Before their merger, the CCG and POG used different NBL staging systems and different biologic factors to determine therapy. The POG relied on tumor ploidy and the CCG on histology; both groups recognized MYCN
amplification as a predictor of poor prognosis. Despite similar therapy approaches, meaningful comparison of results across stages was not possible.12
P9641 and the contemporary study for intermediate-risk NBL13
were the first NBL studies in COG to test risk stratification based on consensus-derived factors. For former POG member institutions, the study represented a reduction in therapy for patients with stage 2a, 2b, and 4s disease.
In P9641, asymptomatic patients with INSS stage 2a and 2b disease achieved 5-year EFS and OS rates of 87% ± 2% and 96% ± 1%, respectively. These are similar to the OS rates reported in previous POG studies in which these patients received multiagent chemotherapy for up to 8 months.2,14,15
The EFS and OS rates achieved for patients with stage 1 disease were similar to those achieved with primary surgical approaches in previous POG and CCG studies.1,3
For patients with LR stage 4s disease, the EFS and OS rates were higher than those on earlier POG studies when different factors were used to assign therapy,14,16
but similar to the OS of 92% reported by the CCG.17
Patients on P9641 who received chemotherapy also experienced fewer and less severe toxicities than patients in these earlier studies. Together with recently published International Society of Pediatric Oncology Europe Neuroblastoma Study Group results using a similar approach for the treatment of LR-NBL (LNESG1),18
the results of P9641 demonstrate that surgery alone, even less than complete resection, can cure nearly all patients with stage 1 NBL and the vast majority of patients with asymptomatic, favorable biology, INSS stage 2a and 2b disease.
The difference in OS of patients with stage 4s NBL who were initially observed versus patients who were treated immediately with chemotherapy (5-year OS: 84% ± 7% v
97% ± 3%, respectively) was not significant but was surprising nonetheless. All of these patients had favorable biology tumors. Because earlier work of the POG and CCG suggested that chemotherapy toxicity may have contributed to lower survival of patients with stage 4s disease, we restricted the use of chemotherapy to specific situations and suggested that the number of cycles of chemotherapy be limited if there was clinical improvement. The reason for the potential difference in our patient cohorts is not yet evident. Further analyses are planned for these patients combined with patients with intermediate-risk stage 4s NBL for whom chemotherapy treatment was nearly identical.13
Using the risk classification of P9641, not all LR patients fared equally well. The survival rates for patients with stage 2b NBL with UH or diploid tumors were possibly not high enough to warrant a designation of low risk. These patients seem to have similar survival to that of patients on a POG study (where histology was not examined) who were more than 1 year old with MYCN
-NA diploid stage B tumors and received chemotherapy similar to that given to intermediate-risk patients.15
In an earlier CCG study, UH was a significant prognostic factor in Evans stage II disease, but results were not reported using INSS criteria.3
In the LNESG1 study, ploidy was not prognostic of the survival of patients with INSS stage 2 disease, a cohort that included many patients analogous to those with POG stage B disease; however, UH was associated with a 5-year OS of only 75.9%, worse than what was observed on P9641 (5-year OS: 89% ± 4% for patients with stage 2a and 2b NBL).18
In P9641, MYCN
-A was associated with significantly lower EFS and OS rates in patients with stage 1 disease; the occurrence of MYCN
-A with FH stage 2 disease was quite rare. However, the majority of patients with MYCN
-A tumors did not have an event after surgical resection. De Bernardi et al18
observed similar findings in the LNESG1 study. Taken together, these data suggest that ploidy, histology, and MYCN
status affect patients with LR-NBL differently, particularly with regard to MYCN
in stage 1 NBL and UH and ploidy in stage 2b disease. Further refinements in risk classification to define LR-NBL will need to be tested prospectively.
Results of the companion biology study onto which patients were enrolled revealed that patients whose tumors harbored 1p36 loss of heterozygosity (LOH), unbalanced 11qLOH, or both had a significantly worse outcomes than patients whose tumors lacked these characteristics.19
Furthermore, because unbalanced 11qLOH was not associated with MYCN
-A, these factors may independently reflect more aggressive clinical behavior in what otherwise appears to be LR disease. In the COG NBL intermediate-risk trial ongoing at the time of this report, 1pLOH and unbalanced 11qLOH are used in addition to the factors of P9641 to assign risk and therapy. Whether these alone will improve prognostication remains to be seen. Microarray profiling has also shown promise in identifying patients with LR-NBL at greater risk for recurrence,20–23
and results of these studies might be evaluated for future risk stratification.
The chemotherapy regimen used in this study had not been used in earlier trials. At the end of scheduled chemotherapy, 81% of patients had a partial response or better. In earlier POG trials, patients with less than complete response to chemotherapy would have proceeded to surgery to remove residual disease or to additional chemotherapy. In P9641, in which 79% of patients had less than complete response after chemotherapy, delayed resection was optional. Given the survival rates achieved on P9641, delayed resection of residual disease may not be necessary for cure of patients with LR-NBL.
In conclusion, our data demonstrate that the use of surgery alone is curative therapy for most patients with LR-NBL and that the use of chemotherapy may be restricted to specific situations. Patients need not undergo complete resection of disease to be cured by surgery alone. Children with MYCN-A stage 1 NBL and those with MYCN-NA stage 2b NBL who are ≥ 18 months of age or who have UH or diploid disease have a less favorable outcome than other low-risk patients. Further refinements of risk classification schema are needed for these patients. These refinements, further restriction of chemotherapy, and questions about the extent of surgical resection necessary for cure will be the goals of future studies.