Ten Challenges in the Management of Neuroblastoma
With less than 40% of high-risk neuroblastoma patients becoming long-term survivors, novel treatments are required for relapsed or refractory disease to improve outcome. Survival after relapse is poor with no currently universally effective regime. The Italian neuroblastoma registry published the long-term outcome of the largest-ever cohort of patients with neuroblastoma registered in prospective clinical trials with disease progression or relapse. They found prognosis overall to be very poor with a median survival of less than 1 year and less than 10% of children surviving more than 10 years after relapse. For stage 4 patients who had progressed or relapsed the 10-year OS was only 2%.
A recent report from the INRG project examined clinical and biological features predicting survival after relapse. The significant prognostic factors for postrelapse survival were age, stage, MYCN status and time from diagnosis to first relapse. Patients relapsing between 6 and 18 months after diagnosis had the lowest OS, whereas those relapsing after 36 months or longer had a better OS.
Drug Treatments
Cytotoxic chemotherapy strategies for relapsed or refractory high-risk neuroblastoma have in recent years concentrated on agents such as irinotecan, temozolomide and topotecan. These agents have been examined alone and subsequently in various combinations with each other, or in combinations with other more established agents.
A recent retrospective analysis of the use of a multiagent regime of high-dose cyclophosphamide, topotecan and vincristine found major responses (CR/VGPR and partial response) statistically more common (52%) in children with a new (first) disease recurrence compared with children with primary refractory disease (19%), secondary refractory disease (29%) or progressive disease that occurred during induction therapy (0%).
Conventional cytotoxic chemotherapies may be reaching their maximum potential in terms of efficacy and toxicity; however, strategies aimed at improving efficacy and reducing toxicity are focusing on new molecular targets. Collaborative research efforts are focusing on rapidly evaluating and screening preclinically promising agents that hold potential or have been used with success in adult cancers and bringing them to the pediatric setting for early clinical trials. Several early-phase trials have been conducted including those on tyrosine kinase inhibitors, histone deacetylase inhibitors, VEGF receptor inhibitors, β-tubulin inhibitors and mTOR inhibitors. The relationships between different receptor pathways are complex and inhibition at one point often activates another pathway through feedback and so these agents need to be further tested in combination.
There is currently wider interest in developing randomized Phase II trials using the latest cytotoxics as a 'backbone' and adding new molecular targets to assess a multimodal molecularly targeted therapy in relapsed high-risk neuroblastoma.
Zoledronic acid is a bisphosphonate that has shown efficacy in adult patients with bone metastases in several malignancies, including breast and prostate. A Phase I study of zoledronic acid and oral metronomic cyclophosphamide has been completed and this agent has been proposed for further study in combination with other agents.
Molecular Radiotherapy
Targeted radionuclide therapy is a recognized treatment approach for relapsed or refractory disease. Being a tumor derived from the sympathetic nervous system, neuroblastoma expresses the noradrenaline transporter molecule, which takes up the catecholamine analog mIBG. I-mIBG has been used in the treatment of neuroblastoma for the past 25 years.
Most studies using I-mIBG have been pilot, Phase I or II clinical trials with response rates reported of between 20 and 50%. The largest of these studies was a Phase II monotherapy trial that included 164 patients receiving a prescribed dose of 12 or 18 mCi/kg of I-mIBG. The overall response rate was 36%, with another 34% of patients exhibiting stable disease. Univariate analysis of these findings indicated that age >12 years at the time of treatment was a positive prognostic factor for response compared with patients who were aged 22 months to 6 years. There have been no Phase III clinical trials with I-mIBG. The dose-limiting toxicity is myelosuppression.
Attempts to increase the response to I-mIBG have included dose escalation and the addition of radiosensitizers such as topotecan, both of which methods have used PBSC support to circumnavigate the myelosuppression caused by higher administered activities.
Recent preclinical studies have demonstrated that vorinostat (an inhibitor of histone deacetylase) can increase the expression of the norepinephrine transporter in neuroblastoma in vitro and in vivo, which could have potential for enhancing I-mIBG therapy. The combination of vorinostat and I-mIBG is now being evaluated in a Phase I study.
Early studies on an alternative form of molecular radiotherapy with radiolabeled somatostatin analogs have also been reported. These agents are targeted against the somatostatin receptor type 2 expressed frequently on neuroblastoma cells. These somatostatin analogs, labeled with either Lu or Y, are an alternative way of delivering radiation to widespread neuroblastoma deposits to I-mIBG as they are aimed at a distinct and separate molecular target to I-mIBG. Future developments may, however, focus on combining or alternating I-mIBG and a radiolabeled somatostatin analog. The two agents studied clinically in neuroblastoma are Y-DOTA-TOC and Lu-DOTATATE (Figure 5).
(Enlarge Image)
Figure 5.
Ga-DOTATATE PET/CT scan: axial sections through the pelvis to show a metastasis.
(A) Before and (B) after four courses of Lu-DOTATATE therapy (partial response).
Challenge 6
Refractory & Relapsed Disease
With less than 40% of high-risk neuroblastoma patients becoming long-term survivors, novel treatments are required for relapsed or refractory disease to improve outcome. Survival after relapse is poor with no currently universally effective regime. The Italian neuroblastoma registry published the long-term outcome of the largest-ever cohort of patients with neuroblastoma registered in prospective clinical trials with disease progression or relapse. They found prognosis overall to be very poor with a median survival of less than 1 year and less than 10% of children surviving more than 10 years after relapse. For stage 4 patients who had progressed or relapsed the 10-year OS was only 2%.
A recent report from the INRG project examined clinical and biological features predicting survival after relapse. The significant prognostic factors for postrelapse survival were age, stage, MYCN status and time from diagnosis to first relapse. Patients relapsing between 6 and 18 months after diagnosis had the lowest OS, whereas those relapsing after 36 months or longer had a better OS.
Drug Treatments
Cytotoxic chemotherapy strategies for relapsed or refractory high-risk neuroblastoma have in recent years concentrated on agents such as irinotecan, temozolomide and topotecan. These agents have been examined alone and subsequently in various combinations with each other, or in combinations with other more established agents.
A recent retrospective analysis of the use of a multiagent regime of high-dose cyclophosphamide, topotecan and vincristine found major responses (CR/VGPR and partial response) statistically more common (52%) in children with a new (first) disease recurrence compared with children with primary refractory disease (19%), secondary refractory disease (29%) or progressive disease that occurred during induction therapy (0%).
Conventional cytotoxic chemotherapies may be reaching their maximum potential in terms of efficacy and toxicity; however, strategies aimed at improving efficacy and reducing toxicity are focusing on new molecular targets. Collaborative research efforts are focusing on rapidly evaluating and screening preclinically promising agents that hold potential or have been used with success in adult cancers and bringing them to the pediatric setting for early clinical trials. Several early-phase trials have been conducted including those on tyrosine kinase inhibitors, histone deacetylase inhibitors, VEGF receptor inhibitors, β-tubulin inhibitors and mTOR inhibitors. The relationships between different receptor pathways are complex and inhibition at one point often activates another pathway through feedback and so these agents need to be further tested in combination.
There is currently wider interest in developing randomized Phase II trials using the latest cytotoxics as a 'backbone' and adding new molecular targets to assess a multimodal molecularly targeted therapy in relapsed high-risk neuroblastoma.
Zoledronic acid is a bisphosphonate that has shown efficacy in adult patients with bone metastases in several malignancies, including breast and prostate. A Phase I study of zoledronic acid and oral metronomic cyclophosphamide has been completed and this agent has been proposed for further study in combination with other agents.
Molecular Radiotherapy
Targeted radionuclide therapy is a recognized treatment approach for relapsed or refractory disease. Being a tumor derived from the sympathetic nervous system, neuroblastoma expresses the noradrenaline transporter molecule, which takes up the catecholamine analog mIBG. I-mIBG has been used in the treatment of neuroblastoma for the past 25 years.
Most studies using I-mIBG have been pilot, Phase I or II clinical trials with response rates reported of between 20 and 50%. The largest of these studies was a Phase II monotherapy trial that included 164 patients receiving a prescribed dose of 12 or 18 mCi/kg of I-mIBG. The overall response rate was 36%, with another 34% of patients exhibiting stable disease. Univariate analysis of these findings indicated that age >12 years at the time of treatment was a positive prognostic factor for response compared with patients who were aged 22 months to 6 years. There have been no Phase III clinical trials with I-mIBG. The dose-limiting toxicity is myelosuppression.
Attempts to increase the response to I-mIBG have included dose escalation and the addition of radiosensitizers such as topotecan, both of which methods have used PBSC support to circumnavigate the myelosuppression caused by higher administered activities.
Recent preclinical studies have demonstrated that vorinostat (an inhibitor of histone deacetylase) can increase the expression of the norepinephrine transporter in neuroblastoma in vitro and in vivo, which could have potential for enhancing I-mIBG therapy. The combination of vorinostat and I-mIBG is now being evaluated in a Phase I study.
Early studies on an alternative form of molecular radiotherapy with radiolabeled somatostatin analogs have also been reported. These agents are targeted against the somatostatin receptor type 2 expressed frequently on neuroblastoma cells. These somatostatin analogs, labeled with either Lu or Y, are an alternative way of delivering radiation to widespread neuroblastoma deposits to I-mIBG as they are aimed at a distinct and separate molecular target to I-mIBG. Future developments may, however, focus on combining or alternating I-mIBG and a radiolabeled somatostatin analog. The two agents studied clinically in neuroblastoma are Y-DOTA-TOC and Lu-DOTATATE (Figure 5).
(Enlarge Image)
Figure 5.
Ga-DOTATATE PET/CT scan: axial sections through the pelvis to show a metastasis.
(A) Before and (B) after four courses of Lu-DOTATATE therapy (partial response).