The induction regimen from the COG ANBL02P1 study demonstrates tolerability and feasibility of delivering a dose-intensive TopoCy regimen to newly diagnosed patients with high-risk neuroblastoma. The regimen uses a dose-intensive chemotherapy backbone previously described by Kushner et al10
(Memorial Sloan-Kettering Cancer Center [MSKCC] regimen) and used in the completed COG A3973 study.13
The MSKCC regimen's initial induction cycles—high-dose cyclophosphamide plus doxorubicin and vincristine—cause significant mucosal and infectious toxicities10
similar to those observed during ANBL02P1 cycles 3 to 6. In comparison, dose-intensive TopoCy rarely caused severe mucositis and documented infection and did not limit the ability to deliver the subsequent intended dose-intensive chemotherapy.
The use of myeloablative consolidation chemotherapy and autologous bone marrow infusion improves EFS of high-risk neuroblastoma.2,46,47
PBSCs carry less burden of collection48
and are less likely to contain tumor cells49
than bone marrow although the optimal timing of PBSC collection remains controversial. Our study confirmed prior results from Bensihom et al50
that sufficient PBSC cells without tumor contamination can be harvested after two cycles of chemotherapy. Sufficient numbers of stem cells were harvested for a minimum of two PBSC infusions in all but one patient, which was essential when planning the current COG tandem transplantation study. The occurrence of secondary malignancy following intensive neuroblastoma therapy51
may be related to the mutagenic potential of induction alkylator or topoisomerase 1 inhibitor chemotherapy, further providing a rationale for earlier PBSC harvest.
Kretchmar et al18
reported no improvement in outcome when adding cyclophosphamide and topotecan to neuroblastoma induction therapy. However, topotecan doses were significantly lower than those used in ANBL02P1 (0.75 mg/m2
/d) and may not provide maximal antitumor activity.31,32
Indeed, the response rate observed following two cycles of ANBL02P1 TopoCy are similar to the response rate in recurrent disease following lower-dose topotecan.30
Within the context of the entire ANBL02P1 induction regimen, patients achieved an overall response rate of 84% and 15 (48%) of 31 patients achieved CR or VGPR. These induction response rates are similar to metastatic response of CR in 17 of 44 patients observed in a multicenter trial52
and the 47% CR or VGPR response rate observed with the European Neuroblastoma Study Group 5 (ENSG5) cooperative trial.12
These similarities highlight the need for a larger phase III clinical trial to more accurately assess the efficacy of the ANBL02P1 induction regimen.
ANBL02P1 and previous pediatric topotecan trials demonstrate marked interpatient variability in clearance suggesting that pharmacokinetically guided dosing may be of clinical benefit.33,53
We were able to achieve the target exposure in 84% of patients. The median topotecan dose required to achieve the target AUC (cycle 1, 1.2 mg/m2
/d; cycle 2, 1.3 mg/m2
/d), achieved by either a dose increase or decrease, supports the use of 1.2 mg/m2
/d dosing administered daily for 5 days in future trials. The ANBL02P1 trial was not intended to assess the maximum tolerated topotecan dose that could be combined into induction therapy. Higher topotecan (6 to 8 mg/m2
per cycle) and cyclophosphamide dosages (approximately 4,200 mg/m2
per cycle) have been successfully administered to patients with recurrent neuroblastoma.28,29
Future trials incorporating a higher topotecan dosage into induction therapy may be warranted given ANBL02P1 results, although feasibility studies may be needed given the risk for increased mucositis24
and infection associated with higher topotecan dosages.30
ANBL02P1 confirmed the feasibility of incorporating pharmacokinetically guided dosing in an international multi-institutional clinical trial among institutions equipped with personnel and resources to perform real-time sampling and processing. However, in this patient population, more intrapatient variability in topotecan clearance was observed than in previous studies. Changing clinical factors (eg, renal function, extent of disease, concomitant medications) may account for some of this variability,54
but since this was, to the best of our knowledge, the first COG study of its kind, unfamiliarity with logistic aspects of the study also may have contributed to the greater intrapatient variability observed. Regardless, our study shows that although feasible, current real-time sampling techniques are time and labor intensive and are not likely to be feasible in a COG group-wide study because most sites do not have the appropriate infrastructure. Ultimately, methods must be developed to individualize therapy without burdening the health care system, either by minimization of the number of topotecan samples required or determination of a population model to predict topotecan exposure.
The feasibility of PBSC harvest and tolerability of the ANBL02P1 induction regimen support further investigation of its efficacy in a phase III clinical trial. However, suboptimal response still occurs in a subset of patients with neuroblastoma. Future trials need to translate our improved understanding of the neuroblastoma genetic signature by introducing novel molecularly targeted therapy. The tolerability of the topotecan-containing induction regimen provides a backbone regimen on which to add such agents.