Consolidation phase

A large European multicenter trial of consolidation therapy randomly assigned patients who had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate response to receive either busulfan/melphalan or carboplatin/etoposide/melphalan.[29][Level of evidence A1]

A large European multicenter trial of consolidation therapy randomly assigned patients who had completed a multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin) and achieved an adequate response to receive either busulfan/melphalan or carboplatin/etoposide/melphalan.[29][Level of evidence A1]

Induction therapy with cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, and consolidation for HSCT with busulfan/melphalan resulted in an improved EFS, without an effect on OS or severe adverse events.

A randomized clinical study (COG-ANBL0532) tested the efficacy of two cycles versus one cycle of myeloablative chemotherapy with stem cell rescue.[30][Level of evidence A1] Children older than 18 months with stage 4 neuroblastoma who had received six cycles of induction chemotherapy were then randomly assigned to receive a single autologous HSCT with carboplatin/etoposide/melphalan or tandem transplants with cyclophosphamide/thiotepa followed by reduced-dose carboplatin/etoposide/melphalan. After tumor bed radiation therapy, most patients were randomly assigned to a second separate trial to receive isotretinoin alone or isotretinoin with dinutuximab and immune enhancement.

A randomized clinical study (COG-ANBL0532) tested the efficacy of two cycles versus one cycle of myeloablative chemotherapy with stem cell rescue.[30][Level of evidence A1] Children older than 18 months with stage 4 neuroblastoma who had received six cycles of induction chemotherapy were then randomly assigned to receive a single autologous HSCT with carboplatin/etoposide/melphalan or tandem transplants with cyclophosphamide/thiotepa followed by reduced-dose carboplatin/etoposide/melphalan. After tumor bed radiation therapy, most patients were randomly assigned to a second separate trial to receive isotretinoin alone or isotretinoin with dinutuximab and immune enhancement.

The 3-year EFS rate from the time of randomization was 62% for tandem transplants and 48% for single HSCT (P = .006). The 3-year OS rate was 74% for tandem autologous HSCTs and 69% for single autologous HSCT (P = .25).

A randomized clinical study (COG-ANBL0532) tested the efficacy of two cycles versus one cycle of myeloablative chemotherapy with stem cell rescue.[30][Level of evidence A1] Children older than 18 months with stage 4 neuroblastoma who had received six cycles of induction chemotherapy were then randomly assigned to receive a single autologous HSCT with carboplatin/etoposide/melphalan or tandem transplants with cyclophosphamide/thiotepa followed by reduced-dose carboplatin/etoposide/melphalan. After tumor bed radiation therapy, most patients were randomly assigned to a second separate trial to receive isotretinoin alone or isotretinoin with dinutuximab and immune enhancement.

For randomized patients who subsequently received dinutuximab and immune enhancement, the 3-year EFS rate was 73% for tandem HSCTs and 55% for single HSCT (P = .004), while the OS rate was 84% and 74%, respectively.[30][Level of evidence B1]

A randomized clinical study (COG-ANBL0532) tested the efficacy of two cycles versus one cycle of myeloablative chemotherapy with stem cell rescue.[30][Level of evidence A1] Children older than 18 months with stage 4 neuroblastoma who had received six cycles of induction chemotherapy were then randomly assigned to receive a single autologous HSCT with carboplatin/etoposide/melphalan or tandem transplants with cyclophosphamide/thiotepa followed by reduced-dose carboplatin/etoposide/melphalan. After tumor bed radiation therapy, most patients were randomly assigned to a second separate trial to receive isotretinoin alone or isotretinoin with dinutuximab and immune enhancement.

These study results have an important limitation: a substantial portion of the patients were not randomly assigned to therapy (because of patient and provider preference), introducing a potential selection bias.

An updated Cochrane review evaluated three randomized clinical trials comparing autologous bone marrow transplant (BMT) with standard chemotherapy.[25-27,31,32]

An updated Cochrane review evaluated three randomized clinical trials comparing autologous bone marrow transplant (BMT) with standard chemotherapy.[25-27,31,32]

EFS was significantly better for autologous BMT, but there was no statistically significant difference in OS.

A review of 147 allogeneic transplant cases submitted to the Center for International Blood and Marrow Transplant Research found no advantage for allogeneic transplant over autologous transplant, even if the allogeneic transplant recipient had received a previous autologous transplant.[33]

Because of the high rates of local recurrence after incomplete surgical resection, the COG ANBL0532 (NCT00567567) trial prospectively evaluated the potential benefit of boost radiation therapy for patients with gross-residual tumor and compared the results with the preceding COG clinical trial for high-risk neuroblastoma (A3973 [NCT00004188]), in which patients did not receive boost radiation therapy. All patients on the ANBL0532 trial received 21.6 Gy of radiation to the preoperative primary tumor volume after induction chemotherapy.[38][Level of evidence C1]

Because of the high rates of local recurrence after incomplete surgical resection, the COG ANBL0532 (NCT00567567) trial prospectively evaluated the potential benefit of boost radiation therapy for patients with gross-residual tumor and compared the results with the preceding COG clinical trial for high-risk neuroblastoma (A3973 [NCT00004188]), in which patients did not receive boost radiation therapy. All patients on the ANBL0532 trial received 21.6 Gy of radiation to the preoperative primary tumor volume after induction chemotherapy.[38][Level of evidence C1]

There were no differences in outcomes between the patients in the ANBL0532 trial who received a single HSCT and boost radiation therapy (n = 74) and the patients in the A3973 trial who underwent an incomplete resection and received no boost radiation therapy (n = 47).

Because of the high rates of local recurrence after incomplete surgical resection, the COG ANBL0532 (NCT00567567) trial prospectively evaluated the potential benefit of boost radiation therapy for patients with gross-residual tumor and compared the results with the preceding COG clinical trial for high-risk neuroblastoma (A3973 [NCT00004188]), in which patients did not receive boost radiation therapy. All patients on the ANBL0532 trial received 21.6 Gy of radiation to the preoperative primary tumor volume after induction chemotherapy.[38][Level of evidence C1]

The 5-year cumulative incidence of local progression was 16.3% for patients in the ANBL0532 trial versus 10.6% for patients in the A3973 trial (P = .4126).

Because of the high rates of local recurrence after incomplete surgical resection, the COG ANBL0532 (NCT00567567) trial prospectively evaluated the potential benefit of boost radiation therapy for patients with gross-residual tumor and compared the results with the preceding COG clinical trial for high-risk neuroblastoma (A3973 [NCT00004188]), in which patients did not receive boost radiation therapy. All patients on the ANBL0532 trial received 21.6 Gy of radiation to the preoperative primary tumor volume after induction chemotherapy.[38][Level of evidence C1]

The EFS rate was 50.9% for patients in the ANBL0532 trial versus 48.9% for patients in the A3973 trial (P = .5084).

Because of the high rates of local recurrence after incomplete surgical resection, the COG ANBL0532 (NCT00567567) trial prospectively evaluated the potential benefit of boost radiation therapy for patients with gross-residual tumor and compared the results with the preceding COG clinical trial for high-risk neuroblastoma (A3973 [NCT00004188]), in which patients did not receive boost radiation therapy. All patients on the ANBL0532 trial received 21.6 Gy of radiation to the preoperative primary tumor volume after induction chemotherapy.[38][Level of evidence C1]

The OS rate was 68.1% for patients in the ANBL0532 trial versus 56.9% for patients in the A3973 trial (P = .2835).

Because of the high rates of local recurrence after incomplete surgical resection, the COG ANBL0532 (NCT00567567) trial prospectively evaluated the potential benefit of boost radiation therapy for patients with gross-residual tumor and compared the results with the preceding COG clinical trial for high-risk neuroblastoma (A3973 [NCT00004188]), in which patients did not receive boost radiation therapy. All patients on the ANBL0532 trial received 21.6 Gy of radiation to the preoperative primary tumor volume after induction chemotherapy.[38][Level of evidence C1]

Boost radiation therapy administered to gross residual tumor that was present at the end of induction did not significantly improve the 5-year cumulative incidence of local progression; therefore, it is not recommended.[38]

The 5-year control rate of irradiated metastatic sites was 81%.

Metastases that became MIBG negative after chemotherapy were significantly less likely to recur than the sites that remained MIBG positive.

Patients whose disease did not relapse in their irradiated metastatic sites had improved OS.

When feasible to deliver radiation therapy, including to sites that resolved with induction chemotherapy, radiation therapy was more than 90% effective in providing disease control in those metastatic sites.