Letter to the Editor: Impact of the First Generation of Children’s Oncology Group Clinical Trials on Clinical Practice for Wilms Tumor

Author: Daniel M. Green MD1
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  • 1 Departments of Oncology, and Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee

Re: Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children’s Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw 2021;19:978–985.

I read with interest the article titled, “Impact of the First Generation of Children’s Oncology Group Clinical Trials on Clinical Practice for Wilms Tumor” by Dome et al,1 which provides an excellent summary of some of the results from the recent clinical trials for children with favorable or anaplastic histology Wilms tumor conducted by the Children’s Oncology Group (COG). However, the article discusses a treatment approach that they identify as “a good standard of care,” a claim they suggest is justified by the results of the studies they have summarized. The results of 2 of their published studies require careful review and I assert do not establish the treatment approaches evaluated as a good standard of care.

Dome et al1 suggest that regimen M is a good standard of care for patients with favorable-histology Wilms tumor (FHWT) and pulmonary metastases limited to the lungs that fail to resolve completely after an initial 5-week period of chemotherapy with the combination of vincristine/dactinomycin/doxorubicin, based on a comparison of the event-free and overall survival of patients with FHWT and metastases limited to the lungs treated on AREN0533 versus the treatment outcomes for a control group of patients treated on National Wilms Tumor Study (NWTS)-5.2 There are, however, details regarding the control group that render the comparison invalid.

Patients were eligible for AREN0533 if they had pulmonary metastases identified on a chest CT. The comparison group was defined by the presence of pulmonary metastases on a chest radiograph or chest CT and treatment with whole-lung radiation therapy (WLRT). Thus, patients with pulmonary metastases who were not treated with WLRT on NWTS-5 were considered by the COG investigators to not have stage IV disease and were not included in the comparison group. Only 42% of patients enrolled on NWTS-5 who had pulmonary nodules were treated with WLRT.3 Thus, the NWTS-5 comparison group of patients used by the COG investigators was clinically different from the patients enrolled on AREN0533.

The COG investigators did not state how many potentially eligible patients enrolled on AREN03B2 during the period when AREN0533 was open for accrual were actually enrolled on AREN0533. In another study conducted by the group that examined augmentation of treatment for patients with FHWT and combined loss of heterozygosity (LOH) of 1p and 16q, only 65.3% (32/49) of eligible patients with stage I or II FHWT and 62.2% (51/82) of eligible patients with stage III or IV FHWT were enrolled.4 No comparison of the differences between the eligible and enrolled populations was published. It is not clear from the published data what percentage of potentially eligible patients was enrolled on AREN0533.

The COG investigators reported that the comparison group from NWTS-5 included 268 patients with stage IV FHWT and pulmonary metastases only. NWTS-5 enrolled only 242 patients with stage IV FHWT in the “studied” category (biology and clinical data). If 14.9% (the percentage with extrapulmonary metastases enrolled on AREN05335) had extrapulmonary metastases, there would have been only 204 available for comparison, not 268. If all but those NWTS-5 patients who were included in the “registered only” category are included in the comparison group, the total with stage IV FHWT would be 310 (S.M. Peterson, 2021, unpublished data). Excluding those with extrapulmonary metastases produces a total of 264. The reason for the discrepancy is not clear, but a previous publication from the COG Renal Tumor Committee required correction because the initial published version included patients with both favorable and other histologies when only favorable histology patients were to be included in the comparison group.6 The revised comparisons to NWTS-5 were no longer statistically significant.7

Evaluation of the effectiveness of regimen M for patients whose pulmonary nodules do not respond completely to 6 weeks of 3-drug chemotherapy is limited by the removal from the analysis of 2 patients who developed progressive disease prior to completion of 4 cycles of regimen M chemotherapy and WLRT.2 The COG investigators did not indicate that they had removed patients who developed progressive disease prior to 3 months after diagnosis from the NWTS-5 comparison group.

The COG investigators state that, “Augmentation of therapy for patients with FHWT and combined LOH 1p/16q reduces the risk for relapse.”1 However, as noted earlier, not all eligible patients were enrolled in the study. Because the COG investigators defined stage IV based on the presence of pulmonary nodules only, whereas they defined stage IV for the NWTS-5 patients as the presence of pulmonary nodules and treatment with WLRT, the stage distribution of those enrolled on AREN0532 and AREN0533 was very different from that of the comparison sample from NWTS-5. AREN0522 appeared to have substantially more patients with stage IV disease (24.1% vs 5.9%), whereas NWTS-5 appeared to have more patients with stage I (17.6% vs 9.6%) and stage II disease (38.8% vs 28.9%). Augmented therapy did not produce a statistically significant improvement in overall survival compared with NWTS-5, and did expose all patients with stage I and II disease to doxorubicin, rather than only the 31.2% who would have received it as relapse treatment, and exposed all patients with stage III and IV disease to etoposide and cyclophosphamide, which would have been included in a relapse treatment regimen for only the 39.7% who experienced relapse.4 In the absence of a comparison between all of those enrolled in AREN03B2 who had FHWT and combined LOH at 1p and 16q versus those actually enrolled on AREN0532 and AREN0533 with the same characteristics, and modification of the definition of stage IV for the NWTS-5 patients used for comparisons with AREN0533 patients with stage IV FHWT, suggestions that augmentation of therapy benefits patients with FHWT and combined LOH at 1p and 16q are not justified.

The phrase “good standard of care” does not imply that the recommendation is based on high-quality data, such as from a randomized clinical trial or a confirmatory single-arm trial. Given the significant shortcomings of the studies reported by the COG investigators, I believe the approaches outlined in the 2 published manuscripts2,4 should not be interpreted as a standard of care, but as results of 2 studies with significant methodological flaws that require replication in appropriately designed, randomized studies.

References

  • 1.

    Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children’s Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw 2021;19:978985.

    • Crossref
    • PubMed
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  • 2.

    Dix DB, Seibel NL, Chi YY, et al. Treatment of stage IV favorable histology Wilms tumor with lung metastases: a report from the Children’s Oncology Group AREN0533 study. J Clin Oncol 2018;36:15641570.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Grundy PE, Green DM, Dirks AC, et al. Clinical significance of pulmonary nodules detected by CT and not CXR in patients treated for favorable histology Wilms tumor on national Wilms tumor studies-4 and -5: a report from the Children’s Oncology Group. Pediatr Blood Cancer 2012;59:631635.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Dix DB, Fernandez CV, Chi YY, et al. Augmentation of therapy for combined loss of heterozygosity of chromosomes 1p and 16q in favorable histology Wilms tumor: a Children’s Oncology Group AREN0532 and AREN0533 study report. J Clin Oncol 2019;37:27692777.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Ehrlich PF, Ferrer FA, Ritchey ML, et al. Hepatic metastasis at diagnosis in patients with Wilms tumor is not an independent adverse prognostic factor for stage IV Wilms tumor: a report from the Children’s Oncology Group/National Wilms Tumor Study Group. Ann Surg 2009;250:642648.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Fernandez CV, Mullen EA, Chi YY, et al. Outcome and prognostic factors in stage III favorable-histology Wilms tumor: a report from the Children’s Oncology Group study AREN0532. J Clin Oncol 2019;37:2710

    • Search Google Scholar
    • Export Citation
  • 7.

    Fernandez CV, Mullen EA, Chi YY, et al. Outcome and prognostic factors in stage III favorable-histology Wilms tumor: a report from the Children’s Oncology Group study AREN0532. J Clin Oncol 2018;36:254261.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 1.

    Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children’s Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw 2021;19:978985.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Dix DB, Seibel NL, Chi YY, et al. Treatment of stage IV favorable histology Wilms tumor with lung metastases: a report from the Children’s Oncology Group AREN0533 study. J Clin Oncol 2018;36:15641570.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Grundy PE, Green DM, Dirks AC, et al. Clinical significance of pulmonary nodules detected by CT and not CXR in patients treated for favorable histology Wilms tumor on national Wilms tumor studies-4 and -5: a report from the Children’s Oncology Group. Pediatr Blood Cancer 2012;59:631635.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Dix DB, Fernandez CV, Chi YY, et al. Augmentation of therapy for combined loss of heterozygosity of chromosomes 1p and 16q in favorable histology Wilms tumor: a Children’s Oncology Group AREN0532 and AREN0533 study report. J Clin Oncol 2019;37:27692777.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Ehrlich PF, Ferrer FA, Ritchey ML, et al. Hepatic metastasis at diagnosis in patients with Wilms tumor is not an independent adverse prognostic factor for stage IV Wilms tumor: a report from the Children’s Oncology Group/National Wilms Tumor Study Group. Ann Surg 2009;250:642648.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Fernandez CV, Mullen EA, Chi YY, et al. Outcome and prognostic factors in stage III favorable-histology Wilms tumor: a report from the Children’s Oncology Group study AREN0532. J Clin Oncol 2019;37:2710

    • Search Google Scholar
    • Export Citation
  • 7.

    Fernandez CV, Mullen EA, Chi YY, et al. Outcome and prognostic factors in stage III favorable-histology Wilms tumor: a report from the Children’s Oncology Group study AREN0532. J Clin Oncol 2018;36:254261.

    • Crossref
    • Search Google Scholar
    • Export Citation
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