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Doxorubicin can be omitted from postoperative Wilms’ tumor treatment
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The exclusion of doxorubicin from standard postoperative treatment did not worsen EFS in children with stage II to III intermediate-risk Wilms’ tumor, according to results of a phase 3 trial.
Thus, doxorubicin can be safely omitted from therapy in order to spare these patients from long-term adverse treatment effects, according to the researchers.
The standard postoperative chemotherapy regimen for patients with stage II to III Wilms’ tumor pretreated with chemotherapy includes doxorubicin. However, avoiding doxorubicin-related cardiotoxicity is important for improving long-term outcomes for survivors of childhood cancers, according to study background.
Kathy Pritchard-Jones, MD, professor of pediatric oncology at the University College London Institute of Childhood Health, and colleagues initiated the randomized controlled phase 3 SIOP WT 2001 trial to determine whether doxorubicin could be safely omitted from postoperative chemotherapy for patients with histological immediate-risk Wilms’ tumor.
The analysis included 583 children (stage II, n = 341; stage III = 242) aged 6 months to 18 years at the time of diagnosis of a primary renal tumor. All patients underwent 4 weeks of preoperative chemotherapy with vincristine and actinomycin-D followed by nephrectomy.
Researchers randomly assigned patients to a postoperative treatment regimen of vincristine (1.5 mg/m2 at weeks 1-8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26 and 27) and actinomycin-D (45 μg/kg every 3 weeks after week 2), with (n = 291) or without (n = 292) doxorubicin (50 mg/m2 every 6 weeks after week 2).
Noninferiority of EFS at 2 years — analyzed in the intention-to-treat population with a 10% margin — served as the primary endpoint.
Median follow-up was 60.8 months (interquartile range, 40.8-79.8).
The researchers observed a 2-year EFS rate of 92.6% (95% CI, 89.6-95.7) for patients treated with doxorubicin and 88.2% (95% CI, 84.5-92.1) for patients who did not receive doxorubicin. The 4.4% difference in EFS stayed within the predefined 10% margin.
The 5-year OS rate was 95.8% (95% CI, 93.3-98.4) among patients who did not receive doxorubicin compared with 96.5% (95% CI, 94.3-98.8) for patients who did.
Four children died from a treatment-related adverse event, including one patient on the doxorubicin arm who died from sepsis. Three deaths occurred on the doxorubicin exclusion arm due to varicella, metabolic seizure and sepsis during treatment for relapse.
Hepatic veno-occlusive disease occurred in 17 patients, and cardiotoxic events occurred in 5% (n = 15) of patients who received doxorubicin.
Twelve children who received doxorubicin and 10 children who did not died due to tumor recurrence.
“Thanks to the results of this trial, fewer children with this disease will have to have treatment that could cause them lifelong side effects without much benefit,” Pritchard-Jones said in a press release.
It is important that doxorubicin treatment not be excluded for pediatric patients who may still benefit from it, Daniel M. Green, MD, of the department of epidemiology and cancer control at St. Jude Children’s Research Hospital, wrote in an accompanying editorial.
Daniel M. Green
“This result is, however, dependent upon the accurate diagnosis of intermediate-risk histology,” Green wrote. “The risk of generalizing these results to children with stage II-III, histological intermediate-risk Wilms’ tumor is that some (2% in Pritchard-Jones and colleagues’ study) will still be high risk after central pathological review, and will be undertreated if chemotherapy with only two drugs is continued.”
Further, preoperative chemotherapy is not the standard of care around the world, according to Green.
“Many children in North America and elsewhere routinely undergo immediate nephrectomy for a suspected Wilms’ tumor, which is a decision based on the preference to treat them using more accurate surgical-pathological staging information,” he wrote. “Pritchard-Jones and colleagues’ findings … apply only to children who receive pre-nephrectomy chemotherapy with vincristine and actinomycin D.” – by Cameron Kelsall
Disclosure: Cancer Research U.K. provided funding for this study. The researchers and Green report no relevant financial disclosures.
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