Bladder carcinoma Results with preoperative radiation therapy and radical cystectomy

SCIENTIFIC

BLADDER

CARCINOMA

Results with Preoperative and Radical Cystectomy MICHEL

A. BOILEAU,

DOUGLAS RAFAEL MARIO

ARTICLES

M.D.

E. JOHNSON, C. CHAN,

Radiation Therapy

M.D.

M.D.

0. GONZALES,

M.D.

From the Departments of Urology and Radiotherapy, The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas

ABSTRACT - The records of 159 patients treated with preoperative radiotherapy and radical cystectomy were reviewed to ascertain the influence on survival rates and disease-free intervals of tumor stage, tumor grade, tumor appearance, lymphatic permeation, history of previous bladder tumors, and downstaging (pathologic stage < clinical stage). Knowledge of grade, tumor appearance, lymphatic invasion, and history of previous bladder tumors did not make possible an accurate prediction of response to integrated therapy. However, both downstaging and the absence of muscle invasion were associated with signi,flcantly improved survival rates and disease-free intervals. ____ _______~~_ -~

The role of integrated therapy in the treatment of bladder carcinoma remains controversial. Early experience with radiotherapy or surgery alone resulted in five-year survival rates, approximating 20 per cent, for patients with invasive tumors. l-3 Consequently, MacKenzie, \Vhitmore, and Nickson initiated studies evaluating the combined use of radiotherapy and cystectomy in treating bladder cancer.4 In 1970 they reported a crude five-year survival rate of 40 per cent for patients with Stage B, or Stage C disease who had been treated preoperatively with 4,000 rads followed by cystectomy and pelvic lymphadenectomy.5 In 1973 their experience Miller and Johnson’ reported with integrated therapy, employing 5,000 rads in five weeks followed six weeks later by radical cystectomy without pelvic lymph node dissection, They achieved a five-year survival rate of 53 per cent for patients with clinical Stage B2 or Stage C disease.

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Further experience with integrated therapy has led to the realization that preoperative irradiation reduces the extent of disease present in the bladder in the majority of patients who have invasive tumors, resulting in downstaging. The cystectomy specimen from approximately one third of the patients so treated has no evidence of viable tumor.7Vg Survival rates are significantly higher for patients in whom downstaging has occurred. Recently Prout, Griffin, and Shipley” reported that papillary invasive lesions are the tumors which predominantly respond to preoperative irradiation, as opposed to solid invasive tumors which do not. They suggested that preoperative irradiation may be worthwhile only for a small, specific group of patients. If their findings can be substantiated, then identifying those factors that will predict a given patient’s response to preoperative irradiation, and limiting its use to those patients who can be

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expected to benefit, would greatly enhance the efficacy of integrated therapy. We have therefore evaluated our experience at 41. D. ,4nderson Hospital and Tumor Institute to define more clearly the role of combined radiotherapy and cystectomy. Material

and Methods

The records of I59 patients with bladder carcinoma who underwent preoperative irradiation followed by radical cystectomy and ileal conduit urinary diversion at this center between January 1, 1969, and December 30, 1977, were reviewed. One hundred thirty-one were men and 28 were women, yielding a maleto-female ratio of 5: 1. Each patient was assigned a stage classification based both on the system originally proposed by Jewett and Strong” and later modified by Marshall,” and on that recommended by the American Joint Committee for Clinical Staging and End-Result Reporting. l3 It should be emphasized that assignment to a clinical stage higher than 0 or A required histologic proof of muscle invasion, whether or not bimanual examination revealed thickening or a mass. Techniques for clinical staging have been described in previous publications6*7 and include a history and physical examination, a chest roentgenogram, complete skeletal survey, bilateral pedal lymphangiography, serum multiple analysis (SMA), complete blood count, and urinalysis. Excretory urography did not influence staging. Using the three-grade system defined by Mostofi, Sobin, and Torlain, and the World Health Organization, l4 grade was determined by examining the preirradiation biopsy specimen. The distinction between papillary and solid tumors was made at the time of staging endoscopy. Radiotherapy consisted of external irradiation with 25 me\’ x-rays delivering 5,000 rads in 25

570

fractions over five weeks. Anterior and posterior fields were 10 by 12 cm.; lateral fields were 10 by 10 cm. This provided adequate coverage of the entire bladder, prostate, prostatic urethra, anterior wall of the rectum, distal ureter, and medial and intermediate divisions of the external iliac alld hypogastric lymph nodes. After the patient had rested for six weeks, a single stage radical cystectomy as defined by Whitmorel5 and an ileal conduit urinary diversion without pelvic lymphadenectomy were performed. The cystectomy specimen was examined carefully for evidence of residual tumor. The pathologist’s report identified the presence or absence of lymphatic permeation in the pretreatment biopsies and cystectomy specimens. Results Forty-seven patients were clinically assigned to Stage 0 or A, 29 to Stage Bl, 38 to Stage Bz, and 45 to Stage C. One hundred forty-seven patients had transitional cell carcinomas, 10 had squamous carcinomas, and 2 had adenocarcinomas. Ninety-one patients are alive and free of disease, four to one hundred-five months after treatment. Eleven patients are alive with distant metastases and 2 are alive with local recurrence. Eleven patients have died of locally recurrent disease and 29 of distant metastases (Table I). Seventy per cent of locally recurrent disease and 80 per cent of distant metastases occurred within two years. Fifteen patients have died without evidence of tumor. Six of these succumbed to treatment complications which included, in 1 patient each, pelvic abscess, wound dehiscence, unexplained electrolyte abnormalities, and an enteric fistula, and in 2 others. a small-bowel obstruction. Two patients have died because of lymphoma, 2 as a

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L-.-

B

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hGURE 1. (A) Stirvival r&T related to nonincasice disease (Strlge O,A) and invasive clisensc (Stage Bi, 132, C). (B) Survival rates r&ted to clinicul stqy. (C) Disease:free intervals related to clinicnl stage.

result of myocardial infarction, 1 with congestive heart failure, and 1 with chronic obstructive pulmonary disease. One man died in a motor vehicle accident, and the cause of death of the other 2 patients remains unknown. Survival rates and disease-free intervals, as influenced by the various parameters, were determined by the method of Berkson and (;age. 16,17

patients having histologic proof of muscle invasion showed statistically significant dif‘ferences (p = 0.003: Fig. 1A). However, there were no statistically significant differences in survival rates among patients with Stage BI, B2, or C disease (p = 0.52: Fig. 1B). Muscle invasion significantly shortened the disease-free interval (p = 0.04), but th e d ep tl 1 o f muscle invasion did not have a significant effect (Fig. ICI).

1 njluence

Influence

of stage

A comparison of survival curves between patients with noninvasive disease (Stage 0,A) and

After mained

of clowrwtnging irradiation no malignant disease rein 56 patients (35 per cent), whereas

I-J

12

36

24

4660

Months

FIGURE 2. (A) Survicul r&es related to response to preoperative irradintion. irrdution increased ~survivul rates both in patients with no evidence of muscle invnsion (B) untl itr those lcith proved mucle invasion (C).

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1.0

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FIGURE 3. (A) Diseme-free intercals related to rcspo~w to preoperr~tiw irradiation. Respnse to preoperative irradiation lengthened disease-free interds both in patient.7 with no evidence of muscle invasion (Bj and in those with proved mrrscl~ incclsion (C ).

there was evidence of residual malignanq~ in 103 patients (65 per cent). The relationship between tumor eradication and stage is shown in Table II. Those patients whose cystectomy specimen contained no residual tumor showed a significant improvement in survival rates over those patients whose cystectomy specimen contained viable tumor (p = 0.008). Patients with no residual tumor had a 90-per cent two-year

survival rate, while the two-year survival fog patients with residual disease was 72 per cent (Fig. 2A). The prognostic significance of tumor eradication was evident whether the patient had noninvasive (Fig. 2B: p = 0.03) or invasive malignant disease (Fig. 2C: p = 0.015). Similarly, the disease-free interval was greatly enhanced for those patients whose bladders were tumor-free (Fig. 3A). Again, this beneficial effect was clearly evident whether the patients had superficial (Fig. 3B) or invasive disease (Fig. 3C). This d’ff 1 ‘erence in disease-free interval approached significance both in patients with superficial lesions (p = 0.09) and in those with muscle invasion (p = 0.07).

II. Response to preopemtice rcdiatior~ therapy related to clinical .stagc of tumor*

TABLE

Stage

No. of Patients

0

8

A Bl

39 29

BS

38

C

45

“Figures

Residual Tumor

No Residual Tumor

6 (75) 21(54) 17 (59) 25 (66) 34 (76)

in pnwntlwaea

indicatr

TABLE

Stage

2 18 12 13 11

Lymphatic invasion was noted in 44 patients (Table III). Patients in whom lymphatic involvement was demonstrated only in the preoperative specimen had better survival rates (Fig. 4A) and longer disease-free inten,als (Fig. 4B) than those

per ctvlt

Relationship

III.

of lymphatic

prrmeatiorl

to clir~icd stage of’ tumor

~~~ --~---Evidence of 1,ymphatic Invasion~‘~~~-~~~ Preoperative Postoperativr Both None Unknown

0

0

A Bl B2 C

5 5 9 3

,.Figures

(25) (46) (41) (34) (24)

(12.h) (17.2) (23.71 (6.7)

in parenth~~v~\

Indic~utc

0

0

4 (10.3) 0 :3 (7.9) 8 (17.8!

0 2 (6.9) :3 (7.9) 2 (4.41

0 5 7 6 11

[12.8) (24.1) (15.8) (24.4)

8 25 15 17 21

(100) (64.1) (51.7) (44.7) (46.7)

pm cwt.

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TABLE Stage -__-

Relationship of tumor appearance to clinical stage*

IV. Papillary

0 A B1

3 (38) (28)

11

8 (28)

B2

4 (10)

C

2 (4)

*Figures

in parentheses

Both

Solid

2 (25) 14 (36) 9 (31) 20 (W

26 (58) indicate

2 (25) 3 (8)

(28)

9 (31)

3 WY

8 (21) 3 (7)

6 (16) 14 (31)

Znjluence

per cent.

of tumor

appearance

The relationship of tumor appearance to the stage of disease is shown in Table IV. Sixty-five per cent of the tumors in this series were either solid in appearance or combined solid and papillary, whereas 18 per cent were exclusively papillary. Residual tumor was present in the

TABLE

Residual Tumor

15 45 25 18

Papillary Solid Both Unknown *Figures

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V. Relationship of tumor appearance to response to preoperative irradiation*

Tumor Appearance

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13 (46) 26 (37)

(W

10 (36)

indicate

*Figures

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bladder

tumors

patients (19 per cent) had history of previous bladder

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a docucancer.

Incidence of tumor grade” Number of Patients

2 (1.3)

I II III Indeterminate

7 (22)

VOLUME

grade

Grade

per cent.

1980 /

of previous

TABLE

No Residual Tumor

(63) (78)

of histologic

All but 2 of the patients in this series had tumors that were moderately or poorly differentiated (Table VI). The grade of tumor produced no statistical difference in survival rate (p = 0.31) or disease-free interval (p = 0.52) for patients with noninvasive lesions. Likewise, histologic grade did not influence survival rate (p = 0.66) or disease-free interval (p = 0.90) for those patients with muscle invasion.

who had tumor present in lymphatics postoperatively. These differences were statistically significant (p = 0.002). Influence

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cystectomy specimens of 68 per cent of those patients with solid or combined tumors and in 54 per cent of those with papillary lesions (Table V). There was no statistically significant difference in either rate of survival (p = 0.37: Fig. 5A) or disease-free interval (p = 0.45: Fig. 5B) for patients when categorized by tumor appearance.

Unknown

1 (12) 11

40

FIGURE 4. (A) Survival rates related to lymphatic invasion in preoperative biopsies or post-cystectomy specimens.

in parentheses

51 (32.1) 95 (59.7) 11 (6.9) indicate

per cent.

573

Survival rate (1) = 0.61) and discasc-t;.cc intcr\2ls (p = 0.40) were not significantly influenced by previous lesions, regardless of whethel inuscle invasion was present or uot.

U’idespread experience with integrated therapy has led to the obser\,ation that Maddel carcinomas vary in their response to prcoperati\,e radiotherapy. \‘an der Flierf- Messing”~‘x has suggested that combined therapy is of value only for patients with T3 lesions a1~1that the addition of cystectomy for those with Tl and T2 lesions offers no demonstrable advantage ovel definitive radiation therapy alone. Our results have not supported this conclusion. Although we have not randomized patients with superficial disease into those treated hy cystectom) alone and those treated with combined preoperative irradiation and cystectomy, ollr finding of an 80-per cent five-year srmival rate foi these patients would appear better than the 40 per cent achieved with radiation therap)alone.” Likelvisc, the %-per cent five-yciii survival rate of our patients mith ‘K2 lesions treated l)y iutegrated therapy c~cecds thrx SOper cent rate of patients treated with radiation therapy alone.’ The depth of muscle invasion does Ilot appeal to influence survival. There wxs no significant differeiice in the five-year sllrvi\xl rates among patients with clinical Stage HI. H2, or C tlisease. This finding is supported 111, Richic. Skinner, and Kauf~mm~” who reported a JO-per cent fi\fc-year survival rate for patients with

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caithcr Stage HI or B2 lesion\ treated \vith cystectoniy. Tutnor eradication hy preoperative radiotherapy appears to have a marked impact on sllrvival rate. As seen in Table II, tumor disappeared in 24 to 46 per cent of our patients depending on the stage of the disease; and Figure 2 illustrates that m,hen patients had negative c!.stectomy specimens (PO). both survival rates and disease-free intervals increased. Thesr~ findings support those of others who have reported up to SO-per cent five-)car survival rates for patients with PO cystectomy specimens. xz” Slack and Prout”’ have claimed that preoperati\Te transurethral resection of the bladder tumor was responsible for 10 per cent of PO specimens. thus accomplishing therapeutic as well as diagnostic results. Obviously this could he true only for small well-localized lesions. The advantage of preoperative irradiation is that it eradicates tumors of various stages and sizes, and may destroy microextensions and regional lymphatic metastases. However. the dose of preoperative radiotherapy is important; \Vliitmore cut(11.“’ hare reported downstaging in only 27 per (tent of patients rccei\fing 2,000 rads, as opposed to the 73 per cent downstagiiig noted in the M. 11. Anderson series using 5,000 Ids.

“”

In 1X6 Baker”’ demonstrated that the degree of lymphatic permeation within the bladder wall mm related to the depth of infiltration. In patients with infiltration half-way through muscle, 66 per cent had lymphatic iuvolvrrnent in a diameter tmm times the diameter of the tumor base. FVhen the primary tumor penetrated more

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than half way through the bladder muscle, lymphatic involvement was evident in 60 per cent of the bladder wall circumference. Earlier Marshall’2 had demonstrated the close relationship between nodal metastases and depth of invasion. Recently Slack and Prout*” reported that lymphatic invasion appeared to influence survival, but that in most instances lymphatic permeation was associated with solid tumors which tended to be invasive and radioresistant. The present series suggests that lymphatic permeation per se does not indicate a poor prognosis when preoperative radiotherapy is administered. Additionally, Wallace and Bloom*” reported that the expected 40 to 50-per cent incidence of lymph node involvement in patients with invasive bladder carcinoma was reduced to 23 per cent by preoperative radiation therapy. It seems clear that radiation therapy can eradicate tumor in lymphatics and that patients so treated benefit with increased survival rates. It has been suggested that tumor appearance, papillary or solid, directly influences response to radiotherapy and thus affects survival rates and disease-free intervals. Prout et (11.I” have stated that papillary tumors respond to radiation therapy but solid tumors do not, so that integrated therapy benefits only those patients with papillary lesions. Slack and Prout”’ reported an 80-per cent five-year survival rate for patients with papillary lesions, no lymphatic permeation, and tumor-free cystectomy specimens, and a 20per cent five-year survival rate for patients with solid lesions, lymphatic permeation, and residual neoplasm in the bladder. In our series, however, we could not prove a significant difference in survival rates or disease-free intervals based on tumor appearance. Admittedly, only 18 per cent (28) of our patients had purely papillary lesions, but 54 per cent of them, as well as 68 per cent of patients with solid or combined lesions, had residual tumor in their cystectomy specimens. It is axiomatic that high-grade, poorly differentiated lesions are more aggressive, metastasize earlier, and result in decreased survival. Propheticallv, in 1926 Broders*’ stated, “The time is not tar distant when not only physicians but also the patients and their relatives, as well as life insurance companies, will be interested in the grade of malignancy of cancer.” However, histologic grade does not appear to be related to response to radiation therapy. Fletcher*” has hypothesized that all epithelial tumor cells

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have the same radiosensitivity, and the difference in tumor responses is due to tumor vohlme and the relative complement of anoxic cells. Our study and those of Van der We&blessing*’ agree that, with integrated therapy, histologic grade does not significantly influence survival rates or disease-free intervals. Theoretically, the evaluation and the treatment of previous bladder tumors could result in tumor gaining access to blood vessels, lymph channels, or the perivesical space with subsequent deleterious effect on survival or disease-free intervals after later definitive treatment. However, although 19 per cent of OUI 159 patients had had previous bladder tumors treated, we could discern no significant effect on either survival rates or disease-free intervals. The idea of avoiding cystectomy for those bladders in which tumor disappears due to radiotherapy is attractive but dangerous, as reports by Sagerman et ~1.~~ and Engle et (11.“” demonstrate. Sagerman et (11. described 2 patients with negative histologic evaluation after 3,000 rads external radiation therapy in whom radiotherapy was then carried to 6,000 rads in lieu of surgery. Both suffered recurrence in less than a year. Engle et (11.*’ described 12 patients who had a partial cystectomy after apparent disappearance of tumor due to preoperative radiation therapy; 6 of them suffered recurrence. These reports suggest that irradiation may eradicate invasive cancer but does not change the potential for tumor formation in any given patient’s bladder. In addition, it is difficult to stage a patient accurately after radiation therapy. Van der Werf-Messing27 reported that although 21 patients had a persistent palpable mass after 4,000 rads external radiotherapy, the cystectomy specimen of nine revealed only a fibrotic mass and no viable tumor. The idea of reserving preoperative radiation therapy for those patients who will predictabl) benefit is worthwhile. However, our findings do not yet allow us to discriminate clearly between those patients who will respond to radiation therapy and those who will not. Thus we cannot support the suggestion that cystectomy alone is as good as integrated therapy, tbven fol those patients who have solid tumors and demonstrated lymphatic permeation prior to any treatment. Department ot’ Urology 6723 Bertner Avenue Houston, Texas 77030 (DR. JOHNSOiV)

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!iCKNOWLEDGMENT.

excellent retrieval.

assistance

with

To Mary computer

Jane Oswald programming

for and

her data

References 1. Bowles WT, and Cordonnier JJ: Total cystectomy for carcinoma of the bladder, J, Urol. 90: 731 (1963). 2. Crigler CM, Miller LS, Guinn GA, and Schillaci HG: Radiotherapy for carcinoma of the bladder, ihid. 96: 55 (1966). 3. Whitmore WF Jr, and Marshall VF: Radical total cystectomy for cancer of the bladder: 230 consecutive cases five years later, ibid. 87: 853 (1962). 4. MacKenzie AR, Whitmore WF Jr, and Nickson JJ: Supervoltage x-ray therapy for bladder cancer, Cancer 18: 1255 (1965). 5. Whitmore WF Jr: Preoperative irradiation with cystectomy in management of bladder cancer, in Vaeth JM, Ed: Frontiers Radiation Therapy and Oncology, Basel, Karger, 1970, vol. 5, pp. 231-239. 6. Miller LS, and Johnson DE: Megavoltage irradiation for bladder cancer: alone, postoperative or preoperative? Natl. Cancer Conf. Proc. 7: 77? (1973). 7. Chan RC. and lohnson DE: Intezrated therapv for invasive bladder carcinoma: experience with 108 patients, Urology 12: 547 (1978). 8. DeWeerd JH, Colby MY Jr, Myers RP, and Cupps RE: Cystectomv after radiotherapeutic ablation of invasive transitional &I1 cancer; J, Urol. 118: 260 (1977). 9. Van der Werf-Messing B: Carcinoma of the bladder treated by preoperative irradiationfollowed by cystectomy: the second rep&t, Cancer 32: 1084 (1973). 10. Prout GR Jr, Griffin PP, and Shipley WC’: Bladder carcinoma as a systemic disease, ibid. 43: 3532 (1979). 11. Jewett HJ, and Strong GH: Infiltrating carcinoma of the bladder: relation of deuth of Denetration of the bladder with incidence of local extehsion aid metastases, J. Urol. 55: 366 (1946). 12. Marshall VF: The relation of the preoperative estimate to the pathologic demonstration of the extent of vesical neoplasms, ibid. 68: 714 (1952). 13. American Joint Committee on Cancer Staging and EndResults Reporting: Clinical Staging System for Carcinoma of the Urinary Bladder, Chicago, 1967. 14. Mostofi FK, Sobin LH, and Torlain H: Histological Typing

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of Urinary Bladder Tumors, Geneva, World Health Organization, 1973. 15. Whitmore W’F: Total cystectomy. in Cooper EH, and Williams RE, Eds.: The Bioloev and Clinical Management of Bladder Cancer, Oxford, EnglanYd, Oxford Scientific P&cations, 1975, p. 193. 16. Berkson J, and Gage RP: Calculation of survival rates for cancer, Proc. Staff Meet. Mayo Clin. 25: 270 (1950). 17. IDEM: Survival curie for cancer patients following treatment, J. Am. Stat. Assoc. 47: 501 (1952). 18. Van der Werf-Messing B: Preoperative irradiation followed by cystectomy to treat carcinoma of the urinary bladder category Ta Nr, O-4Mo, Int. J. Rad. Oncol. Biol. Physics 5: 395 (1979). 19. Ritchie JP, Skinner DG, and Kaufman JJ: Radical cystectomy for carcinoma of the bladder: 16 years’ experience, J. Ural. 113: 186 (1975). 20. Slack NH, and Prout GR Jr: The heterogeneity of invasive bladder carcinoma and different responses to treatment, ibid. 123: 644 (1980). 21. Whitmore WF Jr, et ul: A comparative study of two preoperative radiation regimens with cystectomy for bladder cancer, Cancer 40: 1077 (1977). 22. Miller LS: Bladder cancer: superiority of preoperative irradiation cystectomy in clinical Bz and C, ibid. 39: 973 (1977). 23. Baker R: Correlation of circumferential lymphatic spread of vesical cancer with depth of infiltration: relation to present methods of treatment, 1. Urol. 73: 681 (1955). 24. Wallace DM, and Bloom HJG: The management of deeply infiltrating jTa) bladder carcinoma: controlled trial of radical radiotherapy versus preoperative radiotherapy and radial cystectomy (first report), Br. J. Ural. 48: 587 (1976). 25. Broders AC: Carcinoma: grading and practical application, Arch. Pathol. 2: 376 (1926). 26. Fletcher GH: Clinical dose response curves of human malignant epithelial tumours, Br. J. Radio]. 46: 1 (1973). 27. Van der Werf-Messing B: Carcinoma of the bladder, T3N .M o, treated by preoperative irradiation followed by cystectomy (third report of the Rotterdam Radio-therapy Institute), Cancer 36: 718 (1975). 28. Sagerman RH, et ul: Preoperative irradiation for carcinoma of the bladder, AJR 102: 577 (1968). 29. Engle R.M, Urtasum RC, Jewett JH, and Lott SJ: Treatment of infiltrating bladder cancer by cobalt 60 radiation: recurrence of tumor in bladder after initial disappearance, J. Ural. 101: 859 (1969). . I

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