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Prognostic factors in bladder and bladder-prostate rhabdomyosarcoma
Prognostic
Factors in Bladder and Bladder-Prostate Rhabdomyosarcoma
By Michael P. La Quaglia, Fereshteh Ghavimi, Harry Herr, Lynda Mandell, Darryl Pennenberg, Steven Hajdu, and Philip R. Exelby New
York, New York
0 In order to examine surgical factors predictive of fatal outcome in patients presenting with histologically verified rhabdomyosarcoma of the urinary bladder, we performed a retrospective analysis of cases presenting between the years 1970 and 1985 and treated by protocol. Twenty-five patients were identified and data were complete for univariate and multivariate analysis on all. Staging was done according to the criteria of the International Union Against Cancer (TNM). Median age at presentation was 14.7 years and IO patients were younger than IO years. Median follow-up was 4.8 yeers overall and 8.4 years in survivors. Four patients presented with involvement of regional lymph nodes and three with distant metastases. Complete surgical resection. defined as negative microscopic margins. was accomplished by total cystectomy in 14 patients, and partial cystectomy in two. In this group cystectomy was performed prior to chemotherapy and radiation in five and after in IO (persistent disease). Three salvage cystectomias ware performed in patients who recurred after initial complete responses to chemotherapy and radiation therapy. Thirteen patients received a median of 3,000 cGy (range. 1,800 to 5,000 cGy) of external beam pelvic irradiation, and two received brachytherapy. All patients received multiple agent chemotherapy according to either the T2 or T6 protocol. There are 11 disease-free survivors (44%) and 10 of these have been followed for more than 6 years. One patient is alive with disease 6.5 years after diagnosis. Four variables were analyzed to determine their predictive effect on survival: (I) completeness of surgical resection; (2) prostatic involvement; (3) involvement of the urethral-trigonal area independent of the prostate; and (41 Primary tumor size (55 cm or >5 cm). In univariate analysis, using the maximum likelihood ratio test. prostatic involvement was the most significant predictor of mortality (P 5 .04). whereas resectability (P : .07) and tumor size (P 5.06) showed evidence of effect on survival. Urethral-trigonal origin of the primary was not associated with worsened prognosis. The associated relative risk of fatal outcome was 6.5 for prostatic involvement. Prostatic involvement was the most significant predictor of fatal outcome in multivariate analysis. We conclude that patients with rhabdomyosarcoma of the
From the Divisions of Pediatric Surgery and Urology, Department of Surgery, and the Departments of Pediatrics, Radiation Oncology, Biostatistics, and Pathology, Memorial Sloan-Kettering Cancer Center, New York. NY. Presented at the 38th Annual Meeting of the Surgical Section of the American Academy of Pediatrics, Chicago, Illinois, October 21-23.1989. Address reprint requests to Michael P. Ln Quagh’a, MD, Memorial Sloan-Kettering Cancer Center, Department of Surgery (Pediatric Surgery). 1275 York Ave. New York, NY 10075. 8 1990 by W.B. Saunders Company. 0022-3468/90/251 O-0012$03.00/O 1066
urinary bladder originating in the prostate comprise a high-risk group. Q 1990 by W. 8. Saunders Company. INDEX WORDS: Rhabdomyosarcoma, bladder-prostate.
T
HE INTRODUCTION of multidisciplinary therapy for rhabdomyosarcoma arising in childhood has greatly improved the outlook for children with these embryonal tumors.’ In particular the once dismal prognosis for tumors arising in the bladder or prostate has improved significantly.2*3 However, despite this progress overall survival is still less than 50%. Also, quite a price must often be paid for cure. This involves not only the necessity of permanent urinary, and possibly fecal diversions but also the myriad late effects caused by the use of alkylating agents and radiation therapy.4V5 These include chronic intestinal dysfunction, growth retardation, gonadal dysfunction, and secondary malignancy. In view of this, there is great interest in identifying risk factors that would stratify patients, at initial staging, into high- and low-risk groups. Patients with relatively low-risk tumors would undergo less-intense and, therefore, less-toxic regimens, whereas those at high risk would undergo more aggressive treatment from the time of diagnosis. In order to identify factors predictive of mortality in pediatric patients presenting with rhabdomyosarcoma of the urinary bladder or prostate we reviewed our experience with 25 patients seen over a 15year period and treated by protocol. Special attention was given to variables of surgical interest. MATERIALS AND METHODS
All patientspresentingbetween January 1, 1970 and December 31, 1985 with a diagnosis of rhabdomyosarcoma of the urinary bladder or prostate and treated by protocol were entered into this retrospective study. Of the 25 patients identified, 21 (84%) were 21 years of age or less at diagnosis. The remaining four patients were between 20 and 30 years of age and underwent essentially the same management as the younger patients. All pathological diagnoses were reviewed and confirmed at Memorial Hospital. Data were obtained from patient charts, office records, operative reports, and the pediatric data base. Patient characteristics that were considered for their association with time to failure (death) included: (1) primary tumor originating in the prostate; (2) urethral-trigonal origin of tumor independent of the prostate; (3) tumor size; (4) tumor invasiveness; (5) regional lymphatic involvement; (6) distant metastases at diagnosis; (7) completeness of surgical resection; and (8) age at diagnosis. Tumor origin was based on evaluation of
Journalof
Pediatric Surgery, Vol 25, No 10 Kktober),
1990: pp 1066-1072
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BLADDER AND PROSTATE RHA6DOMYOSARCOMA
pathological reports as well as operative and cystoscopic findings. Tumor size was divided into two groups: 55 cm or >5 cm. Local tumor invasiveness was defined using the TNM classification of pediatric soft tissue sarcomas of the International Union Against Cancer.’ The clinical staging system was used, but surgical and histological information were also used, when available, to determine stage. Initial evaluation of pelvic bladder tumors consisted of bimanual examination with the patient under anesthesia, and transurethral biopsies of the bladder, bladder neck, and prostatic urethra, even when endoscopically normal. In addition transrectal biopsies of the prostate, bladder base, and perivesical tissues were performed. Chest x-rays, computed tomography (CT) of the abdomen and pelvis, and bone marrow biopsies were also obtained. Tumors that invaded beyond the bladder wall and through fascia1 planes were classified as T-2; those confined to the wall were T-l. Nodal involvement was usually based on histopathologic examination of pelvic lymph nodes removed at the time of cystectomy. Distant metastases included dissemination to lungs, cortical, and medullary bone. Complete surgical resection was defined by total removal of the primary tumor with negative microscopic margins and complete removal of all gross disease in regional nodes. All patients were treated under one of two pediatric rhabdomyosarcoma protocols in use at our institution: T2 or T6. The T2 regimen’ consisted of sequential 90-day administration of actinomycin D, doxorubicin, vincristine, and cyclophosphamide. The T6’ protocol was T2 plus bleomycin, BCNU (carmustine; Bristol-Meyers, New York, NY), and methotrexate. External beam pelvic radiation was given under both protocols. From 1975 the majority of unresectable patients received one to two cycles of T6 chemotherapy in a span of 4 to 12 weeks for induction of response. Follow-up after induction consisted of repeat CT scan, cystoendoscopy, and transurethral as well as needle biopsies of the primary tumor, as well as perivesical tissues. Because of the prevalence of submucosal tumor extension, histological confirmation of response was thought to be extremely important, even when bimanual examination and endoscopy appeared normal. If a complete response was obtained after T6 induction, T6 maintenance chemotherapy was continued and follow-up evaluations repeated until termination of chemotherapy in 12 to 14 months, when staging laparotomy and regional node dissections were performed. If a complete response was not obtained, radiation therapy or extirpative surgery was performed. Probability estimates of time to failure (death) were obtained by the product limit method* and differences between failure patterns were evaluated using log-rank statistics’ or the maximum likelihood ratio test. A proportional hazards regression analysis was then performed using the following variables: (1) prostatic involvement; (2) completeness of surgical resection; (3) tumor size; and (4) urethral-trigonal origin of primary independent of prostatic involvement (females).‘“,” Covariates were considered for the proportional hazards model if their significance level based on the log-rank test was less than 0.2. All covariates that added information to the model at the 0.1 level of significance as measured by the maximum likelihood ratio test were included in the final proportional hazards model. Reported relative risks are measures of the increased risk of death associated with the presence of a given variable compared with its absence. Mean values are reported with the accompanying standard deviation.
age or less. All patients were white and there were 18 males (median age, 13.1 years) and seven females (median age, 18.2 years). The age distribution of the entire group is depicted in Fig 1. The overall interval of follow-up ranged from 0.9 to 14.9 years with a median of 4.8. The median follow-up in survivors was 8.4 years (mean, 8.2 + 3.3 years), whereas the median interval to death was 2.0 years (mean, 3.2 f. 2.9 years). The most common mode of presentation was urinary retention, followed by urinary tract infection, hematuria, and palpation of a suprapubic mass. Staging Twenty tumors (80%) were locally invasive (T-2) and five did not invade surrounding tissues. Nineteen patients (76%) had lesions that were greater than 5 cm (Tb) whereas six primary tumors were 55 cm (Ta) at diagnosis. Regional lymph nodes, defined as the obturator, iliac, and paraaortic chains, were involved in only four patients (16%). Three children (12%) presented with distant metastases; two to lung and one to bone marrow. Seventeen primary tumors (68%) originated in the prostate; eight arose in the bladder. Only one rhabdomyosarcoma in a male was a bladder primary. The results of TNM staging along with a correlation with the Intergroup Rhabdomyosarcoma Study clinical groupings is presented in Table 1. Treatment Total cystectomy was performed in 13 (52%) patients, and partial cystectomy in two (8%) as part of the primary treatment. Eleven of the 13 total cystectomies (85%) resulted in total surgical removal of the primary tumor with negative microscopic margins, whereas residual tumor was left in two patients. Three of the total cystectomies in this group were performed before chemotherapy or radiation was given and the
6 MEDIAN=
a’ F 2
6
g
4
E Z i:
2
14.7 YRS.
RESULTS
Population Characteristics There were 25 patients included in this study with a median age at diagnosis of 14.7 years (mean, 13.1 ‘- 9.2 years) and including 10 patients who were 10 years of
o-5
5-10
10-1515-20
20-25
)25
AGE AT DIAGNOSIS IN YEARS Fig 1. Frequency distribution of age at diagnosis for patients in this series.
LA QUAGLIA ET AL
1068
Table 1. Correlation of TNM Staging With IRS Clinical Grouping No.
No. of Patients
TZ:T6
of LOCal Recurrences
I
3
2:l
1
0
TlbNOMO
I
2
0:2
1
0
T2aNOMO
II
3
2:l
0
1 (33%)
TPbNOMO
II
10
2:8
4
7 (70%)
TPbN 1 MO
III
4
0:4
0
2 (50%)
TZbNOMl
IV
3
0:3
1
3 1100%)
TNM Staae TlaNOMO
IRS GKWD
No. of Deaths IRateI
remaining 10 were performed because of tumor progression or inadequate response to chemotherapy and radiation. Both patients who underwent partial cystectomy as part of initial management had total removal of the primary tumor and neither received chemotherapy or radiation prior to surgery. Thus a total of 15 patients underwent surgical removal of the primary tumor as part of initial therapy. Three additional patients underwent salvage cystectomy for local recurrence after an initial complete response to chemotherapy and radiation therapy, making the number of total cystectomies 16 and partial cystectomies two for the entire study group. Surgical excision was complete in all three patients undergoing a salvage procedure. Pelvic lymph node dissections were routinely performed on patients undergoing cystectomy. Seven patients (28%) underwent biopsy alone and no attempt at total excision was made. Ail patients received chemotherapy by protocol. Six received the T2 (24%) and 19 the T6 (76%) regimen. As noted previously, both protocols involve intensive chemotherapy. The T6 was used more often in higher stage disease and statistical comparison between the two is, therefore, not possible. The overall median duration of chemotherapy administration was 15.6 months (mean, 16.0 * 4.1 months). The median dura-
MEDIAN=30 p is F 2 k
Gy. (N=l3)
6
. All Patients
0.01 0
I
I
I
t
I
3
6
9
12
15
Years to La!4 Follow-Up or Death Fig 3. The Kaplan-Meier curve for overall survival in this group of patients.
tion of administration for those receiving the T2 regimen was 20.7 months (mean, 20.3 + 2.6 months), whereas patients receiving the T6 were treated for a median of 14.4 months (mean, 14.6 f 3.4 months). Thirteen patients (52%) received external beam radiation therapy as part of the treatment protocol. Radiation was delivered at megavoltage energy levels and conventional fractionation (180 to 200 cGy/d, five treatments per week). Total dosage ranged from 1,800 to 5,000 cGy with a median of 3,000 cGy. Two patients were treated with interstitial implants of “‘1 seeds. Figure 2 shows the distribution of external beam radiation dosage in this series (n = 13). Outcome
Overall there are 12 survivors (48%), with 11 having no evidence of disease and one alive with disease 6.5 years after diagnosis. Figure 3 is the Kaplan-Meier curve for the entire group. Survival and disease-free survival were essentially the same, indicating that salvage after treatment failure was low. Table 2 categorizes survivors and treatment failures with regard to staging variables, anatomical origin of the primary, and completeness of surgical resection. It is
4 Table 2. Comparison of Survivors and Deaths With Regard To Individual Staging Variables, Prostatic Involvement, and
fz g 2
Completeness of Surgical Resection
2
Variable
0
IO-19
20-29 RADIATION
30-39
40-49
DOSAGE
50
IN GRAYS
Fig 2. Frequency distribution of radiation dosages for the 13 patients undergoing external beam radiation therapy.
J
16
Survivors (n = 12)
Deaths bl = 13)
Ta:Tb
6:7
1:12
Tl:T2
5:7
0:13
NO:N 1
10:2
11:2
MO:M 1
12:o
10:3
Bladder:prostate
75
1:12
Complete:incomplete
8:4
5:8
BLADDER AND PROSTATE RHABDOMYOSARCOMA
evident that treatment failures had higher stage malignancies at diagnosis and that primary tumor size and invasiveness, as well as distant metastases were the main determinants of this stage difference. The NO:N 1 ratio was almost the same for survivors and nonsurvivors. The ratio of prostatic primaries was greatly increased in patients dying of disease whereas the complete:incomplete resection ratio was higher in survivors. Three patients who were classified and analyzed as deaths from disease did not succumb to the cancer itself but rather to complications of treatment. All three had no evidence of rhabdomyosarcoma at the time of death. Two of these patients died of fungal sepsis. A third died of overwhelming cytomegalovirus infection after failure of engraftment of a bone marrow transplant. One of the patients who died of fungal sepsis was noted to have an incidental adenocarcinoma in an isolated colon conduit at autopsy. Another who died with active rhabdomyosarcoma developed a subacute myeloid leukemia during treatment, making a total of two secondary malignancies in this group. There were seven local recurrences (28%) with a median interval from diagnosis to relapse of 1.4 years (interval, 1.0 to 2.6 years). Of these, two had undergone total cystectomy as part of initial treatment, and the rest biopsy alone. In the two patients undergoing total cystectomy, surgical margins were clear in one and positive in the other. Three of the five not treated with initial total resection underwent salvage cystectomy. Of the three treated with a salvage procedure, one is disease-free 5 years after treatment, one rerecurred in the pelvis and bones 8 years after treatment, and one died of disease. Overall, of the seven patients with local recurrence, one is alive without evidence of disease, one is alive with disease, and five died of disease. Eleven patients (44%) developed distant metastases on treatment. The median interval from diagnosis to dissemination was 1.7 years and ranged from 0.6 to 3.5 years. Anatomic sites of metastases included cortical bone, lungs, and peritoneum in three patients each. One additional patient developed distant nodal metastases in the paraaortic and supraclavicular chains and died because of bone marrow transplantation failure. A final child suffered dissemination to both the lungs and soft tissues. Of these 11 patients, two had undergone complete surgical excision as part of initial therapy and two were treated with salvage cystectomy. Ten patients (91%) in this group developing distant metastases on treatment have died of disease. Bladder Salvage Of the 17 patients with prostatic primaries, five are alive without evidence of disease but only one has a
functional bladder. The other survivors were treated with cystectomy. In the eight patients with bladder primaries there are seven survivors (one presently alive with disease) and three have functional bladders. Two of these three underwent partial cystectomy for tumors localized to the cystic dome. Overall, there are four functional bladders in 12 survivors. Univariate Analysis The results of univariate analysis are summarized in Table 3. Variables found to be significant predictors of fatal outcome (time to death) in univariate analysis included: (1) prostatic origin of the primary tumor (P 5 .04; Fig 4A); (2) local invasiveness by the primary (P 5 .03; Fig 5A); and (3) distant metastases at diagnosis (P 5 .Ol; Fig 6B). Variables that approached significance in univariate analysis included: (1) primary tumor size (P cr .06; Fig 5B); and (2) completeness of surgical resection (P _= .07; Fig 4C). Regional nodal involvement (Fig 6A), age at diagnosis, and urethraltrigonal origin of the primary tumor (Fig 4B) were not significant predictors of fatal outcome. Multivariate Analysis Four variables of special surgical interest were compared in multivariate analysis: (1) prostatic origin of the primary tumor; (2) urethral-trigonal origin independent of the prostate; (3) tumor size; and (4) completeness of surgical resection. In a Cox proportional hazards model with endpoint being death from disease, only prostatic origin of the primary tumor added information. Thus, prostatic involvement was the only significant predictor of time to death (mortality) when completeness of resection, size, and trigonalurethral involvement were simultaneously analyzed. The associated relative risk of death from disease was 6.5 if the tumor originated in the prostate. DISCUSSION
Initially, radical cystectomy was the only treatment capable of producing cures in rhabdomyosarcoma of the urinary bladder.” Later, multidisciplinary protocols using multiagent chemotherapy and radiation as well as resection were developed. Most recently, treatTable 3. Results of Statistical Variable
Analysis
Significance
RelativeRusk
Local invasion
P<
Prostatic primary
P4.04
6.5
Metastases at diagnosis
Ps
.Ol
5.7
Tumor size
P_c .06
4.8
Complete resection
PC .07 Ps .2
3.4 -
Urethral-trigonal primary
.03
Regional nodes positive
P>
Age at diagnosis
P>_ .2
.2
Undefined
1070
LA QUAGLIA
ET AL
. NolTU
OS
. Inwmplda A Complets
0.0’ 9
3
6
9
15
12
IS
Yeas la lasl Follow-Up at Dualh Fig 4. (Al Survival curves for patients with and without prostatic primary. (B) Comparison of the survival of patients whose tumors arose in the urethral-trigonal area with those with bladder cancars. There was no significant difference in this group. (C) The survival of patients who underwent complete surgical excision versus those who did not.
ment regimens were designed to preserve bladder and sexual function by increased use of nonsurgical modalities.13 Although initial results were encouraging, longer follow-up has demonstrated an increased rate of both local recurrence and death from disease in patients undergoing primary chemotherapy.“‘6 A desirable goal would be stratification of patients at initial staging, or very early in therapy into high- and low-risk groups. Patients who were at low risk for relapse would undergo a less intensive regimen, and as a corollary, bladder salvage would receive a higher priority in the overall treatment plan. On the other hand, high-risk patients would be treated by more aggressive protocols from the time of diagnosis. This would include the early, high-dose use of chemotherapeutic agents active
against advanced or refractory sarcomas and the possible inclusion of myeloablative regimens.” Also, surgical removal of the primary tumor would receive a higher priority. In the present study significant predictors of death in univariate analysis included metastases at diagnosis, local tissue invasion, and prostatic origin of the primary. Both local tissue invasion and distant metastases have had prognostic importance for patients with rhabdomyosarcomas arising in other anatomical sites.‘8*‘9Indeed, local invasiveness may be a primary determinant of biological aggressiveness. Prostatic involvement was also a significant predictor of death in univariate analysis. Controversy exists concerning the importance of the prostate in predicting
B
A
L
I’----. No Tumor Invasiveness A Tumor Invasiveness
-4
= Size 6 5 cm A Size > 5 cm
P60.03
J
1
1
’
~60.06 L
3
I
1
I
I
6 9 12 15 Years to Last Follow-Up or Death
I
18
0.0’
0
I
I
I
I
1
,
3
6
9
12
15
18
Years to Last Follow-Up or Death
Fig 5. (A) Comparison of the survival of patients with and without locally invasive tumors. IB) Comparison of survival in patients with tumors 56 cm or >6 cm.
1071
BLADDER AND PROSTATE RHABDOMYOSARCOMA
A
6
mNo Node A Node
No MET!? . METS
n
p>o.2 ‘1 I z ‘E E lz
0.4 e a.
0.2-
0.0 0
1 3
I 6
I 9
I 12
1 15
J 18
Years to Last Follow-Up or Death
p< 0.01
0.2-
0.0 o
3
L 6
9
12
I 15
, 18
Years to Last Follow-Up or Death
Fia 6. IA) Comoarison of survival for patients with and without regional lymph node involvement. (B) Comparison of survival between patients who did 0; did not present with distant metastases.
death, especially in patients undergoing multiagent chemotherapy.‘4*20 In the present study, all patients received intensive, multiagent chemotherapy, and prostatic origin of the primary was associated with a relative risk of fatal outcome of 6.5. Also, when compared in multivariate analysis with completeness of resection, tumor size, and urethral-trigonal involvement, only prostatic primary was a significant predictor of mortality. Involvement of the prostatic stroma in transitional cell carcinomas of the bladder in adults has been associated with an increased incidence of nodal and distant metastasis and a worse prognosis stage for stage.*’ A possible explanation for the importance of prostatic involvement is reluctance to perform early extirpation because of the increased morbidity associated not only with urinary tract diversion but also loss of sexual function. Alternatively, the rich venous and lymphatic channels in the prostate may allow earlier dissemination. Finally, tumors in this region may have an increased biological aggressiveness. Complete surgical resection approached statistical significance in univariate analysis. This was close enough to speculate that this variable is important in overall outcome and statistical significance at the .05 level would be attained by the addition of more cases. Complete removal of all tumor tissue in the case of partial cystectomy has been previously emphasized by others,14 and was an important predictor of outcome in both extremity and paratesticular rhabdomyosarcoma studies reported from this institution.** Only four bladders in this series could be preserved and are
functional. In two of these, primary, complete resection could be accomplished using partial cystectomy. In all other patients tumor progression or local recurrence necessitated total cystectomy, or resulted in death. These data suggest that bladder resection may have relevance to survival and bladder preservation is very difficult except for anatomically favorable lesions. Finally, primary tumor size approached significance as a prognostic indicator but did not have the same strong influence as local tumor invasiveness. Regional lymph node involvement had no effect on survival in this study, consistent with the findings of the IRS for this anatomical site. It should be noted that only four patients in this series had regional nodal metastases. We conclude that local tissue invasion, distant metastases at diagnosis, and prostatic origin of the primary are significant predictors of mortality in rhabdomyosarcoma of the bladder, and place patients into high-risk groups requiring more aggressive treatment using all modalities. Complete surgical resection of the primary tumor, usually necessitating cystectomy, may also be an important determinant of outcome. We suggest that complete surgical excision be strongly considered in high-risk groups. A reasonable approach would include initial diagnosis and staging followed by high-dose multiagent chemotherapy. If tumor burden is reduced to microscopic levels as determined by imaging procedures and cystoscopy, further chemotherapy combined with radiation may be effective and cystectomy would be reserved for local recurrence. If chemotherapy produced less than 50%
1072
LA QUAGLIA ET AL
tumor regression or had no effect, total cystectomy would then be performed. With recent advances in bladder reconstruction using intestinal segments, future protocols might evaluate a more aggressive surgical approach that would allow extirpation of tumor
with immediate bladder reconstruction in an unirradiated field. Removal of all gross, and possibly microscopic tumor from the primary site might allow subsequent elimination of the need for irradiation or reduction in dosage.
REFERENCES 1. Maurer HM, Beltangady M, Gehan EA, et al: The Intergroup Rhabdomyosarcoma Study (IRS-I): A final report. Cancer 61:209220,1988 2. Ghavimi F, Exelby PR, D’Angio GJ, et al: Combination therapy of urogenital embryonal rhabdomyosarcoma in children. Cancer 32:1178-l 185, 1973 3. Hays DM, Raney RB, Lawrence W, et al: Bladder and prostatic tumors in the Intergroup Rhabdomyosarcoma Study (IRS1). Cancer 50:1472-1482,1982 4. El-Mahdi AM, Marks R Jr, Thornton WN, et al: Sequelae of pelvic irradiation in infancy. Radiology 110:665-666, 1974 5. Tucker MA, D’Angio GJ, Boice JD, et al: Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med 317588-593, 1987 6. Harmer MH (ed): TNM Classification of Pediatric Tumors. Geneva, Switzerland, International Union Against Cancer, 1982, pp 23-28 7. Ghavimi F, Exelby PR, D’Angio GJ, et al: Multidisciplinary treatment of embryonal rhabdomyosarcoma in children. Cancer 35~677-686, 1975 8. Ghavimi F, Exelby PR, Jereb B, et al: Multidisciplinary treatment of advanced stages of embryonal rhabdomyosarcoma in children. NC1 Monogr 56:103-109,198l 9. Kaplan EL, Meier R: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-581, 1958 10. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Sot 135:185-206, 1977 11. Cox DR: Regression models and life tables. J R Stat SOC 34:187-220, 1972
12. Mackenzie A, Whitmore WF, Melamed MR: Myosarcomas of the bladder and prostate. Caiicer 22:833-844, 1968 13. Hays DM. Raney RB Jr, Lawrence W Jr, et al: Primary chemotherapy in the treatment of children with bladder-prostate tumors in the Intergroup Rhabdomyosarcoma Study (IRS-II). J Pediatr Surg 17:8 12-8 19, 1982 14. Hays DM, Raney RB, Lawrence W, et al: Bladder and prostatic tumors in the Intergroup Rhabdomyosarcoma Study: Results of therapy. Cancer 50:1472-1482, 1982 15. Ghavimi F, Herr H, Jereb B, et al: Treatment of genitourinary rhabdomyosarcoma in children. J Urol 132:3 13-3 19, 1984 16. Loughlin KR, Retik AB, Weinstein HJ, et al: Genitourinary rhabdomyosarcoma in children. Cancer 63:1600-1606, 1989 17. de Kraker J, Voute PA: The role of ifosfamide in paediatric soft tissue sarcomas. Cancer Chemother Pharmacol 18:s23-~24, 1986 (suppl2) 18. LaQuaglia MP, Ghavimi F, Penenberg D, et al: Factors predictive of mortality in pediatric extremity rhabdomyosarcoma. J Pediatr Surg 25:1-7, 1990 19. Enneking WF, Spanier SS, Goodman MA: The surgical staging of musculoskeletal sarcoma. J Bone Joint Surg 62:10271030,198O 20. Timmons JW, Burgert EO, Soule EH, et al: Embryonal rhabdomyosarcoma of the bladder and prostate in childhood. J Urol 113:694-697, 1975 21. Schellhammer PF, Bean MA, Whitmore WF: Prostatic involvement by transitional cell carcinoma: Pathogenesis, patterns and prognosis. J Urol 118:399-403, 1977 22. La Quaglia MP, Ghavimi F, Heller G, et al: Mortality in pediatric paratesticular rhabdomyosarcoma: A multivariate analysis. J Urol 142:473-478,1989
Factors in Bladder and Bladder-Prostate Rhabdomyosarcoma
By Michael P. La Quaglia, Fereshteh Ghavimi, Harry Herr, Lynda Mandell, Darryl Pennenberg, Steven Hajdu, and Philip R. Exelby New
York, New York
0 In order to examine surgical factors predictive of fatal outcome in patients presenting with histologically verified rhabdomyosarcoma of the urinary bladder, we performed a retrospective analysis of cases presenting between the years 1970 and 1985 and treated by protocol. Twenty-five patients were identified and data were complete for univariate and multivariate analysis on all. Staging was done according to the criteria of the International Union Against Cancer (TNM). Median age at presentation was 14.7 years and IO patients were younger than IO years. Median follow-up was 4.8 yeers overall and 8.4 years in survivors. Four patients presented with involvement of regional lymph nodes and three with distant metastases. Complete surgical resection. defined as negative microscopic margins. was accomplished by total cystectomy in 14 patients, and partial cystectomy in two. In this group cystectomy was performed prior to chemotherapy and radiation in five and after in IO (persistent disease). Three salvage cystectomias ware performed in patients who recurred after initial complete responses to chemotherapy and radiation therapy. Thirteen patients received a median of 3,000 cGy (range. 1,800 to 5,000 cGy) of external beam pelvic irradiation, and two received brachytherapy. All patients received multiple agent chemotherapy according to either the T2 or T6 protocol. There are 11 disease-free survivors (44%) and 10 of these have been followed for more than 6 years. One patient is alive with disease 6.5 years after diagnosis. Four variables were analyzed to determine their predictive effect on survival: (I) completeness of surgical resection; (2) prostatic involvement; (3) involvement of the urethral-trigonal area independent of the prostate; and (41 Primary tumor size (55 cm or >5 cm). In univariate analysis, using the maximum likelihood ratio test. prostatic involvement was the most significant predictor of mortality (P 5 .04). whereas resectability (P : .07) and tumor size (P 5.06) showed evidence of effect on survival. Urethral-trigonal origin of the primary was not associated with worsened prognosis. The associated relative risk of fatal outcome was 6.5 for prostatic involvement. Prostatic involvement was the most significant predictor of fatal outcome in multivariate analysis. We conclude that patients with rhabdomyosarcoma of the
From the Divisions of Pediatric Surgery and Urology, Department of Surgery, and the Departments of Pediatrics, Radiation Oncology, Biostatistics, and Pathology, Memorial Sloan-Kettering Cancer Center, New York. NY. Presented at the 38th Annual Meeting of the Surgical Section of the American Academy of Pediatrics, Chicago, Illinois, October 21-23.1989. Address reprint requests to Michael P. Ln Quagh’a, MD, Memorial Sloan-Kettering Cancer Center, Department of Surgery (Pediatric Surgery). 1275 York Ave. New York, NY 10075. 8 1990 by W.B. Saunders Company. 0022-3468/90/251 O-0012$03.00/O 1066
urinary bladder originating in the prostate comprise a high-risk group. Q 1990 by W. 8. Saunders Company. INDEX WORDS: Rhabdomyosarcoma, bladder-prostate.
T
HE INTRODUCTION of multidisciplinary therapy for rhabdomyosarcoma arising in childhood has greatly improved the outlook for children with these embryonal tumors.’ In particular the once dismal prognosis for tumors arising in the bladder or prostate has improved significantly.2*3 However, despite this progress overall survival is still less than 50%. Also, quite a price must often be paid for cure. This involves not only the necessity of permanent urinary, and possibly fecal diversions but also the myriad late effects caused by the use of alkylating agents and radiation therapy.4V5 These include chronic intestinal dysfunction, growth retardation, gonadal dysfunction, and secondary malignancy. In view of this, there is great interest in identifying risk factors that would stratify patients, at initial staging, into high- and low-risk groups. Patients with relatively low-risk tumors would undergo less-intense and, therefore, less-toxic regimens, whereas those at high risk would undergo more aggressive treatment from the time of diagnosis. In order to identify factors predictive of mortality in pediatric patients presenting with rhabdomyosarcoma of the urinary bladder or prostate we reviewed our experience with 25 patients seen over a 15year period and treated by protocol. Special attention was given to variables of surgical interest. MATERIALS AND METHODS
All patientspresentingbetween January 1, 1970 and December 31, 1985 with a diagnosis of rhabdomyosarcoma of the urinary bladder or prostate and treated by protocol were entered into this retrospective study. Of the 25 patients identified, 21 (84%) were 21 years of age or less at diagnosis. The remaining four patients were between 20 and 30 years of age and underwent essentially the same management as the younger patients. All pathological diagnoses were reviewed and confirmed at Memorial Hospital. Data were obtained from patient charts, office records, operative reports, and the pediatric data base. Patient characteristics that were considered for their association with time to failure (death) included: (1) primary tumor originating in the prostate; (2) urethral-trigonal origin of tumor independent of the prostate; (3) tumor size; (4) tumor invasiveness; (5) regional lymphatic involvement; (6) distant metastases at diagnosis; (7) completeness of surgical resection; and (8) age at diagnosis. Tumor origin was based on evaluation of
Journalof
Pediatric Surgery, Vol 25, No 10 Kktober),
1990: pp 1066-1072
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BLADDER AND PROSTATE RHA6DOMYOSARCOMA
pathological reports as well as operative and cystoscopic findings. Tumor size was divided into two groups: 55 cm or >5 cm. Local tumor invasiveness was defined using the TNM classification of pediatric soft tissue sarcomas of the International Union Against Cancer.’ The clinical staging system was used, but surgical and histological information were also used, when available, to determine stage. Initial evaluation of pelvic bladder tumors consisted of bimanual examination with the patient under anesthesia, and transurethral biopsies of the bladder, bladder neck, and prostatic urethra, even when endoscopically normal. In addition transrectal biopsies of the prostate, bladder base, and perivesical tissues were performed. Chest x-rays, computed tomography (CT) of the abdomen and pelvis, and bone marrow biopsies were also obtained. Tumors that invaded beyond the bladder wall and through fascia1 planes were classified as T-2; those confined to the wall were T-l. Nodal involvement was usually based on histopathologic examination of pelvic lymph nodes removed at the time of cystectomy. Distant metastases included dissemination to lungs, cortical, and medullary bone. Complete surgical resection was defined by total removal of the primary tumor with negative microscopic margins and complete removal of all gross disease in regional nodes. All patients were treated under one of two pediatric rhabdomyosarcoma protocols in use at our institution: T2 or T6. The T2 regimen’ consisted of sequential 90-day administration of actinomycin D, doxorubicin, vincristine, and cyclophosphamide. The T6’ protocol was T2 plus bleomycin, BCNU (carmustine; Bristol-Meyers, New York, NY), and methotrexate. External beam pelvic radiation was given under both protocols. From 1975 the majority of unresectable patients received one to two cycles of T6 chemotherapy in a span of 4 to 12 weeks for induction of response. Follow-up after induction consisted of repeat CT scan, cystoendoscopy, and transurethral as well as needle biopsies of the primary tumor, as well as perivesical tissues. Because of the prevalence of submucosal tumor extension, histological confirmation of response was thought to be extremely important, even when bimanual examination and endoscopy appeared normal. If a complete response was obtained after T6 induction, T6 maintenance chemotherapy was continued and follow-up evaluations repeated until termination of chemotherapy in 12 to 14 months, when staging laparotomy and regional node dissections were performed. If a complete response was not obtained, radiation therapy or extirpative surgery was performed. Probability estimates of time to failure (death) were obtained by the product limit method* and differences between failure patterns were evaluated using log-rank statistics’ or the maximum likelihood ratio test. A proportional hazards regression analysis was then performed using the following variables: (1) prostatic involvement; (2) completeness of surgical resection; (3) tumor size; and (4) urethral-trigonal origin of primary independent of prostatic involvement (females).‘“,” Covariates were considered for the proportional hazards model if their significance level based on the log-rank test was less than 0.2. All covariates that added information to the model at the 0.1 level of significance as measured by the maximum likelihood ratio test were included in the final proportional hazards model. Reported relative risks are measures of the increased risk of death associated with the presence of a given variable compared with its absence. Mean values are reported with the accompanying standard deviation.
age or less. All patients were white and there were 18 males (median age, 13.1 years) and seven females (median age, 18.2 years). The age distribution of the entire group is depicted in Fig 1. The overall interval of follow-up ranged from 0.9 to 14.9 years with a median of 4.8. The median follow-up in survivors was 8.4 years (mean, 8.2 + 3.3 years), whereas the median interval to death was 2.0 years (mean, 3.2 f. 2.9 years). The most common mode of presentation was urinary retention, followed by urinary tract infection, hematuria, and palpation of a suprapubic mass. Staging Twenty tumors (80%) were locally invasive (T-2) and five did not invade surrounding tissues. Nineteen patients (76%) had lesions that were greater than 5 cm (Tb) whereas six primary tumors were 55 cm (Ta) at diagnosis. Regional lymph nodes, defined as the obturator, iliac, and paraaortic chains, were involved in only four patients (16%). Three children (12%) presented with distant metastases; two to lung and one to bone marrow. Seventeen primary tumors (68%) originated in the prostate; eight arose in the bladder. Only one rhabdomyosarcoma in a male was a bladder primary. The results of TNM staging along with a correlation with the Intergroup Rhabdomyosarcoma Study clinical groupings is presented in Table 1. Treatment Total cystectomy was performed in 13 (52%) patients, and partial cystectomy in two (8%) as part of the primary treatment. Eleven of the 13 total cystectomies (85%) resulted in total surgical removal of the primary tumor with negative microscopic margins, whereas residual tumor was left in two patients. Three of the total cystectomies in this group were performed before chemotherapy or radiation was given and the
6 MEDIAN=
a’ F 2
6
g
4
E Z i:
2
14.7 YRS.
RESULTS
Population Characteristics There were 25 patients included in this study with a median age at diagnosis of 14.7 years (mean, 13.1 ‘- 9.2 years) and including 10 patients who were 10 years of
o-5
5-10
10-1515-20
20-25
)25
AGE AT DIAGNOSIS IN YEARS Fig 1. Frequency distribution of age at diagnosis for patients in this series.
LA QUAGLIA ET AL
1068
Table 1. Correlation of TNM Staging With IRS Clinical Grouping No.
No. of Patients
TZ:T6
of LOCal Recurrences
I
3
2:l
1
0
TlbNOMO
I
2
0:2
1
0
T2aNOMO
II
3
2:l
0
1 (33%)
TPbNOMO
II
10
2:8
4
7 (70%)
TPbN 1 MO
III
4
0:4
0
2 (50%)
TZbNOMl
IV
3
0:3
1
3 1100%)
TNM Staae TlaNOMO
IRS GKWD
No. of Deaths IRateI
remaining 10 were performed because of tumor progression or inadequate response to chemotherapy and radiation. Both patients who underwent partial cystectomy as part of initial management had total removal of the primary tumor and neither received chemotherapy or radiation prior to surgery. Thus a total of 15 patients underwent surgical removal of the primary tumor as part of initial therapy. Three additional patients underwent salvage cystectomy for local recurrence after an initial complete response to chemotherapy and radiation therapy, making the number of total cystectomies 16 and partial cystectomies two for the entire study group. Surgical excision was complete in all three patients undergoing a salvage procedure. Pelvic lymph node dissections were routinely performed on patients undergoing cystectomy. Seven patients (28%) underwent biopsy alone and no attempt at total excision was made. Ail patients received chemotherapy by protocol. Six received the T2 (24%) and 19 the T6 (76%) regimen. As noted previously, both protocols involve intensive chemotherapy. The T6 was used more often in higher stage disease and statistical comparison between the two is, therefore, not possible. The overall median duration of chemotherapy administration was 15.6 months (mean, 16.0 * 4.1 months). The median dura-
MEDIAN=30 p is F 2 k
Gy. (N=l3)
6
. All Patients
0.01 0
I
I
I
t
I
3
6
9
12
15
Years to La!4 Follow-Up or Death Fig 3. The Kaplan-Meier curve for overall survival in this group of patients.
tion of administration for those receiving the T2 regimen was 20.7 months (mean, 20.3 + 2.6 months), whereas patients receiving the T6 were treated for a median of 14.4 months (mean, 14.6 f 3.4 months). Thirteen patients (52%) received external beam radiation therapy as part of the treatment protocol. Radiation was delivered at megavoltage energy levels and conventional fractionation (180 to 200 cGy/d, five treatments per week). Total dosage ranged from 1,800 to 5,000 cGy with a median of 3,000 cGy. Two patients were treated with interstitial implants of “‘1 seeds. Figure 2 shows the distribution of external beam radiation dosage in this series (n = 13). Outcome
Overall there are 12 survivors (48%), with 11 having no evidence of disease and one alive with disease 6.5 years after diagnosis. Figure 3 is the Kaplan-Meier curve for the entire group. Survival and disease-free survival were essentially the same, indicating that salvage after treatment failure was low. Table 2 categorizes survivors and treatment failures with regard to staging variables, anatomical origin of the primary, and completeness of surgical resection. It is
4 Table 2. Comparison of Survivors and Deaths With Regard To Individual Staging Variables, Prostatic Involvement, and
fz g 2
Completeness of Surgical Resection
2
Variable
0
IO-19
20-29 RADIATION
30-39
40-49
DOSAGE
50
IN GRAYS
Fig 2. Frequency distribution of radiation dosages for the 13 patients undergoing external beam radiation therapy.
J
16
Survivors (n = 12)
Deaths bl = 13)
Ta:Tb
6:7
1:12
Tl:T2
5:7
0:13
NO:N 1
10:2
11:2
MO:M 1
12:o
10:3
Bladder:prostate
75
1:12
Complete:incomplete
8:4
5:8
BLADDER AND PROSTATE RHABDOMYOSARCOMA
evident that treatment failures had higher stage malignancies at diagnosis and that primary tumor size and invasiveness, as well as distant metastases were the main determinants of this stage difference. The NO:N 1 ratio was almost the same for survivors and nonsurvivors. The ratio of prostatic primaries was greatly increased in patients dying of disease whereas the complete:incomplete resection ratio was higher in survivors. Three patients who were classified and analyzed as deaths from disease did not succumb to the cancer itself but rather to complications of treatment. All three had no evidence of rhabdomyosarcoma at the time of death. Two of these patients died of fungal sepsis. A third died of overwhelming cytomegalovirus infection after failure of engraftment of a bone marrow transplant. One of the patients who died of fungal sepsis was noted to have an incidental adenocarcinoma in an isolated colon conduit at autopsy. Another who died with active rhabdomyosarcoma developed a subacute myeloid leukemia during treatment, making a total of two secondary malignancies in this group. There were seven local recurrences (28%) with a median interval from diagnosis to relapse of 1.4 years (interval, 1.0 to 2.6 years). Of these, two had undergone total cystectomy as part of initial treatment, and the rest biopsy alone. In the two patients undergoing total cystectomy, surgical margins were clear in one and positive in the other. Three of the five not treated with initial total resection underwent salvage cystectomy. Of the three treated with a salvage procedure, one is disease-free 5 years after treatment, one rerecurred in the pelvis and bones 8 years after treatment, and one died of disease. Overall, of the seven patients with local recurrence, one is alive without evidence of disease, one is alive with disease, and five died of disease. Eleven patients (44%) developed distant metastases on treatment. The median interval from diagnosis to dissemination was 1.7 years and ranged from 0.6 to 3.5 years. Anatomic sites of metastases included cortical bone, lungs, and peritoneum in three patients each. One additional patient developed distant nodal metastases in the paraaortic and supraclavicular chains and died because of bone marrow transplantation failure. A final child suffered dissemination to both the lungs and soft tissues. Of these 11 patients, two had undergone complete surgical excision as part of initial therapy and two were treated with salvage cystectomy. Ten patients (91%) in this group developing distant metastases on treatment have died of disease. Bladder Salvage Of the 17 patients with prostatic primaries, five are alive without evidence of disease but only one has a
functional bladder. The other survivors were treated with cystectomy. In the eight patients with bladder primaries there are seven survivors (one presently alive with disease) and three have functional bladders. Two of these three underwent partial cystectomy for tumors localized to the cystic dome. Overall, there are four functional bladders in 12 survivors. Univariate Analysis The results of univariate analysis are summarized in Table 3. Variables found to be significant predictors of fatal outcome (time to death) in univariate analysis included: (1) prostatic origin of the primary tumor (P 5 .04; Fig 4A); (2) local invasiveness by the primary (P 5 .03; Fig 5A); and (3) distant metastases at diagnosis (P 5 .Ol; Fig 6B). Variables that approached significance in univariate analysis included: (1) primary tumor size (P cr .06; Fig 5B); and (2) completeness of surgical resection (P _= .07; Fig 4C). Regional nodal involvement (Fig 6A), age at diagnosis, and urethraltrigonal origin of the primary tumor (Fig 4B) were not significant predictors of fatal outcome. Multivariate Analysis Four variables of special surgical interest were compared in multivariate analysis: (1) prostatic origin of the primary tumor; (2) urethral-trigonal origin independent of the prostate; (3) tumor size; and (4) completeness of surgical resection. In a Cox proportional hazards model with endpoint being death from disease, only prostatic origin of the primary tumor added information. Thus, prostatic involvement was the only significant predictor of time to death (mortality) when completeness of resection, size, and trigonalurethral involvement were simultaneously analyzed. The associated relative risk of death from disease was 6.5 if the tumor originated in the prostate. DISCUSSION
Initially, radical cystectomy was the only treatment capable of producing cures in rhabdomyosarcoma of the urinary bladder.” Later, multidisciplinary protocols using multiagent chemotherapy and radiation as well as resection were developed. Most recently, treatTable 3. Results of Statistical Variable
Analysis
Significance
RelativeRusk
Local invasion
P<
Prostatic primary
P4.04
6.5
Metastases at diagnosis
Ps
.Ol
5.7
Tumor size
P_c .06
4.8
Complete resection
PC .07 Ps .2
3.4 -
Urethral-trigonal primary
.03
Regional nodes positive
P>
Age at diagnosis
P>_ .2
.2
Undefined
1070
LA QUAGLIA
ET AL
. NolTU
OS
. Inwmplda A Complets
0.0’ 9
3
6
9
15
12
IS
Yeas la lasl Follow-Up at Dualh Fig 4. (Al Survival curves for patients with and without prostatic primary. (B) Comparison of the survival of patients whose tumors arose in the urethral-trigonal area with those with bladder cancars. There was no significant difference in this group. (C) The survival of patients who underwent complete surgical excision versus those who did not.
ment regimens were designed to preserve bladder and sexual function by increased use of nonsurgical modalities.13 Although initial results were encouraging, longer follow-up has demonstrated an increased rate of both local recurrence and death from disease in patients undergoing primary chemotherapy.“‘6 A desirable goal would be stratification of patients at initial staging, or very early in therapy into high- and low-risk groups. Patients who were at low risk for relapse would undergo a less intensive regimen, and as a corollary, bladder salvage would receive a higher priority in the overall treatment plan. On the other hand, high-risk patients would be treated by more aggressive protocols from the time of diagnosis. This would include the early, high-dose use of chemotherapeutic agents active
against advanced or refractory sarcomas and the possible inclusion of myeloablative regimens.” Also, surgical removal of the primary tumor would receive a higher priority. In the present study significant predictors of death in univariate analysis included metastases at diagnosis, local tissue invasion, and prostatic origin of the primary. Both local tissue invasion and distant metastases have had prognostic importance for patients with rhabdomyosarcomas arising in other anatomical sites.‘8*‘9Indeed, local invasiveness may be a primary determinant of biological aggressiveness. Prostatic involvement was also a significant predictor of death in univariate analysis. Controversy exists concerning the importance of the prostate in predicting
B
A
L
I’----. No Tumor Invasiveness A Tumor Invasiveness
-4
= Size 6 5 cm A Size > 5 cm
P60.03
J
1
1
’
~60.06 L
3
I
1
I
I
6 9 12 15 Years to Last Follow-Up or Death
I
18
0.0’
0
I
I
I
I
1
,
3
6
9
12
15
18
Years to Last Follow-Up or Death
Fig 5. (A) Comparison of the survival of patients with and without locally invasive tumors. IB) Comparison of survival in patients with tumors 56 cm or >6 cm.
1071
BLADDER AND PROSTATE RHABDOMYOSARCOMA
A
6
mNo Node A Node
No MET!? . METS
n
p>o.2 ‘1 I z ‘E E lz
0.4 e a.
0.2-
0.0 0
1 3
I 6
I 9
I 12
1 15
J 18
Years to Last Follow-Up or Death
p< 0.01
0.2-
0.0 o
3
L 6
9
12
I 15
, 18
Years to Last Follow-Up or Death
Fia 6. IA) Comoarison of survival for patients with and without regional lymph node involvement. (B) Comparison of survival between patients who did 0; did not present with distant metastases.
death, especially in patients undergoing multiagent chemotherapy.‘4*20 In the present study, all patients received intensive, multiagent chemotherapy, and prostatic origin of the primary was associated with a relative risk of fatal outcome of 6.5. Also, when compared in multivariate analysis with completeness of resection, tumor size, and urethral-trigonal involvement, only prostatic primary was a significant predictor of mortality. Involvement of the prostatic stroma in transitional cell carcinomas of the bladder in adults has been associated with an increased incidence of nodal and distant metastasis and a worse prognosis stage for stage.*’ A possible explanation for the importance of prostatic involvement is reluctance to perform early extirpation because of the increased morbidity associated not only with urinary tract diversion but also loss of sexual function. Alternatively, the rich venous and lymphatic channels in the prostate may allow earlier dissemination. Finally, tumors in this region may have an increased biological aggressiveness. Complete surgical resection approached statistical significance in univariate analysis. This was close enough to speculate that this variable is important in overall outcome and statistical significance at the .05 level would be attained by the addition of more cases. Complete removal of all tumor tissue in the case of partial cystectomy has been previously emphasized by others,14 and was an important predictor of outcome in both extremity and paratesticular rhabdomyosarcoma studies reported from this institution.** Only four bladders in this series could be preserved and are
functional. In two of these, primary, complete resection could be accomplished using partial cystectomy. In all other patients tumor progression or local recurrence necessitated total cystectomy, or resulted in death. These data suggest that bladder resection may have relevance to survival and bladder preservation is very difficult except for anatomically favorable lesions. Finally, primary tumor size approached significance as a prognostic indicator but did not have the same strong influence as local tumor invasiveness. Regional lymph node involvement had no effect on survival in this study, consistent with the findings of the IRS for this anatomical site. It should be noted that only four patients in this series had regional nodal metastases. We conclude that local tissue invasion, distant metastases at diagnosis, and prostatic origin of the primary are significant predictors of mortality in rhabdomyosarcoma of the bladder, and place patients into high-risk groups requiring more aggressive treatment using all modalities. Complete surgical resection of the primary tumor, usually necessitating cystectomy, may also be an important determinant of outcome. We suggest that complete surgical excision be strongly considered in high-risk groups. A reasonable approach would include initial diagnosis and staging followed by high-dose multiagent chemotherapy. If tumor burden is reduced to microscopic levels as determined by imaging procedures and cystoscopy, further chemotherapy combined with radiation may be effective and cystectomy would be reserved for local recurrence. If chemotherapy produced less than 50%
1072
LA QUAGLIA ET AL
tumor regression or had no effect, total cystectomy would then be performed. With recent advances in bladder reconstruction using intestinal segments, future protocols might evaluate a more aggressive surgical approach that would allow extirpation of tumor
with immediate bladder reconstruction in an unirradiated field. Removal of all gross, and possibly microscopic tumor from the primary site might allow subsequent elimination of the need for irradiation or reduction in dosage.
REFERENCES 1. Maurer HM, Beltangady M, Gehan EA, et al: The Intergroup Rhabdomyosarcoma Study (IRS-I): A final report. Cancer 61:209220,1988 2. Ghavimi F, Exelby PR, D’Angio GJ, et al: Combination therapy of urogenital embryonal rhabdomyosarcoma in children. Cancer 32:1178-l 185, 1973 3. Hays DM, Raney RB, Lawrence W, et al: Bladder and prostatic tumors in the Intergroup Rhabdomyosarcoma Study (IRS1). Cancer 50:1472-1482,1982 4. El-Mahdi AM, Marks R Jr, Thornton WN, et al: Sequelae of pelvic irradiation in infancy. Radiology 110:665-666, 1974 5. Tucker MA, D’Angio GJ, Boice JD, et al: Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med 317588-593, 1987 6. Harmer MH (ed): TNM Classification of Pediatric Tumors. Geneva, Switzerland, International Union Against Cancer, 1982, pp 23-28 7. Ghavimi F, Exelby PR, D’Angio GJ, et al: Multidisciplinary treatment of embryonal rhabdomyosarcoma in children. Cancer 35~677-686, 1975 8. Ghavimi F, Exelby PR, Jereb B, et al: Multidisciplinary treatment of advanced stages of embryonal rhabdomyosarcoma in children. NC1 Monogr 56:103-109,198l 9. Kaplan EL, Meier R: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-581, 1958 10. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Sot 135:185-206, 1977 11. Cox DR: Regression models and life tables. J R Stat SOC 34:187-220, 1972
12. Mackenzie A, Whitmore WF, Melamed MR: Myosarcomas of the bladder and prostate. Caiicer 22:833-844, 1968 13. Hays DM. Raney RB Jr, Lawrence W Jr, et al: Primary chemotherapy in the treatment of children with bladder-prostate tumors in the Intergroup Rhabdomyosarcoma Study (IRS-II). J Pediatr Surg 17:8 12-8 19, 1982 14. Hays DM, Raney RB, Lawrence W, et al: Bladder and prostatic tumors in the Intergroup Rhabdomyosarcoma Study: Results of therapy. Cancer 50:1472-1482, 1982 15. Ghavimi F, Herr H, Jereb B, et al: Treatment of genitourinary rhabdomyosarcoma in children. J Urol 132:3 13-3 19, 1984 16. Loughlin KR, Retik AB, Weinstein HJ, et al: Genitourinary rhabdomyosarcoma in children. Cancer 63:1600-1606, 1989 17. de Kraker J, Voute PA: The role of ifosfamide in paediatric soft tissue sarcomas. Cancer Chemother Pharmacol 18:s23-~24, 1986 (suppl2) 18. LaQuaglia MP, Ghavimi F, Penenberg D, et al: Factors predictive of mortality in pediatric extremity rhabdomyosarcoma. J Pediatr Surg 25:1-7, 1990 19. Enneking WF, Spanier SS, Goodman MA: The surgical staging of musculoskeletal sarcoma. J Bone Joint Surg 62:10271030,198O 20. Timmons JW, Burgert EO, Soule EH, et al: Embryonal rhabdomyosarcoma of the bladder and prostate in childhood. J Urol 113:694-697, 1975 21. Schellhammer PF, Bean MA, Whitmore WF: Prostatic involvement by transitional cell carcinoma: Pathogenesis, patterns and prognosis. J Urol 118:399-403, 1977 22. La Quaglia MP, Ghavimi F, Heller G, et al: Mortality in pediatric paratesticular rhabdomyosarcoma: A multivariate analysis. J Urol 142:473-478,1989