M. and Bloom, H.J. G.: The management of deeply infiltrating (T 3) bladder carcinoma: controlled trial of radical radiotherapy versus preoperative radiotherapy and radical cystectomy (first report). Brit. J. Urol., 48: 587, 1976. 28. Daughtry, J. D., Susan, L. P., Stewart, B. H. and Straffon, R. A.: Ilea! conduit and cystectomy: a 10-year retrospective study of ilea! conduits performed in conjunction with cystectomy and with a minimum 5-year followup. J. Urol., 118: 556, 1977. 29. Whitmore, W. F., Jr.: Integrated radiation and cystectomy for 1
1
No in any of the ther-e is a definite decrease in ity. The decision a urologist to abandon ;;:;uuv"'"''f·"" ment and to ~'"''"""',., with M,e+o,o+-~ may be made that the procedure is safer. This, itself, leads to earlier referral to a major cancer center for operative treatment. Our presents data suggesting that the result with cystectomy alone may be comparable with that of cystectomy with preoperative radiation therapy. Patient selection is a major obstacle in evaluating the reliability of these data. Indeed, our results may have been improved if preoperative radiation therapy were administered. Only a well designed clinical trial will resolve this issue. REFERENCES 1. Cutler, S. J. and Ederer, F.: Maximum utilization of the life table
method in analyzing survival. J. Chron. Dis., 8: 699, 1958.
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482
MONTIE, STRAFFON AND STEWART bladder cancer. In: Carcinoma of the Bladder. Edited by J. G. Connolly. New York: Raven Press, p. 235, 1981. EDITORAL COMMENTS
These authors report a contemporary series of patients who have undergone cystectomy for muscle-invasive bladder cancer and the results appear to be comparable to those presented in other studies in which preoperative radiation had been part of the over-all treatment regimen. Although the majority of cases presented is recent and final survival rates will require continued analysis, the suggestion in these estimates of survival is that preoperative radiation therapy may add to the therapeutic efficacy in the management of bladder cancer only in a small, select group of patients. It should be noted that a substantial number of patients in this study had stage T2 disease and that bladder cancer deaths were substantially lower in this group than they were in the more advanced stages (T3 and T4). The success of surgical treatment in this group may have reflected in part the intrinsic behavior of the cancer with the greater likelihood that it was confined within the bladder. 1•2 Similar suggestions have been made in analyzing the hypothetical therapeutic benefits of radiation in patients whose tumors were found either to be papillary or to have penetrated only the superficial layers of muscle (reference 18 in article). 3 Figures presented for pelvic recurrence in these series also may reflect these suggestions. Clearly, our failure in the management of this disease is related to the development of distant metastases and the absence of any predictably effective systemic treatment in such situations. Results in this and previous studies suggest that the metastatic event probably has occurred already by the time patients with muscle invasive disease initially present. The tasks are, therefore, to identify patients at potential risk and to obtain effective systemic treatment. Accomplishment of these goals will then assure a quantum improvement in our ability to control these cancers whether or not radiation has been used. Michael J. Droller Department of Urology The Johns Hopkins Hospital Baltimore, Maryland This report emphasizes the contention of Radwin that contemporary
protocols using planned preoperative radiation therapy and radical cystectomy compared to historic surgery only do not prove to be of any benefit or advantage to the group of patients receiving combination therapy. 4 Rather, improved surgical technique, better preoperative and postoperative care resulting in lowered operative morbidity and mortality, the possible addition of a pelvic node dissection and, perhaps more importantly, patient selection have produced substantially better 5-year survival rates than reported historically. Figure 4 emphasizes this fact, yet the projected 5-year survival rate of nearly 80 per cent in the contemporary surgical group with clinical stages T3a, T3b and T4a disease is too good to be realistic, implying short followup. Nonetheless, their report and unpublished personal data suggest that preoperative radiation therapy adds little, if anything, to a meticulous properly performed radical cystectomy with pelvic lymphadenectomy. The low pelvic recurrence rate reported (9 per cent) supports the probability that patient selection and an earlier appropriate operation in patients with high grade invasive bladder cancer are more important factors to )mproved survival than any combination of planned irradiation precedmg surgery. These data, in addition to personal experience to be reported soon, make 1t hard to generate enthusiasm for initiation of another prospective randomized study designed to determine the possible benefit of preoperative radiation therapy. Instead, we must look to systemic therapy to reduce the nearly 50 per cent death rate from disseminated metastases following cystectomy in patients presenting with advanced yet apparently localized disease. Donald G. Skinner Division of Urology University of Southern California Medical Center Los Angeles, California 1. Droller, M. J.: Bladder cancer. Curr. Prob. Surg., 18: 205, 1981. 2. Soto, E. A., Friedell, G. H. and Tiltman, A. J.: Bladder cancer as seen in giant histologic sections. Cancer, 39: 447, 1977. 3. Pryor, J. P.: Factors influencing the survival of patients with transitional cell tumours of the urinary bladder. Brit. J. Urol., 45: 586, 1973. 4. Radwin, H. M.: Radiotherapy and bladder cancer: a critical review. J. Urol., 124: 43, 1980.