the most important clinical and biologic prognostic factors currently used to determine treatment are the age at diagnosis , stage of disease , mycn amplification status , dna ploidy , and histology1 - 7 ) . while the prognosis of low- or intermediate - risk nb is excellent with conventional treatment modalities , the prognosis of high - risk nb is very poor with conventional treatment alone8,9 ) . a strategy using high - dose chemotherapy and autologous stem cell transplantation ( hdct / autosct ) has been explored to improve the prognosis of patients with high - risk nb . this strategy is based on the hypothesis that dose escalation might improve the survival of children with high - risk nb . the results of randomized trials comparing hdct / autosct with chemotherapy alone showed a better event - free survival ( efs ) in the hdct / autosct arm than in the continuous chemotherapy arm9 - 11 ) . thus , hdct / autosct has been the standard consolidation treatment . the current standard treatment for high - risk nb is composed of induction treatment ( conventional chemotherapy and surgery with or without radiotherapy ) , hdct / autosct as a consolidation treatment , and 13-cis - retinoid acid treatment to reduce relapse from minimal residual disease however , the efs rates after single hdct / autosct are in the range of 30 to 40% , which is unsatisfactory . in this context , several clinical trials to further improve the survival of high - risk nb patients are under evaluation . the main cause of failure after single hdct / autosct is relapse or tumor progression rather than treatment - related mortality . thus , some investigators have explored the efficacy of double or triple tandem hdct / autosct to further improve the outcome of high - risk nb patients12 - 14 ) . this strategy is based on the hypothesis that further dose escalation might result in further improvement in survival rates . results from a small number of pilot studies suggest that further dose escalation might result in further improvements in the efs of these patients . although the number of studies employing tandem hdct / autosct strategy is limited , long - term efs rates were around 50 to 60% . george et al.12 ) first carried out a single arm trial of tandem hdct / autosct as consolidation therapy for high - risk nb and reported improved long - term survival ( 5-year efs 47% ) with acceptable toxicity . kletzel et al.13 ) also conducted a single arm trial of triple tandem hdct / autosct and reported improved survival ( 3-year efs 57% ) . sung et al.14 ) also reported the result of our tandem hdct / autosct protocol for high - risk nb . the korean society of pediatric hematology - oncology retrospectively investigated the efficacy of tandem hdct / autosct compared to single hdct / autosct15 ) . data were analyzed according to the intent - to - treat at diagnosis . as a result , 5-year efs rate was higher in the tandem hdct / autosct group than in the single hdct / autosct group ( 51.2% vs. 31.3% , p=0.030 ) . these studies demonstrated that further dose escalation might result in additional improvements in the efs of high - risk nb patients . tandem hdct / autosct has been applied to different patients with different pre - hdct / autosct treatment and with different hdct regimens . in addition , there has been no randomized study to compare the efficacy of tandem hdct / autosct with single hdct / autosct . a randomized trial comparing the efficacy of tandem versus single hdct / autosct strategy another issue to address in the tandem hdct / autosct strategy is toxicity from the more intense treatment . the tandem hdct / autosct strategy is based on the hypothesis that further dose escalation might result in improvement over single hdct / autosct in the efs of high - risk nb patients . encouraging survival rates in a few trials employing the tandem hdct / autosct strategy have been attributed to the intensive treatment protocol . however , intensive treatment can also increase the frequency and severity of various late adverse effects . indeed , many long - term survivors in these studies had late adverse effects and still needed long - term follow - up for observation of additional late adverse effects , although they have demonstrated acceptable levels of cognitive and developmental function16 ) . dental abnormalities , hearing loss , nephropathy , and short stature have been the most prevalent late adverse effects . these findings suggest that further studies employing new treatment modalities are needed to reduce late adverse effects without jeopardizing the survival rate . incorporation of high - dose i - metaiodobenzylguanidine ( i - mibg ) treatment , instead of total body irradiation ( tbi ) , into tandem hdct / autosct , and anti - gd2 treatment after tandem hdct / autosct seem to be possible options . the use of targeted radionuclides allows the delivery of very large radiation doses to the tumor with less radiation to normal tissue . targeted radionuclide therapy using mibg for delivery of radiation in the form of i has been used extensively to treat relapsed or refractory nb . recently , high - dose i - mibg treatment was given with autologous stem cell rescue for the treatment of relapsed and refractory nb . the children 's cancer group ( ccg ) treated relapsed or poor response patients with high - dose i - mibg therapy and stem cell support17 ) . therefore , recently , investigators have incorporated i - mibg treatment into hdct / autosct18,19 ) . this therapy has been feasible and effective at 12 mci / kg i - mibg , and hdct doses minimally decreased from those without i - mibg treatment18 ) . a phase ii study is currently underway for the treatment of newly diagnosed high - risk nb , but not for relapsed tumors . a clinical trial that incorporates high - dose i - mibg treatment , instead of tbi , into tandem hdct / autosct to reduce late adverse effects without jeopardizing preliminary results are encouraging . instead of mibg , anti - gd2 , which is also specific to nb cells , cheung et al.20 ) conducted a pilot study of high - dose i-(anti - gd2 ) and stem cell support , and they reported an encouraging result . to further improve the outcome of high - risk nb patients , various kind of immunotherapy are now under evaluation . anti - gd2 treatment after tandem hdct / autosct might also be an option to further improve the outcome . recently , yu et al.21 ) from cog reported the results of their phase iii trial . high - risk nb patients who remained progression free after single hdct / autosct were eligible in this study . anti - gd2 treatment plus 13-cis - retinoic acid treatment after hdct / autosct was superior to 13-cis - retinoic acid treatment alone for efs and overall survival . interleukin-2 ( il-2 ) treatment to enhance natural killer ( nk ) cell activity might be an option after hdct / autosct because nb cells do not express human leukocyte antigen ( hla ) class i antigen , and therefore , can be an excellent target for nk cell22 . the main cause of failure after single hdct / autosct is relapse or tumor progression rather than treatment - related mortality . thus , some investigators have explored the efficacy of double or triple tandem hdct / autosct to further improve the outcome of high - risk nb patients12 - 14 ) . this strategy is based on the hypothesis that further dose escalation might result in further improvement in survival rates . results from a small number of pilot studies suggest that further dose escalation might result in further improvements in the efs of these patients . although the number of studies employing tandem hdct / autosct strategy is limited , long - term efs rates were around 50 to 60% . george et al.12 ) first carried out a single arm trial of tandem hdct / autosct as consolidation therapy for high - risk nb and reported improved long - term survival ( 5-year efs 47% ) with acceptable toxicity . kletzel et al.13 ) also conducted a single arm trial of triple tandem hdct / autosct and reported improved survival ( 3-year efs 57% ) . sung et al.14 ) also reported the result of our tandem hdct / autosct protocol for high - risk nb . the korean society of pediatric hematology - oncology retrospectively investigated the efficacy of tandem hdct / autosct compared to single hdct / autosct15 ) . data were analyzed according to the intent - to - treat at diagnosis . as a result , 5-year efs rate was higher in the tandem hdct / autosct group than in the single hdct / autosct group ( 51.2% vs. 31.3% , p=0.030 ) . these studies demonstrated that further dose escalation might result in additional improvements in the efs of high - risk nb patients . tandem hdct / autosct has been applied to different patients with different pre - hdct / autosct treatment and with different hdct regimens . in addition , there has been no randomized study to compare the efficacy of tandem hdct / autosct with single hdct / autosct . a randomized trial comparing the efficacy of tandem versus single hdct / autosct strategy another issue to address in the tandem hdct / autosct strategy is toxicity from the more intense treatment . the tandem hdct / autosct strategy is based on the hypothesis that further dose escalation might result in improvement over single hdct / autosct in the efs of high - risk nb patients . encouraging survival rates in a few trials employing the tandem hdct / autosct strategy have been attributed to the intensive treatment protocol . however , intensive treatment can also increase the frequency and severity of various late adverse effects . indeed , many long - term survivors in these studies had late adverse effects and still needed long - term follow - up for observation of additional late adverse effects , although they have demonstrated acceptable levels of cognitive and developmental function16 ) . dental abnormalities , hearing loss , nephropathy , and short stature have been the most prevalent late adverse effects . these findings suggest that further studies employing new treatment modalities are needed to reduce late adverse effects without jeopardizing the survival rate . incorporation of high - dose i - metaiodobenzylguanidine ( i - mibg ) treatment , instead of total body irradiation ( tbi ) , into tandem hdct / autosct , and anti - gd2 treatment after tandem hdct / autosct seem to be possible options . the use of targeted radionuclides allows the delivery of very large radiation doses to the tumor with less radiation to normal tissue . targeted radionuclide therapy using mibg for delivery of radiation in the form of i has been used extensively to treat relapsed or refractory nb . recently , high - dose i - mibg treatment was given with autologous stem cell rescue for the treatment of relapsed and refractory nb . the children 's cancer group ( ccg ) treated relapsed or poor response patients with high - dose i - mibg therapy and stem cell support17 ) . therefore , recently , investigators have incorporated i - mibg treatment into hdct / autosct18,19 ) . this therapy has been feasible and effective at 12 mci / kg i - mibg , and hdct doses minimally decreased from those without i - mibg treatment18 ) . a phase ii study is currently underway for the treatment of newly diagnosed high - risk nb , but not for relapsed tumors . a clinical trial that incorporates high - dose i - mibg treatment , instead of tbi , into tandem hdct / autosct to reduce late adverse effects without jeopardizing preliminary results are encouraging . instead of mibg , anti - gd2 , which is also specific to nb cells , cheung et al.20 ) conducted a pilot study of high - dose i-(anti - gd2 ) and stem cell support , and they reported an encouraging result . to further improve the outcome of high - risk nb patients , various kind of immunotherapy are now under evaluation . anti - gd2 treatment after tandem hdct / autosct recently , yu et al.21 ) from cog reported the results of their phase iii trial . high - risk nb patients who remained progression free after single hdct / autosct were eligible in this study . anti - gd2 treatment plus 13-cis - retinoic acid treatment after hdct / autosct was superior to 13-cis - retinoic acid treatment alone for efs and overall survival . interleukin-2 ( il-2 ) treatment to enhance natural killer ( nk ) cell activity might be an option after hdct / autosct because nb cells do not express human leukocyte antigen ( hla ) class i antigen , and therefore , can be an excellent target for nk cell22 . about half of high - risk nb patients still die from treatment failure even after tandem hdct / autosct . conventional chemotherapy has been ineffective after relapse in these patients , and they can not tolerate additional intensive treatment because they had been intensively treated previously . there has been no realistic chance for cure with conventional options alone23 ) , and therefore , a new modality of treatment is warranted for these patients . in this context , allogeneic sct ( allosct ) is being investigated as a potential curative treatment option for patients who failed previous hdct / autosct because it offers a graft - versus - tumor ( gvt ) effect not seen in autosct . allosct results in recovery of properly functioning immune cells that can correct any functional defects that exist in their autologous counterparts , which may provide a beneficial gvt effect . the graft - versus - leukemia ( gvl ) effect is a widely accepted major component of allosct in leukemias24 ) , and there is emerging evidence for a gvt effect in solid tumors25 ) . a gvt effect has also been demonstrated in patients with advanced nb who received allosct26 - 29 ) . however , regimen - related mortality following standard allosct with an intensive conditioning regimen may be extremely high in patients who have already been heavily treated30 - 32 ) . in recent years , several groups of investigators have developed reduced - intensity conditioning regimens that lead to engraftment of donor lymphoid and hematopoietic stem cells without the extra - hematopoietic toxicities of standard myeloablative conditioning , while conserving the gvl or gvt effect . this reduced regimen - related toxicity may make reduced - intensity allosct ( ri allosct ) especially suitable for patients at high - risk of regimen - related mortality , particularly previous recipients of tandem hdct / autosct . in adults , striking gvt effects after ri allosct have been described in refractory breast cancer and renal cell carcinoma25 ) . however , reports concerning the possible gvt effect of ri allosct remain very limited in pediatric solid tumors . although the number of studies employing ri allosct for nb is currently very limited , early studies suggest that this is a feasible approach that has demonstrated gvt effects that were confirmed by the regression of tumor after induction of acute graft - versus - host disease ( gvhd ) by withdrawal of immunosuppressive drugs or donor leukocyte infusion ( dli ) . for many years , hla - matched donors were the only types of donor routinely employed , however , more recently , mismatched sct has also proved feasible . jubert et al.33 ) applied mismatched cord blood transplantation ( cbt ) for the treatment of refractory / relapsed nb patients . cbt was feasible ; however , relapse was rapid and there was not enough time to establish a gvt effect in patients with high tumor burden . haploidentical sct ( haplosct ) also proved to be feasible . in 2003 , inoue et al.26 ) first described a boy with refractory nb who received cd34-positive haplosct after myeloablative conditioning . the tumor ultimately regressed and the authors stressed the possibility of a gvt effect against nb . lang et al.27 ) evaluated the feasibility and toxicity of haploidentical t- and b - cell depleted ri allosct with high numbers of nk cells and showed the feasibility and low toxicity of this approach even in intensively pre - treated nb patients . sung et al.34 ) also reported the results of ri allosct for nb patients who failed previous tandem hdct / autosct . regimen - related short - term toxicity was manageable and a gvt effect was observed in 2 of 6 patients after induction of acute gvhd ; however , it was not sufficiently strong to control tumor progression in patients who had a significant tumor burden at transplant . early studies of ri allosct , including haplosct , suggest that this is a feasible approach . they also demonstrated gvt effect that was confirmed by regression of tumor after induction of acute gvhd . however , the control of gvhd by immunosuppressive drugs resulted in the reemergence of nb . gvt effect was not enough to control tumor proliferation , particularly in patients who had a significant tumor burden at transplant . however , it was difficult to effectively reduce tumor burden prior to transplant with conventional treatment modalities . therefore , a new modality of treatment to effectively reduce tumor burden prior to transplant along with post - transplant adjuvant treatment to increase the antitumor effects is needed to improve the outcome after ri allosct . for efficient reduction of tumor burden prior to ri allosct without significant toxicity , high - dose i - mibg treatment might be an option because it has no significant toxicity other than hematologic toxicity . recently , investigators have incorporated high - dose i - mibg treatment into ri allosct and demonstrated that it is a feasible approach35,36 ) . another approach is to develop a new salvage treatment regimen with new drugs ; however , at present , an effective salvage regimen using new drugs is not available . more gvhd and probably a stronger gvt effect are expected in unrelated or mismatched sct compared to related or matched sct . therefore , in a specific subpopulation of patients , unrelated or mismatched sct might be a preferred option , and not merely an alternative to related or matched sct . killer immunoglobulin - like receptor ( kir ) ligand mismatched sct is also a possible option to enhance gvt effect in nb because nb cells do not express hla class i antigen , and therefore , can be an excellent target for nk cell alloimmunity . dli or nk cell infusion after sct and nb specific antibody treatment with or without cytokine treatment might be options to enhance the gvt effect against nb cells . nk cell- or complement - mediated immune response might be more important than t cell - mediated immune response because nb cells generally do not express class i antigen37 ) . toporski et al.36 ) incorporated high - dose i - mibg into haplosct with t cell depleted graft , and donor leukocytes were infused if gvhd was absent . lang et al.27 ) recently proposed a multicenter study employing an anti - gd2-based immunotherapy combined with haplosct . prez - martnez et al.37 ) have recently reported their experience using kir ligand mismatched haplosct in 3 refractory metastatic solid tumors including 1 nb . this approach was also feasible and gvt effect was demonstrated . a clinical trial that incorporates high - dose i - mibg treatment into ri allosct in patients who failed previous tandem hdct / autosct is under evaluation at samsung medical center . il-2 infusion is administered if the tumor has progressed or persisted at 6 months after ri allosct . one of recent approaches for the treatment of newly diagnosed high - risk nb is use of allosct . the first alloscts for nb were reported in the 1980s and the early 1990s38,39 ) . allosct was used as an alternative to autosct when autologous bone marrow had not been cleared of tumor or was impossible to harvest , but not really in an attempt to harness an immunotherapeutic effect . both the ccg38 ) and european group39 ) reported no difference in relapse between autosct and allosct , with higher toxic death rate in the allosct group . no beneficial antitumor effect of conventional allosct was demonstrated and allosct was finally , possibly too hastily , largely abandoned in nb treatment for more than 10 years . although the initial studies of conventional allosct failed to showed clear benefit , interest was recently renewed with the first successful reports of ri allosct in solid tumors , and with a few promising experimental studies that demonstrated a measurable antitumor immune response against nb . goi et al.40 ) evaluated the feasibility of ri cbt following autosct in newly diagnosed nb patients . takahashi et al.35 ) also developed a novel sct protocol to treat newly diagnosed very high - risk nb patients as well as relapsed patients . these approaches are based on the hypothesis that immunological effects of allosct will be most beneficial in children with minimal tumor burden in their early disease process before relapse . in summary , the advent of ri allosct has provided hope that treatment - related mortality will be reduced and therapeutic benefit will be detected . as an alternative to autosct early studies of allosct in children with newly diagnosed high - risk nb suggest that this is a feasible approach that may improve the outcome in this deadly disease . however , allosct for newly diagnosed nb is still investigational and there remain many issues to be elucidated in many areas . therefore , at present , allosct is reserved for specific clinical trials testing its immunomodulatory effect , although investigators are beginning to explore the possibility of an allogeneic effect in high - risk nb .
although high - dose chemotherapy and autologous stem cell transplantation ( hdct / autosct ) have improved the prognosis for patients with high - risk neuroblastoma ( nb ) , event - free survival rates remain in the range of 30 to 40% , which is unsatisfactory . to further improve outcomes , several clinical trials , including tandem hdct / autosct , high - dose 131i - metaiodobenzylguanidine treatment , and immunotherapy with nb specific antibody , have been undertaken and pilot studies have reported encouraging results . nonetheless , about half of high - risk nb patients still experience treatment failure and have no realistic chance for cure with conventional treatment options alone after relapse . 
 therefore , a new modality of treatment is warranted for these patients . in recent years 
 , several groups of investigators have examined the feasibility and effectiveness of reduced - intensity allogeneic stem cell transplantation ( ri allosct ) for the treatment of relapsed / progressed nb . although a graft - versus - tumor effect has not yet been convincingly demonstrated in the setting of relapsed nb , the strategy of employing ri allosct has provided hope that treatment - related mortality will be reduced and a therapeutic benefit will emerge . 
 however , allosct for nb is still investigational and there remain many issues to be elucidated in many areas . at present 
 , allosct is reserved for specific clinical trials testing the immunomodulatory effect against nb .