LESS CHEMOTHERAPY FOR INTERMEDIATE RISK NEUROBLASTOMA

September 29, 2010 — Less chemotherapy than usual produced excellent outcomes in children with intermediate-risk neuroblastoma, according to a new multicenter study from Australian and American researchers.

The trial used a "substantially reduced" duration of chemotherapy, compared with previously used regimens, as well as reduced doses, and produced a "very high rate of survival," write the study authors in the September 30 issue of the New England Journal of Medicine.

"These data provide support for further reduction in chemotherapy with more refined risk stratification," conclude the authors, led by David Baker, MD, from the Princess Margaret Hospital for Children in Perth, Australia.

A 3-year overall survival estimate of 96% ± 1% (95% confidence interval [CI], 94 - 97) was achieved with a substantial reduction in cytotoxic therapy for the rare disease, which affects the sympathetic nervous system and most commonly develops in the adrenal glands, say the authors, who are all members of the Children's Oncology Group (COG) research collaborative.

The 3-year event-free survival estimate was 88% ± 2% (95% CI, 84 - 90). In intermediate-risk neuroblastoma, 3 years of survival without relapse generally means that a patient is cured, note the authors.

"Our goal was to reduce the level of chemotherapy needed to effectively treat intermediate-risk neuroblastoma patients while maintaining an excellent rate of survival, and that is exactly what we did," said senior coauthor Katherine Matthay, MD, in a press statement. She is from the University of California San Francisco Benioff Children's Hospital.

"This trial will lead to permanent treatment reductions in our protocol for treating this disease and will have a significant impact on the hundreds of children who are diagnosed with neuroblastoma each year," said Dr. Matthay.

Duration of Chemotherapy at Least 40% Less

In 1998, the COG established a system of risk stratification for neuroblastoma that was based on clinical data (the patient's age at diagnosis and the tumor stage) and tumor-derived biologic data (histopathological classification, MYCN oncogene amplification status, and ploidy).

In the COG system, intermediate-risk neuroblastoma was defined as stage 3 or 4 disease without MYCN amplification in an infant, stage 3 disease and favorable histopathological features in a child, and stage 4S disease with a diploid tumor-cell DNA index, unfavorable histopathological features, or both.

The study, which examined children with stages 3, 4, and 4S disease, involved 479 patients, is the largest trial focused on reducing the amount of chemotherapy needed to treat intermediate-risk neuroblastoma.

According to the researchers, they sought to reduce exposure to chemotherapy by at least 40% while maintaining the same 90% survival rate achieved in earlier trials using higher doses.

For instance, in the largest previously published study of treatment for intermediate-risk neuroblastoma (J Clin Oncol. 1998;16:1256-1264), the overall survival estimates among the cohorts with stages 4S, 4, and 3 disease were 92%, 93%, and 100%, respectively, among patients with tumors that had favorable biologic features. However, this outcome was achieved with 9 months of chemotherapy (10 cycles), consisting of cisplatin, doxorubicin, etoposide, and cyclophosphamide, administered in total cumulative doses substantially exceeding those in the current study.

In contrast, the new trial called for only 4 cycles (for patients with tumors with favorable biologic features) or 8 cycles (for unfavorable biologic features). The chemotherapy consisted of carboplatin, etoposide, cyclophosphamide, and doxorubicin, and was administered at 3-week intervals. This treatment was followed by surgical excision of the primary tumor.

The new trial was prospective, uncontrolled, and nonrandomized. The respective 3-year overall survival estimates were 98% ± 1%, 97% ± 3%, and 93% ± 2% for stages 3, 4S, and 4, respectively. Ploidy, but not histopathological features, was a significant predictor of outcome, the authors report.

In the 479 patients, 59 first events were documented: disease progression in 42 patients, death in 14 patients, and secondary leukemia in 3 patients.

The median follow-up time for patients who survived without an event was 5.2 years.

Severe adverse events without disease progression occurred in 10 patients (2.1%). The events were secondary leukemia (3 patients), death from infection (3 patients), and death at surgery (4 patients).

No Chemotherapy in Some Patients

This is not the first time investigators have experimented with reductions in chemotherapy in this setting.

However, as the current study authors point out, because of differences in the staging and risk factors used, and because of the wide variation within studies of cumulative chemotherapy doses, the results cannot be directly compared.

Nevertheless, the overall survival estimates in these studies were "generally similar" to those in the current study, ranging from 87% to 95%, say the authors.

However, interestingly, some of the patients in those studies received no chemotherapy.

"Some groups have successfully used observation alone in selected infants who had stage 4 disease without radiologic evidence of bone involvement or progression; in these groups, the 2-year overall survival estimate was 95%," write the authors.

The study was funded by the National Cancer Institute. The authors have disclosed no relevant financial relationships.

N Engl J Med. 2010;363:1313-1323.