High risk neuroblastoma: Small steps towards cure

I n this issue of Pediatric Blood & Cancer, Valteau-Couanet et al. [1] update the results of the NB97SFOP protocol activated in 1997 by the French Pediatric Oncology Group for children with stage 4 neuroblastoma older than 1 year. In this protocol, the induction phase was taken from the N7 regimen, and was followed by a consolidation phase with high dose Busulfan and Melphalan (BuMel). N7, a highly dose-intense combination of cyclophosphamide, vincristine, doxorubicin, cisplatinum, and etoposide, was designed in 1994 by Kushner et al. [2] of the Sloan-Kettering Cancer Center in NewYork City. In the hands of these investigators, N7 was quite effective since it was able to induce 80% of response rate including complete response plus very good partial response. Subsequently, the same French Group, and then the English UKCCSG (both in a multi-center setting compared to the monocenter study of Kushner et al.) were not able to confirm the results of N7 combination, achieving response rates of 47% and a 60%, respectively [3,4]. In the present report, Valteau-Couanet et al. focus on the long-term survival rate of their N7-treated patients, who had achieved CR before BuMel consolidation (52% EFS at 8 years), a result that suggests the ability of this regimen to eradicate minimal residual disease in a significant number of patients, and that could be further improved by the subsequent administration of retinoic acid and immunotherapy. On the other hand, some N7-treated patients failed to respond at all and died, and others, who underwent high-doses consolidation therapy because of a partial tumor response, had a poor survival probability. Thus, only one third of all the children in the cohort survived at 8 years, a result that represents an improvement compared to the previous experiences [5], but that is far from being satisfactory. It must also be kept in mind that the original N7 regimen, followed by high-dose chemotherapy resulted in (i) significant early and late toxicity, including a number of toxic deaths due to surgery, respiratory failure and secondary malignancies, and (ii) important adverse effects particularly concerning hearing loss and endocrine deficits in 60% survivors. Of note, the occurrence of second malignancies decreased in the Kushner et al. [6] experience when the number of chemotherapy courses was reduced from 7 to 5, and this is confirmed by Valteau-Couanet et al., who report no cases of second malignancies. The degree to which patient outcome was influenced by controlling the primary tumor through surgery and irradiation is not addressed in the Valteu-Couanet et al. paper. It is conceivable that the aggressive multi-modality therapy may be effective in lowering the local recurrence rate. Current studies in Europe and the U.S. are exploring this important issue. Together with a number of other similar clinical studies, each reporting significant progresses [7,8], the report of Valteau-Couanet et al. strengthens the concept that the management of patients with stage 4 neuroblastoma over 1 year remains an unsolved challenge due to several factors, including disease heterogeneity, tumor resistance to treatment, and dose-limiting toxicity of chemotherapeutic agents. Efforts have been made and should be further implemented to better define a number of risk categories in the context of high-risk neuroblastoma. It is well known that patients between 12 and 18months of age at diagnosis have a better outcome and are currently treated differently on the basis of combined clinical (age) and genetic (structural chromosomal alterations) characteristics. On the other hand, approximately one quarter of all patients fail to have a good response to first line therapy and thus have a very poor prognosis. This group of patients could also likely be identified at diagnosis on the basis of biological characteristics, or early during treatment, on the basis of biological markers of response, including residual disease in peripheral blood, or MIBG response. Resistance to treatment, as well as organ toxicity could be at least partially overcome by using new drugs having potential non cross-resistance mechanisms of action. Topotecan is known to be active in relapsed or refractory neuroblastoma patients and it is currently used by the COG, German and SIOPEN Groups. New drugs with different biological mechanisms of action and different toxicities should be included in the induction therapy to increase the efficacy of the old chemotherapeutic combinations. Angiogenesis, multi-kinase, aurora-kinase, and proteosome inhibitors have shown both in vitro and preclinically in vivo increased activity when combined with chemotherapy. Identifying the mechanisms at the basis of tumor development might open the way to biologically driven treatments. ALK inhibitors have recently demonstrated activity in neuroblastoma, but ALK activatingmutations are present in only 8–12% of neuroblastoma [9]. Further improvement could be achieved by new high-dose regimens [10] or tandem high-dose regimens [11], and by including radiometabolic I131-MIBG therapy in the high-dose schemes [12]. However, despite successful induction treatment and aggressive consolidation, patients with high risk disease continue to show a high incidence of relapse, mainly occurring at metastatic sites. Some approaches using differentiating agents, retinoic acid and, more recently, immunotherapy based onmonoclonal antibodies and interleukin 2 have shown an improvement in event-free and overall survivals [13]. This improvement, however, is still far from being