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Survival Benefit of Myeloablative Therapy with Autologous Stem Cell Transplantation in High-Risk Neuroblastoma: A Systematic Literature Review
Żebrowska, U., Balwierz, W., Wechowski, J., Wieczorek, A.
Targeted oncology. 2024
Abstract
BACKGROUND Multimodal treatment of newly diagnosed high-risk neuroblastoma (HRNB) includes induction chemotherapy, consolidation with myeloablative therapy (MAT) and autologous stem cell transplantation (ASCT), followed by anti-disialoganglioside 2 (GD2) immunotherapy, as recommended by the Children's Oncology Group (COG) and the Society of Paediatric Oncology European Neuroblastoma (SIOPEN). Some centres proposed an alternative approach with induction chemotherapy followed by anti-GD2 immunotherapy, without MAT+ASCT. OBJECTIVE The aim of this systematic literature review was to compare survival outcomes in patients with HRNB treated with or without MAT+ASCT and with or without subsequent anti-GD2 immunotherapy. PATIENTS AND METHODS The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE via PubMed and EMBASE databases were systematically searched for randomised controlled trials (RCT) and observational comparative studies in patients with HRNB using search terms for 'neuroblastoma' and ('myeloablative therapy' OR 'stem cell transplantation'). Reporting of at least one survival outcome [event-free survival (EFS), progression-free survival, relapse-free survival and/or overall survival (OS)] was required for inclusion. Outcomes from RCTs were synthesized in meta-analysis, while meta-analysis of non-RCTs was not planned owing to expected heterogeneity. RESULTS Literature searches produced 2587 results with 41 publications reporting 34 comparative studies included in the review. Of these, 7 publications reported 4 RCTs, and 34 publications reported 30 non-RCT studies. Studies differed with respect to included populations, induction regimen, response to induction, additional treatments and transplantation procedures. Subsequent treatments of relapse were rarely reported and could not be compared. In the meta-analysis, EFS was in favour of MAT+ASCT over conventional chemotherapy or no further treatment [hazard ratio (HR) = 0.78, 95% confidence interval (CI) 0.67-0.91, p = 0.001] with a trend favouring MAT+ASCT for OS (HR = 0.86, 95% CI 0.73-1.00, p = 0.05). Tandem MAT+ASCT was found to improve EFS compared with the single procedure, with improvement in both EFS and OS in patients treated with anti-GD2 therapy. Non-RCT comparative studies were broadly consistent with evidence from the RCTs; however, not all reported survival benefits of MAT+ASCT (single or tandem). Limited comparative evidence on treatment without MAT+ASCT in patients treated with anti-GD2 immunotherapy suggests an increased risk of relapse. In relapsed patients, MAT+ASCT appears to improve OS, but evidence remains scarce. CONCLUSIONS Survival benefits in patients treated with MAT+ASCT confirm that the procedure should remain an integral part of multimodal therapy. In patients treated with anti-GD2 immunotherapy, limited evidence suggests that omitting MAT+ASCT is associated with an increased risk of relapse, and therefore, a change in clinical practice can currently not be recommended. Evidence suggests the use of tandem MAT+ASCT compared with the single procedure, with greater benefits observed in patients treated with anti-GD2 immunotherapy. Limited evidence also suggests improved survival following MAT+ASCT in relapsed patients, which needs to be viewed in light of emerging chemoimmunotherapy in this setting.
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The Impact of (131)I-Metaiodobenzylguanidine as a Conditioning Regimen of Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation for High-Risk Neuroblastoma
Park, H. J., Choi, J. Y., Kim, B. K., Hong, K. T., Kim, H. Y., Kim, I. H., Cheon, G. J., Cheon, J. E., Park, S. H., Kang, H. J.
Children (Basel, Switzerland). 2023;10(12)
Abstract
BACKGROUND The optimal conditioning regimen of tandem high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) for high-risk neuroblastoma (HR-NBL) has not been established. The efficacy of (131)I-MIBG therapy is under exploration in newly diagnosed HR-NBL patients. Here, we compared the outcomes of tandem HDC/ASCT between the (131)I-MIBG combination and non-MIBG groups. METHODS We retrospectively analyzed the clinical data of 33 HR-NBL patients who underwent tandem HDC/ASCT between 2007 and 2021 at the Seoul National University Children's Hospital. RESULTS The median age at diagnosis was 3.6 years. (131)I-MIBG was administered to 13 (39.4%) of the patients. Thirty patients (90.9%) received maintenance therapy after tandem HDC/ASCT, twenty-two were treated with isotretinoin ± interleukin-2, and eight received salvage chemotherapy. The five-year overall survival (OS) and event-free survival (EFS) rates of all patients were 80.4% and 69.4%, respectively. Comparing the (131)I-MIBG combined group and other groups, the five-year OS rates were 82.1% and 79.7% (p = 0.655), and the five-year EFS rates were 69.2% and 69.6% (p = 0.922), respectively. Among the adverse effects of grade 3 or 4, the incidence of liver enzyme elevation was significantly higher in the non-(131)I-MIBG group. CONCLUSIONS Although tandem HDC/ASCT showed promising outcomes, the (131)I-MIBG combination did not improve survival rates.
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Efficacy of post-induction therapy for high-risk neuroblastoma patients with end-induction residual disease
Desai, A. V., Applebaum, M. A., Karrison, T. G., Oppong, A., Yuan, C., Berg, K. R., MacQuarrie, K., Sokol, E., Hall, A. G., Pinto, N., et al
Cancer. 2022
Abstract
BACKGROUND High-risk neuroblastoma patients with end-induction residual disease commonly receive post-induction therapy in an effort to increase survival by improving the response before autologous stem cell transplantation (ASCT). The authors conducted a multicenter, retrospective study to investigate the efficacy of this approach. METHODS Patients diagnosed between 2008 and 2018 without progressive disease with a partial response or worse at end-induction were stratified according to the post-induction treatment: 1) no additional therapy before ASCT (cohort 1), 2) post-induction "bridge" therapy before ASCT (cohort 2), and 3) post-induction therapy without ASCT (cohort 3). χ(2) tests were used to compare patient characteristics. Three-year event-free survival (EFS) and overall survival (OS) were estimated by the Kaplan-Meier method and survival curves were compared by log-rank test. RESULTS The study cohort consisted of 201 patients: cohort 1 (n = 123), cohort 2 (n = 51), and cohort 3 (n = 27). Although the end-induction response was better for cohort 1 than cohorts 2 and 3, the outcomes for cohorts 1 and 2 were not significantly different (P = .77 for EFS and P = .85 for OS). Inferior outcomes were observed for cohort 3 (P < .001 for EFS and P = .06 for OS). Among patients with end-induction stable metastatic disease, 3-year EFS was significantly improved for cohort 2 versus cohort 1 (P = .04). Cohort 3 patients with a complete response at metastatic sites after post-induction therapy had significantly better 3-year EFS than those with residual metastatic disease (P = .01). CONCLUSIONS Prospective studies to confirm the benefits of bridge treatment and the prognostic significance of metastatic response observed in this study are warranted.
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Late effects in survivors of high-risk neuroblastoma following stem cell transplant with and without total body irradiation
Hobbie, W. L., Li, Y., Carlson, C., Goldfarb, S., Laskin, B., Denburg, M., Goldmuntz, E., Mostoufi-Moab, S., Wilkes, J., Smith, K., et al
Pediatric blood & cancer. 2022;69(3):e29537
Abstract
BACKGROUND Neuroblastoma is the most common extracranial solid tumor in children. Those with high-risk disease are treated with multimodal therapy, including high-dose chemotherapy, stem cell transplant, radiation, and immunotherapy that have led to multiple long-term complications in survivors. In the late 1990s, consolidation therapy involved myeloablative conditioning including total body irradiation (TBI) with autologous stem cell rescue. Recognizing the significant long-term toxicities of exposure to TBI, more contemporary treatment protocols have removed this from conditioning regimens. This study examines an expanded cohort of 48 high-risk neuroblastoma patients to identify differences in the late effect profiles for those treated with TBI and those treated without TBI. PROCEDURE Data on the study cohort were collected from clinic charts, provider documentation in the electronic medical record of visits to survivorship clinic, including all subspecialists, and ancillary reports of laboratory and diagnostic tests done as part of risk-based screening at each visit. RESULTS All 48 survivors of BMT for high-risk neuroblastoma had numerous late effects of therapy, with 73% having between five and 10 late effects. TBI impacted some late effects significantly, including growth hormone deficiency (GHD), bone outcomes, and cataracts. CONCLUSION Although high-risk neuroblastoma survivors treated with TBI have significant late effects, those treated without TBI also continue to have significant morbidity related to high-dose chemotherapy and local radiation. A multidisciplinary care team assists in providing comprehensive care to those survivors who are at highest risk for significant late effects.
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High-dose chemotherapy for relapsed germ cell tumours: outcomes in low-volume specialized centres
Connolly, E. A., Weickhardt, A., Grimison, P., Asher, R., Heller, G. Z., Lewin, J., Liow, E., Toner, G., Tung, I. L. Y., Tran, B., et al
BJU international. 2022
Abstract
OBJECTIVE To report treatment patterns and survival outcomes of patients with relapsed and refractory metastatic germ cell tumours (GCTs) treated with high-dose chemotherapy (HDCT) and autologous stem-cell transplantation in low-volume specialized centres within the widely dispersed populations of Australia and New Zealand between 1999 and 2019. PATIENTS AND METHODS We conducted a retrospective analysis of 111 patients across 13 institutions. Patients were identified from the Australasian Bone Marrow Transplant Recipient Registry. We reviewed treatment regimens, survival outcomes, deliverability and toxicities. Primary endpoints included overall (OS) and progression-free survival (PFS). Cox proportional hazards models were used to test the association of survival outcomes with patient and treatment factors. RESULTS The median (range) age was 30 (14-68) years and GCT histology was non-seminomatous in 84% of patients. International Prognostic Factors Study Group (IPFSG) prognostic risk category was very low/low, intermediate, high and very high in 18%, 36%, 25% and 21% of patients, respectively. Salvage conventional-dose chemotherapy (CDCT) was administered prior to HDCT in 59% of patients. Regimens included paclitaxel, ifosfamide, carboplatin and etoposide (50%), carboplatin and etoposide (CE; 28%), carboplatin, etoposide and ifosfamide (CEI; 6%), carboplatin, etoposide and cyclophosphamide (CEC; 5%), CEC-paclitaxel (6%) and other (5%). With a median follow-up of 4.4 years, the 1-, 2- and 5-year PFS rates were 62%, 57% and 52%, respectively, and OS rates were 73%, 65% and 61%, respectively. There were five treatment-related deaths. Progression on treatment occurred in 17%. In a univariable analysis, worse International Germ Cell Cancer Collaborative Group (IGCCCG) and IPFSG prognostic groups were associated with inferior survival outcomes. An association of inferior survival was not found with the number of high-dose cycles received nor when HDCT was delivered after salvage CDCT. CONCLUSION This large dual-national registry-based study reinforces the efficacy and deliverability of HDCT for relapsed and refractory metastatic GCT in low-volume specialized centres in Australia and New Zealand, with survival outcomes comparable to those found in international practice.
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Radiation Therapy for Young Children Treated With High-Dose Chemotherapy and Autologous Stem Cell Transplant for Primary Brain Tumors
Milgrom, S. A., Koo, J., Foreman, N., Liu, A. K., Campbell, K., Dorris, K., Green, A. L., Dahl, N., Donson, A. M., Vibhakar, R., et al
Advances in radiation oncology. 2022;7(4):100945
Abstract
PURPOSE : The role of peri-transplant radiation therapy (RT) in children with primary brain tumors is unclear. We characterized our institutional practice patterns and patient outcomes. METHODS AND MATERIALS The cohort included all patients treated with high-dose chemotherapy and autologous stem cell transplant for primary brain tumors at our institution from 2011 to 2017. Rates of local control, progression-free survival, overall survival, and radiation-associated injury were assessed. RESULTS Of the 37 eligible patients, 29 (78%) received peri-transplant RT. Patients treated with RT were more likely to have metastatic (P = .0121) and incompletely resected (P = .056) disease. Of those treated with RT, 13 (45%) received craniospinal irradiation (CSI) and 16 (55%) received focal RT. The median CSI dose was 23.4 Gy (interquartile range [IQR], 18-36 Gy; boost: median, 54 Gy [IQR, 53.7-55.8 Gy]) and focal RT dose was 50.4 Gy [IQR, 50.4-54.5 Gy]). Compared with the focal RT group, patients treated with CSI were older (P = .0499) and more likely to have metastatic disease (P = .0004). For the complete cohort, 2-year local control was 82% (95% confidence interval [CI], 70%-96%), progression-free survival 63% (95% CI, 49%-81%), and overall survival 65% (95% CI, 51%-82%). These rates did not differ significantly between patients treated with and without peri-transplant RT. Two cases of fatal myelopathy were observed after spinal cord doses within the highest tertile (41.4 cobalt Gy equivalent and 36 Gy). CONCLUSIONS Peri-transplant RT was used for high-risk disease. Oncologic outcomes after RT were encouraging. However, 2 cases of grade 5 myelopathy were observed. If used cautiously, RT may contribute to durable remission in patients at high risk of relapse.
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High-dose thiotepa, in conjunction with melphalan, followed by autologous hematopoietic stem cell transplantation in patients with pediatric solid tumors, including brain tumors
Hara, J., Matsumoto, K., Maeda, N., Takahara-Matsubara, M., Sugimoto, S., Goto, H.
Bone marrow transplantation. 2022
Abstract
Among pediatric malignancies, solid tumors, particularly within the central nervous system (CNS), are common. Thiotepa, a myeloablative, high-dose chemotherapeutic (HDT) treatment administered prior to autologous hematopoietic stem cell transplantation (HSCT), can cross the blood-brain barrier and rapidly penetrate the CNS. We evaluated thiotepa HDT in conjunction with melphalan in Japanese patients with pediatric CNS/non-CNS solid tumors in a multicenter, open-label, non-comparative study. Thiotepa (200 mg/m(2)/day) was administered intravenously (IV) over 24 h on days -12, -11, -5, and -4 before scheduled HSCT. Melphalan (70 mg/m(2)/day) was administered IV over 1 h on days -11, -5, and -4. The safety analysis population comprised 41 patients, of whom 16 (39.0%) had solid tumors and 25 (61.0%) had brain tumors. The most frequently reported adverse events were diarrhea (40/41 [97.6%] patients) and febrile neutropenia (34/41 [82.9%]). No unexpected safety events were observed, and no events resulted in death or treatment discontinuation. All patients experienced bone marrow suppression and 39/41 (95.1%) achieved engraftment (neutrophil count ≥500/mm(3) for 3 consecutive days after HSCT). The survival rate at day 100 post-autologous HSCT was 100%. These data confirm the safety of IV thiotepa plus melphalan HDT prior to autologous HSCT for patients with pediatric CNS/non-CNS solid tumors. Trial registration: JapicCTI-173654.
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Treating relapsed and refractory metastatic germ cell tumours with high-dose chemotherapy with carboplatin and etoposide and autologous haematopoietic stem cell transplantation
Erturk, I., Karadurmus, N., Kızıloz, H., Acar, R., Yildiz, B., Aykan, M. B., Esen, R., Buyukturan, G., Urun, Y., Erdem, G., et al
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2021;27(7):1657-1664
Abstract
INTRODUCTION AND AIM To demonstrate the real-life data about patients who underwent AHSCT due to GCT. METHODS Between November 2016 and April 2020, 64 patients who received CE as high-dose chemotherapy for AHSCT in the Gulhane Education and Research Hospital were included in the study. Sixty-one patients received one AHSCT with CE chemotherapy regimen. Survival data and clinical characteristics were evaluated retrospectively. RESULTS The mean age of the patients were 31.9 ± 9 (min-max:18-55). With a median follow-up of 10.7 ± 8.7 months, the 1-year progression-free survival (PFS) rate was 57.8%, and the 1-year overall survival rate was 77.5%. Median overall survival (OS) and progression-free survival (PFS) times were 21.5 ± 1.8 (95% CI: 14.5-33.4) and 20 ± 2 months, respectively. The response rate was 72%. There were three treatment-related deaths. CONCLUSION This sizeable single-centre study shows that patients with relapsed metastatic GCT are curable by CE as high dose chemotherapy plus AHSCT with reliable toxicity even for a single cycle.
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Autologous or allogeneic hematopoietic stem cells transplantation combined with high-dose chemotherapy for refractory neuroblastoma: A protocol for systematic review and meta-analysis
Zhao, Z. S., Shao, W., Liu, J. K.
Medicine. 2021;100(49):e28096
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Abstract
BACKGROUND Neuroblastoma is a common solid malignant tumor in children. Despite the development of new treatment options, the prognosis of high-risk neuroblastoma patients is still poor. High-dose chemotherapy and hematopoietic stem cell (HSC) transplantation might improve survival of patients with refractory neuroblastoma. In this study, we aimed to summarize the efficacy of autologous or allogeneic HSC transplantation combined with high-dose chemotherapy for patients with refractory neuroblastoma through the meta-analysis. METHODS AND ANALYSIS Relevant clinical trials of autologous or allogeneic HSC transplantation for the treatment refractory neuroblastoma patients will be searched in Web of Science, Cochrane Library, PubMed, Google Scholar, Embase, Medline, China National Knowledge Infrastructure, China Scientific Journal Database, Chinese Biomedical Literature Database and Wanfang Database from their inception to December 2020. Two researchers will perform data extraction and risk of bias assessment independently. The clinical outcomes including tumor response, overall survival, event-free survival (EFS), quality of life (QoL) and adverse events, were systematically evaluated by using Review Manager 5.3 and Stata 14.0 statistical software. RESULTS The results of this study will provide high-quality evidence for the effect of autologous or allogeneic HSC transplantation combined with high-dose chemotherapy on tumor response, survival, and QoL in patients with refractory neuroblastoma. CONCLUSIONS The conclusions of this meta-analysis will be published in a peer-reviewed journal, and provide more evidence-based guidance in clinical practice.
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Randomized Phase II Trial of MIBG Versus MIBG, Vincristine, and Irinotecan Versus MIBG and Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A Report From NANT Consortium
DuBois, S. G., Granger, M. M., Groshen, S., Tsao-Wei, D., Ji, L., Shamirian, A., Czarnecki, S., Goodarzian, F., Berkovich, R., Shimada, H., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021;:Jco2100703
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Abstract
PURPOSE (131)I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely associated with the highest true response rate. PATIENTS AND METHODS Patients 1-30 years were eligible if they had relapsed or refractory neuroblastoma, at least one MIBG-avid site, and adequate autologous stem cells. Patients received MIBG 18 mCi/kg on day 1 and autologous stem cell on day 15. Patients randomly assigned to arm A received only MIBG; patients randomly assigned to arm B received intravenous vincristine on day 0 and irinotecan daily on days 0-4; patients randomly assigned to arm C received vorinostat (180 mg/m(2)/dose) orally once daily on days 1 to 12. The primary end point was response after one course by New Approaches to Neuroblastoma Therapy criteria. The trial was designed with 105 patients to ensure an 80% chance that the arm with highest response rate was selected. RESULTS One hundred fourteen patients were enrolled, with three ineligible and six unevaluable, leaving 105 eligible and evaluable patients (36 in arm A, 35 in arm B, and 34 in arm C; 55 boys; and median age 6.5 years). After one course, the response rates (partial response or better) on arms A, B, and C were 14% (95% CI, 5 to 30), 14% (5 to 31), and 32% (18 to 51). An additional five, five, and four patients met New Approaches to Neuroblastoma Therapy Minor Response criteria on arms A, B, and C, respectively. On arms A, B, and C, rates of any grade 3+ nonhematologic toxicity after first course were 19%, 49%, and 35%. CONCLUSION Vorinostat and MIBG is likely the arm with the highest true response rate, with manageable toxicity. Vincristine and irinotecan do not appear to improve the response rate to MIBG and are associated with increased toxicity.