Treatment of Infiltrating Bladder Cancer by Cobalt60 Radiation: Recurrence of Tumor in Bladder after Initial Disappearance

VoL 101, Jmw

T'nE JoUHNc\.l, OF UROLOGY

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Copyright© 1D69 by T!Je Willian,s & Wilkins Co.

TREAT~\JENT OF INFILTRATING BLADDER CANCER BY COBAI/rrrn RADIATION: RECURRENCE OF TUMOR IN BLADDER AFTER INITIAL DISAPPEARANCE HAINER 1\L ENGEL, RAUL C. URTASUN, IIUGII .J. JEWETT

AND

STEWART J. LOTT

From the James Buchanan Brady Urological lnslitute ancl /he Division of Radiotherapy, Department of Radiology, The Johns Hopkins Hospital, Baltimore, Marylancl

the American Committee, would br substituted as follows:

Megavoltage radical radiation therapy of infiltrating bladder cancer can oft.en cause it to disappear from cystoscopic view. l~nfortunately, a significant number of cancers treated in this manner recur at variable intervals. Therefore, it is apparent that some bladders appearing normal on cystoscopy after radiation do harbor hidden nests of tumor cells deep in their wall. This hypothesis led us to study the results of radiation in a selected group of patient~ with bladder cancer.

Stage A. Stage B1 .. Stage B2 and str,ge G. Extension and fixati011.

MATERIAL

From January 1960 to December 1967, 125 patients with infiltrating bladder cancer received treatment with megavoltage radiotherapy. Of these, 62 patients were treated radically for eradication of the disea,,e and, of this sub-group, only 21 patients fulfilled the following criteria: histological diagnosis of infiltrating bladder cancer, single course of cobalt 60 therapy, no other radiotherapeutic or chemotherapeutic procedure, followup cystoscopy about 2 months after completion of radiotherapy and thereafter at 3-month intervals and bladder availability in toto [or histological sectiorn; obtained by cystectomy or autopsy. :\IBTHODS

Pre-irradiation histology specimens ,vere obtained by transurethral resection or open routes and classified according to the TN1\f system as suggested by Jewett and associates who state: "the four distinguishing characteristics of a tumor (stage, pattern, grade, lymphatic permeation) furnish its identity as completely as is possible by routine hi.~tological techniques .... The conversion of these four basic characteristics of a tumor to the TN_:\I system, as proposed by the International Union Agai1rnt Cancer, is not difficult. The T categmy, as recommended b)· Accepted for publication A ngust 6, HJ(\8. 85U

Tl T:Z

The three remaining characteristics may be lll·· eluded as a subscript, using first the initial letter of the cell type (T = transitio11al, S = squamous,. U = undifferentiated, A = adenocarcinorrw,) Then comes the numeral indicating the grade of malignancy, and finally the letter L with a plus or minus sign to signify whether the local have been invaded." 1 This scheme ~ives a com· plete pathological identification of the tant characteristics of each tumor. The majority of the patients were treated with the theratron isocentric eobalt 60 unit. All received between 5,500 and 6,500 rads maximum tumor dose (normalized to the 100 per cent isodose), in 25 treatments and in an oYer-all time of 5 weeks, using a 240 degree are rotation tech· nique. The cobalt 60 Eldorado unit was used in the patients treated in the early yearn, using one anterior and two oblique fields and pin and arc technique. The waiting period between transmethral resection and beginning of radiotherapy was at least 2 weeb. This was clone to avoid risk of bladder complications if treated too soon after surgical manipulation. Anteroposterior and lateral cystograms were performed the clay before treatment for localization JJlll'lJOSc>s and for cBtirnation of volume of treatment a11cl depth. The average radius was obtained by nwasuri11g depth with the isocentric unit at every 1.5 degree 1 Jewett, H.J., King, L. R and Shelley, \V. i\L A study of 3(15 cases of infiltrating bladder cancer relation of certain pathological clrnrncteristic,s to prog11osis after extirpation. J. U rol., 92: CiG8, Hlt\4

860

ENGEL AND ASSOCIATES TABLE

1

Cystoscopy Pt. No.

4 5

8 10 11 12 13 14 15 16

17 18 19

20 21

JHH No.

811351 851414 1143827 978414 517458 1224248 1002750 008334 1234577 231071 1195103 1189307 1214704 1139567 984490 1220212 1214527 227787 1014600 1192302 206918

TNM Classif.

Tlt2LTlt2LTlt21,Tlt2LT2tsL+

T3t2LT3s2L+

T3t3LT2-3tsLT3tsLT3t:
T2-3taL+ T3t,L+ T2-3ts3LT2-3t,sL+ T2-3t
Init. Post. Co6o

Neg. Neg. Neg. Pos. Neg. Pos. Neg. Neg. Neg. Pos. Pos. Neg. Neg. Pos. Neg. Pos. Neg. Pos. Pos. Pos. Neg.

Tumor In Tumor Out Followup Bladder Spec. of Bladder Pos. Neg. Pos. Pos. Neg. Pos. Pos. Pos.

Pos. Pos. Pos. Pos. Pos.

Pos. Neg. Pos. Pos. Pos. Pos. Pos. Neg.

Distant Metast.

+ + + + + + + + + + + + + + + + +

+

+

+ + + + + + + + + + +

+ + + +

Dead

+· + +· + + + + + + + +· + + + + + +·

Alive

+ +

+

+

* Death not related to bladder cancer.

along the 240 degree arc sector and obtaining an average. Contour of patient drawing the 100 and 90 per cent isodose distribution was also done in each case. The tumor dose rate was obtained from precalculated tumor dose rate tables. The entire bladder, as seen in the cystogram, with a 2 cm. margin, was encompassed in the volume of treatment. The 240 degree arc rotation technique was used in those cases without evidence of extravesical extension. The field size did not exceed 10 by 10 cm. in these cases. No urinary diversions were done before radiotherapy; cystectomy was performed when the followup cystoscopy showed persistence of tumor or recurrence in those patients in whom the tumor initially had disappeared after radiotherapy. RESULTS

Of the 21 patients suitable for this followup study, the distribution was as follows: stage Tl, 4 patients; T2, 1 patient; T3, 15 patients and T4, 1 patient. The T3 group also includes those patients in whom the biopsy specimens did not yield enough muscle to exclude invasion into the deep muscle layers; therefore, they were classified as T2 to 3. Tables 1 and 2 show the results of the cystoscopic followup in these patients. Initial cystoscopy after cobalt 60 therapy was negative in 12 patients. The remaining 9 patients had gross

TABLE

TNM Classif.

2. Cystoscopic behavior of tumors .following Co'° No. of Pts.

Tumor Persist.

Never Tumor

2

Tlt2L-

T3t2L+

11 11

T3tsLT3t,L+

6\ 4 r15

T3ts3LT3ts3L+

~I

T3t
1J

T4aL-

0

0

T2tsL+ T3t2L-

Init. Neg. Later Pos.

~1

f1

~J

o)

ns

~1

~( l)' 0

evidence of persistent tumor. Followup of the 12 patients whose bladders were initially free of tumors on cystoscopic examinations showed tumor recurrence in 8 cases. The longest interval between disappearance and recurrence was 3 years, in a patient with a T2 to 3t3L--tumor; the shortest interval was 2 months in a patient with a Tlt2L--tumor. In 4 patients cystoscopy showed that the bladder was normal, and the bladder specimens were also free of tumor on microscopic examination. One each was staged as Tl, T2, T3 and T4 (patient 2, 5, 15 and 21). In 2 of these patients lymphatic invasion was present at the time of their initial biopsy. One of

'l'REA'l'ME?sT OF INFIL'J'RATING BLADDltR CANCER BY COBALT 60 RADIATION

Survival Time Of Deceased Pts. Following Bladder Spec. Survival No. Pts. - - - - - - - - -----·-----Free Tumor Dead Alive

%

Co 60

~ Pis.

T1 Group-4 Pts. ITlt21,-l Persist. tumor Persist. free

l

l

1

Init. neg. but later rncur.

2 T2 Group-! Pt. [T2t2I

2

:.I

Persist. tum.or Persist, .free Init. neg. but

0

2

3

4

5

Time In Years

later recur.

"' Died from cause other than Ca.

TABLE

Pts.

Persist. tumor Persist. free Init. neg. but later recur.

4:

Bladder Spec. -------· Free Tumor

Survival Dead

Alive

T3 Group-·15 Pts 8 8 0

6 15

14

13

T1 Group -·1 Pt. [T4aL-l

Persist. tumor Persist. free Init. neg. cysto. but later recur.

these, despite a bladder free of tumor, died with metastatic disease involving liver and lungs (patient 15). None of these 4 patients showed any r,umor nests below the bladder mucosa on multiple sections. The bladder biopsy before cobalt 60 therapy failed to show lymphatic permeation in 13 of 21 natients but in 6 of these the tumor was found ~ubsequ~ntly to have grown outside the bladder. Disease outside the bladder was seen in 12 of 21 patients, and distant metastases were found in 5 patients (Nos. 3, 15, 16, 19 and 20). Tables 3 and 4 show our findings of the complete TNM classification groups. No fistula or bowel gangrene was observed in this small series; however, 2 patients died of complications following cystectomy. One patient died of peritonitis; the other of septicemia. Survival time of the 17 deceased patients in our series after radiotherapy is shown in the .figure. Four patients had cystectomy only a few months ago and are, therefore, not included in this

correlation. The average survival time for patients in stage T3 was 2.2 years, with the survival time 4 years and the n1onths., DISCUSSION

Of the total group of 21 patients, 12 had nonrwJ bladders on cystoscopy after radiation. In 8 of these, later cystoscopic examination showed recurrent tumor and, in the final bladder sn.P0.,m,m cancer was found in the bladder walL not statistically significant, this is strong presumptive evidence that negative findings may not be reliable evidence for the absence of tumor. Galleher and associates reported on 7 with negative post-irradiation biopsies who had tumor in their subsequently excised bladders.? The combination of negative biopsy with subse-· quent finding of cancer in the specimen seems to support our hypothesis that negative cystoscopy after irradiation therapy is not a reliable index of presence or absence of residual disease. vVe have not encountered as many po.stoperative complications as have been reported Galleher and associates 20 3 and by Whitmore.' However, our operative mortality rate of 2 of 21 2 Galleher, E. P., Jr., Young, J. D,, Jr., Beyer, 0. C., Bloedorn, F. G. and Dow, J.: Supravoltage irradiation followed by cystectomy for bladder cancer. J. Urol., 93: 598, 1965. . 3 Galleher, E. P., Jr., Young, J. D,, Jr., J. J., Wizenberg, M. J. and Bloe_dorn, F_. G< followup study of supervoltage 1rradmt10n followed by cystectomy for bladder cancer. .J UroL, 99: 59, 1968. . . 4 Whitmore, W. F., Jr.: Experience with pre-operative irradiation combined with cystectomy in the treatment of bladder cancer. In: XIII Congres de la Societe Internationale d'Urologi~ . Edited by J. D. Fergusson. ~ondon: E;: & S. Livingstone Ltd., vol. 2, pp. lb2-165, 196n.

862

ENGEL AND ASSOCIA'rES

patients is essentially the same as that in the Galleher series. \Vhitmore gives a 3-year survival in patients receiving 4,000 rads followed by immediate cystectomy as 4 of 9 patients for stage T2 to 3; Galleher and associates report 7 of 15 patients for the same stage. Our survival rate for the 3-year period for patients in stage T3 is only 3 of 13 patients. Five of 21 patients had metastatic disease proved by autopsy and, in 4 of these lymphatic invasion was demonstrated in the initial biopsy. Four of the 5 patients showed residual cancer in the bladder, whereas 1 had distant metastases without persistence of the bladder tumor, thus confirming our suspicions that although local disease rnay be eradicated with radiation, distant microscopic spread may already have been established. It should be noted that in a few patients there was a long interval between the initial diagnosis of bladder cancer and cobalt 60 therapy, and there also has been a variable time interval between radiation and cystectomy. Cystectomy was done in 7 patients one year after radiation and in 2 patients as late as 3 years afterwards. Spread of the disease through the perivesical area was demonstrated in 12 patients, but only in 6 of these was lymphatic spread seen in the pretreatment biopsy. Six of these 12 patients were among those whose bladders showed tumor recurrence after varying intervals of apparent tumor eradication after radiotherapy. We believe that this fact again is strongly in favor of our theory, that tumor after radiotherapy may be hidden deep within the bladder wall and not show on cystoscopy, while at the same time growing actively in the deep tissue layers and perhaps even disseminating. It would be desirable to correlate this conver-

sion from absence to presence of tumor on cystoscopy with the initial stage and grade of the tumor and the subsequent microscopic findings of the excised bladder specimens (tables 3 and 4). With a series as small as ours this is not feasible. However, we hope that our study will serve as a stimulus to others to evaluate their data in a similar manner. SUMMARY AND CONCLUSION

The cystoscopic behavior of infiltrating bladder cancer was evaluated in 21 patients who were treated with radical cobalt 60 therapy. The cystoscopic followup was correlated to the microscopic sections of their bladder specimens, which were obtained subsequently by cystectomy or autopsy. In 12 patients, cystoscopic disappearance of the tumor was seen 2 to 3 months after radiotherapy. Tumor reappeared in 8 of these. Permanent cystoscopic eradication was observed in 4 patients; in these, the bladder specimens were negative. The high incidence of conversion from postirradiation normal bladders to regrowth of tumor indicates that in many cases viable tumor cells or cell-nests keep growing within the bladder wall after radiotherapy and cause subsequent reappearance and spread outside of the bladder. Although the results of this retrospective study are suggestive, more convincing data and wellplanned prospective studies should be accumulated in order to support the routine use of cystectomy for bladders that appear cystoscopically normal after radiation. Furthermore, the study suggests in view of the absence of significant radiation damage that preoperative radiation, when indicated, should be at the cancericidal radical dose level of 5,500 to 6,500 rac!s within 5 weeks.