Reducing postoperative chemotherapy schedules in children with Wilms' tumor from the standard 18 weeks to only four weeks has been shown to be just as effective, according to data reported by the International Society of Pediatric Oncology (SIOP) Nephroblastoma Trial Committee.
The study, led by Jan de Kraker, MD, from the Academic Medical Centre of the University of Amsterdam, of 410 children with Stage I intermediate-risk or anaplastic Wilms' tumor and published in the October 2 issue of The Lancet (2004;364:1229–1235), suggests that shorter courses of chemotherapy may not only be as effective as conventional longer treatment, but also have fewer side effects, greater convenience for patients and parents, and lower health care costs.
“An abbreviated schedule not only can ameliorate acute and late side effects but also eliminate the need for radiotherapy,” he said in an interview. “Continuous international collaboration is necessary to address the many issues involved.”
Dr. de Kraker noted that investigators from medical centers in Italy, France, Austria, Germany, Sweden, Slovenia, and the Netherlands have been working with the SIOG, and their series of clinical trials since the 1960s have helped raise management of Wilms' tumor to its current level, often in collaboration with the North American National Wilms' Tumor Study Group-4 (NWTS-4) and the British Children's Cancer Study Group.
In the latest reported trial (SIOP 93-01), conducted between June 1993 and June 2000, 410 youngsters (age 6 months to 18 years) with early Wilms' tumor were pretreated with the standard four doses of vincristine plus two courses of dactinomycin.
After surgical resection of their tumors and postoperative chemotherapy consisting of four doses of vincristine plus one dose of dactinomycin, patients were randomly assigned to either stop receiving chemotherapy at that point, or continue with standard practice—i.e., receive an additional two courses of the same treatment.
“This means that 200 patients experimentally received two-drug postoperative chemotherapy for four weeks while 210 received it in traditional fashion for 18 weeks,” Dr. de Kraker said. “The primary endpoint of this equivalency trial was two-year event-free survival.”
After two years of follow-up, the researchers found no statistical difference in disease recurrence between the groups. Notably, in the standard 18-week postoperative chemotherapy group, 18 patients had a tumor recurrence compared with 22 in the experimental four-week treatment group.
Similarly, there was no significant difference in the two-year survival rate, which was about 90% in both groups. Nor were there important differences in overall five-year survival—which approached 95%.
In further analysis, the investigators observed that a minimal amount of additional toxicity occurred during the additional eight weeks of therapy in the control (standard-treatment) group.
In all, 95 out of 410 eligible patients required dose modifications, which had little effect on dose intensity, Dr. de Kraker said.
Among 10 different kinds of toxicities evaluated, 11 patients developed thrombocytopenia; 11, neuropathy; 11, infection; and 12, increased concentrations of liver enzymes. Of these, only thrombocytopenia had a statistically higher rate of being Grade 3 or 4.
The toxicity recorded in this study is no different from that of other SIOP studies with the same preoperative treatment, the investigators remarked.
Due to the promising results of this trial, for the next trial, the now ongoing SIOP-2001 study, all patients with Stage I intermediate-risk histology Wilms' tumor/nephroblastoma after preoperative chemotherapy and surgery will receive the short treatment regimen, Dr. de Kraker reported.
Comment from Archie Bleyer
Asked to comment on the study, W. Archie Bleyer, MD, Professor at the University of Texas M. D. Anderson Cancer Center and former Chair of the Children's Cancer Group, said that the results show that more than half of all children with Wilms' tumor can now be treated with four weeks of chemotherapy, surgery, and eight weeks of postoperative chemotherapy without radiotherapy—“That's a total of 12 doses of vincristine and 11 doses of actinomycin-D,” the latter over two three-day courses and one five-day course.
“Moreover, based on results of another trial conducted primarily in North America [NWTS-4],” the SIOP investigators combined the results of both trials and came up with their current schedule of one dose of actinomycin-D for each three- and five-day course.
“This is the least amount of therapy in the largest proportion of patients since the 1960s when multiple-drug, prolonged therapy became the standard treatment for Wilms' tumor,” he said. “It's hard to imagine that less chemotherapy can be given.”
He said he was not surprised by the minimal number of toxicities that occurred during the additional eight weeks of treatment in the conventional/control group: “The number of dose modifications was large—95 out of 410 eligible patients—such that most patients had already had their therapy individualized before being randomized to receive two additional courses,” he explained.
Dr. Bleyer said he regretted that the investigators did not analyze the number of days the patients spent in the hospital—“a simple parameter of toxicity and cost”—to determine the real benefits of therapy reduction.
In his view, the study lacked an important component: a comparison of the financial costs and the quality of life in each treatment group.
Even so, he said, “The safe elimination of eight doses of vincristine and two courses of actinomycin-D has all kinds of benefits—social, psychological, physical, and financial—that are apparent whether actual toxicities can be shown to have been decreased or not.”
Another plus is that fewer patients required radiotherapy, Dr. Bleyer added. “The four weeks of preoperative chemotherapy results in downward stage migration and decreases the proportion of patients needing irradiation.”
Overall, Dr. Bleyer applauded the research. He said he hoped North American oncologists would note that oral informed consent was used in the reported trial “as it is throughout Europe.”
“There is every indication that the trial was safe, ethical, and replete with benefits to generations of Wilms' tumor patients to come,” he said, wondering why this “efficient” approach can't be used in North America “rather than maintaining the cumbersome written informed consent required for each and every clinical trial.”
Dr. Bleyer emphasized how important the continuing collaboration—as well as competition—between the International Society of Pediatric Oncology and the North American National Wilms Tumor Study Group is for science and urged more adult cooperative groups to emulate it.
By combining the results of the SIOP 93-01 and the NWTS-4 trial, he reiterated, SIOP is now likely curing more than half of its patients with the least amount of therapy—“What a wonderful outcome for patients, parents, relatives, friends, and insurers!”
Regarding costs and quality of life, Dr. de Kraker responded that he and his coauthors also regret that the differences between both arms were not as well documented as they would have liked.
“The problem has to do with the complexity of arriving at estimates when so many different countries are involved,” he said. “Health care and politics can differ widely among our participating European countries,” making comparisons complex and expensive.
“Additionally, since the trial was largely financed by charitable organizations, you can imagine that we also must take the latter into account.”