Induction phase

The backbone of the most commonly used induction therapy includes dose-intensive cycles of cisplatin and etoposide alternating with vincristine, cyclophosphamide, and doxorubicin.[6] Topotecan and cyclophosphamide were added to this regimen based on the antineuroblastoma activity seen in patients with relapsed disease.[7] Response to therapy after four cycles of chemotherapy or at the end of induction chemotherapy correlates with EFS at the completion of high-risk therapy.[8-10]

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Evidence (induction chemotherapy with or without additional treatments):

In one study, the addition of anti-GD2 antibody therapy with GM-CSF and low-dose interleukin-2 (IL-2), given with each induction chemotherapy course, had encouraging outcomes in 42 children with newly diagnosed stage 4 disease.[11]

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In one study, the addition of anti-GD2 antibody therapy with GM-CSF and low-dose interleukin-2 (IL-2), given with each induction chemotherapy course, had encouraging outcomes in 42 children with newly diagnosed stage 4 disease.[11]

This induction therapy, followed by standard consolidation and postconsolidation therapy, produced early partial responses or better in most patients, reduced tumor volumes, and an encouraging 3-year EFS rate of 73.7%.

A European prospective randomized controlled trial investigated extended induction therapy in 422 patients with newly diagnosed high-risk neuroblastoma. Patients were randomly assigned to receive either standard induction chemotherapy with six chemotherapy courses or experimental induction chemotherapy that began with two additional courses of topotecan, cyclophosphamide, and etoposide, followed by standard induction chemotherapy.[12][Level of evidence B3]

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A European prospective randomized controlled trial investigated extended induction therapy in 422 patients with newly diagnosed high-risk neuroblastoma. Patients were randomly assigned to receive either standard induction chemotherapy with six chemotherapy courses or experimental induction chemotherapy that began with two additional courses of topotecan, cyclophosphamide, and etoposide, followed by standard induction chemotherapy.[12][Level of evidence B3]

The 3-year EFS rate was 34% for patients who received the experimental induction regimen and 32% for patients who received the standard induction regimen.

A European prospective randomized controlled trial investigated extended induction therapy in 422 patients with newly diagnosed high-risk neuroblastoma. Patients were randomly assigned to receive either standard induction chemotherapy with six chemotherapy courses or experimental induction chemotherapy that began with two additional courses of topotecan, cyclophosphamide, and etoposide, followed by standard induction chemotherapy.[12][Level of evidence B3]

The addition of two topotecan-containing chemotherapy courses did not improve the EFS of patients with high-risk neuroblastoma and resulted in more toxicity per patient.

European investigators completed another randomized study of induction regimens for patients with high-risk neuroblastoma. A total of 630 patients were randomly assigned to receive either cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide (rCOJEC regimen; n = 313) or the Memorial Sloan Kettering Cancer Center N5 induction regimens (MSKCC-N5; n = 317).[13][Level of evidence B1]

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European investigators completed another randomized study of induction regimens for patients with high-risk neuroblastoma. A total of 630 patients were randomly assigned to receive either cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide (rCOJEC regimen; n = 313) or the Memorial Sloan Kettering Cancer Center N5 induction regimens (MSKCC-N5; n = 317).[13][Level of evidence B1]

There were no significant differences in metastatic complete response rates between the two regimens (32% for rCOJEC vs. 35% for MSKCC-N5; P = .368) or 3-year EFS rates (44% for rCOJEC vs. 47% for MSKCC-N5; P = .527).

European investigators completed another randomized study of induction regimens for patients with high-risk neuroblastoma. A total of 630 patients were randomly assigned to receive either cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide (rCOJEC regimen; n = 313) or the Memorial Sloan Kettering Cancer Center N5 induction regimens (MSKCC-N5; n = 317).[13][Level of evidence B1]

Patients who received the rCOJEC regimen experienced less acute toxicity.

European investigators completed another randomized study of induction regimens for patients with high-risk neuroblastoma. A total of 630 patients were randomly assigned to receive either cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide (rCOJEC regimen; n = 313) or the Memorial Sloan Kettering Cancer Center N5 induction regimens (MSKCC-N5; n = 317).[13][Level of evidence B1]

The rCOJEC regimen has been selected as the standard induction regimen for the current International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) trial.

After a response to induction chemotherapy, resection of the primary tumor is recommended by most treatment protocols. Whether a gross-total resection is beneficial is controversial.[14]

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Evidence (extent of resection of the primary tumor):

The COG A3973 (NCT00004188) study had central surgical review of 220 patients who underwent attempted gross-total resection after induction chemotherapy. By the surgeon’s estimate, the degree of resection was determined to be 90% or greater versus less than 90%, but only 63% concordance with central review of imaging was found.[15][Level of evidence C1]

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The COG A3973 (NCT00004188) study had central surgical review of 220 patients who underwent attempted gross-total resection after induction chemotherapy. By the surgeon’s estimate, the degree of resection was determined to be 90% or greater versus less than 90%, but only 63% concordance with central review of imaging was found.[15][Level of evidence C1]

Nevertheless, the surgeon’s assessment of 90% or greater resection versus less than 90% resection predicted an EFS rate of 46% versus 38% (P = .01), respectively, and a cumulative incidence of local relapse rate of 8.5% versus 20%, respectively.

The COG A3973 (NCT00004188) study had central surgical review of 220 patients who underwent attempted gross-total resection after induction chemotherapy. By the surgeon’s estimate, the degree of resection was determined to be 90% or greater versus less than 90%, but only 63% concordance with central review of imaging was found.[15][Level of evidence C1]

OS rates were not significantly different between the two groups (57% vs. 49%, P = .3).

The COG A3973 (NCT00004188) study had central surgical review of 220 patients who underwent attempted gross-total resection after induction chemotherapy. By the surgeon’s estimate, the degree of resection was determined to be 90% or greater versus less than 90%, but only 63% concordance with central review of imaging was found.[15][Level of evidence C1]

The authors' conclusion supports continued efforts to achieve greater than 90% resection to decrease local recurrence.

A single-center retrospective study of 87 children with high-risk neuroblastoma demonstrated no significant benefit of gross-total resection compared with near-total (>90%) resection.[16][Level of evidence C2]

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A single-center retrospective study of 87 children with high-risk neuroblastoma demonstrated no significant benefit of gross-total resection compared with near-total (>90%) resection.[16][Level of evidence C2]

However, the results suggest that greater than 90% resection is associated with improved OS compared with less than 90% resection.

The potential benefit of aggressive surgical approaches in high-risk patients with metastatic disease to achieve complete tumor resection, either at the time of diagnosis or after chemotherapy, has not been unequivocally demonstrated. Several studies have reported that complete resection of the primary tumor at diagnosis improved survival. However, the outcome in these patients may be more dependent on the biology of the tumor, which itself may determine resectability, than on the extent of surgical resection.[17-19]

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In patients older than 18 months with stage 4 neuroblastoma, controversy exists about whether there is any advantage to gross-total resection of the primary tumor after chemotherapy.[15,18-20] In some studies, patients who underwent incomplete resections fared less well than those who underwent complete resections.[21] These outcomes could have resulted from either the biology of unresectable tumors or reduction of tumor bulk.[22][Level of evidence B1] Complete resection that requires nephrectomy is not recommended because of the nephrotoxic nature of standard chemotherapy and unproven effect of complete resection on outcome.

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In most group studies, surgical resection of the primary tumor is performed during the induction phase. However, the JN-H-11 trial evaluated the feasibility of delayed resection after high-dose chemotherapy with stem cell rescue, with the goal of prioritizing systemic therapy.[23] Rates of complete or greater-than-90% resection were similar to those seen in a previous trial, in which surgery was performed during induction. The rate of nephrectomy was nominally lower (5.8% vs. 17%), and the 3-year cumulative incidence of local failure rate was nominally higher (17.3% vs. 11.6%), compared with the rates found in the previous trial.

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At the end of induction therapy, patients with high-risk disease typically undergo a full disease evaluation. Management of patients with residual disease at the end of conventional induction therapy is not standardized. A retrospective study analyzed 201 patients with high-risk disease who had a partial response or less at the end of induction therapy. Patients were selected to immediately receive either high-dose chemotherapy (cohort 1), bridging therapy (usually chemoimmunotherapy or iodine I 131-metaiodobenzylguanidine [MIBG]) followed by high-dose chemotherapy (cohort 2), or additional therapy but not high-dose chemotherapy (cohort 3).[24]

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Despite having less-favorable features, patients in cohort 2 had similar EFS compared with patients in cohort 1, while patients in cohort 3 had inferior EFS.

Among patients with stable disease in metastatic sites at the end of induction therapy, patients in cohort 2 had superior EFS compared with patients in cohort 1.

These retrospective data suggest a role for bridging therapy in patients with incomplete response to conventional induction therapy.

Studies cited in this source section

Publication references