- Email: [email protected]
or radical cystectomy
BLADDER
CANCER IN MEN AND WOMEN TREATED BY
RADIATION
THERAPY AND/OR RADICAL
CYSTECTOMY
M. A. BATATA,
M.D.
M.D.
W. F. WHITMORE
F. C. H. CHU,
M.D.
Y. S. KIM,
B. S. HILARIS,
M.D.
M. Z. LEE,
From the Departments of Radiation Therapy (Urologic Service), Memorial Sloan-Kettering Center, New York
M.D. M.D.
and Surgery Cancer
ABSTRACT
- Four-hundred fifty-one patients with bladder cancer, 348 men and 103 women, were treated by radiation therapy andlor radical cystectomy during the last two decades at Memorial Sloan-Kettering Cancer Center. Radical cystectomy alone was the treatment in 98 men and 39 women. Radical radiation therapy to an average tumor dose of 6,000 rad in six weeks was given to 79 men and 30 women + one year before salvage cystectomy was done for recurrent or persistent tumors. Planned preoperative irradiation was delivered to the true pelvis either 4,000 rad in four weeks in 95 men and 24 women or 2,000 rad in one week in 76 men and 10 women ? six weeks and two days, respectively, before radical cystectomy. Over-all survival and recurrence results in both sexes were similar; 40 per cent of men and 36 per cent of women were alive at five years without recurrence, 45 per cent of men and 48 per cent of women died in f;ve or more years with local andlor distant recurrences, and 21 per cent of men and 15 per cent of women died before five years from causes other than cancer recurrence. Higher$ve-year survival for high clinical stage B2 to DI tumors was noted similarly in the irradiated men (30 per cent) and women (37 per cent) than in the cystectomy alone patients (19 per cent in men and 4 per cent in women). Similar survival rates (52 to 57 per cent) were observed in men and women with low clinical stage 0 to BI tumors treated with or without irradiation.
Previous reports on bladder cancer indicate that the combination of external irradiation and radical cystectomy improved the results as compared to surgery alone.‘-4 The reported series include 348 men and 103 women who underwent radical cystectomy either alone, or after unsuccessful radical radiotherapy, or following planned preoperative irradiation delivered by conventional or shorter regimens. The clinical features, pathologic findings, and therapeutic modalities in men versus women are correlated with the corresponding survival or recurrence results to evaluate such factors in the management of bladder cancer. Material
and Methods
Three-hundred forty-eight women with bladder cancer
UROLOGY
/
JULY 1981
/
men and 103 were treated by
VOLUME XVIII, NUMBER
1
external megavoltage irradiation and/or radical cystectomy at Memorial Sloan-Kettering Cancer Center during 1949 to 1971. Radical cystectomy alone was the treatment in 98 men and 39 women. Radical irradiation5 to an average tumor dose of 6,000 rad in 30 fractions of 200 rad over six weeks was given in 79 men and 30 women who subsequently underwent cystectomy after periods ranging from two months to eight years, mainly because of cancer recurrence or persistence. Planned preoperative irradiation was delivered to the true pelvis either 4,000 rad in 20 fractions of 200 rad over four weeks in 95 men and 24 women or 2,000 rad in 5 daily fractions of 400 rad over one week in 76 men and 10 women; radical cystectomy was performed within four to twelve weeks and one week, respectively. The total dose in the 6,000-rad regimen
15
TABLE
I.
Clinical features in 348 male and 103 female patients
Clinical Presentation
30-40
41-50
51-60 Aqe
61-70
71-80
(years)
FIGURE 1. Age distribution bladder cancer.
of 451 patients with
is equivalent to 1,760 ret and 99 TDF (timedose fractionation),’ and the 4,000-rad regimen is equivalent to 1,170 ret and 66 TDF. The 2,000-rad regimen is equivalent to about 3,000 rad given in 15 fractions of 200 rad over three weeks-850 ret and 48 TDF. The patients underwent cystectomy because their bladder tumors were either diffuse, multiple, rapidly recurrent noninfiltrating or superficially infiltrating cancers, or deeply invasive lesions not suitable for transurethral or segmental resection. The usual procedure was radical cystectomy with bilateral pelvic lymph node dissection in men and women.3-4 There was follow-up of five or more years after treatment or until death in 343 men and 102 women. Five male patients and 1 female patient were lost to follow-up after cystectomy; they were excluded from the survival and recurrence results. Autopsy data were obtained in 56 patients, 44 men and 12 women. Results Clinical
and pathologicfindings
All patients were adults, their ages ranged from thirty to eighty years in men and from thirty-five to seventy-nine in women. The median age was sixty years in men and fiftyeight years in women, with the peak incidence in the sixth and seventh decades in both sexes (Fig. 1). A history of bladder tumor resections was noted in approximately two thirds of men and women (Table I). Pretreatment excretion urography revealed unilateral or bilateral hydronephrosis or nonfunctioning kidney in about one third of male and female patients. Urine cytology usually was positive for malignant cells in patients of both sexes in whom cytologic studies were obtained.
16
Prior tumor resection None TUR, suprapubic or segmental Excretion urography Normal Hydronephrosis or nonfunction Urine cytology Positive for malignant cells Negative, equivocal, or none Bimanual examination Palpable tumor Nonpalpable
TABLE
Men
Women
133 215
43 60
224 124
61 42
218 130
45 58
232 116
70 33
Gross and microscopic findings on pretreatment cystoscopy
II.
Bladder Cancer Type Papillary Solid* Number Solitary Multifocal Size G 4 cm. Larger Histologic grade Low (0, I, II) High (III, IV)
Men
Women
132 216
22 81
234 114
78 25
212 136
59 44
187 161
48 55
*Solid and papillary or solid alone.
The tumor or induration was palpable in almost two thirds of men and women on bimanual examination at the time of staging cystoscopy in anesthetized patients. Cystoendoscopy in both sexes showed that more frequently the tumors were solid or solid and papillary than papillary alone, apparently were more often solitary than multifocal, usually larger than 2 cm. in diameter, and similarly distributed in the bladder, predominantly on one side or the other (Table II). Histologic grading of the cancer on cystoscopic biopsy showed that low grade (0, I, II) or high grade (III, IV) tumors occurred in similar proportions of men and of women. Pretreatment clinical stage of the tumor was estimated according to the gross findings of bimanual palpation and cystoendoscopy under anesthesia and the microscopic depth of invasion seen in multiple biopsies. The distribution of the clinical stages (Table III) was comparable in men and women: 41 to 45 per cent
UROLOGY
/ JULY 1981 / VOLUME
XVIII, NUMBER
1
TABLE
111.
Pretreatment clinical stage and postcystectomy pathologic stage -Clinical 348 Men
Cancer Extent No tumor Low stage O-In situ A-Subepithelial Br- Superficial muscle
0 158
High stage
190
0 42 15 37 106
B2- Deep muscle
-Pathologic Stag348 Men 103 Women
Stag103 Women
31 134 ? ;; 31
6 34 29 52 53
61
183
63
122
35
58
50 18 0 0
18 8 0 0
41 36 46 2
C- Perivesical fat Dr-Adjacent organs Dz-Pelvic lymph nodes Da- Extrapelvic*
4 16 14 21 11 12 18 1
*Lower para-aortic or upper inguinal lymph nodes.
Pathologic (P) versus clinical (T) stage according to methods of treatment
TABLE
IV.
Men
Treatment Cystedomy
alone
Women
98
4 2
(4) (5)
94 37
(96) (95)
6,000 rad + cystectomy
79
30
35 12
(44) (40)
;;
(‘J
4,000 rad + cystectomy
95
24
;q
76
(42) (33) (28) (20)
::
2,000 rad + cystectomy
408 21 2
55 8
(72) (80)
*Pathologic iPathologic
stage lower than clinical stage. stage same as or higher than clinical stage.
had low-stage (0, A, B1) tumors, and 55 to 59 per cent had high stage (B2, C, D1) tumors. Invasive cancers without in situ carcinoma were found in 292 men and 89 women, most of the other patients had invasive cancers with in situ cancers; there were few instances of carcinoma in situ alone. Histopathologically, 332 men and 97 women had transitional carcinoma, 16 men and 6 women had squamous or adenocarcinoma. Postcystectomy pathologic stage determined by histologic examination of the operative specimens showed either no tumor or noninvasive or superficially invasive (Stage 0, A, B1) tumors in 47 per cent of men and 39 per cent of women, and deeply invasive (Stage B2, C, D1-3) tumors in 53 per cent of men and 61 per cent of women (Table III). Extravesical tumor was histologically found only in adjacent male or female pelvic organs such as prostate or seminal vesicles, vagina or uterus (Stage D1) in 10 per cent of men and 12 per cent of women. Pelvic lymph node involvement (Stage D2) was recognized in 13 per cent of men and 17 per cent of women,
/
P 2 Tt No. (%)
39
10
UROLOGY
-P < T*No. (%)
JULY 1931 / VOLUME
XVIII, NUMBER
1
mainly in the obturator and external iliac nodes and less frequently in the common iliac and hypogastric nodes. The pathologic stage was lower than the clinical stage (P < T) in 4 per cent of men and 5 per cent of women in the cystectomy alone group, 44 per cent of men and 40 per cent of women in the 6,000 rad-cystectomy group, 42 per cent of men and 33 per cent of women in the 4,000 rad-cystectomy group, and 28 per cent of men and 20 per cent of women in the 2,000 rad-cystectomy group (Table IV). The pathologic stage was the same as the clinical stage (P = T) in 28 to 61 per cent of men and 30 to 51 per cent of women in the four treatment groups; it was higher (P > T) in 28 to 44 per cent of male and female patients in the four groups. Suruiual
and recwrence
results
Over-all survival determined at five years was 39 per cent in the determinate patients; 40 per cent ( 138/343) in men and 36 per cent (37/102)
17
in women. The five-year survival rates with cystectomy alone were 36 per cent in men versus 26 per cent in women, and with radical or preoperative irradiation before cystectomy the survival rates were 41 to 43 per cent in men versus 38 to 50 per cent in women. About one half of the men and the women with clinically low-stage tumors (0, A, Bi) were alive at five years after cystectomy alone or with prior irradiation (Table V). For clinically high-stage tumors (B2, C, Dl), the five-year survival rates were 19 per cent in men versus 4 per cent in women treated with cystectomy alone and 27 to 35 per cent in men versus 31 to 50 per cent in women treated with precystectomy radical or subradical irradiation. Rates of over-all five-year cancer mortality were 38 per cent (133) in men and 48 per cent (50) in women. Deaths without recurrence under five years from postoperative or later complications or from other causes, occurred in 21 per cent (72) of the men and in 15 per cent (15) of the women. The cancer recurred locally within the pelvis and/or distally outside the pelvis in 44 per cent of the determinate patients; 42 per cent (144/ 343) of men and 49 per cent (50/102) of women. Recurrences were detected within two years in 96 men and 45 women, after two to five years in TABLE V.
Five-year
Treatment Cystectomy 6,000 rad + 4,000 rad + 2,000 rad +
alone cystectomy cystectomy cystectomy
TOTALS*
38 men and 5 women, and after periods longer than five years in 10 male five-year survivors. Pelvic recurrences alone occurred in 17 per cent (60) of men and 23 per cent (24) of women, extrapelvic metastases alone in 16 per cent (54) of men and 18 per cent (18) of women, and local with distal recurrences occurred in 9 per cent (30) of men and 8 per cent (8) of women. Rates of pelvic recurrence alone were 30 per cent in men versus 41 per cent in women treated with cystectomy alone, and 20 to 24 per cent in men versus 20 to 29 per cent in women treated with precystectomy radical or subradical irradiation (Table VI). The incidences of extrapelvic metastases with or without local recurrence were 19 per cent in men versus 28 per cent in women who had cystectomy alone and 23 to 31 per cent in men versus 21 to 40 per cent in women who received prior definitive or preoperative irradiation. Pelvic recurrence in men and women was usually palpable on bimanual examination or at laparotomy, either medially involving mainly soft tissue structures, or laterally on the pelvic wall with or without pelvic bone involvement. Bone, lung, and liver were the most common sites of extrapelvic metastases in both sexes on follow-up investigations, including surgical exploration and autopsy (Table VII).
survival rate according methods of treatment
to clinical stages, and
(Bz, C/Dl) Stage Men Women No. (%) No. (%)
-Low (0, A, Bl) StageMen Women No. No. (%) (%)
-High
26/50 20/32 28150 14/27
(52) (63) (56) (52)
9/16 6/15 618 l/2
(56) (40) (75) (50)
9/47 12/43 12145 17/49
(19) (28) (27) (35)
l/23 S/14 S/16 4/8
(4) (36) (31) (50)
88/159
(55)
22/41
(54)
50/184
(27)
15/61
(25)
*Other5 male and 1 female patients were lost to follow-up. TABLE VI.
Incidence of local or distant recurrence in five more years according to treatment methods
Treatment Cystectomy 6,000 rad + 4,000 rad + 2,000 rad + TOTALS*
alone cystectomy cystectomy cystectomy
Pelvic Only--Women Men No. (%) No. (%)
or
-Extrapelvic Men No. (%)
2 Pelvic;LWomen No. (%)
37/97 15/75 23/95 15/76
(38) (20) (24) (20)
16/39 6/29 7/24 2/10
(41) (21) (29) (20)
18/97 17/75 29/95 20/76
(19) (23) (31) (26)
11/39 6/29 s/24 4/10
(28) (21) (21) (40)
90043
(26)
31/102
(30)
84/343
(24)
26/102
(25)
*Ten male five-year survivors had recurrences later than five years.
18
UROLOGY
I
JULY 1931
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VOLUME XVIII, NUMBER
1
TABLE VII. Extrapelvic
Sites of extrapelvic metastases
Site*
Bone Lung Liver Para-aortic nodes Inguinal nodes Neck nodes Bowel Mesenteric nodes Peritoneum Pleura Brain Chest wall Axillary nodes Adrenal Heart Spleen
Men
Women
29 27 19 8 6 8 7 4 5 5 4 3 2
9
8 4 2 3 0 1 1 0 1 1 0 0
1
1
2 1
0 0
*Patients usually had more than one site involved
Complications and deaths underfive without recurrence
years
Postoperative pelvic sepsis or bleeding and/or wound dehiscence and later bowel fistulas or obstruction by adhesions were the main pelvic complications observed within the irradiated volume and/or operative field of radical cystectomy. The pelvic complications occurred during the postoperative stay in hospital or later without local or distant tumor recurrence in 11 men and 2 women who had cystectomy alone, 7 men arid 3 women who had prior radical radiotherapy, 13 men and 2 women who received conventional preoperative irradiation, and 8 men who were treated with the shorter preoperative radiation regimen. Of these 46 patients (39 men and 7 women), 25 initially had arteriosclerotic cardiovascular disease and/or obesity, 21 had had prior pelvic surgery before cystectomy, and 16 patients had ureterosigmoidostomy or ureterocutaneous diversion on radical cystectomy. Pelvic complications were fatal, mainly due to septicemia or pulmonary embolism, in 25 patients (18 men and 7 women). Other known causes of death within five years without recurrence were mainly cardiovascular or pulmonary diseases in 17 patients (14 men and 3 women) in the cystectomy alone group, 19 patients (15 men and 4 women) in the 6,000 rad-cystectomy group, 14 male patients in the 4,000 rad-cystectomy group, and 9 male patients in the 2,000 rad-cystectomy group. Three other male patients in the preoperative radiation groups died of advanced primary cancers of
UROLOGY I JULY 1931 / VOLUME XVIII, NUMBER 1
the renal pelvis (2) and rectum (1). The majority of these men and women (49/62) initially were older than sixty-five years, or had arteriosclerotic cardiovascular disease or obstructive uropathy before treatment. Comment The men and women with bladder cancer, reported herein, had radical cystectomy either alone, or following unsuccessful radical irradiation, or after planned subradical irradiation given in conventional or shorter regimens. Since the male and female patients in the four groups were neither randomly selected nor concurrently treated, the validity of intergroup comparisons may be questioned. Nonetheless, in the four groups the pretreatment clinicopathologic features, the methods of staging and grading bladder tumors, the criteria of selecting patients for treatment, and the techniques of radical cystectomy3” were basically similar in men and women (Fig. 1; Tables I-III). The cancer downstaging (P < T) in the irradiated men and women increased proportionately (20 to 44 per cent) with increasing total radiation doses; thus it can be attributed to the effects of radiation rather than overestimation of the cancer clinical stage. The greater tendency in men and women was to underestimate clinically (P > T: 28 to 42 per cent) rather than overestimate (P < T: 4 to 5 per cent with cystectomy alone) the extent of the tumor (Table IV). Downstaging of tumors in men and women was less frequent with the 2,000-rad regimen (20 to 28 per cent) than with the higher dose 4,000 or 6,000-rad regimens (29 to 44 per cent); the latter patients underwent cystectomy after longer intervals that allowed more time for further tumor regression. Five-year survival in men and women was similarly higher in patients treated by the various precystectomy radiation regimens than in those patients treated by cystectomy alone. The improved survival results with precystectomy irradiation were consistently evident in the male and female patients, especially in women, with clinically high-stage (B2, C, D1) tumors. By contrast, the five-year survival for clinically low-stage (0, A, Bi) tumors was relatively high with and without precystectomy irradiation (Table V). Thus, precystectomy irradiation, given radically or preoperatively by conventional or shorter regimens, similarly improved the survival in men and women with high-stage tumors.
19
Although the over-all incidence of cancer recurrences was analogous in men and women, the rates of local recurrence within the pelvis were similarly lower in the radically or preoperatively irradiated men and women than in those patients treated with cystectomy alone (Table VI). There was no comparable effect with prior radical or preoperative irradiation on the frequency of extrapelvic metastases in men and women after cystectomy. Distant metastases occurred in similar or higher frequencies in the irradiated men and women relative to the nonirradiated patients in the cystectomy alone group, suggesting that irradiated patients may live without local recurrence to develop distant metastases. The basically similar five-year survival rates, rates of postoperative or later complications and of cancer recurrence or mortality, coupled with the improved rates of survival and pelvic recurrence in the men and women radically or preoperatively irradiated, indicate similar advantageous radiobiologic effects of local radical or preoperative radiation therapy before cystectomy. However, the relatively high incidence of subsequent distant metastases among the male and female patients in the four treatment groups indicates that the local radiation
20
and surgical treatment is inadequate in preventing intrapelvic spread. Adjuvant therapeutic modalities such as chemotherapy and/or immunotherapy might be helpful in the control or prevention of the potential spread in men and women patients with bladder cancer. 1275 York Avenue New York, New York 10021 (DR. BATATA) ACKNOWLEDGMENT. To Mrs. Joan Giacomantonio for preparation of the manuscript. References 1. Batata MA, et al: Patterns of recurrence in bladder cancer treated by irradiation and/or cystectomy, Int. J. Radiat. On&. Biol. Phys. 6: 155 (1980). 2. Whitmore WF, and Batata MA: Preoperative irradiation with cystectomy for bladder cancer, in Johnson DE, and Samuels ML (Eds): Cancer of the Genitourinary Tract, New York, Raven Press, 1979, pp. 89-100. 3. Whitmore WF, et al: Radical cystectomy with or without prior irradiation in the treatment of bladder cancer, J. Ural. 118: 184 (1977). 4. Whitmore WF, et al: A comparative study of two preoperative radiation regimens with cystectomy for bladder cancer, Cancer 40: 1077 (1977). 5. Batata MA, and Hilaris BS: Radiation therapy techniques in uroloaic cancer, in Devine CT, and Strecker IF Jr. (Eds): Urolo& in Practice, Boston, Little, Brown and do., -1978, pp. 785- 792.
UROLOGY
/
JULY 1981
/
VOLUME XVIII, NUMBER
1
CANCER IN MEN AND WOMEN TREATED BY
RADIATION
THERAPY AND/OR RADICAL
CYSTECTOMY
M. A. BATATA,
M.D.
M.D.
W. F. WHITMORE
F. C. H. CHU,
M.D.
Y. S. KIM,
B. S. HILARIS,
M.D.
M. Z. LEE,
From the Departments of Radiation Therapy (Urologic Service), Memorial Sloan-Kettering Center, New York
M.D. M.D.
and Surgery Cancer
ABSTRACT
- Four-hundred fifty-one patients with bladder cancer, 348 men and 103 women, were treated by radiation therapy andlor radical cystectomy during the last two decades at Memorial Sloan-Kettering Cancer Center. Radical cystectomy alone was the treatment in 98 men and 39 women. Radical radiation therapy to an average tumor dose of 6,000 rad in six weeks was given to 79 men and 30 women + one year before salvage cystectomy was done for recurrent or persistent tumors. Planned preoperative irradiation was delivered to the true pelvis either 4,000 rad in four weeks in 95 men and 24 women or 2,000 rad in one week in 76 men and 10 women ? six weeks and two days, respectively, before radical cystectomy. Over-all survival and recurrence results in both sexes were similar; 40 per cent of men and 36 per cent of women were alive at five years without recurrence, 45 per cent of men and 48 per cent of women died in f;ve or more years with local andlor distant recurrences, and 21 per cent of men and 15 per cent of women died before five years from causes other than cancer recurrence. Higher$ve-year survival for high clinical stage B2 to DI tumors was noted similarly in the irradiated men (30 per cent) and women (37 per cent) than in the cystectomy alone patients (19 per cent in men and 4 per cent in women). Similar survival rates (52 to 57 per cent) were observed in men and women with low clinical stage 0 to BI tumors treated with or without irradiation.
Previous reports on bladder cancer indicate that the combination of external irradiation and radical cystectomy improved the results as compared to surgery alone.‘-4 The reported series include 348 men and 103 women who underwent radical cystectomy either alone, or after unsuccessful radical radiotherapy, or following planned preoperative irradiation delivered by conventional or shorter regimens. The clinical features, pathologic findings, and therapeutic modalities in men versus women are correlated with the corresponding survival or recurrence results to evaluate such factors in the management of bladder cancer. Material
and Methods
Three-hundred forty-eight women with bladder cancer
UROLOGY
/
JULY 1981
/
men and 103 were treated by
VOLUME XVIII, NUMBER
1
external megavoltage irradiation and/or radical cystectomy at Memorial Sloan-Kettering Cancer Center during 1949 to 1971. Radical cystectomy alone was the treatment in 98 men and 39 women. Radical irradiation5 to an average tumor dose of 6,000 rad in 30 fractions of 200 rad over six weeks was given in 79 men and 30 women who subsequently underwent cystectomy after periods ranging from two months to eight years, mainly because of cancer recurrence or persistence. Planned preoperative irradiation was delivered to the true pelvis either 4,000 rad in 20 fractions of 200 rad over four weeks in 95 men and 24 women or 2,000 rad in 5 daily fractions of 400 rad over one week in 76 men and 10 women; radical cystectomy was performed within four to twelve weeks and one week, respectively. The total dose in the 6,000-rad regimen
15
TABLE
I.
Clinical features in 348 male and 103 female patients
Clinical Presentation
30-40
41-50
51-60 Aqe
61-70
71-80
(years)
FIGURE 1. Age distribution bladder cancer.
of 451 patients with
is equivalent to 1,760 ret and 99 TDF (timedose fractionation),’ and the 4,000-rad regimen is equivalent to 1,170 ret and 66 TDF. The 2,000-rad regimen is equivalent to about 3,000 rad given in 15 fractions of 200 rad over three weeks-850 ret and 48 TDF. The patients underwent cystectomy because their bladder tumors were either diffuse, multiple, rapidly recurrent noninfiltrating or superficially infiltrating cancers, or deeply invasive lesions not suitable for transurethral or segmental resection. The usual procedure was radical cystectomy with bilateral pelvic lymph node dissection in men and women.3-4 There was follow-up of five or more years after treatment or until death in 343 men and 102 women. Five male patients and 1 female patient were lost to follow-up after cystectomy; they were excluded from the survival and recurrence results. Autopsy data were obtained in 56 patients, 44 men and 12 women. Results Clinical
and pathologicfindings
All patients were adults, their ages ranged from thirty to eighty years in men and from thirty-five to seventy-nine in women. The median age was sixty years in men and fiftyeight years in women, with the peak incidence in the sixth and seventh decades in both sexes (Fig. 1). A history of bladder tumor resections was noted in approximately two thirds of men and women (Table I). Pretreatment excretion urography revealed unilateral or bilateral hydronephrosis or nonfunctioning kidney in about one third of male and female patients. Urine cytology usually was positive for malignant cells in patients of both sexes in whom cytologic studies were obtained.
16
Prior tumor resection None TUR, suprapubic or segmental Excretion urography Normal Hydronephrosis or nonfunction Urine cytology Positive for malignant cells Negative, equivocal, or none Bimanual examination Palpable tumor Nonpalpable
TABLE
Men
Women
133 215
43 60
224 124
61 42
218 130
45 58
232 116
70 33
Gross and microscopic findings on pretreatment cystoscopy
II.
Bladder Cancer Type Papillary Solid* Number Solitary Multifocal Size G 4 cm. Larger Histologic grade Low (0, I, II) High (III, IV)
Men
Women
132 216
22 81
234 114
78 25
212 136
59 44
187 161
48 55
*Solid and papillary or solid alone.
The tumor or induration was palpable in almost two thirds of men and women on bimanual examination at the time of staging cystoscopy in anesthetized patients. Cystoendoscopy in both sexes showed that more frequently the tumors were solid or solid and papillary than papillary alone, apparently were more often solitary than multifocal, usually larger than 2 cm. in diameter, and similarly distributed in the bladder, predominantly on one side or the other (Table II). Histologic grading of the cancer on cystoscopic biopsy showed that low grade (0, I, II) or high grade (III, IV) tumors occurred in similar proportions of men and of women. Pretreatment clinical stage of the tumor was estimated according to the gross findings of bimanual palpation and cystoendoscopy under anesthesia and the microscopic depth of invasion seen in multiple biopsies. The distribution of the clinical stages (Table III) was comparable in men and women: 41 to 45 per cent
UROLOGY
/ JULY 1981 / VOLUME
XVIII, NUMBER
1
TABLE
111.
Pretreatment clinical stage and postcystectomy pathologic stage -Clinical 348 Men
Cancer Extent No tumor Low stage O-In situ A-Subepithelial Br- Superficial muscle
0 158
High stage
190
0 42 15 37 106
B2- Deep muscle
-Pathologic Stag348 Men 103 Women
Stag103 Women
31 134 ? ;; 31
6 34 29 52 53
61
183
63
122
35
58
50 18 0 0
18 8 0 0
41 36 46 2
C- Perivesical fat Dr-Adjacent organs Dz-Pelvic lymph nodes Da- Extrapelvic*
4 16 14 21 11 12 18 1
*Lower para-aortic or upper inguinal lymph nodes.
Pathologic (P) versus clinical (T) stage according to methods of treatment
TABLE
IV.
Men
Treatment Cystedomy
alone
Women
98
4 2
(4) (5)
94 37
(96) (95)
6,000 rad + cystectomy
79
30
35 12
(44) (40)
;;
(‘J
4,000 rad + cystectomy
95
24
;q
76
(42) (33) (28) (20)
::
2,000 rad + cystectomy
408 21 2
55 8
(72) (80)
*Pathologic iPathologic
stage lower than clinical stage. stage same as or higher than clinical stage.
had low-stage (0, A, B1) tumors, and 55 to 59 per cent had high stage (B2, C, D1) tumors. Invasive cancers without in situ carcinoma were found in 292 men and 89 women, most of the other patients had invasive cancers with in situ cancers; there were few instances of carcinoma in situ alone. Histopathologically, 332 men and 97 women had transitional carcinoma, 16 men and 6 women had squamous or adenocarcinoma. Postcystectomy pathologic stage determined by histologic examination of the operative specimens showed either no tumor or noninvasive or superficially invasive (Stage 0, A, B1) tumors in 47 per cent of men and 39 per cent of women, and deeply invasive (Stage B2, C, D1-3) tumors in 53 per cent of men and 61 per cent of women (Table III). Extravesical tumor was histologically found only in adjacent male or female pelvic organs such as prostate or seminal vesicles, vagina or uterus (Stage D1) in 10 per cent of men and 12 per cent of women. Pelvic lymph node involvement (Stage D2) was recognized in 13 per cent of men and 17 per cent of women,
/
P 2 Tt No. (%)
39
10
UROLOGY
-P < T*No. (%)
JULY 1931 / VOLUME
XVIII, NUMBER
1
mainly in the obturator and external iliac nodes and less frequently in the common iliac and hypogastric nodes. The pathologic stage was lower than the clinical stage (P < T) in 4 per cent of men and 5 per cent of women in the cystectomy alone group, 44 per cent of men and 40 per cent of women in the 6,000 rad-cystectomy group, 42 per cent of men and 33 per cent of women in the 4,000 rad-cystectomy group, and 28 per cent of men and 20 per cent of women in the 2,000 rad-cystectomy group (Table IV). The pathologic stage was the same as the clinical stage (P = T) in 28 to 61 per cent of men and 30 to 51 per cent of women in the four treatment groups; it was higher (P > T) in 28 to 44 per cent of male and female patients in the four groups. Suruiual
and recwrence
results
Over-all survival determined at five years was 39 per cent in the determinate patients; 40 per cent ( 138/343) in men and 36 per cent (37/102)
17
in women. The five-year survival rates with cystectomy alone were 36 per cent in men versus 26 per cent in women, and with radical or preoperative irradiation before cystectomy the survival rates were 41 to 43 per cent in men versus 38 to 50 per cent in women. About one half of the men and the women with clinically low-stage tumors (0, A, Bi) were alive at five years after cystectomy alone or with prior irradiation (Table V). For clinically high-stage tumors (B2, C, Dl), the five-year survival rates were 19 per cent in men versus 4 per cent in women treated with cystectomy alone and 27 to 35 per cent in men versus 31 to 50 per cent in women treated with precystectomy radical or subradical irradiation. Rates of over-all five-year cancer mortality were 38 per cent (133) in men and 48 per cent (50) in women. Deaths without recurrence under five years from postoperative or later complications or from other causes, occurred in 21 per cent (72) of the men and in 15 per cent (15) of the women. The cancer recurred locally within the pelvis and/or distally outside the pelvis in 44 per cent of the determinate patients; 42 per cent (144/ 343) of men and 49 per cent (50/102) of women. Recurrences were detected within two years in 96 men and 45 women, after two to five years in TABLE V.
Five-year
Treatment Cystectomy 6,000 rad + 4,000 rad + 2,000 rad +
alone cystectomy cystectomy cystectomy
TOTALS*
38 men and 5 women, and after periods longer than five years in 10 male five-year survivors. Pelvic recurrences alone occurred in 17 per cent (60) of men and 23 per cent (24) of women, extrapelvic metastases alone in 16 per cent (54) of men and 18 per cent (18) of women, and local with distal recurrences occurred in 9 per cent (30) of men and 8 per cent (8) of women. Rates of pelvic recurrence alone were 30 per cent in men versus 41 per cent in women treated with cystectomy alone, and 20 to 24 per cent in men versus 20 to 29 per cent in women treated with precystectomy radical or subradical irradiation (Table VI). The incidences of extrapelvic metastases with or without local recurrence were 19 per cent in men versus 28 per cent in women who had cystectomy alone and 23 to 31 per cent in men versus 21 to 40 per cent in women who received prior definitive or preoperative irradiation. Pelvic recurrence in men and women was usually palpable on bimanual examination or at laparotomy, either medially involving mainly soft tissue structures, or laterally on the pelvic wall with or without pelvic bone involvement. Bone, lung, and liver were the most common sites of extrapelvic metastases in both sexes on follow-up investigations, including surgical exploration and autopsy (Table VII).
survival rate according methods of treatment
to clinical stages, and
(Bz, C/Dl) Stage Men Women No. (%) No. (%)
-Low (0, A, Bl) StageMen Women No. No. (%) (%)
-High
26/50 20/32 28150 14/27
(52) (63) (56) (52)
9/16 6/15 618 l/2
(56) (40) (75) (50)
9/47 12/43 12145 17/49
(19) (28) (27) (35)
l/23 S/14 S/16 4/8
(4) (36) (31) (50)
88/159
(55)
22/41
(54)
50/184
(27)
15/61
(25)
*Other5 male and 1 female patients were lost to follow-up. TABLE VI.
Incidence of local or distant recurrence in five more years according to treatment methods
Treatment Cystectomy 6,000 rad + 4,000 rad + 2,000 rad + TOTALS*
alone cystectomy cystectomy cystectomy
Pelvic Only--Women Men No. (%) No. (%)
or
-Extrapelvic Men No. (%)
2 Pelvic;LWomen No. (%)
37/97 15/75 23/95 15/76
(38) (20) (24) (20)
16/39 6/29 7/24 2/10
(41) (21) (29) (20)
18/97 17/75 29/95 20/76
(19) (23) (31) (26)
11/39 6/29 s/24 4/10
(28) (21) (21) (40)
90043
(26)
31/102
(30)
84/343
(24)
26/102
(25)
*Ten male five-year survivors had recurrences later than five years.
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TABLE VII. Extrapelvic
Sites of extrapelvic metastases
Site*
Bone Lung Liver Para-aortic nodes Inguinal nodes Neck nodes Bowel Mesenteric nodes Peritoneum Pleura Brain Chest wall Axillary nodes Adrenal Heart Spleen
Men
Women
29 27 19 8 6 8 7 4 5 5 4 3 2
9
8 4 2 3 0 1 1 0 1 1 0 0
1
1
2 1
0 0
*Patients usually had more than one site involved
Complications and deaths underfive without recurrence
years
Postoperative pelvic sepsis or bleeding and/or wound dehiscence and later bowel fistulas or obstruction by adhesions were the main pelvic complications observed within the irradiated volume and/or operative field of radical cystectomy. The pelvic complications occurred during the postoperative stay in hospital or later without local or distant tumor recurrence in 11 men and 2 women who had cystectomy alone, 7 men arid 3 women who had prior radical radiotherapy, 13 men and 2 women who received conventional preoperative irradiation, and 8 men who were treated with the shorter preoperative radiation regimen. Of these 46 patients (39 men and 7 women), 25 initially had arteriosclerotic cardiovascular disease and/or obesity, 21 had had prior pelvic surgery before cystectomy, and 16 patients had ureterosigmoidostomy or ureterocutaneous diversion on radical cystectomy. Pelvic complications were fatal, mainly due to septicemia or pulmonary embolism, in 25 patients (18 men and 7 women). Other known causes of death within five years without recurrence were mainly cardiovascular or pulmonary diseases in 17 patients (14 men and 3 women) in the cystectomy alone group, 19 patients (15 men and 4 women) in the 6,000 rad-cystectomy group, 14 male patients in the 4,000 rad-cystectomy group, and 9 male patients in the 2,000 rad-cystectomy group. Three other male patients in the preoperative radiation groups died of advanced primary cancers of
UROLOGY I JULY 1931 / VOLUME XVIII, NUMBER 1
the renal pelvis (2) and rectum (1). The majority of these men and women (49/62) initially were older than sixty-five years, or had arteriosclerotic cardiovascular disease or obstructive uropathy before treatment. Comment The men and women with bladder cancer, reported herein, had radical cystectomy either alone, or following unsuccessful radical irradiation, or after planned subradical irradiation given in conventional or shorter regimens. Since the male and female patients in the four groups were neither randomly selected nor concurrently treated, the validity of intergroup comparisons may be questioned. Nonetheless, in the four groups the pretreatment clinicopathologic features, the methods of staging and grading bladder tumors, the criteria of selecting patients for treatment, and the techniques of radical cystectomy3” were basically similar in men and women (Fig. 1; Tables I-III). The cancer downstaging (P < T) in the irradiated men and women increased proportionately (20 to 44 per cent) with increasing total radiation doses; thus it can be attributed to the effects of radiation rather than overestimation of the cancer clinical stage. The greater tendency in men and women was to underestimate clinically (P > T: 28 to 42 per cent) rather than overestimate (P < T: 4 to 5 per cent with cystectomy alone) the extent of the tumor (Table IV). Downstaging of tumors in men and women was less frequent with the 2,000-rad regimen (20 to 28 per cent) than with the higher dose 4,000 or 6,000-rad regimens (29 to 44 per cent); the latter patients underwent cystectomy after longer intervals that allowed more time for further tumor regression. Five-year survival in men and women was similarly higher in patients treated by the various precystectomy radiation regimens than in those patients treated by cystectomy alone. The improved survival results with precystectomy irradiation were consistently evident in the male and female patients, especially in women, with clinically high-stage (B2, C, D1) tumors. By contrast, the five-year survival for clinically low-stage (0, A, Bi) tumors was relatively high with and without precystectomy irradiation (Table V). Thus, precystectomy irradiation, given radically or preoperatively by conventional or shorter regimens, similarly improved the survival in men and women with high-stage tumors.
19
Although the over-all incidence of cancer recurrences was analogous in men and women, the rates of local recurrence within the pelvis were similarly lower in the radically or preoperatively irradiated men and women than in those patients treated with cystectomy alone (Table VI). There was no comparable effect with prior radical or preoperative irradiation on the frequency of extrapelvic metastases in men and women after cystectomy. Distant metastases occurred in similar or higher frequencies in the irradiated men and women relative to the nonirradiated patients in the cystectomy alone group, suggesting that irradiated patients may live without local recurrence to develop distant metastases. The basically similar five-year survival rates, rates of postoperative or later complications and of cancer recurrence or mortality, coupled with the improved rates of survival and pelvic recurrence in the men and women radically or preoperatively irradiated, indicate similar advantageous radiobiologic effects of local radical or preoperative radiation therapy before cystectomy. However, the relatively high incidence of subsequent distant metastases among the male and female patients in the four treatment groups indicates that the local radiation
20
and surgical treatment is inadequate in preventing intrapelvic spread. Adjuvant therapeutic modalities such as chemotherapy and/or immunotherapy might be helpful in the control or prevention of the potential spread in men and women patients with bladder cancer. 1275 York Avenue New York, New York 10021 (DR. BATATA) ACKNOWLEDGMENT. To Mrs. Joan Giacomantonio for preparation of the manuscript. References 1. Batata MA, et al: Patterns of recurrence in bladder cancer treated by irradiation and/or cystectomy, Int. J. Radiat. On&. Biol. Phys. 6: 155 (1980). 2. Whitmore WF, and Batata MA: Preoperative irradiation with cystectomy for bladder cancer, in Johnson DE, and Samuels ML (Eds): Cancer of the Genitourinary Tract, New York, Raven Press, 1979, pp. 89-100. 3. Whitmore WF, et al: Radical cystectomy with or without prior irradiation in the treatment of bladder cancer, J. Ural. 118: 184 (1977). 4. Whitmore WF, et al: A comparative study of two preoperative radiation regimens with cystectomy for bladder cancer, Cancer 40: 1077 (1977). 5. Batata MA, and Hilaris BS: Radiation therapy techniques in uroloaic cancer, in Devine CT, and Strecker IF Jr. (Eds): Urolo& in Practice, Boston, Little, Brown and do., -1978, pp. 785- 792.
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