- Email: [email protected]
Bilateral Wilms' Tumors: Single-center Experience With 22 Cases and Literature Review
Pediatric Urology Bilateral Wilms’ Tumors: Single-center Experience With 22 Cases and Literature Review Osama M. Sarhan, Mahmoud El-Baz, Mohamed M. Sarhan, Ahmed M. Ghali, and Mohamed A. Ghoneim OBJECTIVES
METHODS
RESULTS
CONCLUSIONS
Bilateral Wilms’ tumors represent a therapeutic challenge. The primary aim of management is eradication of the neoplasm and preservation of renal function. We present our experience in the management of such cases in a single-center experience. This was a retrospective study of 22 patients with histologically proven bilateral nephroblastoma who were treated from 1993 to 2008 at our center. Of the 22 patients, 12 were girls and 10 were boys, with a median age of 3 years (range 1-9); 19 had a synchronous presentation and 3 a metachronous presentation. Of the 22 patients, 6 underwent initial surgical resection followed by chemotherapy and 16 underwent initial biopsy and preoperative chemotherapy. The final oncologic and renal outcomes were assessed. The median follow-up period was 3 years (range 1-11). Of the 22 patients, 8 died, for an overall survival rate of 63.5%. The survival for the initial chemotherapy and initial surgery groups was essentially similar. Of all the variables studied, unfavorable histologic findings had a significant negative effect on survival. Of the 5 patients with unfavorable histologic findings, 4 died during the follow-up period. The median volume of preserved renal parenchyma was 40%. All patients had good renal function during follow-up, except for 1 patient who had undergone bilateral nephrectomy. Bilateral Wilms’ tumors impose 2 conflicting issues: elimination of the pathology and preservation of the renal function. Currently, treatment regimens involving initial chemotherapy followed by conservative surgery can achieve these goals in an important proportion of patients. UROLOGY 76: 946 –951, 2010. © 2010 Elsevier Inc.
W
ilms tumor comprises the vast majority of renal tumors in children and bilaterality is observed in 4%-8%.1-4 The multimodality treatments for such tumors, including surgery, chemotherapy, and radiotherapy, has undergone several refinements in the past 3 decades.1-7 This has resulted in a survival rate approaching that of unilateral Wilms tumor.1,4,5 We report our experience with 22 patients with bilateral Wilms’ tumor seen and treated at 1 center.
MATERIAL AND METHODS During a 15-year period (1993-2008), 246 patients with histologically proven Wilms’ tumor were treated at our center. Of these, 22 (9%) had bilateral disease (12 girls and 10 boys). The age range was 1-9 years (median 3). The medical records of
From the Department of Urology, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt Reprint requests: Osama M. Sarhan, M.D., Department of Urology, Urology and Nephrology Center, Mansoura University, Mansoura 35516 Egypt. E-mail: [email protected] Submitted: January 11, 2010; received (with revisions): March 21, 2010
946
© 2010 Elsevier Inc. All Rights Reserved
these patients were reviewed for their demographics, mode of presentation, investigations, preoperative treatment, type of surgery, tumor stage and tumor grade, postoperative treatment, and final outcome. This cohort of 22 patients included 19 with synchronous and 3 with metachronous tumors. The patients with metachronous tumors had undergone initial nephrectomy elsewhere and were referred to our institution after a mean interval of 10 months (range 5-15) from their initial presentation. The basic investigations included complete blood count, serum creatinine, liver function tests, and serum electrolytes. These were performed before therapy and repeated during the chemotherapy course. Initial computed tomography and/or magnetic resonance imaging were performed to evaluate the tumor size, tumor stage, operability, and tumor multiplicity. According to the treatment protocol, the patients were divided into 2 groups. The first group underwent initial surgery followed by chemotherapy (6 patients), and the second group underwent initial biopsy and preoperative chemotherapy followed by surgery (16 patients). In all patients, histopathologic classification and staging were performed according to the third and fourth National Wilms’ Tumor Study (NWTS) groups.6,7 The initial surgery group (6 patients, 12 renal units) included 3 with metachronous tumors and 3 with synchronous tumors. 0090-4295/10/$34.00 doi:10.1016/j.urology.2010.03.055
The surgical interventions in this group included radical nephrectomy for 1 side (6 renal units). For the contralateral side, nephron-sparing surgery was performed for 5 units and open biopsy for the sixth. The initial chemotherapy group (16 patients, 32 renal units) underwent initial biopsy and preoperative chemotherapy followed by surgery. After establishment of the diagnosis and initiation of chemotherapy, surgery was performed 1.5-6 months later for all patients but 1. That patient died preoperatively of a complication of chemotherapy. The preoperative chemotherapy regimen was tailored to the tumor stage and the histopathologic type (favorable or unfavorable). The 10 patients with organ-confined disease underwent the standard 4-week protocol of actinomycin D (AMD) and vincristine. The 6 patients with advanced disease and/or unfavorable histologic features underwent a 3-drug regimen of AMD, vincristine, and doxorubicin for 5-10 weeks. For 3 patients with nonresponsive disease, a more intensive protocol was necessary: doxorubicin alternating with ifosfamide, etoposide, and 2-mercaptoethane sulfonate sodium (MESNA) every 3 weeks. After their initial chemotherapy regimen, computed tomography and/or magnetic resonance imaging was performed to assess the tumor response and operability. The radiologic response was determined by measuring the change in the maximal tumor diameter between the initial images obtained at diagnosis and those taken after chemotherapy. A good radiologic response was defined as a reduction of ⬎50% of the maximal tumor diameter.4 Of these 16 patients, a stage reduction was observed in 13 (81%), with no response in 3, all of whom had had unfavorable histologic findings. Surgical intervention included radical nephrectomy on 1 side and nephron-sparing surgery on the contralateral side in 9 patients. For 2 patients, radical nephrectomy was performed, with open renal biopsy on the contralateral side. Bilateral nephron-sparing surgery was performed in 3 patients. In 1 patient, bilateral nephrectomy was necessary. All patients underwent postoperative chemotherapy for 4 months to ⱕ2 years. This adjuvant chemotherapy regimen was dependent on the individual tumor stage and the presence of unfavorable histologic findings. Patients with organ-confined disease received AMD and vincristine for 18 weeks (n ⫽ 10). Patients with more advanced disease received AMD, vincristine, and doxorubicin for 24 weeks (n ⫽ 7). In the patients with unfavorable histologic findings, intensive chemotherapy consisting of AMD, vincristine, doxorubicin, ifosfamide, and etoposide was given for 12 months (n ⫽ 4). Patients were regularly followed up for evidence of disease recurrence and/or metastases and for an estimation of the renal function status. The percentage of the preserved renal mass after all surgical interventions was estimated from the surgical, pathologic, and imaging reports. Each kidney was considered as 50% of the total renal mass.4 All the collected data were analyzed using the Statistical Package for Social Sciences software, version 11.5 (SPSS, Chicago, IL). The Kaplan-Meier method was used to assess the survival rates. Censored values represented surviving patients. Patients lost to follow-up were considered to have died of their disease. The survival rates were compared using the log-rank test. P ⱕ.05 was considered statistically significant.
RESULTS A palpable abdominal mass was the most common presentation. Pain, fever, and failure to thrive were also UROLOGY 76 (4), 2010
encountered. The mean follow-up period was 3 years (range 1-11). Of the 22 patients, 3 were lost to follow-up. Five patients died; 1 preoperatively of chemotherapy toxicity, 1 died postoperatively of gastrointestinal bleeding, 2 died of widespread metastases, and 1 had local recurrence. Table 1 lists the detailed account of the profile of the individual patient data. The overall survival rate was 61% ⫾ 11% (14 of 22 patients; Fig. 1). The survival for the initial chemotherapy and initial surgery groups was comparable. Moreover, in the initial chemotherapy group, the survival rate of the patients who responded well to preoperative chemotherapy was better than that of those with a poor response to the chemotherapy (77% vs 33%). Table 2 lists the effect of some of the patient and tumor characteristics on survival. Patient sex, patient age (ⱕ2 vs ⬎2 years), local tumor stage of the more advanced side, and whether the tumors were synchronous or metachronous had no significant effect on survival. In contrast, a significant difference in survival when the histopathologic features (favorable or unfavorable) were considered (Fig. 2). The percentage of the preserved renal mass was greater in the patients who were initially treated with chemotherapy than in the patients treated with initial surgery (mean 44% vs 35.5%, respectively). All the surviving patients, but 1, had normal renal function at the last follow-up visit. The mean serum creatinine value at the last follow-up visit was 0.55 mg/dL (range 0.3-0.8). One patient was rendered anephric and required regular hemodialysis.
COMMENT In the present study, we evaluated our experience in the management of 22 cases of bilateral Wilms’ tumor. These tumors impose a special challenge: establishing local tumor control and preserving renal function. For a long time, bilateral Wilms’ tumors were considered to convey a poor prognosis. Initially, treatment relied only on surgical extirpation, with subsequent renal transplantation for many of these patients.8-10 The results of this approach proved to be poor.9 Subsequently, surgical procedures were initially used in most centers, followed by chemotherapy.5,11 Later, the treatment protocols were modified to use initial chemotherapy, followed by conservative surgical resection.5,11,15 By 1979, the NWTS group 3 recommended that the practice of initial resection of all tumors should be replaced with initial biopsy and staging followed by chemotherapy and subsequent surgery.1,6 Nevertheless, other investigators provided evidence that no difference was present in the survival rate between the patients initially treated with chemotherapy and those who had initially undergone surgical resection.1,2,11-13 In our experience, the expected 5-year overall survival rate was 61, which compares favorably with the 5-year rate in published reports from a low of 51% to a high of 73%.1,13,16 947
948 Table 1. Patient Characteristics Pt. No.
Age at Diagnosis (y)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
1 1 1 5 3 3 4 6 1 7 2 3 3 2 2 5 6 2 5 4 1 3
Sex
Initial Treatment Protocol
Preoperative Chemotherapy
Stage
Right Kidney
Male Female Female Female Female Male Male Male Male Male Male Female Female Female Male Female Female Female Male Female Female Male
Surgery Surgery Surgery Surgery Surgery Surgery Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy
None None None None None None VA VA VAD VA VA VA VA VAD VAD VAD VA VAD VA VAD VA VA
II I I II II I I I II II I II I II II I I I I II II II
Nephrectomy Nephrectomy Nephrectomy Nephrectomy Nephrectomy Nephrectomy Open biopsy NSS Nephrectomy NSS NSS None NSS Nephrectomy Nephrectomy NSS Nephrectomy NSS Open biopsy NSS NSS Nephrectomy
Left Kidney
Preserved Volume (%)
Histologic Type
Open biopsy NSS NSS NSS NSS NSS Nephrectomy Open biopsy Nephrectomy Nephrectomy NSS None Nephrectomy NSS NSS NSS NSS Nephrectomy Nephrectomy Nephrectomy NSS NSS
45 40 30 30 40 35 45 75 0 40 65 100 40 35 30 70 40 40 45 35 70 40
FH FH FH UH FH UH FH FH FH FH FH UH FH FH UH FH UH FH FH FH FH FH
Surgical Procedure
Outcome
Last Creatinine Level
Follow-Up (y)
ADF ADF ADF DOD DOD DOD ADF ADF ADF ADF ADF DOD ADF ADF DOD ADF ADF ADF DOD ADF DOD DOD
0.4 0.4 0.5 0.6 0.6 — 0.5 0.8 4.2 0.7 0.5 0.6 0.8 0.7 0.8 0.3 0.4 0.4 0.3 0.7 — —
11 3 7 3 2 Lost 1 1.5 0.5 1 5 — 5 4 1 2 7 6 2 4 Lost Lost
FH, favorable histologic type; ADF, alive disease-free; NSS, nephron-sparing surgery; UH, unfavorable histologic type; DOD, died of disease; V, vincristine; A, actinomycin; D, doxorubicin.
UROLOGY 76 (4), 2010
Figure 1. Kaplan-Meier survival curve of entire study group. Table 2. Univariate analysis of factors affecting outcome Characteristic Age (y) ⱕ2 ⬎2 Sex Male Female Presentation Synchronous Metachronous Treatment protocol Initial surgery Initial chemotherapy Local tumor stage Low stage High stage Histopathologic type Favorable Unfavorable
Patients Survival Rate (n) (%) P Value .28 9 13
77 54
10 12
64 57
19 3
61 67
6 16
50 65
11 11
82 45
17 5
76 20
.64 .70 .58 .10 .02*
* Significant.
Figure 2. Kaplan-Meier survival relative to histopathologic type.
Our data have also indicated that the overall survival for patients treated with initial chemotherapy was better than that for those treated with initial surgery (68% and UROLOGY 76 (4), 2010
50%, respectively). However, this difference did not reach statistical significance. This might have been the result of a type II statistical error owing to the small sample size. However, other series have reached the opposite conclusion that survival is better with initial surgery11 or that survival was the same with both approaches.1,2,13 Other factors might influence the outcome of patients with bilateral Wilms’ tumors, including age at diagnosis, stage of the most advanced tumor, and histologic features.1,3,5,11,12,14 A poor prognosis was associated with an older age at diagnosis, unfavorable histologic findings, and advanced local stage.1,11,14 The importance of age as a prognostic factor has been previously emphasized. A better prognosis was associated with a younger age at diagnosis.1,3,5,11,12 Asch et al14 reported that significantly better survival was seen in children whose tumors were diagnosed before 2 years of age. Our data were essentially similar, although the difference was not statistically significant, again possibly owing to the small sample size. An explanation for this finding is that older patients present with more advanced disease and that anaplasia in patients ⬍2 years old is infrequent.11 The incidence of tumors with an unfavorable histologic type was reported to be about 10% in some large series,1,2,11 with a greater incidence among girls.2,11 These tumors include several morphologic patterns, such as anaplastic and rhabdoid tumors and clear cell sarcoma of the kidney.6,7 It has been uniformly agreed that these tumors convey a significantly poorer prognosis than those with a favorable histologic type.1-3,11,12 It was also noted that these tumors are less responsive to the standard chemotherapy protocols.17 In a study by Cooper et al3 in 2000, a significantly decreased survival rate in children with bilateral Wilms’ tumor and anaplasia was noted (10%-26%). Furthermore, de Lorimier et al,8 recommended prompt bilateral nephrectomy, dialysis, and transplantation when a tumor was not controlled by radiotherapy and chemotherapy. Because an unfavorable histologic type represents a poor prognostic factor, Kumar et al2 and Blute et al11 suggested that renal preservation should be a secondary consideration. In our study, 5 patients had an unfavorable histologic type, an incidence of 23%, which was slightly greater than that in previous reports. Of these 5 patients, 3 were girls. The 5-year overall survival rate was significantly lower than that for patients with tumors with a favorable histologic type (20% vs 76%; P ⫽ .02). This was the only significant variable affecting the prognosis in our study. The stage of the most advanced tumor was also noted as a prognostic factor; the greater the stage, the poorer the prognosis.1,11,12,14 Our results might compare favorably with this observation, but our data did not reach statistical significance. Preoperative chemotherapy often results in a significant reduction in tumor size, thereby facilitating subse949
quent renal salvage and complete surgical resection of the tumor.13-17 In our study, of the patients treated with initial chemotherapy, a stage reduction was observed in 13 (81%), with no response observed in 3 patients, all of whom had an unfavorable histologic type. The survival of patients who responded well to the preoperative chemotherapy was much better than that of those without a response (77% vs 33%). Metachronous bilateral Wilms’ tumor accounts for approximately 2% of all Wilms’ tumors.16,18-20 The prognostic effect of whether the bilateral Wilms’ tumor is synchronous or metachronous is unclear, because the number of patients with the latter has been very small. The NWTS group has reported lower survival rates for patients with metachronous tumors.18,19 A review of the published data by Paulino et al19 showed that the overall survival rate for patients with metachronous bilateral Wilms’ tumor was only 49% at 5 years and 47% at 10 years. Children in whom a contralateral tumor developed ⬎18 months after the initial diagnosis had better survival than those in whom it developed within ⬍18 months (55.2% vs 39.6%). A metachronous presentation in our study occurred in 3 patients a mean interval of 10 months after the initial diagnosis. However, this was not associated with a poorer prognosis, as was previously reported. Our findings are similar to those reported by Millar et al16 and Casale et al.20 A poorer prognosis for patients with metachronous tumors was not identified by these investigators. Kumar et al2 analyzed the outcome of patients with bilateral Wilms’ tumors in 71 children and found that the preserved renal mass among those treated with initial chemotherapy was greater than in those treated with initial surgery (45% vs 35%). The same observation was noted in our study (44% vs 35.5%). However, such an observation was not observed by Shaul et al.13 Children with Wilms’ tumor are at a greater risk of impaired renal function because of the potentially nephrotoxic chemotherapeutic agents and a theoretical risk owing to hyperfiltration injury of the remaining nephrons after removal of a critical mass of renal tissue.21 Children with bilateral Wilms’ tumor frequently require removal of ⬎50% of their renal tissue. Parenchymal-sparing procedures have been advocated to preserve as much functioning renal tissue as possible.1,2,5,11,15,22 It was reported that satisfactory renal function after renal salvage surgery can be achieved if 30% of the renal volume had been saved.4,13,14 The incidence of renal failure in bilateral Wilms’ tumor was reported as 16.4% by NWTS-1 and -2, 9.9% by NWTS-3, and 3.8% by NWTS-4.21 These progressive improvements were the result of improvement in chemotherapy regimens, the adoption of initial chemotherapy, and the limitation of the use of radiotherapy. The incidence of renal failure in our study was 4.5%. Rates within the same range were also reported by Kumar et al2 and Ritchey et al.21 In contrast, Breslow et al23 documented an 11.5% incidence 950
of renal failure in patients with bilateral Wilms’ tumor, greater than that seen in our series. In our series, only 1 patient was rendered anephric because bilateral nephrectomy was mandatory. The risk of patients with bilateral Wilms’ tumor becoming anephric decreased from 60% in older reports8 to a range of 0%-11.7% in recent studies.4,11,15,22,24 This resulted from the more conservative approach conducted recently in many centers. Finally, our study had some limitations. First, it was retrospective, with a relatively short mean follow-up period. Also, the selection of patients for either initial surgery or initial biopsy was done on an individual basis. However, it is clear that most of the deaths from Wilms’ tumor occur within 3 years of diagnosis.1 This was within the range of our follow-up period. However, these patients still need to be followed up indefinitely for both treatment-related complications and recurrence and secondary tumor development. In addition, monitoring the patients’ renal function is an essential aspect of the long-term follow-up of these children.
CONCLUSIONS Bilateral Wilms’ tumors impose 2 conflicting issues: the elimination of the pathologic findings and preservation of renal function. Currently, treatment regimens involving initial chemotherapy followed by conservative surgery can achieve these goals in an important proportion of patients. References 1. Montgomery BT, Kelalis PP, Blute ML, et al. Extended follow-up of bilateral Wilms tumour: results of the National Wilms Tumor Study. J Urol. 1991;146:514-518. 2. Kumar R, Fitzgerald R, Breatnach F. Conservative surgical management of bilateral Wilms tumor: results of the United Kingdom Children’s Cancer Study Group. J Urol. 1998;160:1450-1453. 3. Cooper CS, Jaffe WI, Huff DS, et al. The role of renal salvage procedures for bilateral Wilms’ tumor: a 15-year review. J Urol. 2000;163:265-268. 4. Kubiak R, Gundeti M, Duffy PG, et al. Renal function and outcome following salvage surgery for bilateral Wilms tumor. J Pediatr Surg. 2004;39:1667-1672. 5. Bishop HC, Tefft M, Evans AE, et al. Survival in bilateral Wilms tumor: review of 30 National Wilms Tumor Study cases. J Pediatr Surg. 1977;12:631-638. 6. D’Angio GJ, Breslow N, Beckwith JB, et al. Treatment of Wilms tumor: results of the third National Wilms Tumor Study. Cancer. 1989;64:349-360. 7. Neville HL, Ritchey ML. Wilms tumor: overview of National Wilms Tumor Study Group results. Urol Clin North Am. 2000;27: 435-442. 8. de Lorimier AA, Belzer FO, Kountz SL, et al. Treatment of bilateral Wilms tumor. Am J Surg. 1971;122:275-281. 9. DeMaria JE, Hardy BE, Brezinski A, et al. Renal transplantation in patients with bilateral Wilms tumor. J Pediatr Surg. 1979;14:577579. 10. Penn I. Renal transplantation for Wilms tumor: report of 20 cases. J Urol. 1979;122:793-794. 11. Blute ML, Kelalis PP, Offord KP, et al. Bilateral Wilms tumor. J Urol. 1987;138:968-973.
UROLOGY 76 (4), 2010
12. Tucker OP, McGill CW, Pokorny WJ, et al. Bilateral Wilms tumor. J Pediatr Surg. 1986;21:1110-1113. 13. Shaul DB, Srikanth MM, Ortega JA, et al. Treatment of bilateral Wilms tumor: comparison of initial biopsy and chemotherapy to initial surgical resection in the preservation of renal mass and function. J Pediatr Surg. 1992;27:1009-1015. 14. Asch MJ, Siegel S, White L, et al. Prognostic factors and outcome in bilateral Wilms tumor. Cancer. 1985;56:2524-2529. 15. Horwitz JR, Ritchey ML, Moksness J, et al. Renal salvage procedures in patients with synchronous bilateral Wilms’ tumors: a report from the National Wilms Tumor Study Group. J Pediatr Surg. 1996;31:1020-1025. 16. Millar AJ, Davidson A, Rode H, et al. Bilateral Wilms’ tumors: a singlecenter experience with 19 cases. J Pediatr Surg. 2005;40:1289-1294. 17. Hamilton TE, Green DM, Perlman EJ, et al. Bilateral Wilms tumor with anaplasia: lessons from the National Wilms Tumor Study. J Pediatr Surg. 2006;41:1641-1644. 18. Coppes MJ, Arnold M, Beckwith JB, et al. Factors affecting the risk of contralateral Wilms tumor development: a report from the National Wilms Tumor Study Group. Cancer. 1999;85:1616-1625.
UROLOGY 76 (4), 2010
19. Paulino AC, Thakkar B, Henderson WG. Metachronous bilateral Wilms tumor: the importance of time interval to the development of a second tumor. Cancer. 1998;82:415-420. 20. Casale AJ, Flanigan RC, Moore PJ, et al. Survival in bilateral metachronous (asynchronous) Wilms tumor. J Urol. 1982;128:766768. 21. Ritchey ML, Green DM, Thomas PRM, et al. Renal failure in Wilms tumor patients: a report from the National Wilms Tumor Study Group. Med Pediatr Oncol. 1996;26:75-80. 22. Davidoff AM, Giel DW, Jones DP, et al. The feasibility and outcome of nephron-sparing surgery for children with bilateral Wilms tumor: the St. Jude children’s Research Hospital experience: 1999-2006. Cancer. 2008;112:2060-2070. 23. Breslow NE, Collins AJ, Ritchey ML, et al. End stage renal disease in patients with Wilms tumor: results from the National Wilms Tumor Study Group and the United States Renal Data System. J Urol. 2005;174:1972-1975. 24. Giel DW, Williams MA, Jones DP, et al. Renal function outcomes in patients treated with nephron sparing surgery for bilateral Wilms tumor. J Urol. 2007;178:1786-1789.
951
METHODS
RESULTS
CONCLUSIONS
Bilateral Wilms’ tumors represent a therapeutic challenge. The primary aim of management is eradication of the neoplasm and preservation of renal function. We present our experience in the management of such cases in a single-center experience. This was a retrospective study of 22 patients with histologically proven bilateral nephroblastoma who were treated from 1993 to 2008 at our center. Of the 22 patients, 12 were girls and 10 were boys, with a median age of 3 years (range 1-9); 19 had a synchronous presentation and 3 a metachronous presentation. Of the 22 patients, 6 underwent initial surgical resection followed by chemotherapy and 16 underwent initial biopsy and preoperative chemotherapy. The final oncologic and renal outcomes were assessed. The median follow-up period was 3 years (range 1-11). Of the 22 patients, 8 died, for an overall survival rate of 63.5%. The survival for the initial chemotherapy and initial surgery groups was essentially similar. Of all the variables studied, unfavorable histologic findings had a significant negative effect on survival. Of the 5 patients with unfavorable histologic findings, 4 died during the follow-up period. The median volume of preserved renal parenchyma was 40%. All patients had good renal function during follow-up, except for 1 patient who had undergone bilateral nephrectomy. Bilateral Wilms’ tumors impose 2 conflicting issues: elimination of the pathology and preservation of the renal function. Currently, treatment regimens involving initial chemotherapy followed by conservative surgery can achieve these goals in an important proportion of patients. UROLOGY 76: 946 –951, 2010. © 2010 Elsevier Inc.
W
ilms tumor comprises the vast majority of renal tumors in children and bilaterality is observed in 4%-8%.1-4 The multimodality treatments for such tumors, including surgery, chemotherapy, and radiotherapy, has undergone several refinements in the past 3 decades.1-7 This has resulted in a survival rate approaching that of unilateral Wilms tumor.1,4,5 We report our experience with 22 patients with bilateral Wilms’ tumor seen and treated at 1 center.
MATERIAL AND METHODS During a 15-year period (1993-2008), 246 patients with histologically proven Wilms’ tumor were treated at our center. Of these, 22 (9%) had bilateral disease (12 girls and 10 boys). The age range was 1-9 years (median 3). The medical records of
From the Department of Urology, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt Reprint requests: Osama M. Sarhan, M.D., Department of Urology, Urology and Nephrology Center, Mansoura University, Mansoura 35516 Egypt. E-mail: [email protected] Submitted: January 11, 2010; received (with revisions): March 21, 2010
946
© 2010 Elsevier Inc. All Rights Reserved
these patients were reviewed for their demographics, mode of presentation, investigations, preoperative treatment, type of surgery, tumor stage and tumor grade, postoperative treatment, and final outcome. This cohort of 22 patients included 19 with synchronous and 3 with metachronous tumors. The patients with metachronous tumors had undergone initial nephrectomy elsewhere and were referred to our institution after a mean interval of 10 months (range 5-15) from their initial presentation. The basic investigations included complete blood count, serum creatinine, liver function tests, and serum electrolytes. These were performed before therapy and repeated during the chemotherapy course. Initial computed tomography and/or magnetic resonance imaging were performed to evaluate the tumor size, tumor stage, operability, and tumor multiplicity. According to the treatment protocol, the patients were divided into 2 groups. The first group underwent initial surgery followed by chemotherapy (6 patients), and the second group underwent initial biopsy and preoperative chemotherapy followed by surgery (16 patients). In all patients, histopathologic classification and staging were performed according to the third and fourth National Wilms’ Tumor Study (NWTS) groups.6,7 The initial surgery group (6 patients, 12 renal units) included 3 with metachronous tumors and 3 with synchronous tumors. 0090-4295/10/$34.00 doi:10.1016/j.urology.2010.03.055
The surgical interventions in this group included radical nephrectomy for 1 side (6 renal units). For the contralateral side, nephron-sparing surgery was performed for 5 units and open biopsy for the sixth. The initial chemotherapy group (16 patients, 32 renal units) underwent initial biopsy and preoperative chemotherapy followed by surgery. After establishment of the diagnosis and initiation of chemotherapy, surgery was performed 1.5-6 months later for all patients but 1. That patient died preoperatively of a complication of chemotherapy. The preoperative chemotherapy regimen was tailored to the tumor stage and the histopathologic type (favorable or unfavorable). The 10 patients with organ-confined disease underwent the standard 4-week protocol of actinomycin D (AMD) and vincristine. The 6 patients with advanced disease and/or unfavorable histologic features underwent a 3-drug regimen of AMD, vincristine, and doxorubicin for 5-10 weeks. For 3 patients with nonresponsive disease, a more intensive protocol was necessary: doxorubicin alternating with ifosfamide, etoposide, and 2-mercaptoethane sulfonate sodium (MESNA) every 3 weeks. After their initial chemotherapy regimen, computed tomography and/or magnetic resonance imaging was performed to assess the tumor response and operability. The radiologic response was determined by measuring the change in the maximal tumor diameter between the initial images obtained at diagnosis and those taken after chemotherapy. A good radiologic response was defined as a reduction of ⬎50% of the maximal tumor diameter.4 Of these 16 patients, a stage reduction was observed in 13 (81%), with no response in 3, all of whom had had unfavorable histologic findings. Surgical intervention included radical nephrectomy on 1 side and nephron-sparing surgery on the contralateral side in 9 patients. For 2 patients, radical nephrectomy was performed, with open renal biopsy on the contralateral side. Bilateral nephron-sparing surgery was performed in 3 patients. In 1 patient, bilateral nephrectomy was necessary. All patients underwent postoperative chemotherapy for 4 months to ⱕ2 years. This adjuvant chemotherapy regimen was dependent on the individual tumor stage and the presence of unfavorable histologic findings. Patients with organ-confined disease received AMD and vincristine for 18 weeks (n ⫽ 10). Patients with more advanced disease received AMD, vincristine, and doxorubicin for 24 weeks (n ⫽ 7). In the patients with unfavorable histologic findings, intensive chemotherapy consisting of AMD, vincristine, doxorubicin, ifosfamide, and etoposide was given for 12 months (n ⫽ 4). Patients were regularly followed up for evidence of disease recurrence and/or metastases and for an estimation of the renal function status. The percentage of the preserved renal mass after all surgical interventions was estimated from the surgical, pathologic, and imaging reports. Each kidney was considered as 50% of the total renal mass.4 All the collected data were analyzed using the Statistical Package for Social Sciences software, version 11.5 (SPSS, Chicago, IL). The Kaplan-Meier method was used to assess the survival rates. Censored values represented surviving patients. Patients lost to follow-up were considered to have died of their disease. The survival rates were compared using the log-rank test. P ⱕ.05 was considered statistically significant.
RESULTS A palpable abdominal mass was the most common presentation. Pain, fever, and failure to thrive were also UROLOGY 76 (4), 2010
encountered. The mean follow-up period was 3 years (range 1-11). Of the 22 patients, 3 were lost to follow-up. Five patients died; 1 preoperatively of chemotherapy toxicity, 1 died postoperatively of gastrointestinal bleeding, 2 died of widespread metastases, and 1 had local recurrence. Table 1 lists the detailed account of the profile of the individual patient data. The overall survival rate was 61% ⫾ 11% (14 of 22 patients; Fig. 1). The survival for the initial chemotherapy and initial surgery groups was comparable. Moreover, in the initial chemotherapy group, the survival rate of the patients who responded well to preoperative chemotherapy was better than that of those with a poor response to the chemotherapy (77% vs 33%). Table 2 lists the effect of some of the patient and tumor characteristics on survival. Patient sex, patient age (ⱕ2 vs ⬎2 years), local tumor stage of the more advanced side, and whether the tumors were synchronous or metachronous had no significant effect on survival. In contrast, a significant difference in survival when the histopathologic features (favorable or unfavorable) were considered (Fig. 2). The percentage of the preserved renal mass was greater in the patients who were initially treated with chemotherapy than in the patients treated with initial surgery (mean 44% vs 35.5%, respectively). All the surviving patients, but 1, had normal renal function at the last follow-up visit. The mean serum creatinine value at the last follow-up visit was 0.55 mg/dL (range 0.3-0.8). One patient was rendered anephric and required regular hemodialysis.
COMMENT In the present study, we evaluated our experience in the management of 22 cases of bilateral Wilms’ tumor. These tumors impose a special challenge: establishing local tumor control and preserving renal function. For a long time, bilateral Wilms’ tumors were considered to convey a poor prognosis. Initially, treatment relied only on surgical extirpation, with subsequent renal transplantation for many of these patients.8-10 The results of this approach proved to be poor.9 Subsequently, surgical procedures were initially used in most centers, followed by chemotherapy.5,11 Later, the treatment protocols were modified to use initial chemotherapy, followed by conservative surgical resection.5,11,15 By 1979, the NWTS group 3 recommended that the practice of initial resection of all tumors should be replaced with initial biopsy and staging followed by chemotherapy and subsequent surgery.1,6 Nevertheless, other investigators provided evidence that no difference was present in the survival rate between the patients initially treated with chemotherapy and those who had initially undergone surgical resection.1,2,11-13 In our experience, the expected 5-year overall survival rate was 61, which compares favorably with the 5-year rate in published reports from a low of 51% to a high of 73%.1,13,16 947
948 Table 1. Patient Characteristics Pt. No.
Age at Diagnosis (y)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
1 1 1 5 3 3 4 6 1 7 2 3 3 2 2 5 6 2 5 4 1 3
Sex
Initial Treatment Protocol
Preoperative Chemotherapy
Stage
Right Kidney
Male Female Female Female Female Male Male Male Male Male Male Female Female Female Male Female Female Female Male Female Female Male
Surgery Surgery Surgery Surgery Surgery Surgery Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy Chemotherapy
None None None None None None VA VA VAD VA VA VA VA VAD VAD VAD VA VAD VA VAD VA VA
II I I II II I I I II II I II I II II I I I I II II II
Nephrectomy Nephrectomy Nephrectomy Nephrectomy Nephrectomy Nephrectomy Open biopsy NSS Nephrectomy NSS NSS None NSS Nephrectomy Nephrectomy NSS Nephrectomy NSS Open biopsy NSS NSS Nephrectomy
Left Kidney
Preserved Volume (%)
Histologic Type
Open biopsy NSS NSS NSS NSS NSS Nephrectomy Open biopsy Nephrectomy Nephrectomy NSS None Nephrectomy NSS NSS NSS NSS Nephrectomy Nephrectomy Nephrectomy NSS NSS
45 40 30 30 40 35 45 75 0 40 65 100 40 35 30 70 40 40 45 35 70 40
FH FH FH UH FH UH FH FH FH FH FH UH FH FH UH FH UH FH FH FH FH FH
Surgical Procedure
Outcome
Last Creatinine Level
Follow-Up (y)
ADF ADF ADF DOD DOD DOD ADF ADF ADF ADF ADF DOD ADF ADF DOD ADF ADF ADF DOD ADF DOD DOD
0.4 0.4 0.5 0.6 0.6 — 0.5 0.8 4.2 0.7 0.5 0.6 0.8 0.7 0.8 0.3 0.4 0.4 0.3 0.7 — —
11 3 7 3 2 Lost 1 1.5 0.5 1 5 — 5 4 1 2 7 6 2 4 Lost Lost
FH, favorable histologic type; ADF, alive disease-free; NSS, nephron-sparing surgery; UH, unfavorable histologic type; DOD, died of disease; V, vincristine; A, actinomycin; D, doxorubicin.
UROLOGY 76 (4), 2010
Figure 1. Kaplan-Meier survival curve of entire study group. Table 2. Univariate analysis of factors affecting outcome Characteristic Age (y) ⱕ2 ⬎2 Sex Male Female Presentation Synchronous Metachronous Treatment protocol Initial surgery Initial chemotherapy Local tumor stage Low stage High stage Histopathologic type Favorable Unfavorable
Patients Survival Rate (n) (%) P Value .28 9 13
77 54
10 12
64 57
19 3
61 67
6 16
50 65
11 11
82 45
17 5
76 20
.64 .70 .58 .10 .02*
* Significant.
Figure 2. Kaplan-Meier survival relative to histopathologic type.
Our data have also indicated that the overall survival for patients treated with initial chemotherapy was better than that for those treated with initial surgery (68% and UROLOGY 76 (4), 2010
50%, respectively). However, this difference did not reach statistical significance. This might have been the result of a type II statistical error owing to the small sample size. However, other series have reached the opposite conclusion that survival is better with initial surgery11 or that survival was the same with both approaches.1,2,13 Other factors might influence the outcome of patients with bilateral Wilms’ tumors, including age at diagnosis, stage of the most advanced tumor, and histologic features.1,3,5,11,12,14 A poor prognosis was associated with an older age at diagnosis, unfavorable histologic findings, and advanced local stage.1,11,14 The importance of age as a prognostic factor has been previously emphasized. A better prognosis was associated with a younger age at diagnosis.1,3,5,11,12 Asch et al14 reported that significantly better survival was seen in children whose tumors were diagnosed before 2 years of age. Our data were essentially similar, although the difference was not statistically significant, again possibly owing to the small sample size. An explanation for this finding is that older patients present with more advanced disease and that anaplasia in patients ⬍2 years old is infrequent.11 The incidence of tumors with an unfavorable histologic type was reported to be about 10% in some large series,1,2,11 with a greater incidence among girls.2,11 These tumors include several morphologic patterns, such as anaplastic and rhabdoid tumors and clear cell sarcoma of the kidney.6,7 It has been uniformly agreed that these tumors convey a significantly poorer prognosis than those with a favorable histologic type.1-3,11,12 It was also noted that these tumors are less responsive to the standard chemotherapy protocols.17 In a study by Cooper et al3 in 2000, a significantly decreased survival rate in children with bilateral Wilms’ tumor and anaplasia was noted (10%-26%). Furthermore, de Lorimier et al,8 recommended prompt bilateral nephrectomy, dialysis, and transplantation when a tumor was not controlled by radiotherapy and chemotherapy. Because an unfavorable histologic type represents a poor prognostic factor, Kumar et al2 and Blute et al11 suggested that renal preservation should be a secondary consideration. In our study, 5 patients had an unfavorable histologic type, an incidence of 23%, which was slightly greater than that in previous reports. Of these 5 patients, 3 were girls. The 5-year overall survival rate was significantly lower than that for patients with tumors with a favorable histologic type (20% vs 76%; P ⫽ .02). This was the only significant variable affecting the prognosis in our study. The stage of the most advanced tumor was also noted as a prognostic factor; the greater the stage, the poorer the prognosis.1,11,12,14 Our results might compare favorably with this observation, but our data did not reach statistical significance. Preoperative chemotherapy often results in a significant reduction in tumor size, thereby facilitating subse949
quent renal salvage and complete surgical resection of the tumor.13-17 In our study, of the patients treated with initial chemotherapy, a stage reduction was observed in 13 (81%), with no response observed in 3 patients, all of whom had an unfavorable histologic type. The survival of patients who responded well to the preoperative chemotherapy was much better than that of those without a response (77% vs 33%). Metachronous bilateral Wilms’ tumor accounts for approximately 2% of all Wilms’ tumors.16,18-20 The prognostic effect of whether the bilateral Wilms’ tumor is synchronous or metachronous is unclear, because the number of patients with the latter has been very small. The NWTS group has reported lower survival rates for patients with metachronous tumors.18,19 A review of the published data by Paulino et al19 showed that the overall survival rate for patients with metachronous bilateral Wilms’ tumor was only 49% at 5 years and 47% at 10 years. Children in whom a contralateral tumor developed ⬎18 months after the initial diagnosis had better survival than those in whom it developed within ⬍18 months (55.2% vs 39.6%). A metachronous presentation in our study occurred in 3 patients a mean interval of 10 months after the initial diagnosis. However, this was not associated with a poorer prognosis, as was previously reported. Our findings are similar to those reported by Millar et al16 and Casale et al.20 A poorer prognosis for patients with metachronous tumors was not identified by these investigators. Kumar et al2 analyzed the outcome of patients with bilateral Wilms’ tumors in 71 children and found that the preserved renal mass among those treated with initial chemotherapy was greater than in those treated with initial surgery (45% vs 35%). The same observation was noted in our study (44% vs 35.5%). However, such an observation was not observed by Shaul et al.13 Children with Wilms’ tumor are at a greater risk of impaired renal function because of the potentially nephrotoxic chemotherapeutic agents and a theoretical risk owing to hyperfiltration injury of the remaining nephrons after removal of a critical mass of renal tissue.21 Children with bilateral Wilms’ tumor frequently require removal of ⬎50% of their renal tissue. Parenchymal-sparing procedures have been advocated to preserve as much functioning renal tissue as possible.1,2,5,11,15,22 It was reported that satisfactory renal function after renal salvage surgery can be achieved if 30% of the renal volume had been saved.4,13,14 The incidence of renal failure in bilateral Wilms’ tumor was reported as 16.4% by NWTS-1 and -2, 9.9% by NWTS-3, and 3.8% by NWTS-4.21 These progressive improvements were the result of improvement in chemotherapy regimens, the adoption of initial chemotherapy, and the limitation of the use of radiotherapy. The incidence of renal failure in our study was 4.5%. Rates within the same range were also reported by Kumar et al2 and Ritchey et al.21 In contrast, Breslow et al23 documented an 11.5% incidence 950
of renal failure in patients with bilateral Wilms’ tumor, greater than that seen in our series. In our series, only 1 patient was rendered anephric because bilateral nephrectomy was mandatory. The risk of patients with bilateral Wilms’ tumor becoming anephric decreased from 60% in older reports8 to a range of 0%-11.7% in recent studies.4,11,15,22,24 This resulted from the more conservative approach conducted recently in many centers. Finally, our study had some limitations. First, it was retrospective, with a relatively short mean follow-up period. Also, the selection of patients for either initial surgery or initial biopsy was done on an individual basis. However, it is clear that most of the deaths from Wilms’ tumor occur within 3 years of diagnosis.1 This was within the range of our follow-up period. However, these patients still need to be followed up indefinitely for both treatment-related complications and recurrence and secondary tumor development. In addition, monitoring the patients’ renal function is an essential aspect of the long-term follow-up of these children.
CONCLUSIONS Bilateral Wilms’ tumors impose 2 conflicting issues: the elimination of the pathologic findings and preservation of renal function. Currently, treatment regimens involving initial chemotherapy followed by conservative surgery can achieve these goals in an important proportion of patients. References 1. Montgomery BT, Kelalis PP, Blute ML, et al. Extended follow-up of bilateral Wilms tumour: results of the National Wilms Tumor Study. J Urol. 1991;146:514-518. 2. Kumar R, Fitzgerald R, Breatnach F. Conservative surgical management of bilateral Wilms tumor: results of the United Kingdom Children’s Cancer Study Group. J Urol. 1998;160:1450-1453. 3. Cooper CS, Jaffe WI, Huff DS, et al. The role of renal salvage procedures for bilateral Wilms’ tumor: a 15-year review. J Urol. 2000;163:265-268. 4. Kubiak R, Gundeti M, Duffy PG, et al. Renal function and outcome following salvage surgery for bilateral Wilms tumor. J Pediatr Surg. 2004;39:1667-1672. 5. Bishop HC, Tefft M, Evans AE, et al. Survival in bilateral Wilms tumor: review of 30 National Wilms Tumor Study cases. J Pediatr Surg. 1977;12:631-638. 6. D’Angio GJ, Breslow N, Beckwith JB, et al. Treatment of Wilms tumor: results of the third National Wilms Tumor Study. Cancer. 1989;64:349-360. 7. Neville HL, Ritchey ML. Wilms tumor: overview of National Wilms Tumor Study Group results. Urol Clin North Am. 2000;27: 435-442. 8. de Lorimier AA, Belzer FO, Kountz SL, et al. Treatment of bilateral Wilms tumor. Am J Surg. 1971;122:275-281. 9. DeMaria JE, Hardy BE, Brezinski A, et al. Renal transplantation in patients with bilateral Wilms tumor. J Pediatr Surg. 1979;14:577579. 10. Penn I. Renal transplantation for Wilms tumor: report of 20 cases. J Urol. 1979;122:793-794. 11. Blute ML, Kelalis PP, Offord KP, et al. Bilateral Wilms tumor. J Urol. 1987;138:968-973.
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12. Tucker OP, McGill CW, Pokorny WJ, et al. Bilateral Wilms tumor. J Pediatr Surg. 1986;21:1110-1113. 13. Shaul DB, Srikanth MM, Ortega JA, et al. Treatment of bilateral Wilms tumor: comparison of initial biopsy and chemotherapy to initial surgical resection in the preservation of renal mass and function. J Pediatr Surg. 1992;27:1009-1015. 14. Asch MJ, Siegel S, White L, et al. Prognostic factors and outcome in bilateral Wilms tumor. Cancer. 1985;56:2524-2529. 15. Horwitz JR, Ritchey ML, Moksness J, et al. Renal salvage procedures in patients with synchronous bilateral Wilms’ tumors: a report from the National Wilms Tumor Study Group. J Pediatr Surg. 1996;31:1020-1025. 16. Millar AJ, Davidson A, Rode H, et al. Bilateral Wilms’ tumors: a singlecenter experience with 19 cases. J Pediatr Surg. 2005;40:1289-1294. 17. Hamilton TE, Green DM, Perlman EJ, et al. Bilateral Wilms tumor with anaplasia: lessons from the National Wilms Tumor Study. J Pediatr Surg. 2006;41:1641-1644. 18. Coppes MJ, Arnold M, Beckwith JB, et al. Factors affecting the risk of contralateral Wilms tumor development: a report from the National Wilms Tumor Study Group. Cancer. 1999;85:1616-1625.
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19. Paulino AC, Thakkar B, Henderson WG. Metachronous bilateral Wilms tumor: the importance of time interval to the development of a second tumor. Cancer. 1998;82:415-420. 20. Casale AJ, Flanigan RC, Moore PJ, et al. Survival in bilateral metachronous (asynchronous) Wilms tumor. J Urol. 1982;128:766768. 21. Ritchey ML, Green DM, Thomas PRM, et al. Renal failure in Wilms tumor patients: a report from the National Wilms Tumor Study Group. Med Pediatr Oncol. 1996;26:75-80. 22. Davidoff AM, Giel DW, Jones DP, et al. The feasibility and outcome of nephron-sparing surgery for children with bilateral Wilms tumor: the St. Jude children’s Research Hospital experience: 1999-2006. Cancer. 2008;112:2060-2070. 23. Breslow NE, Collins AJ, Ritchey ML, et al. End stage renal disease in patients with Wilms tumor: results from the National Wilms Tumor Study Group and the United States Renal Data System. J Urol. 2005;174:1972-1975. 24. Giel DW, Williams MA, Jones DP, et al. Renal function outcomes in patients treated with nephron sparing surgery for bilateral Wilms tumor. J Urol. 2007;178:1786-1789.
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