Ten Challenges in the Management of Neuroblastoma
Ten Challenges in the Management of Neuroblastoma
Those high-risk patients that demonstrate a good response to induction and consolidation therapies are still at a significant risk of relapse and this is due to the presence of MRD. The current multimodality therapy of high-risk neuroblastoma therefore includes a 'maintenance' phase of treatment at the end of therapy aimed at the eradication of MRD.
Differentiating Agents
In vitro studies conducted 30 years ago showed that retinoic acid could induce differentiation and apoptosis in neuroblastoma cell lines. Following early-phase trials, prospective randomized controlled clinical trials were performed in which patients completing consolidation therapy without disease progression were randomized to receive no further therapy or 13-cis-retinoic acid therapy for 6 months. The long-term results of one of these studies were recently published showing a statistically significant increase in 5-year OS for the patients given 13-cis-retinoic acid after consolidation with myeloablative chemotherapy and autologous bone marrow transplantation, as opposed to those given no 13-cis-retinoic acid (5-year OS: 59 vs 41%). EFS and OS from second randomization did not differ between patients who had or did not have 13-cis-retinoic acid. Significance for EFS was only reached by comparing all four groups and for OS only after logarithmic transformation (which is rather uncommon in oncology trials). 13-cis-retinoic acid has subsequently been included in current high-risk protocols as standard therapy for patients in first remission.
The method of administration of 13-cis-retinoic acid to young children remains problematic, however, as the preparation is currently available only in large capsules. Young children require the capsules to be opened and mixed with food for administration. As the drug is vulnerable to degradation by light, this could have important implications for the therapeutic levels of the drug received. A study by the UK Children's Cancer Study Group found a high degree of variability in the pharmacokinetics and metabolism of 13-cis-retinoic acid in 28 children with high-risk neuroblastoma, which could impact on both efficacy and toxicity.
Fenretinide is a synthetic retinoid derivative with potentially lower toxicity that is currently being examined in early-phase clinical trials. It has a different mechanism of action to 13-cis-retinoic acid, as it causes cells to apoptose and necrose via the production of reactive oxygen species. Administration has been difficult for small children due to fenretinide also being available in a capsule. New Approaches to Neuroblastoma Therapy Phase I clinical trials using an intravenous formulation and an oral lipid matrix formulation (Lym-X-Sorb®, BioMolecular Products, Inc., Newburyport, MA, USA) are underway.
Immunotherapy
Alternative approaches to treat MRD have included immunotherapy. GD2 is a ganglioside found on the surface of the majority of neuroblastomas. It has limited distribution in other tissues (neurons, melanocytes and peripheral pain fibers in human tissues) making anti-GD2 monoclonal antibodies suitable for immunotherapy. Several anti-GD2 monoclonal antibodies have been developed, both murine and humanized. Early studies examined the murine monoclonal antibodies, 3F8 and 14G2a; however, more recent studies have focused on the human–mouse chimeric monoclonal antibody, ch14.18. After binding to neuroblastoma cells the monoclonal antibody induces complement-dependent and antibody-dependent cytotoxic lysis of tumor cells. Activity of ch14.18 in neuroblastoma was demonstrated in preclinical and early-phase clinical trials. The monoclonal antibody ch14.18 was then combined with IL-2 and GM-CSF in two Phase I feasibility studies. There were considerable but manageable toxicities, which included pain, fever, hypotension and capillary leak.
A subsequent Phase III randomized clinical trial was performed to determine whether the addition of ch14.18, GM-CSF and IL-2 to standard 13-cis-retinoic acid therapy after intensive multimodality therapy would improve outcomes in high-risk neuroblastoma. Patients with high-risk disease with a good response to induction therapy and PBSC transplantation were randomly assigned to receive the standard therapy (six cycles of 13-cis-retinoic acid) or immunotherapy (six cycles of 13-cis-retinoic acid and five concomitant cycles of ch14.18 in combination with alternating GM-CSF or IL-2). This trial was stopped early due to superior efficacy in the immunotherapy arm. Immunotherapy was superior to standard therapy, with an EFS of 66 versus 46% at 2 years (p = 0.01). OS at 2 years was also significantly different (86 vs 75%). There were, however, significant treatment-related toxic effects with pain of grade 3, 4 or 5 in 52%, capillary leak syndrome in 23% and hypersensitivity reactions in 25% of the patients in the immunotherapy arm.
The question as to whether there is a benefit of the addition of IL-2 to ch14.18 compared with ch14.18 alone remains. The current European high-risk neuroblastoma trial aims to discover whether there is a survival benefit for patients receiving IL-2 in addition to 13-cis-retinoic acid and ch14.18/CHO. All patients having received myeloablative chemotherapy and PBSC transplantation will receive ch14.18/CHO and 13-cis-retinoic acid with or without IL-2.
Managing the side effects of immunotherapy is challenging and currently all patients require intravenous narcotics to manage the pain. Further studies into the pharmacokinetics of immunotherapy agents are required. A current European Phase I/II dose-escalation study to assess whether long-term infusion of the antibody could reduce the pain and maintain efficacy and thereby minimize the morphine requirement and eventually the need for hospitalization is ongoing.
Developments to increase the efficacy of antibody therapy have included the addition of immunocytokines and the development of fusion antibodies, in which the cytokine is linked to the Fc end of the monoclonal antibody. The antibody binds to the tumor cell and delivers high concentrations of cytokine directly to the tumor microenvironment to attract immune effector cells.
Challenge 4
Risk of Relapse
Those high-risk patients that demonstrate a good response to induction and consolidation therapies are still at a significant risk of relapse and this is due to the presence of MRD. The current multimodality therapy of high-risk neuroblastoma therefore includes a 'maintenance' phase of treatment at the end of therapy aimed at the eradication of MRD.
Differentiating Agents
In vitro studies conducted 30 years ago showed that retinoic acid could induce differentiation and apoptosis in neuroblastoma cell lines. Following early-phase trials, prospective randomized controlled clinical trials were performed in which patients completing consolidation therapy without disease progression were randomized to receive no further therapy or 13-cis-retinoic acid therapy for 6 months. The long-term results of one of these studies were recently published showing a statistically significant increase in 5-year OS for the patients given 13-cis-retinoic acid after consolidation with myeloablative chemotherapy and autologous bone marrow transplantation, as opposed to those given no 13-cis-retinoic acid (5-year OS: 59 vs 41%). EFS and OS from second randomization did not differ between patients who had or did not have 13-cis-retinoic acid. Significance for EFS was only reached by comparing all four groups and for OS only after logarithmic transformation (which is rather uncommon in oncology trials). 13-cis-retinoic acid has subsequently been included in current high-risk protocols as standard therapy for patients in first remission.
The method of administration of 13-cis-retinoic acid to young children remains problematic, however, as the preparation is currently available only in large capsules. Young children require the capsules to be opened and mixed with food for administration. As the drug is vulnerable to degradation by light, this could have important implications for the therapeutic levels of the drug received. A study by the UK Children's Cancer Study Group found a high degree of variability in the pharmacokinetics and metabolism of 13-cis-retinoic acid in 28 children with high-risk neuroblastoma, which could impact on both efficacy and toxicity.
Fenretinide is a synthetic retinoid derivative with potentially lower toxicity that is currently being examined in early-phase clinical trials. It has a different mechanism of action to 13-cis-retinoic acid, as it causes cells to apoptose and necrose via the production of reactive oxygen species. Administration has been difficult for small children due to fenretinide also being available in a capsule. New Approaches to Neuroblastoma Therapy Phase I clinical trials using an intravenous formulation and an oral lipid matrix formulation (Lym-X-Sorb®, BioMolecular Products, Inc., Newburyport, MA, USA) are underway.
Immunotherapy
Alternative approaches to treat MRD have included immunotherapy. GD2 is a ganglioside found on the surface of the majority of neuroblastomas. It has limited distribution in other tissues (neurons, melanocytes and peripheral pain fibers in human tissues) making anti-GD2 monoclonal antibodies suitable for immunotherapy. Several anti-GD2 monoclonal antibodies have been developed, both murine and humanized. Early studies examined the murine monoclonal antibodies, 3F8 and 14G2a; however, more recent studies have focused on the human–mouse chimeric monoclonal antibody, ch14.18. After binding to neuroblastoma cells the monoclonal antibody induces complement-dependent and antibody-dependent cytotoxic lysis of tumor cells. Activity of ch14.18 in neuroblastoma was demonstrated in preclinical and early-phase clinical trials. The monoclonal antibody ch14.18 was then combined with IL-2 and GM-CSF in two Phase I feasibility studies. There were considerable but manageable toxicities, which included pain, fever, hypotension and capillary leak.
A subsequent Phase III randomized clinical trial was performed to determine whether the addition of ch14.18, GM-CSF and IL-2 to standard 13-cis-retinoic acid therapy after intensive multimodality therapy would improve outcomes in high-risk neuroblastoma. Patients with high-risk disease with a good response to induction therapy and PBSC transplantation were randomly assigned to receive the standard therapy (six cycles of 13-cis-retinoic acid) or immunotherapy (six cycles of 13-cis-retinoic acid and five concomitant cycles of ch14.18 in combination with alternating GM-CSF or IL-2). This trial was stopped early due to superior efficacy in the immunotherapy arm. Immunotherapy was superior to standard therapy, with an EFS of 66 versus 46% at 2 years (p = 0.01). OS at 2 years was also significantly different (86 vs 75%). There were, however, significant treatment-related toxic effects with pain of grade 3, 4 or 5 in 52%, capillary leak syndrome in 23% and hypersensitivity reactions in 25% of the patients in the immunotherapy arm.
The question as to whether there is a benefit of the addition of IL-2 to ch14.18 compared with ch14.18 alone remains. The current European high-risk neuroblastoma trial aims to discover whether there is a survival benefit for patients receiving IL-2 in addition to 13-cis-retinoic acid and ch14.18/CHO. All patients having received myeloablative chemotherapy and PBSC transplantation will receive ch14.18/CHO and 13-cis-retinoic acid with or without IL-2.
Managing the side effects of immunotherapy is challenging and currently all patients require intravenous narcotics to manage the pain. Further studies into the pharmacokinetics of immunotherapy agents are required. A current European Phase I/II dose-escalation study to assess whether long-term infusion of the antibody could reduce the pain and maintain efficacy and thereby minimize the morphine requirement and eventually the need for hospitalization is ongoing.
Developments to increase the efficacy of antibody therapy have included the addition of immunocytokines and the development of fusion antibodies, in which the cytokine is linked to the Fc end of the monoclonal antibody. The antibody binds to the tumor cell and delivers high concentrations of cytokine directly to the tumor microenvironment to attract immune effector cells.
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