- Email: [email protected]
Invasive bladder carcinoma managed by irradiation and surgery
.-
INVASIVE
BLADDER
IRRADIATION
JAMES JOSEPH
MANAGED
ARTICLE
BY
AND SURGERY
H. DEWEERD,
MALCOLM
CARCINOMA
SCIENTIFIC
Y. COLBY,
W. SEGURA,
M.D. JR.,
M.D.*
DAVID
C. UTZ,
M.D.
ROGER
E. CUPPS,
M.D.
M.D.
From the Department of Urology and Division Mayo Clinic and Mayo Foundation, Rochester,
of Therapeutic Minnesota
Radiology,
_ ABSTRACT - Four hundred forty-four patients with invasive vesical carcinoma were entered in a nonrandomixed treatment program of preoperative irradiation and surgical extirpation of the primary lesion. Fifteen of the patients did not undergo surgery, and an additional 13 we’re found at operation to have an inoperable lesion. Thus, 416 patients, at risk for more than two years, were available for statistical study. Pathologic findings constitute the basis for the calculation of crude survival rates. Five-year survival for 107 patients without residual carcinoma was 66 per cent, approximating the 71 per cent for the 160 patients with low-stage carcinoma. By contrast, 149 patients with high-stage carcinoma had a fke-year survival of 31 per cent. The need for a yet undefined adjuvant modality is evident.
Although the effort to stage the urothelial cancer clinically was recorded in all cases, an attempt to tabulate these efforts statistically failed, because significant inconsistencies existed in the interpretations of findings and conclusions regarding stage as recorded by various urologists. Similarly, although muscle invasion was evident in each instance, recognition of the many possibilities for error in obtaining and processing transurethrally procured or open (or both) surgical specimens made a decision about the precise depth of penetration unreliable in many instances. Thus, any attempt to present a statistical analysis of definite clinical stage becomes invalid. Patients were excluded from the present study if massive local extension or distant metastasis was detected or if concomitant physical, physiologic, or psychologic disease, as determined and evaluated by specialty consultation, precluded a vigorous therapeutic effort, Since failure to cope successfully with this malignancy usually becomes evident within twelve to eighteen months, we included only patients treated more than two years ago. Therefore, data on 444 patients (372 males and 72
The utilization of preoperative irradiation followed by surgical extirpation to improve the heretofore dismal survival of patients with infiltrative urothelial vesical carcinoma has gained widespread, but not universal, acceptance during the past two decades.lm7 Since we treated our first patient in 1958, 527 patients have been managed in a nonrandomized treatment program incorporating these two modalities. Previous publications describe the principles of the prospective protocol we have followed and cite the results achieved in 341 patients treated. *-lo Material
and Methods
As of July 1, 1980, 527 patients (including the 341 previously described) with pathologically confirmed evidence of locally operable, primary invasive bladder carcinoma were entered into the protocol.
*Died September 9, 1979.
UROLOGY
/ NOVEMBER
1982 I
VOLUME
XX, NUMBER
5
471
TABLE I. Treatment of 444 patients with invasive bladder carcinoma * No. of Patients
Treatment
15
Protocol incomplete (radiotherapy only) No operation - metastasis Refused operation Died during radiation treatment - metastasis Died - anesthesia induction - cardiac Medically disqualified Protocol complete (radiotherapy and surgery) Radiotherapy and surgical excision Radiotherapy and palliative diversion Radiotherapy and exploration TOTAL *Atrisk twenty-four
months
9 3 1 1 1 429 416 2 11 444
or more.
after an interval of approximately six weeks and was preceded by repeat cystoscopic examination and bimanual pelvic examination under anesthesia. Sixty-three patients were placed in the group 2 treatment program for several reasons but mainly because the intensity of their bladder symptoms precluded a prolonged (approximately twelve weeks) preliminary treatment phase. These patients received a concentrated three- to five-day course of 1,800 to 2,400 rad delivered through smaller portals to the empty bladder. Operation followed in one to five days. Total cystectomy, pelvic lymphadenectomy, and urinary diversion (done in one stage in all but 4 patients) was performed on 383 patients, and partial cystectomy and pelvic lymphadenectomy was done on 33 patients. In 13 patients, the operation was terminated when inoperable disease was encountered. Four hundred sixteen patients in whom surgical extirpation of the primary lesion was accomplished form the basis for statistical analysis.
Results females; ratio 5.2:1) at risk for twenty-four months or more form the basis for this report. Fifteen patients did not complete the protocol, leaving 429 patients as the basis for statistical analysis (Table I). In our series, 429 patients who were at risk for twenty-four to 238 months were placed into two categories according to the treatment program they received. In group 1, 366 patients with
grade 2, 3, or 4 (Broders classification) urothelial carcinoma of the bladder each received irradiation averaging 4,800 rad delivered to the bladder and adjuvant pelvic lymph nodes through large portals averaging 15 by 15 cm. A split-dose techThe two twelve-day to nique was used. fourteen-day courses were separated by a two- to three-week rest period. Operation was planned
TABLE II. Pathologic findings
Effects
of irradiation
The beneficial effect of the irradiation was evident at cystoscopy in the great majority of group 1 patients. Findings varied considerably from residual erythema and apparent thickening of mucosa to necrosis and ulceration of residual tumor. Bimanual examination findings were generally unchanged from those noted previously. The technical aspects of the surgical procedures were, by our observations, not influenced b, preliminary x-ray treatment. Pathologic findings Final determination of cellular type, grade, and stage of the urothelial cancer was made on the surgical specimen (Table II). One hundred seven of 366 patients (29%) who received split-
in 416 patients with invasive bladder carcinoma* Stage (JeweWTNM)
Grade (Broders) 1 2 3 4 TOTAL
O/pcis
21 27 2 50
A/p,
8 30 1 39
6/P,
J%/Paa
11 49 5 65
4 42 17 63
D/P,
C/P,b
1 28 33 62
19 11 30
Total 0 45 195
*At risk twenty-four months or more. t No residual carcinoma in 107 patients.
472
UROLOGY
/ NOVEMBER 1982
/
VOLUME
XX, NUMBER
5
TABLE
dose therapy had no residual carcinoma at surgical extirpation. Eighty-five per cent of 309 residual cancers were high-grade lesions (grade 3 or 4), and 50 per cent persisted as high-stage lesions (Stage (B2/Paa, C/P,,,, or D/P,). Fifty patients had carcinoma that persisted as carcinoma in situ. Complications,
morbidity,
and mortality
Postoperative problems paralleled those ordinarily anticipated after major operative proce,dures of similar scope. Early and late complications, as well as morbidity, will be considered in depth in a separate article. Acknowledging that the distinction between major and minor complications is ill-defined, we considered that eightyfive major postoperative surgical and medical complications required forty additional surgical procedures for corrections of mainly bowel obstructions and wound disruptions. Seven patients died in the hospital or within thirty days of operation if dismissed from the hospital, for an operative mortality of 1.6 per cent. Associated
urethral
carcinoma
Urethral cancer was diagnosed in 20 of 374 male patients (5.3%). Urethrectomy was performed simultaneously with cystectomy in 4 patients and subsequently (two to six years later) in 16: 7 of these 20 patients died; two deaths were considered due to invasive urethral carcinoma. Survival One hundred ninety-six patients died (Table III); 3 were lost to follow-up, leaving 217 of 413 traced patients alive. One hundred twenty-six died of urothelial cancer, and 12 died of a protocol-related disease process. Sixteen died of a second malignancy. Crude survival statistics for 107 patients with no residual carcinoma found at surgery closely parallel those for 160 patients with low-grade (grade 2) or high-grade (grade 3 or 4), low-stage (Stage A/P, or B,/PJ lesions with five-year survival rates of 66 per cent and 71 per cent, respectively (Table IV). A striking contrast was noted: the five-year survival of the 149 patients with high-grade (grade 3 or 4), high-stage (Stage BJ Psa, C/P,,, or D/P,) lesions was only 31 per cent (Table IV). Th e crude percentage survival curves are graphically illustrated in Figure 1. Comment Contrary to published that bladder carcinoma
UROLOGY
/ NOVEMBER1982
opinions, we believe is, like many other
/ VOLUMEXX,NUMBERS
of
deaths in 196 patients III. Causes with invasive bladder carcinoma Cause
Related to carcinoma and treatment (145 patients) Hospital deaths Cardiovascular-renal failure Gastrointestinal hemorrhage Perforated viscus Deaths attributed to protocol Bowel obstruction Abscess and sepsis Hepatitis Renal failure Recurring urothelial cancer Other (51 patients) Nonmalignant disease Myocardial disease Pulmonary embolus Intestinal disease (misc.) Cerebrovascular accident and respiratory failure Suicide Unknown Secondary malignancy Pulmonary Lymphosarcoma Miscellaneous (colon, hematologic, renal) TOTAL
No. of Patients
7 5 1 1 12 3 3 3 3 126 35 16 4 4 3 1 7 16 6 1 9 196
malignancies, extremely variable and unpredictable. Ordinarily the lesion is not difficult to diagnose, but often it defies the urologist’s best effort to stage it clinically, thus adding support to those who consider the disease to be a systemic one.’ Although our treatment protocol was not randomized, we consider this of no consequence in the analysis because we believe it is impossible to predetermine accurately the clinical stage or match bladder locations and extent, to predetermine radiosensitivity, or to resolve the enigma of host-tumor relationship factors that are required for valid randomization. It was increasingly apparent that, as we cautiously added patients to this combined treatment program, the potential for improved long-term survival was significant. We believe that the homogeneous atmosphere of a single institution largely negates intradisciplinary differences in interpretation, diagnosis, treatment, and data interpretation. We have, therefore, adhered to the thesis that each patient represents an individual entity who is entitled to weigh our advice and, hopefully, benefit from a radiologist’s and surgeon’s attack on his potentially devastating health problem.
473
%
survival
80
-
60
-
4.
-
416 pts. 107 pts. - no residual
20
160 pts. - low-high-stage, low-grade
_
ca
149 pts. - high-stage, high-grade
I
0
I
0
I
I
I
I
4
2
I
I
6
Years
1
8
L 10
at risk
FIGURE 1. Comparison of survival among 416 patients with invasive bladder carcinoma managed by irradiation and surgery. H = low-high-stage, low-grade; X = no residual carcinoma; 0 = all patients; A = high-stage, high-grade.
TABLE
IV.
Survival of 416 patients treated for invasive bladder carcinoma Patients Surviving
Period at Risk (Yr.) 2 3 4 5 6 8 210
Length of Survi& (Yr.) No residual 2 3 4 5 6 8 210 Low-grade
High-grade, 2 3 4 5 6 8 310 *Numbers
in parentheses
high-stage 2 3 4 5 6 8 210
represent
%
(107 patients) 107 96 (2)* 89 80 62 49 35
93 80 66 53 38 27 15
87 83 74 66 61 55 43
low-stage (160 patients) 160 140 141 114 126 93 109 77 92 (l)* 55 62 34 50 25
88 81 74 71 60 55 50
carcinoma (149 patients) 149 74 137 61 120 39 105 33 94 25 67 16 46 8
50 45 33 31 27 24 17
patients lost to follow-up during preceding
Groups 1 and 2 did not derive from purposeful attempts to introduce variations in a treatment form for comparative purposes. Group 2 consisted of a small number of the patient population
474
No.
carcinoma
or high-grade, 2 3 4 5 6 8 210
2 3 4 5 6 8 210
At Risk
*
interval.
under consideration who were different from patients in group 1 only in that, at the time of presentation at our clinic for treatment, the intensity of their usual symptoms (for various reasons)
UROLOGY
/
NOVEMBER
1982
/
VOLUME
XX, NUMBER
5
seemed to preclude a long presurgical treatment period. Data on group 2 were included in the determining of a composite survival rate of the entire series, and they were not considered a randomized segment whose survival could be compared with that of group 1 patients. Nor do we believe that group 2 patients should be excluded because of this variation in management, since we do not know in advance what level of radiosensitivity a given tumor will have. The operative effort reported in this series is one that deals with the surgical extirpation of the malignant lesion. It is evident that the principles of good cancer surgery require that total cystectomy be performed in most cases. In isolated cases, however (33 in this report), the size and position of the malignant lesion allowed wide resection of the cancer. Such segmental resection, coupled with pelvic lymphadenectomy, in our opinion may provide the same potential for control as total cystectomy does, while retaining a measure of continued bladder and prostate function. The variable radiosensitivity of individual vesical carcinomas has been responsible for the reduction in size and extent of some lesions and the physical disappearance of others when treated solely by irradiation. These responses, or the downstaging of the lesion, have been supported by post-treatment clinical observation or, when surgery was performed, by pathologic staging. Since we were unable to tabulate reliably pretreatment clinical stages, we have no statistical evidence to support downstaging in a given percentage of cases. However, all patients had muscle invasion confirmed by biopsy before the therapeutic effort was initiated; thus, 10 per cent of the 416 patients in group 1 with muscle invasion had their lesions downstaged to no residual cancer. Fifty additional lesions were downstaged to residual in situ carcinoma.. Malignant cells can be found in situ, adjacent to invasive cells of the same degree of dedifferentiation. We believe that continued (or new) growth of in situ cancer adds credence to the generally accepted thesis that irradiation is ineffective in the management of carcinoma in situ. Continuous scrutiny of this series during the past twenty years has confirmed the widely accepted impression that there is a distinct difference in survival, depending on the actual depth of penetration of the carcinoma, that is, the stage. While the stage can be determined with reasonable accuracy using microscopic examination, it seems fallacious to categorize other than As a consuperficial or deep muscle penetration.
UROLOGY
/
NOVEMBER
1982
/
VOLUME Xx, NUMBER 5
results were related to three sequence, categories: no residual, low stage, and high stage. The grading of cancer cells depends on the pathologist’s evaluation or opinion of the degree of cellular differentiation and may be, therefore, less consistent than staging. It was immediately apparent that all the high-stage lesions were high grade, whereas low-stage lesions, while predominantly high grade, included a few lower grade carcinomas. Considerable progress has been made in improving survival for patients with invasive carcinoma. While survival for the group with highstage lesions is equal to, or better than, survival in all categories two to three decades ago, a great challenge for the future resides in finding a way to improve survival for this group of high-risk patients. Perhaps ways of augmenting the hosttumor relationship will be found, or, more realistically, the identification of an effective chemotherapeutic agent or agents. It would appear that, beyond improvements in irradiation administration and surgical techniques, improved survival will accrue with the use of adjuvant chemotherapy. In vitro laboratory identification of the sensitivity of an individual tumor to chemotherapeutic agents, alone or in combination, l1 may contribute by guiding clinical trials. Rochester,
Minnesota 55905 (DR. SEGURA)
References 1. Whitmore WF Jr, et al: Preoperative irradiation with cystectomy in the management of bladder cancer, AJR 102: 570 (1968). 2.. Galleher EPJr, et al: Pre-cystectomy radiation for caminoma of the bladder: 17-vear exoerience. T Urol 118: 179 (1977). 3. Miller LS: Bladder &ricer: superiority of preoperative irradiation and cystectomy in clinical stages B.r and C, Cancer 39: 973 (1977). 4. Cummings KB, et al: Observations on definite cobalt 66 radiation for cure in bladder carcinoma: 19year followup, J Ural 115: 152 (1976). 5. Whitmore WF Jr, et al: A comparative study of two preoperative radiation regimens with cystectomy for bladder cancer, Cancer 40: 1077 (1977). 6. Miller LS, and Johnson DE: Megavoltage irradiation foi bladder cancer: alone, postoperative, or preoperative? Proc Nat1 Cancer Conf 7: 771 (1972). 7. Slack NH, and Prom GR Jr: The heterogeneity of invasive bladder carcinoma and different responses to treatment, J Urol 123: 644 (1980). 8. DeWeerd JH, and Colby MY Jr: Bladder carcinoma: combined radiotherapy and surgical treatment, JAMA 199: 109 (1967). 9. IDEM: Invasive vesical carcinoma treated by preoperative radiotherapy and operation, J Urol 107: 51 (1972). 10. DeWeerd JH, Colby MY Jr, Myers RP, and Cupps RE: Cystectomy after radiotherapeutic ablation of invasive transitional cell cancer, ibid 118: 266 (1977). 11. Lieber MM, Ames MM, and Kovach JS: Anticancer drug testing in vitro: use of an activating system with the human tumor stem cell assay, Life Sci 28: 287 (1981).
47s
INVASIVE
BLADDER
IRRADIATION
JAMES JOSEPH
MANAGED
ARTICLE
BY
AND SURGERY
H. DEWEERD,
MALCOLM
CARCINOMA
SCIENTIFIC
Y. COLBY,
W. SEGURA,
M.D. JR.,
M.D.*
DAVID
C. UTZ,
M.D.
ROGER
E. CUPPS,
M.D.
M.D.
From the Department of Urology and Division Mayo Clinic and Mayo Foundation, Rochester,
of Therapeutic Minnesota
Radiology,
_ ABSTRACT - Four hundred forty-four patients with invasive vesical carcinoma were entered in a nonrandomixed treatment program of preoperative irradiation and surgical extirpation of the primary lesion. Fifteen of the patients did not undergo surgery, and an additional 13 we’re found at operation to have an inoperable lesion. Thus, 416 patients, at risk for more than two years, were available for statistical study. Pathologic findings constitute the basis for the calculation of crude survival rates. Five-year survival for 107 patients without residual carcinoma was 66 per cent, approximating the 71 per cent for the 160 patients with low-stage carcinoma. By contrast, 149 patients with high-stage carcinoma had a fke-year survival of 31 per cent. The need for a yet undefined adjuvant modality is evident.
Although the effort to stage the urothelial cancer clinically was recorded in all cases, an attempt to tabulate these efforts statistically failed, because significant inconsistencies existed in the interpretations of findings and conclusions regarding stage as recorded by various urologists. Similarly, although muscle invasion was evident in each instance, recognition of the many possibilities for error in obtaining and processing transurethrally procured or open (or both) surgical specimens made a decision about the precise depth of penetration unreliable in many instances. Thus, any attempt to present a statistical analysis of definite clinical stage becomes invalid. Patients were excluded from the present study if massive local extension or distant metastasis was detected or if concomitant physical, physiologic, or psychologic disease, as determined and evaluated by specialty consultation, precluded a vigorous therapeutic effort, Since failure to cope successfully with this malignancy usually becomes evident within twelve to eighteen months, we included only patients treated more than two years ago. Therefore, data on 444 patients (372 males and 72
The utilization of preoperative irradiation followed by surgical extirpation to improve the heretofore dismal survival of patients with infiltrative urothelial vesical carcinoma has gained widespread, but not universal, acceptance during the past two decades.lm7 Since we treated our first patient in 1958, 527 patients have been managed in a nonrandomized treatment program incorporating these two modalities. Previous publications describe the principles of the prospective protocol we have followed and cite the results achieved in 341 patients treated. *-lo Material
and Methods
As of July 1, 1980, 527 patients (including the 341 previously described) with pathologically confirmed evidence of locally operable, primary invasive bladder carcinoma were entered into the protocol.
*Died September 9, 1979.
UROLOGY
/ NOVEMBER
1982 I
VOLUME
XX, NUMBER
5
471
TABLE I. Treatment of 444 patients with invasive bladder carcinoma * No. of Patients
Treatment
15
Protocol incomplete (radiotherapy only) No operation - metastasis Refused operation Died during radiation treatment - metastasis Died - anesthesia induction - cardiac Medically disqualified Protocol complete (radiotherapy and surgery) Radiotherapy and surgical excision Radiotherapy and palliative diversion Radiotherapy and exploration TOTAL *Atrisk twenty-four
months
9 3 1 1 1 429 416 2 11 444
or more.
after an interval of approximately six weeks and was preceded by repeat cystoscopic examination and bimanual pelvic examination under anesthesia. Sixty-three patients were placed in the group 2 treatment program for several reasons but mainly because the intensity of their bladder symptoms precluded a prolonged (approximately twelve weeks) preliminary treatment phase. These patients received a concentrated three- to five-day course of 1,800 to 2,400 rad delivered through smaller portals to the empty bladder. Operation followed in one to five days. Total cystectomy, pelvic lymphadenectomy, and urinary diversion (done in one stage in all but 4 patients) was performed on 383 patients, and partial cystectomy and pelvic lymphadenectomy was done on 33 patients. In 13 patients, the operation was terminated when inoperable disease was encountered. Four hundred sixteen patients in whom surgical extirpation of the primary lesion was accomplished form the basis for statistical analysis.
Results females; ratio 5.2:1) at risk for twenty-four months or more form the basis for this report. Fifteen patients did not complete the protocol, leaving 429 patients as the basis for statistical analysis (Table I). In our series, 429 patients who were at risk for twenty-four to 238 months were placed into two categories according to the treatment program they received. In group 1, 366 patients with
grade 2, 3, or 4 (Broders classification) urothelial carcinoma of the bladder each received irradiation averaging 4,800 rad delivered to the bladder and adjuvant pelvic lymph nodes through large portals averaging 15 by 15 cm. A split-dose techThe two twelve-day to nique was used. fourteen-day courses were separated by a two- to three-week rest period. Operation was planned
TABLE II. Pathologic findings
Effects
of irradiation
The beneficial effect of the irradiation was evident at cystoscopy in the great majority of group 1 patients. Findings varied considerably from residual erythema and apparent thickening of mucosa to necrosis and ulceration of residual tumor. Bimanual examination findings were generally unchanged from those noted previously. The technical aspects of the surgical procedures were, by our observations, not influenced b, preliminary x-ray treatment. Pathologic findings Final determination of cellular type, grade, and stage of the urothelial cancer was made on the surgical specimen (Table II). One hundred seven of 366 patients (29%) who received split-
in 416 patients with invasive bladder carcinoma* Stage (JeweWTNM)
Grade (Broders) 1 2 3 4 TOTAL
O/pcis
21 27 2 50
A/p,
8 30 1 39
6/P,
J%/Paa
11 49 5 65
4 42 17 63
D/P,
C/P,b
1 28 33 62
19 11 30
Total 0 45 195
*At risk twenty-four months or more. t No residual carcinoma in 107 patients.
472
UROLOGY
/ NOVEMBER 1982
/
VOLUME
XX, NUMBER
5
TABLE
dose therapy had no residual carcinoma at surgical extirpation. Eighty-five per cent of 309 residual cancers were high-grade lesions (grade 3 or 4), and 50 per cent persisted as high-stage lesions (Stage (B2/Paa, C/P,,,, or D/P,). Fifty patients had carcinoma that persisted as carcinoma in situ. Complications,
morbidity,
and mortality
Postoperative problems paralleled those ordinarily anticipated after major operative proce,dures of similar scope. Early and late complications, as well as morbidity, will be considered in depth in a separate article. Acknowledging that the distinction between major and minor complications is ill-defined, we considered that eightyfive major postoperative surgical and medical complications required forty additional surgical procedures for corrections of mainly bowel obstructions and wound disruptions. Seven patients died in the hospital or within thirty days of operation if dismissed from the hospital, for an operative mortality of 1.6 per cent. Associated
urethral
carcinoma
Urethral cancer was diagnosed in 20 of 374 male patients (5.3%). Urethrectomy was performed simultaneously with cystectomy in 4 patients and subsequently (two to six years later) in 16: 7 of these 20 patients died; two deaths were considered due to invasive urethral carcinoma. Survival One hundred ninety-six patients died (Table III); 3 were lost to follow-up, leaving 217 of 413 traced patients alive. One hundred twenty-six died of urothelial cancer, and 12 died of a protocol-related disease process. Sixteen died of a second malignancy. Crude survival statistics for 107 patients with no residual carcinoma found at surgery closely parallel those for 160 patients with low-grade (grade 2) or high-grade (grade 3 or 4), low-stage (Stage A/P, or B,/PJ lesions with five-year survival rates of 66 per cent and 71 per cent, respectively (Table IV). A striking contrast was noted: the five-year survival of the 149 patients with high-grade (grade 3 or 4), high-stage (Stage BJ Psa, C/P,,, or D/P,) lesions was only 31 per cent (Table IV). Th e crude percentage survival curves are graphically illustrated in Figure 1. Comment Contrary to published that bladder carcinoma
UROLOGY
/ NOVEMBER1982
opinions, we believe is, like many other
/ VOLUMEXX,NUMBERS
of
deaths in 196 patients III. Causes with invasive bladder carcinoma Cause
Related to carcinoma and treatment (145 patients) Hospital deaths Cardiovascular-renal failure Gastrointestinal hemorrhage Perforated viscus Deaths attributed to protocol Bowel obstruction Abscess and sepsis Hepatitis Renal failure Recurring urothelial cancer Other (51 patients) Nonmalignant disease Myocardial disease Pulmonary embolus Intestinal disease (misc.) Cerebrovascular accident and respiratory failure Suicide Unknown Secondary malignancy Pulmonary Lymphosarcoma Miscellaneous (colon, hematologic, renal) TOTAL
No. of Patients
7 5 1 1 12 3 3 3 3 126 35 16 4 4 3 1 7 16 6 1 9 196
malignancies, extremely variable and unpredictable. Ordinarily the lesion is not difficult to diagnose, but often it defies the urologist’s best effort to stage it clinically, thus adding support to those who consider the disease to be a systemic one.’ Although our treatment protocol was not randomized, we consider this of no consequence in the analysis because we believe it is impossible to predetermine accurately the clinical stage or match bladder locations and extent, to predetermine radiosensitivity, or to resolve the enigma of host-tumor relationship factors that are required for valid randomization. It was increasingly apparent that, as we cautiously added patients to this combined treatment program, the potential for improved long-term survival was significant. We believe that the homogeneous atmosphere of a single institution largely negates intradisciplinary differences in interpretation, diagnosis, treatment, and data interpretation. We have, therefore, adhered to the thesis that each patient represents an individual entity who is entitled to weigh our advice and, hopefully, benefit from a radiologist’s and surgeon’s attack on his potentially devastating health problem.
473
%
survival
80
-
60
-
4.
-
416 pts. 107 pts. - no residual
20
160 pts. - low-high-stage, low-grade
_
ca
149 pts. - high-stage, high-grade
I
0
I
0
I
I
I
I
4
2
I
I
6
Years
1
8
L 10
at risk
FIGURE 1. Comparison of survival among 416 patients with invasive bladder carcinoma managed by irradiation and surgery. H = low-high-stage, low-grade; X = no residual carcinoma; 0 = all patients; A = high-stage, high-grade.
TABLE
IV.
Survival of 416 patients treated for invasive bladder carcinoma Patients Surviving
Period at Risk (Yr.) 2 3 4 5 6 8 210
Length of Survi& (Yr.) No residual 2 3 4 5 6 8 210 Low-grade
High-grade, 2 3 4 5 6 8 310 *Numbers
in parentheses
high-stage 2 3 4 5 6 8 210
represent
%
(107 patients) 107 96 (2)* 89 80 62 49 35
93 80 66 53 38 27 15
87 83 74 66 61 55 43
low-stage (160 patients) 160 140 141 114 126 93 109 77 92 (l)* 55 62 34 50 25
88 81 74 71 60 55 50
carcinoma (149 patients) 149 74 137 61 120 39 105 33 94 25 67 16 46 8
50 45 33 31 27 24 17
patients lost to follow-up during preceding
Groups 1 and 2 did not derive from purposeful attempts to introduce variations in a treatment form for comparative purposes. Group 2 consisted of a small number of the patient population
474
No.
carcinoma
or high-grade, 2 3 4 5 6 8 210
2 3 4 5 6 8 210
At Risk
*
interval.
under consideration who were different from patients in group 1 only in that, at the time of presentation at our clinic for treatment, the intensity of their usual symptoms (for various reasons)
UROLOGY
/
NOVEMBER
1982
/
VOLUME
XX, NUMBER
5
seemed to preclude a long presurgical treatment period. Data on group 2 were included in the determining of a composite survival rate of the entire series, and they were not considered a randomized segment whose survival could be compared with that of group 1 patients. Nor do we believe that group 2 patients should be excluded because of this variation in management, since we do not know in advance what level of radiosensitivity a given tumor will have. The operative effort reported in this series is one that deals with the surgical extirpation of the malignant lesion. It is evident that the principles of good cancer surgery require that total cystectomy be performed in most cases. In isolated cases, however (33 in this report), the size and position of the malignant lesion allowed wide resection of the cancer. Such segmental resection, coupled with pelvic lymphadenectomy, in our opinion may provide the same potential for control as total cystectomy does, while retaining a measure of continued bladder and prostate function. The variable radiosensitivity of individual vesical carcinomas has been responsible for the reduction in size and extent of some lesions and the physical disappearance of others when treated solely by irradiation. These responses, or the downstaging of the lesion, have been supported by post-treatment clinical observation or, when surgery was performed, by pathologic staging. Since we were unable to tabulate reliably pretreatment clinical stages, we have no statistical evidence to support downstaging in a given percentage of cases. However, all patients had muscle invasion confirmed by biopsy before the therapeutic effort was initiated; thus, 10 per cent of the 416 patients in group 1 with muscle invasion had their lesions downstaged to no residual cancer. Fifty additional lesions were downstaged to residual in situ carcinoma.. Malignant cells can be found in situ, adjacent to invasive cells of the same degree of dedifferentiation. We believe that continued (or new) growth of in situ cancer adds credence to the generally accepted thesis that irradiation is ineffective in the management of carcinoma in situ. Continuous scrutiny of this series during the past twenty years has confirmed the widely accepted impression that there is a distinct difference in survival, depending on the actual depth of penetration of the carcinoma, that is, the stage. While the stage can be determined with reasonable accuracy using microscopic examination, it seems fallacious to categorize other than As a consuperficial or deep muscle penetration.
UROLOGY
/
NOVEMBER
1982
/
VOLUME Xx, NUMBER 5
results were related to three sequence, categories: no residual, low stage, and high stage. The grading of cancer cells depends on the pathologist’s evaluation or opinion of the degree of cellular differentiation and may be, therefore, less consistent than staging. It was immediately apparent that all the high-stage lesions were high grade, whereas low-stage lesions, while predominantly high grade, included a few lower grade carcinomas. Considerable progress has been made in improving survival for patients with invasive carcinoma. While survival for the group with highstage lesions is equal to, or better than, survival in all categories two to three decades ago, a great challenge for the future resides in finding a way to improve survival for this group of high-risk patients. Perhaps ways of augmenting the hosttumor relationship will be found, or, more realistically, the identification of an effective chemotherapeutic agent or agents. It would appear that, beyond improvements in irradiation administration and surgical techniques, improved survival will accrue with the use of adjuvant chemotherapy. In vitro laboratory identification of the sensitivity of an individual tumor to chemotherapeutic agents, alone or in combination, l1 may contribute by guiding clinical trials. Rochester,
Minnesota 55905 (DR. SEGURA)
References 1. Whitmore WF Jr, et al: Preoperative irradiation with cystectomy in the management of bladder cancer, AJR 102: 570 (1968). 2.. Galleher EPJr, et al: Pre-cystectomy radiation for caminoma of the bladder: 17-vear exoerience. T Urol 118: 179 (1977). 3. Miller LS: Bladder &ricer: superiority of preoperative irradiation and cystectomy in clinical stages B.r and C, Cancer 39: 973 (1977). 4. Cummings KB, et al: Observations on definite cobalt 66 radiation for cure in bladder carcinoma: 19year followup, J Ural 115: 152 (1976). 5. Whitmore WF Jr, et al: A comparative study of two preoperative radiation regimens with cystectomy for bladder cancer, Cancer 40: 1077 (1977). 6. Miller LS, and Johnson DE: Megavoltage irradiation foi bladder cancer: alone, postoperative, or preoperative? Proc Nat1 Cancer Conf 7: 771 (1972). 7. Slack NH, and Prom GR Jr: The heterogeneity of invasive bladder carcinoma and different responses to treatment, J Urol 123: 644 (1980). 8. DeWeerd JH, and Colby MY Jr: Bladder carcinoma: combined radiotherapy and surgical treatment, JAMA 199: 109 (1967). 9. IDEM: Invasive vesical carcinoma treated by preoperative radiotherapy and operation, J Urol 107: 51 (1972). 10. DeWeerd JH, Colby MY Jr, Myers RP, and Cupps RE: Cystectomy after radiotherapeutic ablation of invasive transitional cell cancer, ibid 118: 266 (1977). 11. Lieber MM, Ames MM, and Kovach JS: Anticancer drug testing in vitro: use of an activating system with the human tumor stem cell assay, Life Sci 28: 287 (1981).
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