Radiotherapy And Bladder Cancer: A Critical Review

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Vol. 124,

JOURNAL O!F UROLOGY

Copyright© 1980 by The Williams & Wilkins Co.

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RADIOTHERAPY AND BLADDER CANCER: A CRITICAL REVIEW HOWARD M. RADWIN Fram the Division of Urology, University of Texas Health Science Center, San Antonio, Texas

ABSTRACT

Survival of patients undergoing cystectomy for invasive carcinoma of the bladder has improved significantly in recent decades. Although this improved survival is credited widely to the use of preoperative radiation therapy review of the available data raises questions regarding the validity of such conclusions. Important disadvantages, including increased morbidity, are associated with long course (4,000 to 5,000 rad) preoperative radiation. Although these disadvantages are minimized with a short course regimen (1,600 to 2,000 rad) the case for its efficacy remains unconvincing. sponsible for the treatment support the conviction that the results are meaningful relative to the role of preoperative irradiation as an adjunct to cystectomy in the treatment of selected patients with bladder cancer." This claim was made to support the contention that their data demonstrating superiority of preoperative radiotherapy were valid despite the fact that they had compared a course of preoperative radiotherapy followed by cystectomy to a surgical series that preceded the radiation group by 17 years. A summary of the data from van der Werf-Messing,3- 4 and Whitmore 5 and Reid 6 and their associates is presented in table l. The demonstration by van der Werf-Messing that the best 5.. year survival rates were to be found in those patients who had received preoperative radiotherapy and whose tumors either disappeared or regressed was confirmed by virtually all other investigators, including the cooperative study of Prout. The 3 series by Whitmore and associates demonstrated only a 27 per cent 5-year survival rate in those patients receiving 6,000 rad before cystectomy and this group was collected throughout the entire period of study." The group, receiving 4,000 rad, began 10 years after the inception of the study and demonstrated a 38 per cent 5-year survival rate when survival was analyzed pathologic stage, and a 34 per cent rate when analyzed clinical staging. A group that began in 1966 received 2,000 rad before cystectomy and showed a 58 per cent 5-year survival rate by pathologic stage and a 40 per cent rate by clinical staging. Reid and associates' program of short course preoperative radiotherapy produced a 34.5 per cent life table survival rate. 6 None of the aforementioned studies presented data concerning an operation alone performed concomitantly with the study period for preoperative radiotherapy. Indeed, the national cooperative study has demonstrated no mE,,a.u~,~"' difference in 5-year survival rates between the entire group of patients with T3 lesions receiving preoperative radiotherapy and those receiving cystectomy alone. However, the studies reviewed as well as others have established 2 points First, when the tumor regresses after radiotherapy the prognosis greatly improves. Regression occurs in approximately twothirds of the irradiated patients and the tumor apparently disappears in approximately a third. Second, contemporary preoperative irradiation followed by cystectomy yields better over-all results than did an operation alone when it was done 20 years ago. However, the aforementioned 2 statements are all that can be supported by the evidence available currently. There is a striking lack of supportive data favoring preoperative radiotherapy over a contemporary operation alone. Table 2 shows the results from representative series performed contemporaneously, demonstrates no advantage for preoperative radiotherapy and may suggest the reverse. Included in these 3 series are the earlier data of the results from preoperative radiotherapy before subsequent randomized study 7 and these are not superior to the results of an operation alone as

External beam radiotherapy in the treatment of transitional cell carcinoma of the bladder has achieved varying degrees of acceptance over the years. Presently, its use as the sole treatment uuJu,ciwcy in low stage bladder tumors is unusual because l) although external beam radiotherapy can be effective in destroying the lesion it is not more so than is transurethral 2) the technique is ineffective against carcinoma in situ, 3) there is no evidence for protection against new tumor formation, 4) tumoricidal dosages in the range of 6,000 to 7,000 rad may be associated with appreciable morbidity and 5) the use of the technique may compromise future chemotherapy and does make a subsequent operation more difficult if it should become needed. In addition, in this country radiotherapy rarely is used presas the primary treatment for invasive stage T3(B2C) bladder tumors since 1) the method has been demonstrated to produce a 5-year survival rate of only 13 to 15 per cent, 2) the commonly associated carcinoma in situ is unaffected, 3) there is a high risk of new tumor formation even in those patients in whom the primary tumor was destroyed, 4) mortality and morbidity are significant and 5) the problem of compromise of a future operation and chemotherapy again is present. The report of Miller and Johnson in 1973 probably represents the definitive comparison of radiotherapy alone with preoperative radiotherapy followed by simple cystectomy in patients with stage T3 lesions. 1 The former group received 7,000 rad during a 7-week period and the latter was given 5,000 rad preoperative radiotherapy during 5 weeks followed by a simple cystectomy after a period of convalescence. The 5-year survival rate with radiotherapy alone was 13 per cent and with preoperative radiotherapy and cystectomy it was 50 per cent. This study was performed in a prospective manner and was randomized. Surprisingly, this report, which well documented the suof preoperative radiotherapy and cystectomy to radiobegan to be interpreted as demonstrating the of preoperative radiotherapy and simple cystectomy to radical cystectomy alone, although this had not been tested. The well controlled study by Miller and Johnson' was cited widely as evidence to support a proposition that it had never investigated. The implicit rationale was that historic controls could serve to provide the data for an operation alone. The same assumption was apparent in the report of other investigators who compared various treatment methods they had used sequentially during a period of many years. 2 They stated, "Although the data of this experience were not assembled through the mechanism of a controlled, randomized, pro~rn0rtm<> study, overall similarities in the clinical material, methods of staging, surgical treatment methods and physicians refor publication August 17, 1979. at annual meeting of South Central Section, American Urological Association, Colorado Springs, Colorado, October 8-12, 1978. 43

44

RADWIN

reported previously. 8 The series by Richie and associates from 1955 to 1971 is consistent with these results. 9 Historic controls are a convenience often used because of the difficulties entailed in the development of randomized prospective studies and in certain circumstances they may be valid. However, the presumption must be made when a historic control is used that the circumstances were not affected by time. It is my belief that this is invalid when comparing cystectomy as done today and as done i;;;20 years ago (table 3). Not only are the improvements in operative mortality highly significant but they are merely an index of the many other factors contributing to improved patient care in 1975 compared to 1955. Advances in the management of urinary diversion and infection as well as the development of other supportive measures are well known. Therefore, not only a reduced operative mortality but a lesser delayed mortality also may be expected. In addition, the candidates for a radical operation today appear to be a different group from those encountered in the 1950s. In our experience patients now are referred sooner, have had fewer temporizing procedures and, even within a given clinical stage, are not as far along in the natural history of the disease. Third, there have been improvements in the technique of cystectomy. There is good reason to believe that the radical cystectomy performed today in most instances is a better and more complete dissection than that which was standard 20 years ago. There are other problems to be considered when preoperative radiotherapy is delivered. The long course regimen certainly will delay the completion of therapy and may interfere with the patient ever undergoing an operation. In the series of Wallace and Bloom 23 per cent of the patients who received preoperative radiotherapy never underwent cystectomy. 10 Today, greater progress in the development of adjunctive chemotherapeutic agents in this disease makes the limitations imposed by prior radiotherapy a factor to be considered seriously. In addition, radiation is immunosuppressive. It interferes with T-cell and BTABLE

1. Preoperative radiotherapy in patients with stage T3

tumors Yrs.

f

5-Yr. Survival

Dose (rad)

Comment No.(%)

van der WerfMessing•

1966-1974

4,000

89 (50)

Whitmore and associates'

1949-1970

6,000

109 (27)

1959-1965

4,000

119 (38)

1966-1970

2,000

86 (58)

1966-1974

2,000

92 (34.5)

Reid and

70% if postop. stage is less preop. than stage 30% by clinical staging 34% by clinical staging 40% by clinical staging Life table

associates6

TABLE

2. 5-year survival rates with cystectomy

Richie and associates9 Pearse and associates8 Miller7

TABLE

Stage

Preop. Radiotherapy

B2

C

No.(%)

No.(%)

Yes No Yes

22 (40.4) 12 (50) 24 (21)

21 (19.7) 15 (20) 20 (30)

Yrs.

1955-1971 Before 1962 1954-1970

3. Mortality from cystectomy % Mortality

1923 1939 1960s 1970s Selected current series Richie and associates9

53.5 (I-stage) 29.4 (2 stages) 34.2 10.25 5 3

1

cell function. 11 The significance of this interference in cases of carcinoma of the bladder is unknown to date but the evidence suggests that the immune response is of some importance in the course of the disease and warrants consideration. 12• 13 Another relevant factor is the problem of late radiation injury. The small intestine usually is considered to be at significant risk when a dose of >5,000 rad is administered to the abdomen or pelvis. However, serious complications may occur with <5,000 rad, particularly in patients with diabetes, hypertension, pelvic infection or a previous pelvic operation. 14 As has been shown, not only is the evidence comparing preoperative radiotherapy to an operation alone somewhat problematic but there also is a price to be paid for the administration of preoperative radiotherapy. This includes late radiation damage, delay of the completion of treatment, increased surgical complications, immunosuppression, interference with chemotherapy and, of course, expense. There is reason to doubt even the theoretic rationale for this program. The evidence for diminished implantability of tumor cells after low dose radiotherapy can best be described as inconclusive. Demonstration of this effect has been most variable and depends on dose levels, the tumor studied and the animal model in which the study is done. The postulated decreased implantability of cells after low dose radiotherapy of bladder cancer is far from established. In relation to this it is of interest that the national cooperative study demonstrated no reduction of local pelvic recurrence of bladder carcinoma after the use of preoperative radiotherapy for cystectomy. 15 A particularly devastating piece of evidence arguing against the effectiveness of the radiotherapy regimen in prolonging survival was provided by its greatest advocates. In virtually every series they observed that even in those patients in whom the tumors responded to x-ray by disappearance or diminution survival was not improved if the original tumor was of a lower stage than T3(B2C). If the apparent beneficial effect of the radiotherapy on the responder group was owing to destruction or inhibition of the cancer it certainly should have been observed in the patients with stages Tl(A) and T2(Bl) lesions. Its failure to have such an effect may provide a clue to the reason for the improved survival in those patients with stage T3(B2C) lesions that did diminish. If two-thirds of the patients treated with preoperative radiotherapy respond by diminution or disappearance of the lesion and the responder group has a vastly improved prognosis, then the over-all survival advantage in irradiated patients should not be subtle but striking and apparent within 2 years, when most deaths occur. This obvious condition for acceptance of preoperative radiotherapy has not been met. What actually is seen is that the over-all survival rate of the preoperative radiotherapy group when compared to the group with cystectomy alone, as in the cooperative national study, is approximately equal. Therefore, both patient populations consist of some patients for whom the prognosis is good and some patients for whom it is poor. In the patient group receiving preoperative radiation the favorable patients have bee~ identified as those in whom the lesions responded to radiation treatment. Who these patients are in the group receiving cystectomy alone is not clear. However, since there has been no demonstration that they are less prevalent than the favorable group receiving radiotherapy their identification becomes important. Stated differently, the question may be asked why does the patient with a stage T3(B2C) tumor that diminishes after radiotherapy do better than the patient in whom the tumor does not show such a response? Is it the radiation effect? If it were, and as many as two-thirds of the group were so blessed, then the over-all survival rate of irradiated versus non-irradiated patients should be strikingly better and this has not been shown. In addition, since radiation is known to be more effective against lower stage lesions, this effect should be noted at least as impressively in the patients with stages Tl(A) and T2(Bl) tumors as it is in those with

RADIOTHERAPY AND BLADDER CANCER

stage T3(B2C) tumors. This is demonstrably not so. Can it be that radiotherapy and the subsequent observation of tumor response simply serve as a method of patient selection? Consider that the patient group being studied has shown a level of clinical understaging of >40 per cent in most series. Consider, also, the likelihood that those tumors that disappear after radiotherapy are unlikely to be those that were understaged initially. Remember that an understaged T3(B2C) lesion must be a stage T4(D) tumor, and this tumor is highly unlikely to be gone at the time of exploration. Thus, the favorable group of patients with stage T3(B2C) lesions undergoing cystectomy alone may comprise primarily those patients in whom the tumors were staged accurately or perhaps even overstaged. They may well resemble largely those patients in the radiotherapy population in whom the tumors disappeared. This may be a major factor in the observation of improved survival among those patients responding to radiotherapy. They may simply be primarily those in whom the tumors were not understaged and, in addition, the irradiation also may be selecting out those lesions with lesser malignant potential. This is suggested further by the observation that preoperative radiotherapy may only be beneficial with papillary tumors as opposed to the usually more malignant sessile lesions. Thus, the unresolved question is whether radiotherapy actually affects prognosis or is simply an indicator of favorable tumor either by revealing those patients who were not understaged or those patients in whom the tumors were less active biologically. This discussion has not dealt specifically with the differences between long course and short course preoperative radiotherapy. The latter usually involves regimens consisting of the delivery of 1,600 to 2,000 rad over 4 to 5 days followed almost immediately by an operation. Short course preoperative radiotherapy has been shown to be as effective as long course preoperative therapy and to avoid many of the complications of radiotherapy. However, the case for either technique as an improvement in the management of carcinoma of the bladder is not supported by the data for the reasons detailed. Therefore, short course radiotherapy may be simply no more ineffective than long course therapy. However, the considerably lesser morbidity of short course therapy may allow it to become established in therapeutic regimens without appropriate critical evaluation. REFERENCES 1. Miller, L. S. and Johnson, D. E.: Proceedings: megavoltage irradiation for bladder cancer: alone, postoperative or preoperative? Proc. Natl. Cancer Conf., 7: 771, 1973. 2. Whitmore, W. F., Jr., Batata, M.A., Ghoneim, M.A., Grabstald, H. and Unal, A.: Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J. Urol., 118: 184, 1977. 3. van der Werf-Messing, B.: Carcinoma of the bladder treated by preoperative irradiation followed by cystectomy: the second report. Cancer, 32: 1084, 1973. 4. van der Werf-Messing, B. H.P.: Carcinoma of the bladder T 3NxMo treated by preoperative irradiation followed by cystectomy. Cancer, 36: 718, 1975. 5. Whitmore, W. F., Jr., Batata, M. A., Hilaris, B. S., Reddy, G. N., Unal, A., Ghoneim, M.A., Grabstald, H. and Chu, F.: A comparative study of two preoperative radiation regimens with cystectomy for bladder cancer. Cancer, 40: 1077, 1977. 6. Reid, E. C., Oliver, J. A. and Fishman, I. J.: Preoperative irradiation and cystectomy in 135 cases of bladder cancer. Urology, 8: 247, 1976. 7. Miller, L. S.: Bladder cancer. Cancer Bull., 25: 57, 1973. 8. Pearse, H. D., Reed, R. R. and Hodges, C. V.: Radical cystectomy for bladder cancer. J. Urol., 119: 216, 1978. 9. Richie, J.P., Skinner, D. G. and Kaufman, J. J.: Radical cystectomy for carcinoma of the bladder: 16 years of experience. J. Urol., 113: 186, 1975. 10. Wallace, D. M. and Bloom, H.J. G.: The management of deeply infiltrating (T3) bladder carcinoma: controlled trial of radical radiotherapy versus preoperative radiotherapy and radical cystectomy (first report). Brit. J. Urol., 48: 587, 1976.

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11. Hoppe, R. T., Fuks, Z. Y., Strober, S. and Kaplan, H. S.: The longterm effects of radiation on T and B lymphocytes in the peripheral blood after regional irradiation. Cancer, 40: 2071, 1977. 12. Nishio, S., Horii, A., Morikawa, Y., Kawakita, J., Nishijima, T., Kishimoto, T. and Maekawa, M.: Studies of the nonspecific cellular immune response in patients with urinary bladder carcinoma. Invest. Urol., 16: 336, 1979. 13. Brosman, S., Elhilali, M., Vescera, C. and Fahey, J.: Immune response in bladder cancer patients. J. Urol., 121: 162, 1979. 14. Green, N., Iba, G. and Smith, W.R.: Measures to minimize small intestine injury in the irradiated pelvis. Cancer, 35: 1633, 1975. 15. Prout, G. R., Jr., Slack, N. H. and Bross, I. D. J.: Preoperative irradiation as an adjuvant in the surgical management of invasive bladder carcinoma. J. Urol., 105: 223, 1971.

EDITORIAL COMMENT The arguments advanced in this review are based on the observation that no carefully controlled studies comparing cystectomy alone versus cystectomy and preoperative radiation therapy have been done. Therefore, the question is raised as to whether results with cystectomy alone might not be at least as good as cystectomy plus preoperative radiation therapy. If the reason for posing this question is to ask whether radiation therapy does any good at all, I believe this can be answered affirmatively. Approximately 66 per cent of patients with invasive bladder cancer are downstaged 1• 2 and 25 per cent are downstaged to Po.2 The latter group of patients have been found to have a better prognosis than those in whom tumor remains in the surgical specimen. 3 In addition, preoperative radiation has been shown to prevent wound implantation of tumor cells at subsequent open operation (reference 4 in article). 4 Therefore, while it is not at all clear that the delay to operation as a result of radiation therapy permits distant dissemination of disease, it is conceivable that preoperative radiation therapy might prevent dissemination of tumor cells at operation by reducing the viability of the cells that are potentially spread (a course of 4,000 rad is expected to kill 90 per cent of the tumor cells present). 5 Studies in other systems have shown that preoperative radiation may, indeed, be effective in increasing over-all survival or decreasing recurrence. In a recent controlled randomized blind study in which 500 rad were administered preoperatively to patients with rectal carcinoma, survival in patients with Duke stage C lesions was prolonged definitely." Of interest in this study was the fact that when over-all results were examined initially it appeared that no benefit had been obtained. A benefit was only appreciated when patients had been broken down into different groups. This factor might well be relevant in an analysis of patients with bladder cancer. What is needed is a means by which that group of responsive patients can be identified. It would be a mistake to disregard a modality that has been found to be therapeutically effective. Rather, we should attempt to define that group of patients in which radiotherapy is most effective and determine how this modality can be most efficiently and selectively used. Michael J. Droller Brady Urological Institute The Johns Hopkins Hospital Baltimore, Maryland 1. van der Werf-Messing, B.: Carcinoma of the bladder treated by preoperative irradiation followed by cystectomy. Cancer, 32: 1084, 1973. 2. Prout, G. R., Jr.: The surgical management of bladder carcinoma. Urol. Clin. N. Amer., 3: 149, 1976. 3. Slack, N. R. and Prout, G. R., Jr.: The heterogeneity of invasive bladder carcinoma and different responses to treatment. J. Urol., 123: 644, 1980. 4. van der Werf-Messing, B.: Carcinoma of the bladder treated by suprapubic radium implants. Eur. J. Cancer, 5: 277, 1969. 5. Hall, E. J.: Radiology for the Radiologist. New York: Harper & Row, Inc., 1978. 6. Rider, W. D., Palmer, J. A., Mahoney, L. J. and Robertson, C. T.: Preoperative irradiation in operable cancer of the rectum: report of the Toronto trial. Canad. J. Surg., 20: 335, 1977.

REPLY BY AUTHOR There is little to object to in the editor's modest defense of preoperative radiotherapy. It is of interest that the data of Prout to which he refers shows the 5-year survival rate of those patients who were