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Treatment of Anaplastic Histology Wilms' Tumor: Results From the Fifth National Wilms' Tumor Study

Jeffrey S. Dome, Cecilia A. Cotton, Elizabeth J. Perlman, Norman E. Breslow, John A. Kalapurakal, Michael L. Ritchey, Paul E. Grundy, Marcio Malogolowkin, J. Bruce Beckwith, Robert C. Shamberger, Gerald M. Haase, Max J. Coppes, Peter Coccia, Morris Kletzel, Robert M. Weetman, Milton Donaldson, Roger M. Macklis, Daniel M. Green

From the Department of Hematology/Oncology, St Jude Children's Research Hospital, Memphis, TN; Department of Biostatistics, University of Washington; Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Pathology, Loma Linda University, Loma Linda; Department of Pediatrics, Los Angeles Children's Hospital; Department of Pediatrics, School of Medicine, University of Southern California, Los Angeles, CA; Department of Radiation Oncology, Robert H. Lurie Cancer Center, Northwestern University; Departments of Pathology and Laboratory Medicine, and Pediatrics, Children's Memorial Medical Center, Chicago; Department of Pediatrics, School of Medicine, Northwestern University, Evanston, IL; Department of Pediatric Surgery, University of Texas at Houston Health Science Center, Houston, TX; Department of Surgery, Children's Hospital; Department of Surgery, Harvard Medical School, Boston, MA; Department of Pediatric Surgery, Denver Children's Hospital, Denver, CO; Departments of Pediatrics and Oncology, Cross Cancer Institute and the University of Alberta, Edmonton; Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada; Department of Pediatrics, School of Medicine, University of Nebraska, Omaha, NE; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN; Department of Pediatrics, Cooper Hospital, Camden, NJ; Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH; Department of Pediatrics, Roswell Park Cancer Institute; and the School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY.

Address reprint requests to Jeffrey S. Dome, MD, Department of Hematology/Oncology, St Jude Children's Research Hospital, 332 N Lauderdale St, D5048C, Memphis, TN 38105; e-mail: jeff.dome{at}stjude.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Purpose An objective of the fifth National Wilms' Tumor Study (NWTS-5) was to evaluate the efficacy of treatment regimens for anaplastic histology Wilms' tumor (AH).

Patients and Methods Prospective single-arm studies were conducted. Patients with stage I AH were treated with vincristine and dactinomycin for 18 weeks. Patients with stages II to IV diffuse AH were treated with vincristine, doxorubicin, cyclophosphamide, and etoposide for 24 weeks plus flank/abdominal radiation.

Results A total of 2,596 patients with Wilms' tumor were enrolled onto NWTS-5, of whom 281 (10.8%) had AH. Four-year event-free survival (EFS) and overall survival (OS) estimates for assessable patients with stage I AH (n = 29) were 69.5% (95% CI, 46.9 to 84.0) and 82.6% (95% CI, 63.1 to 92.4). In comparison, 4-year EFS and OS estimates for patients with stage I favorable histology (FH; n = 473) were 92.4% (95% CI, 89.5 to 94.5) and 98.3% (95% CI, 96.4 to 99.2). Four-year EFS estimates for patients who underwent immediate nephrectomy with stages II (n = 23), III (n = 43), and IV (n = 15) diffuse AH were 82.6% (95% CI, 60.1 to 93.1), 64.7% (95% CI, 48.3 to 77.7), and 33.3% (95% CI, 12.2 to 56.4), respectively. OS was similar to EFS for these groups. There were no local recurrences among patients with stage II AH. Four-year EFS and OS estimates for patients with bilateral AH (n = 29) were 43.8% (95% CI, 24.2 to 61.8) and 55.2% (95% CI, 34.8 to 71.7), respectively.

Conclusion The prognosis for patients with stage I AH is worse than that for patients with stage I FH. Novel treatment strategies are needed to improve outcomes for patients with AH, especially those with stage III to V disease.

	INTRODUCTION

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In 1978, Beckwith and Palmer¹ published a detailed histopathologic review of Wilms' tumors that were collected on the first National Wilms' Tumor Study (NWTS-1). Approximately 6% of the tumors had cells with nuclear enlargement, nuclear atypia, and irregular mitotic figures, and were considered to have anaplastic histology (AH). The presence of anaplasia was prognostically significant; 44% of patients with AH died as a result of disease, whereas only 7.1% of patients without anaplasia, the so-called favorable histology (FH) subtype, died as a result of disease.¹ Subsequent studies from the NWTS Group (NWTSG) and other groups have confirmed the adverse prognostic significance of anaplasia.^2-5

The first NWTS to stratify patients with AH into a distinct treatment group was NWTS-3 (1979 to 1986). During this study, and during NWTS-4 (1986 to 1993), patients received 15 months of vincristine (VCR), dactinomycin (AMD), and doxorubicin (DOX), and were randomly assigned to receive or not receive cyclophosphamide (CYCLO).⁶ Patients with stage II to IV diffuse AH had an estimated 4-year overall survival (OS) of 27.1% when treated without CYCLO, compared with 52.2% when treated with CYCLO (P = .04).⁷ During NWTS-4, patients with stage I AH had good outcomes when treated with only VCR and AMD, with 2-year OS estimates of 85.5% to 93.3%, depending on the AMD administration regimen.⁸

Although the addition of CYCLO provided a clear benefit for patients with stage II to IV diffuse AH, about half of these patients experienced tumor recurrence and disease-related death. A primary objective of NWTS-5 was to improve the outcomes for these patients using a new treatment regimen containing the combination of CYCLO and etoposide, agents shown to be active against recurrent Wilms' tumor in phase II studies.^9,10 In this report, we present the outcomes of patients with AH who were treated during NWTS-5.

	PATIENTS AND METHODS

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Patients
NWTS-5 was open to accrual between August 1995 and June 2002. Each participating institution obtained local institutional review board approval to conduct the study. Eligibility criteria included no prior chemotherapy or radiation therapy before study enrollment; histologic diagnosis of Wilms' tumor (FH or AH), clear cell sarcoma of the kidney, or rhabdoid tumor of the kidney; nephrectomy or biopsy performed, and provision of informed consent to participate by a parent/legal guardian.

Tumor Stage and Histologic Classification
Patients underwent nephrectomy before chemotherapy using previously described surgical guidelines¹¹ unless the tumor was considered to be unresectable by the treating surgeon, in which case a biopsy was obtained. A tumor stage was assigned using the NWTSG surgical-pathologic staging system.¹¹

Pathology slides, institutional pathology reports, and NWTSG pathology forms were reviewed by the study pathologists. The designation of anaplasia was applied to tumors with cells having major diameters at least three times those of adjacent cells, increased chromatin content (hyperchromaticity), and the presence of atypical polyploid mitotic figures. The criteria distinguishing focal from diffuse anaplasia were based on the distribution of anaplasia within a tumor sample.¹² Tumors with focal anaplasia had anaplastic changes confined to sharply restricted foci within the primary tumor sample. Anaplasia occurring outside the primary tumor, in an extrarenal site such as vessels of the renal sinus, or in a random biopsy specimen, was considered to be diffuse anaplasia.

Treatment Regimens
The treatment regimens are outlined in Figure 1. Patients who received prenephrectomy chemotherapy received regimen DD-4A (Fig 1). All regimens called for 50% reductions of AMD and DOX doses during the 6 weeks after irradiation if the radiation field included the whole lung or whole abdomen. All treatment regimens recommended 50% chemotherapy dose reductions in infants younger than 12 months. Patients with stage I focal or diffuse AH did not receive radiation therapy. Patients with stage II to IV focal or diffuse AH received 10.8 Gy to the abdomen or flank, depending on the extent of disease, with a boost of 10.8 Gy to areas of bulky residual tumor. Patients with lung metastases received 12.0 Gy to the whole lung.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Schema for regimen I. D, doxorubicin 1.5 mg/kg; 45 mg/m2 for patients > 30 kg. V, vincristine 0.05 mg/kg, 1.5 mg/m2 for patients > 30 kg, maximum dose 2 mg. V*, vincristine 0.067 mg/kg; 2 mg/m2 for patients > 30 kg, maximum dose 2 mg. C, cyclophosphamide 14.7 mg/kg/d for 5 days; 440 mg/m2/d for patients > 30 kg. C*, cyclophosphamide 14.7 mg/kg/d for 3 days; 440 mg/m2/d for patients > 30 kg. E, etoposide 3.3 mg/kg/d for 5 days; 100 mg/m2/d for patients > 30 kg. XRT, 10.8 Gy to flank/abdomen.

Event-free survival (EFS) and OS percentages at 4 years after diagnosis were estimated by actuarial methods of Kaplan and Meier. Comparisons of EFS and OS between patient subgroups were made with the log-rank test. Comparisons of mean age at diagnosis by histology were made using the t test. Comparisons of sex and stage distribution by histology were made using the Fisher's exact and related tests.

	RESULTS

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Patient Characteristics
A total of 2,596 patients with Wilms' tumor were enrolled onto NWTS-5, of which 59 had focal AH and 222 had diffuse AH by central pathology review. Anaplasia was not originally recognized by institutional pathologists in 74 of 190 (38.9%) patients who underwent immediate nephrectomy and were considered to have AH by central pathology reviewers. An additional nine patients were considered to have focal AH by institutional pathologists, but diffuse AH by central reviewers. The analyses in this report are based on the central pathology histology designation. Among 158 patients with unilateral anaplastic Wilms' tumor for whom a local tumor stage was assigned (regardless of distant metastases), discordance between institutional stage and central pathology stage was noted in 30 patients (19%). The analyses in this report use the overall stage assigned by the treating institution, which was based on local pathology stage and the presence of distant metastases.

More patients with unilateral Wilms' tumor had AH on NWTS-5 (10.1%) compared with NWTS-4 (7.5%). More patients with unilateral Wilms' tumor received prenephrectomy chemotherapy on NWTS-5 (14.0%) compared with NWTS-4 (9.0%). Anaplasia was more frequently detected in unilateral tumors after preoperative chemotherapy (18.6%) than in tumors resected immediately (8.7%).

The clinical characteristics of the patients with AH are described in Table 1. For demographic comparison, patients with FH Wilms' tumor are included in this table. The female-to-male ratio among patients with AH was 2:1; in comparison, the female-to-male ratio among patients with FH was 1.2:1. Of patients with unilateral AH, 65.4% presented with high-stage (stage III and IV) disease, whereas 45.6% of patients with unilateral FH presented with high-stage disease (odds ratio, 2.26; P < .001). Stage V (bilateral) disease was present in 12.5% of patients with AH and 5.6% of patients with FH. The mean age at presentation for patients with AH was 56.5 months compared with 43.3 months for patients with FH (P < .001).

View larger version (6K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Event-free and overall survival for patients with stage I focal or diffuse anaplastic Wilms' tumor (n = 29).

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Event-free survival for patients with stage II to IV diffuse anaplastic Wilms' tumor.

View larger version (7K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Event-free and overall survival for patients with stage V (bilateral) anaplastic Wilms' tumor.

Patterns of Recurrence
On NWTS-3 and -4, the prescribed dose of flank/abdominal radiation for patients with AH Wilms' tumor increased with patient age. The frequency of operative bed relapse was not greater among patients treated with lower compared with higher radiation doses.⁷ On the basis of this observation, NWTS-5 prescribed a uniform dose of 10.8 Gy for all patients with stage II to IV AH. To estimate the effectiveness of local control, we analyzed the rates of recurrence in the operative bed or the abdomen/pelvis outside the operative bed, which also may have been included in the radiation field (Table 3). None of the patients with stage II disease had first recurrences in the operative bed or abdomen, indicating that local control for these patients was excellent with 10.8 Gy. The rates of operative bed or abdominal recurrences for patients with stages III, IV, and V disease were 12 of 74 (16.2%), six of 40 (15%), and 11 of 29 (37.9%), respectively.

	DISCUSSION

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Despite remarkable success in the treatment of FH Wilms' tumor, the treatment of AH Wilms' tumor remains a clinical challenge. A primary objective of NWTS-5 was to improve the outcomes of patients with stage II to IV diffuse AH using regimen I, a novel treatment regimen containing the CYCLO/etoposide combination. The outcomes of patients treated with regimen I compared favorably with those for historical controls. On NWTS-3 and -4, patients with diffuse AH treated with nephrectomy followed by VCR, AMD, DOX, and CYCLO (regimen J) had 4-year OS estimates of 70.1% for stage II (n = 11), 56.3% for stage III (n = 13), and 16.7% for stage IV (n = 6) disease.⁷ In comparison, the 4-year OS estimates for patients treated on NWTS-5 with immediate nephrectomy and regimen I were 81.5% for stage II (n = 23), 66.7% for stage III (n = 43), and 33.3% for stage IV (n = 15) disease. The local control rate among patients with stage II disease was 100% with a radiation dose of 10.8 Gy.

Although regimen I itself likely contributed to the observed improvement in outcomes between NWTS-4 and NWTS-5, the effect of shifts in the patient population cannot be discounted. A higher percentage of patients with unilateral tumors received prenephrectomy chemotherapy on NWTS-5 (14%) compared with NWTS-4 (9%). The reason for this alteration in clinical practice is unclear, but the result was a migration from stage II to stage III because preoperative chemotherapy was a defining criterion for stage III disease. In addition, there was a higher prevalence of AH among patients enrolled onto NWTS-5 (10.1%) compared with NWTS-4 (7.5%), which is partially explained by the increased detection of anaplasia in tumors treated with preoperative chemotherapy.

What was the cost, in terms of adverse effects, of the switch from regimen J to regimen I? The key differences between the two regimens are that regimen I incorporated etoposide and used a higher cumulative dose of CYCLO. Although augmenting these components of therapy, regimen I eliminated AMD, lowered the cumulative dose of DOX, lowered the flank radiation doses for most patients, and shortened the duration of therapy (Table 4). Short-term toxicities of regimen I were manageable, though one patient developed secondary AML, an uncommon complication that occurs in Wilms' tumor patients even without etoposide therapy.¹³ The effects on fertility of the higher cumulative CYCLO dose remain to be determined.

Previous NWTSG studies have suggested that anaplasia per se is not a marker of aggressiveness.^12,14 The somewhat higher than expected recurrence and death rates for patients with stage I AH on NWTS-5 seem to question that suggestion. Ongoing studies of molecular prognostic markers of tumor invasiveness and metastatic potential will help clarify whether anaplastic Wilms' tumors are inherently aggressive.

The molecular biology of anaplastic Wilms' tumor is only beginning to be defined. Approximately 65% of anaplastic Wilms' tumors studied to date had detectable mutations of the TP53 tumor suppressor gene, whereas such mutations were rare in FH Wilms' tumors.^16-19 The restriction of TP53 mutations to areas of anaplasia within a Wilms' tumor indicates that anaplasia arises in a clonal fashion on a background of favorable histology.²⁰ Because p53 protein plays a central role in the cellular response to DNA-damaging agents,²¹ it is likely that TP53 mutations contribute to the relative unresponsiveness of anaplastic Wilms' tumors to treatment. However, 35% of anaplastic Wilms' tumors lack detectable TP53 mutations. Although these tumors may harbor alterations of other molecules in the p53 pathway, it is possible that TP53 mutations are neither necessary nor sufficient to generate anaplasia. The 2:1 female-to-male ratio observed in patients with anaplastic Wilms' tumor raises the possibility that sex is a determinant of susceptibility to anaplasia. Gene expression studies have uncovered several candidate genes associated with anaplasia, but their role in the pathogenesis of anaplasia remains to be confirmed.²²

Anaplasia was not detected by institutional pathologists in approximately 40% of immediate nephrectomy specimens deemed to have anaplasia by the central reviewers. As a result, a substantial proportion of patients switched treatment regimens in the middle of the study and these patients were considered nonassessable for the primary outcomes analysis. Interestingly, comparison of outcomes in the evaluable and nonassessable patients showed that survival rates were essentially identical between the two groups. Similarly, patients who received preoperative chemotherapy for what eventually proved to be AH did not have compromised outcomes, even though most of these patients initially received treatment regimens for FH. The upcoming Children's Oncology Group studies will require central pathology review to be completed before treatment is initiated.

The results of NWTS-5 provide the framework for future Children's Oncology Group studies of anaplastic Wilms' tumor. On the basis of the lower than expected survival rate for patients with stage I AH, the upcoming study will augment therapy for this group of patients. Although NWTS-5 outcomes for patients with stage II to IV diffuse AH were improved compared with historical regimens, a considerable percentage of patients experienced disease recurrence. A new treatment regimen including carboplatin, which has shown activity against Wilms' tumor,^23-25 will be used for this patient group. Patients with stage IV disease are particularly challenging to treat. A priority of future preclinical and clinical studies will be to identify novel agents.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Jeffrey S. Dome, Norman E. Breslow, Michael L. Ritchey, Paul E. Grundy, Marcio Malogolowkin, J. Bruce Beckwith, Gerald M. Haase, Max J. Coppes, Peter Coccia, Morris Kletzel, Robert M. Weetman, Daniel M. Green Financial support: Daniel M. Green Administrative support: J. Bruce Beckwith, Daniel M. Green Provision of study materials or patients: Elizabeth J. Perlman, Gerald M. Haase, Max J. Coppes, Peter Coccia, Robert M. Weetman, Milton Donaldson Collection and assembly of data: Jeffrey S. Dome, Elizabeth J. Perlman, Norman E. Breslow, Paul E. Grundy, J. Bruce Beckwith, Robert C. Shamberger, Peter Coccia, Robert M. Weetman, Daniel M. Green Data analysis and interpretation: Jeffrey S. Dome, Cecilia A. Cotton, Elizabeth J. Perlman, Norman E. Breslow, John A. Kalapurakal, Michael L. Ritchey, Paul E. Grundy, Marcio Malogolowkin, Peter Coccia, Robert M. Weetman, Roger M. Macklis Manuscript writing: Jeffrey S. Dome, Norman E. Breslow, Michael L. Ritchey, Robert C. Shamberger, Max J. Coppes, Daniel M. Green Final approval of manuscript: Jeffrey S. Dome, Cecilia A. Cotton, Norman E. Breslow, John A. Kalapurakal, Paul E. Grundy, Marcio Malogolowkin, J. Bruce Beckwith, Robert C. Shamberger, Gerald M. Haase, Max J. Coppes, Peter Coccia, Morris Kletzel, Roger M. Macklis, Daniel M. Green

 

	ACKNOWLEDGMENTS

 
We thank the investigators of the Pediatric Oncology Group and the Children's Cancer Group and the health care professionals who took care of the study participants. We thank the members of the NWTSG Data and Statistical Center for their outstanding support.

	NOTES

 
Supported by National Institutes of Health Grant No. CA-42326.

Presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted November 2, 2005; accepted March 1, 2006.

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