The efficacy and toxicity of high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) were investigated for improving the outcomes of patients with relapsed medulloblastoma. A total of 15 patients with relapsed medulloblastoma were enrolled in the KSPNO-S-053 study from May 2005 to May 2007. All patients received approximately 4 cycles of salvage chemotherapy after relapse. Thirteen underwent HDCT/ASCT; CTE and CM regimen were employed for the first HDCT (HDCT1) and second HDCT (HDCT2), respectively, and 7 underwent HDCT2. One transplant related mortality (TRM) due to veno-occlusive disease (VOD) occurred during HDCT1 but HDCT2 was tolerable with no further TRM. The 3-yr overall survival probability and event-free survival rates ±95% confidence intervals (CI) were 33.3±12.2% and 26.7% ±11.4%, respectively. When analysis was confined to only patients who had a complete response (CR) or partial response (PR) prior to HDCT, the probability of 3-yr overall survival rates ±95% CI was 40.0±15.5%. No patients with stable disease (SD) or progressive disease (PD) survived. Survival rates from protocol KSPNO-S-053 are encouraging and show that tumor status prior to HDCT/ASCT is an important factor to consider for improving survival rates of patients with relapsed medulloblastoma.
Recurrence; Medulloblastoma; Transplantation, Autologous; Tandem; Hematopoietic Stem Cell Transplantation
We performed a pilot study to determine the benefit of high-dose chemotherapy and autologous peripheral blood stem cell transplantation (HDCT/autoPBSCT) for patients with Ewing sarcoma family of tumors.
We retrospectively analyzed the data of patients who received HDCT/autoPBSCT at Korea Cancer Center Hospital. Patients with relapsed, metastatic, or centrally located tumors were eligible for the study.
A total of 9 patients (3 male, 6 female), with a median age at HDCT/autoPBSCT of 13.4 years (range, 7.1 to 28.2 years), were included in this study. Patients underwent conventional chemotherapy and local control either by surgery or radiation therapy, and had achieved complete response (CR, n=7), partial response (n=1), or stable disease (n=1) prior to HDCT/autoPBSCT. There was no transplant-related mortality. However, the median duration of overall survival and event-free survival after HDCT/autoPBSCT were 13.3 months (range, 5.3 to 44.5 months) and 6.2 months (range, 2.1 to 44.5 months), respectively. At present, 4 patients are alive and 5 patients who experienced adverse events (2 metastasis, 2 local recur, and 1 progressive disease) survived for a median time of 2.8 months (range, 0.1 to 10.7 months). The 2-year survival after HDCT/autoPBSCT was 44.4%±16.6% and disease status at the time of HDCT/autoPBSCT tended to influence survival (57.1%±18.7% of cases with CR vs. 0% of cases with non-CR, P=0.07).
Disease status at HDCT/autoPBSCT tended to influence survival. Further studies are necessary to define the role of HDCT/autoPBSCT and to identify subgroup of patients who might benefit from this investigational treatment.
Ewing sarcoma; High-dose chemotherapy; Stem cell transplantation
We assessed the feasibility and effectiveness of reduced-dose craniospinal (CS) radiotherapy (RT) followed by tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) in reducing late adverse effects without jeopardizing survival among children with high-risk medulloblastoma (MB).
From October 2005 through September 2010, twenty consecutive children aged >3 years with high-risk MB (presence of metastasis and/or postoperative residual tumor >1.5 cm2) were assigned to receive 2 cycles of pre-RT chemotherapy, CSRT (23.4 or 30.6 Gy) combined with local RT to the primary site (total 54.0 Gy), and 4 cycles of post-RT chemotherapy followed by tandem HDCT/autoSCT. Carboplatin-thiotepa-etoposide and cyclophosphamide-melphalan regimens were used for the first and second HDCT, respectively.
Of 20 patients with high-risk MB, 17 had metastatic disease and 3 had a postoperative residual tumor >1.5 cm2 without metastasis. The tumor relapsed/progressed in 4 patients, and 2 patients died of toxicities during the second HDCT/autoSCT. Therefore, 14 patients remained event-free at a median follow-up of 46 months (range, 23−82) from diagnosis. The probability of 5-year event-free survival was 70.0% ± 10.3% for all patients and 70.6% ± 11.1% for patients with metastases. Late adverse effects evaluated at a median of 36 months (range, 12−68) after tandem HDCT/autoSCT were acceptable.
In children with high-risk MB, CSRT dose might be reduced when accompanied by tandem HDCT/autoSCT without jeopardizing survival. However, longer follow-up is needed to evaluate whether the benefits of reduced-dose CSRT outweigh the long-term risks of tandem HDCT/autoSCT.
autologous stem cell transplantation; high-dose chemotherapy; late effect; medulloblastoma; radiotherapy
Double high-dose chemotherapy (HDCT) was applied to 18 patients with highrisk neuroblastoma including 14 patients who could not achieve complete response (CR) even after the first HDCT. In 12 patients, successive double HDCT was rescued with peripheral blood stem cells collected during a single round of leukaphereses and in 6 patients, second or more rounds of leukaphereses were necessary after the first HDCT to rescue the second HDCT. The median interval between the first and second HDCT (76 days; range, 47-112) in the single harvest group was shorter than that (274.5 days; range, 83-329) in the double harvest group (p<0.01). Hematologic recovery was slow in the second HDCT. Six (33.3%) treatment-related mortalities (TRM) occurred during the second HDCT but were not related to the shorter interval. Disease-free survival rates at 2 years with a median follow-up of 24 months (range, 6-46) in the single and double harvest group were 57.1% and 33.3%, respectively. These results suggest that successive double HDCT using the single harvest approach may improve the survival of high-risk patients, especially who could not achieve CR after the first HDCT despite delayed hematologic recovery and high rate of TRM during the second HDCT.
The feasibility and effectiveness of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) were evaluated in children younger than 3 yr of age with atypical teratoid/rhabdoid tumors (ATRT). Tandem HDCT/autoSCT was administered following six cycles of induction chemotherapy. Radiotherapy (RT) was administered if the tumor relapsed or progressed, otherwise, it was administered after 3 yr of age. Tumors relapsed or progressed during induction chemotherapy in 5 of 9 patients enrolled; 3 of these 5 received tandem HDCT/autoSCT as a salvage treatment. One patient died from sepsis during induction chemotherapy. The remaining 3 patients proceeded to tandem HDCT/autoSCT; however, 2 of these patients showed tumor relapse/progression after tandem HDCT/autoSCT. All 7 relapses/progressions occurred at primary sites even in patients with leptomeningeal seeding. Toxicities during tandem HDCT/autoSCT were manageable. A total of 5 patients were alive with a median follow-up of 20 (range 16-70) months from diagnosis. Four of 5 patients who received RT after relapse/progression are alive. The probability of overall survival at 3 yr from diagnosis was 53.3% ± 17.3%. Our tandem HDCT/autoSCT is feasible; however, early administration of RT prior to tandem HDCT/autoSCT should be considered to improve the outcome after tandem HDCT/autoSCT.
Rhabdoid Tumor; Central Nervous System; Drug Therapy; Stem Cell Transplantation; Radiotherapy; Child
High-dose chemotherapy (HDCT) with autologous stem cell support has been studied in both the salvage and first-line setting in advanced germ cell tumor (GCT) patients with poor-risk features. While early studies reported significant treatment-related mortality, introduction of peripheral blood stem cell transplantation, recombinant growth factors and better supportive care have decreased toxicity; and in more recent reports treatment-related deaths are observed in <3% of patients. Two to three cycles of high-dose carboplatin and etoposide is the standard backbone for HDCT, given with or without additional agents including ifosfamide, cyclophosphamide and paclitaxel. Three large randomized Phase III trials have failed to show a benefit of HDCT over conventional-dose chemotherapy (CDCT) in the first-line treatment of patients with intermediate- or poor-risk advanced GCT, and to date the routine use of HDCT has been reserved for the salvage setting. Several prognostic models have been developed to help predict outcome of salvage HDCT, the most recent of which applies to both CDCT and HDCT in the initial salvage setting. Patients that relapse after HDCT are usually considered incurable, and additional therapy is provided with palliative intent.
chemotherapy; germ cell tumors; high-dose chemotherapy; stem cell transplantation; testicular cancer
Patients with metastatic rhabdomyosarcoma (RMS) have a poor prognosis. The aim of this systematic review is to investigate whether high-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (HSCT) in patients with metastatic RMS has additional benefit or harm compared to standard chemotherapy.
Systematic literature searches were performed in MEDLINE, EMBASE, and The Cochrane Library. All databases were searched from inception to February 2010. PubMed was searched in June 2010 for a last update. In addition to randomized and non-randomized controlled trials, case series and case reports were included to complement results from scant data. The primary outcome was overall survival. A meta-analysis was performed using the hazard ratio as primary effect measure, which was estimated from Cox proportional hazard models or from summary statistics of Kaplan Meier product-limit estimations.
A total of 40 studies with 287 transplant patients with metastatic RMS (age range 0 to 32 years) were included in the assessment. We identified 3 non-randomized controlled trials. The 3-year overall survival ranged from 22% to 53% in the transplant groups vs. 18% to 55% in the control groups. Meta-analysis on overall survival in controlled trials showed no difference between treatments. Result of meta-analysis of pooled individual survival data of case series and case reports, and results from uncontrolled studies with aggregate data were in the range of those from controlled data. The risk of bias was high in all studies due to methodological flaws.
HDCT followed by autologous HSCT in patients with RMS remains an experimental treatment. At present, it does not appear justifiable to use this treatment except in appropriately designed controlled trials.
Despite increasing evidence that high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) might improve the survival of patients with high-risk or recurrent solid tumors, therapy effectiveness for bone and soft tissue sarcoma treatment remains unclear. This study retrospectively investigated the feasibility and effectiveness of HDCT/auto-SCT for high-risk or recurrent bone and soft tissue sarcoma. A total of 28 patients (18 high-risk and 10 recurrent) underwent single or tandem HDCT/auto-SCT between October 2004 and September 2014. During follow-up of a median 15.3 months, 18 patients exhibited disease progression and 2 died of treatment-related toxicities (1 veno-occlusive disease and 1 sepsis). Overall, 8 patients remained alive and progression-free. The 3-year overall survival (OS) and event-free survival (EFS) rates for all 28 patients were 28.7% and 26.3%, respectively. In the subgroup analysis, OS and EFS rates were higher in patients with complete or partial remission prior to HDCT/auto-SCT than in those with worse responses (OS, 39.1% vs. 0.0%, P = 0.002; EFS, 36.8% vs. 0.0%, P < 0.001). Therefore, careful selection of patients who can benefit from HDCT/auto-SCT and maximal effort to reduce tumor burden prior to treatment will be important to achieve favorable outcomes in patients with high-risk or recurrent bone and soft tissue sarcomas.
Bone and Soft Tissue Sarcoma; Children; High-Dose Chemotherapy; Autologous Stem Cell Transplantation
Some men with metastatic germ cell tumours that have progressed after response to initial cisplatin-based combination chemotherapy are cured with conventional dose first salvage chemotherapy (CDCT) – however, many are not. High-dose chemotherapy with autologous stem cell rescue (HDCT) may be of value in these patients. Prognosis has recently been better defined by International Prognostic Factor Study Group (IPFSG) prognostic factors. HDCT after response to CDCT has been offered at our institution over the past two decades. We retrospectively assessed the validity of the IPFSG prognostic factors in our patients and evaluated the value of HDCT.
We identified eligible men with metastatic germ cell tumour progressed after at least 3 cycles of cisplatin-based chemotherapy and treated with cisplatin-based CDCT alone or with carboplatin-based HDCT. We also collected their clinical data. Patients were classified into risk groups using IPFSG factors, and progression-free and overall survival factors were analyzed and compared in patients treated with CDCT alone and with HDCT.
We identified 38 eligible first salvage patients who had received a median of 4 cycles (range, 1 to 7 cycles) of CDCT. Twenty patients received CDCT alone and 18 patients received CDCT plus HDCT. The overall median progression- free survival was 24.6 months (95%CI, 7.3 to 28.7 months) and overall median overall survival was 34.6 months (95%CI, 17.2 to 51.3 months). Distribution by IPFSG category and 2-year progression- free survival and 3-year overall survival rates within each risk category were very similar to the IPFSG results. There were two toxic deaths with CDCT and none with HDCT. Overall, patients treated with CDCT plus HDCT had improved progression- free survival and overall survival.
The IPFSG prognostic risk factors appeared valid in our patient population. The safety of HDCT with etoposide and carboplatin was confirmed. HDCT was associated with improved progression- free survival and overall survival outcomes, consistent with observations of the IPFSG group. Ideally, the value of optimal HDCT should be determined in comparison to optimal CDCT as first salvage therapy in men with metastatic germ cell tumour with a randomized trial.
We retrospectively analyzed infectious complications during tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) in children and adolescents with high-risk or recurrent solid tumors. A total of 324 patients underwent their first HDCT/auto-SCT between October 2004 and September 2014, and 283 of them proceeded to their second HDCT/auto-SCT (a total of 607 HDCT/auto-SCTs). During the early transplant period of 607 HDCT/auto-SCTs (from the beginning of HDCT to day 30 post-transplant), bacteremia, urinary tract infection (UTI), respiratory virus infection, and varicella zoster virus (VZV) reactivation occurred in 7.1%, 2.3%, 13.0%, and 2.5% of HDCT/auto-SCTs, respectively. The early transplant period of the second HDCT/auto-SCT had infectious complications similar to the first HDCT/auto-SCT. During the late transplant period of HDCT/auto-SCT (from day 31 to 1 year post-transplant), bacteremia, UTI, and VZV reactivation occurred in 7.5%, 2.5%, and 3.9% of patients, respectively. Most infectious complications in the late transplant period occurred during the first 6 months post-transplant. There were no invasive fungal infections during the study period. Six patients died from infectious complications (4 from bacterial sepsis and 2 from respiratory virus infection). Our study suggests that infectious complications are similar following second and first HDCT/auto-SCT in children.
Metastatic breast cancer remains a major treatment challenge. The use of high-dose chemotherapy (HDCT) with rescue by autologous mobilized peripheral blood (MPB) is controversial, in part due to contamination of MPB by circulating tumor cells. CD34+Thy- 1+ selected hematopoietic stem cells (HSC) represent a graft source with a greater than 250,000-fold reduction in cancer cells. Here, we present the long-term outcome of a pilot study determining feasibility and engraftment using HDCT and purified HSC in patients with metastatic breast cancer. Twenty-two patients who had been treated with standard chemotherapy were enrolled into a phase I/II trial between 12/1996 to 02/1998, and underwent HDCT followed by rescue with CD34+Thy-1+ HSC isolated from autologous MPB. More than 12 years after the end of the study 23% (5/22) of HSC recipients are alive, 18% (4/22) free of recurrence with normal hematopoietic function. Median PFS was 16 months and median OS was 60 months. Retrospective comparison with 74 patients transplanted between 02/1995 and 06/1999 with the identical HDCT regimen but rescue with unmanipulated MPB show that 9% of patients are alive, and 7% without disease. Median PFS was 10 months and median OS was 28 months. In conclusion, cancer-depleted HSC following HDCT resulted in better than expected 12- 14 year PFS and OS in a cohort of metastatic breast cancer patients. These data prompt us to look once again at purified HSC transplantation in a protocol powered to test for efficacy in advanced stage breast cancer patients.
Background: Circulating tumor cells (CTCs) are an independent prognostic factor in metastatic breast cancer (MBC) patients treated by conventional dose chemotherapy. The aim of this study was to determine the role of CTCs and CTCs undergoing epithelial-mesenchymal transition (EMT) in metastatic breast cancer. We used the platform of high-dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation (AHSCT) to study the CTCs and CTCs with EMT.
Patients and methods: CTCs were enumerated in 21 MBC patients before apheresis and 1 month after AHSCT. CD34-depleted apheresis products were analyzed for CD326+ epithelial and Aldefluor+ cancer stem cells (CSC) by flow cytometry and were depleted of CD45+ cells and assessed for EMT-inducing transcription factors (EMT-TF) by quantitative RT-PCR.
Results: Patients with ≥ 5 CTCs/7.5 mL of peripheral blood 1 month after AHSCT had shorter progression-free survival (PFS) (P=0.02) and overall survival (OS) (P=0.02). Patients with apheresis products containing high percentages of CD326+ epithelial cells or overexpressing EMT-TF had shorter PFS. In multivariate analysis, low percentage of CD326+ epithelial cells and response to HDCT with AHSCT were associated with longer PFS, whereas lower CTCs after AHSCT was associated with longer OS. High CTCs, 1 month after AHSCT correlated with shorter PFS and OS in MBC patients undergoing HDCT and AHSCT, while CTCs with EMT and CSCs phenotype in apheresis products are associated with relapse.
Conclusion: Our data suggest that CTC and CTCs with EMT are prognostic in MBC patients undergoing HDCT followed by AHSCT.
metastatic breast cancer; circulating tumor cells; epithelial-mesenchymal transition; high-dose chemotherapy; autologous hematopoietic stem cell transplantation.
We conducted a systematic review to compare the efficacy and adverse events of autologous haematopoietic stem cell transplantation (HSCT) following high-dose chemotherapy (HDCT) versus standard-dose chemotherapy (SDCT) in patients with locally advanced or metastatic non-rhabdomyosarcoma soft tissue sarcomas (NRSTS).
Patients were observed in hospital units specialised for cancer therapy.
The review evaluated 294 patients with 19 different subtypes of malignant NRSTS. The patients had a median age between 10 and 46 years (range 2–65) and were mostly men.
Primary and secondary outcome measure
The planned and measured primary outcomes were overall survival and treatment-related mortality. The planned and measured secondary outcomes were progression-free survival, grade 3–4 non-haematological toxicity and secondary neoplasia. Other secondary outcomes including disease-free survival, event-free survival and health-related quality of life were not reported.
We included 62 studies reporting on 294 transplanted patients. We identified 1 randomised controlled trial (RCT) with 38 transplanted and 45 non-transplanted patients and judged a low risk of bias. We further identified 61 single-arm studies with 256 transplanted patients. Overall survival in the RCT was reported not statistically significantly different between autologous HSCT following HDCT versus SDCT. The HR was 1.26 (95% CI 0.70 to 2.29; p=0.44) and the point estimates at 3 years were 32.7% vs 49.4%. Data from single-arm studies were used to extract data on adverse events. Treatment-related mortality was reported in 5.1% (15 of 294) transplanted patients.
Overall survival in patients with locally advanced or metastatic NRSTS was not statistically different after autologous HSCT following HDCT compared with SDCT in a single RCT with a total of 83 patients. No other comparative study was available. The proportion of adverse events among the transplanted patients is not clear.
Although the number of studies using tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) for the treatment of high-risk pediatric solid tumors has been increasing, documentation of hematologic recovery after tandem HDCT/autoSCT is very limited. For this reason, we retrospectively analyzed the hematologic recovery of 236 children with high-risk solid tumors who underwent tandem HDCT/autoSCT. The median numbers of CD34+ cells transplanted during the first and second HDCT/autoSCT were 4.3 × 106/kg (range 0.6-220.2) and 4.1 × 106/kg (range 0.9-157.6), respectively (P = 0.664). While there was no difference in neutrophil recovery between the first and second HDCT/autoSCT, platelet and RBC recoveries were significantly delayed in the second HDCT/autoSCT (P < 0.001 and P < 0.001, respectively). Delayed recovery in the second HDCT/autoSCT was more prominent when the number of transplanted CD34+ cells was lower, especially if it was < 2 × 106/kg. A lower CD34+ cell count was also associated with increased RBC transfusion requirements and a higher serum ferritin level after tandem HDCT/autoSCT. More CD34+ cells need to be transplanted during the second HDCT/autoSCT in order to achieve the same hematologic recovery as the first HDCT/autoSCT.
High-Dose Chemotherapy; Autologous Stem Cell Transplantation; CD34+ Cells; Hematologic Recovery; Iron Overload
The records of 63 high-risk neuroblastoma patients with bone marrow (BM) tumors at diagnosis were retrospectively reviewed. All patients received nine cycles of induction chemotherapy followed by tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT). Follow-up BM examination was performed every three cycles during induction chemotherapy and every three months for one year after the second HDCT/auto-SCT. BM tumor cells persisted in 48.4%, 37.7%, 23.3%, and 20.4% of patients after three, six, and nine cycles of induction chemotherapy and three months after the second HDCT/auto-SCT, respectively. There was no difference in progression-free survival (PFS) rate between patients with persistent BM tumor and those without during the induction treatment. However, after tandem HDCT/auto-SCT, the PFS rate was worse in patients with persistent BM tumor than in those without (probability of 5-yr PFS 14.7% ± 13.4% vs. 64.2% ± 8.3%, P = 0.009). Persistent BM tumor during induction treatment is not associated with a worse prognosis when intensive tandem HDCT/auto-SCT is given as consolidation treatment. However, persistent BM tumor after tandem HDCT/auto-SCT is associated with a worse prognosis. Therefore, further treatment might be needed in patients with persistent BM tumor after tandem HDCT/auto-SCT.
Neuroblastoma; Bone Marrow Tumors; Prognosis; Treatment
The efficacy of tandem high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) was investigated in patients with high-risk neuroblastoma. Patients over 1 yr of age who were newly diagnosed with stage 4 neuroblastoma from January 2000 to December 2005 were enrolled in The Korean Society of Pediatric Hematology-Oncology registry. All patients who were assigned to receive HDCT/ASCR at diagnosis were retrospectively analyzed to investigate the efficacy of single or tandem HDCT/ASCR. Seventy and 71 patients were assigned to receive single or tandem HDCT/ASCR at diagnosis. Fifty-seven and 59 patients in the single or tandem HDCT group underwent single or tandem HDCT/ASCR as scheduled. Twenty-four and 38 patients in the single or tandem HDCT group remained event free with a median follow-up of 56 (24-88) months. When the survival rate was analyzed according to intent-to-treat at diagnosis, the probability of the 5-yr event-free survival±95% confidence intervals was higher in the tandem HDCT group than in the single HDCT group (51.2±12.4% vs. 31.3±11.5%, P=0.030). The results of the present study demonstrate that the tandem HDCT/ASCR strategy is significantly better than the single HDCT/ASCR strategy for improved survival in the treatment of high-risk neuroblastoma patients.
Neuroblastoma; High-dose Chemotherapy; Transplantation, Autologous
High-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) was applied to improve the prognosis of patients with high-risk stage 3 neuroblastoma. From January 1997 to December 2006, 28 patients were newly diagnosed as stage 3 neuroblastoma. Nine of 11 patients with N-myc amplification and 5 of 17 patients without N-myc amplification (poor response in 2 patients, persistent residual tumor in 2 and relapse in 1) underwent single or tandem HDCT/ASCR. Patients without high-risk features received conventional treatment modalities only. While 8 of 9 patients underwent single HDCT/ASCR and the remaining one patient underwent tandem HDCT/ASCR during the early study period, all 5 patients underwent tandem HDCT/ASCR during the late period. Toxicities associated with HDCT/ASCR were tolerable and there was no treatment-related mortality. While the tumor relapsed in two of eight patients in single HDCT/ASCR group, all six patients in tandem HDCT/ASCR group remained relapse free. The 5-yr event-free survival (EFS) from diagnosis, in patients with N-myc amplification, was 71.6±14.0%. In addition, 12 of 14 patients who underwent HDCT/ASCR remained event free resulting in an 85.1±9.7% 5-yr EFS after the first HDCT/ASCR. The present study demonstrates that HDCT/ASCR may improve the survival of patients with high-risk stage 3 neuroblastoma.
Neuroblastoma; High-dose Chemotherapy; Autologous Stem Cell Rescue; Prognosis; N-myc
Multiple RBC transfusions inevitably lead to a state of iron overload before and after high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT). Nonetheless, iron status during post-SCT follow-up remains unknown. Therefore, we investigated post-SCT ferritin levels, factors contributing to its sustained levels, and organ functions affected by iron overload in 49 children with high-risk neuroblastoma who underwent tandem HDCT/autoSCT. Although serum ferritin levels gradually decreased during post-SCT follow-up, 47.7% of the patients maintained ferritin levels above 1,000 ng/mL at 1 yr after the second HDCT/autoSCT. These patients had higher serum creatinine (0.62 vs 0.47 mg/mL, P = 0.007) than their counterparts (< 1,000 ng/mL). Post-SCT transfusion amount corresponded to increased ferritin levels at 1 yr after the second HDCT/autoSCT (P < 0.001). A lower CD34+ cell count was associated with a greater need of RBC transfusion, which in turn led to a higher serum ferritin level at 1 yr after HDCT/autoSCT. The number of CD34+ cells transplanted was an independent factor for ferritin levels at 1 yr after the second HDCT/autoSCT (P = 0.019). Consequently, CD34+ cells should be transplanted as many as possible to prevent the sustained iron overload after tandem HDCT/autoSCT and consequent adverse effects.
High-Dose Chemotherapy; Autologous Stem Cell Transplantation; Iron Overload; Deferasirox; Iron Chelation Treatment; Neuroblastoma
In this study, we investigated the effects of reduced-dose craniospinal radiotherapy (CSRT) followed by tandem high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) in children with a newly diagnosed high-risk medulloblastoma (MB) or supratentorial primitive neuroectodermal tumor (sPNET).
Between March 2005 and April 2007, patients older than 3 years with a newly diagnosed high-risk MB or sPNET were enrolled. The patients received two cycles of pre-RT chemotherapy consisting of cisplatin, etoposide, vincristine, and cyclophosphamide (cycle A), and carboplatin, etoposide, vincristine, and ifosphamide (cycle B), followed by CSRT with 23.4 Gy and local RT with 30.6 Gy. After four cycles of post-RT chemotherapy (cycles A, B, A, and B), tandem double HDCT with ASCR was performed.
A total of 13 patients (MB=11, sPNET=2) were enrolled. Of these, one patient progressed, one patient died of septic shock after the second cycle of B, and one patient relapsed after the third cycle of B. The 3-year event-free survival (EFS) rate of the patients intended for HDCT was 76.9%, whereas the 3-year EFS rate of the patients who received HDCT was 100%. No treatment-related mortality occurred during HDCT.
Although the follow-up period was short and the patient cohort was small in size, the results of this study are encouraging. The limited toxicity and favorable EFS rate observed in children treated with reduced-dose CSRT followed by HDCT and ASCR warrant further exploration in a larger study population.
Radiotherapy; High-dose chemotherapy; Autologous stem cell transplantation; Medulloblastoma; Supratentorial primitive neuroectodermal tumor; Children
Aims: To evaluate the usefulness of molecular markers in predicting histopathological and clinical response to preoperative high dose chemotherapy (HDCT) and survival of patients with advanced gastric cancer.
Methods: In a phase II trial, 25 patients with metastatic gastric cancer received preoperative tandem HDCT consisting of etoposide, cisplatin, and mitomycin, followed by autologous bone marrow transplantation to achieve surgical resectability. Samples before and after treatment, from normal and tumour tissue, were characterised histopathologically, and both p53 and BAX expression was analysed by immunohistochemistry. Pretreatment formalin fixed, paraffin wax embedded samples from normal and tumour tissue were microdissected, and the extracted DNA was preamplified using improved primer extension preamplification polymerase chain reaction. Detection of microsatellite instability (MSI) or loss of heterozygosity (LOH) was performed using markers for p53, BAX, BAT25, BAT26, D2S123, D17S250, and APC. Exons 5–9 of the p53 gene were sequenced directly on ABI 373.
Results: Four parameters were significantly associated with response to chemotherapy and prolonged overall survival: positive p53 immunostaining, positive p53 mutation status before chemotherapy, strong histological regression induced by preoperative HDCT, and surgical treatment. Patients’s sex or age, tumour location or stage, lymph node status, Lauren classification, MSI, or LOH did not influence duration of survival significantly in this high risk population.
Conclusion: Positive p53 immunostaining and p53 mutation status in pretreatment tumour biopsies might be useful molecular predictors of response and prognosis in patients with advanced gastric cancer treated by preoperative HDCT.
gastric cancer; preoperative high dose chemotherapy; molecular parameters; histological regression; p53
Anaplastic large cell lymphoma (ALCL) is uncommon in children, accounting for approximately 15% of all cases of childhood non-Hodgkin lymphoma. Despite many studies attempting new treatment strategies, treatment outcomes have not significantly improved, and the optimal treatment for pediatric ALCL has not been established.
The records of newly diagnosed ALCL patients at our institute between July 1998 and April 2013 were reviewed. We evaluated the general characteristics of the patients, chemotherapy regimens, overall survival (OS) rates, and event-free survival (EFS) rates.
Twenty-eight ALCL patients were eligible. The median age at diagnosis was 10.8 years. Lymph node involvement was the most common presentation (79%). CCG-5941, a multi-agent T-cell lineage chemotherapy, was the predominant treatment regimen (57%). The five-year OS and EFS rates were 88% and 69%, respectively. Stage, the presence of B symptoms, lung involvement, and bone marrow involvement were significant prognostic factors for EFS (P=0.02, 0.01, 0.01, and 0.02, respectively). Eight patients relapsed, and three died during the study period. Four of the eight patients who relapsed were treated with high-dose chemotherapy and autologous stem cell transplantation (HDCT-ASCT). Two of the four who had undergone HDCT-ASCT developed secondary relapses and were subsequently treated with allogeneic SCT or brentuximab.
We found that treatment outcomes with multi-agent chemotherapy in children with ALCL were similar to those of previous reports, and that relapsed patients could be salvaged with HDCT-ASCT or allogeneic SCT. A prospective, larger cohort study is warranted to define the optimal treatment for pediatric ALCL.
Anaplastic large cell lymphoma; Childhood; Prognosis; Relpase
The objective of the study is to conduct a systematic review to compare the effects of high-dose chemotherapy (HDCT) with autologous haematopoietic stem cell transplantation (HSCT) versus standard-dose chemotherapy (SDCT) in children with malignant central nervous system (CNS) tumours.
Standard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Ten electronic databases will be searched, along with citation searching and reference checking. Studies assessing the effects of HDCT with HSCT in children with CNS tumours will be included. The outcomes are survival (overall, progression-free, event-free, disease-free), response rates, short- and long-term adverse events and health-related quality of life (HRQoL). Two reviewers will independently screen and select randomised and non-randomised controlled trials and controlled and uncontrolled observational studies for inclusion. Quality assessment will be tailored to the different study designs. Where possible data will be summarised using combined estimates of effect for the hazard ratio for survival outcomes and the risk ratio for response rates. A fixed effect model will be used; sub-group analyses and meta-regression will be used to explore potential sources of heterogeneity between studies.
Given the poor prognosis of malignant brain tumours in children in terms of survival and quality of life, this review will help guide clinical practice by summarising the current evidence on the use of high-dose myeloblative chemotherapy with stem cell support in children with CNS tumours.
Children; Central nervous system tumours; High-dose chemotherapy; Haematopoietic stem cell transplantation; Systematic review
We prospectively evaluated the effectiveness of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) in improving the survival of patients with atypical teratoid/rhabdoid tumors while reducing the risks of late adverse effects from radiotherapy (RT).
Materials and Methods
For young children (< 3 years old), tandem HDCT/auto-SCT was administered after six cycles of induction chemotherapy. RT was deferred until after 3 years of age unless the tumor showed relapse or progression. For older patients (> 3 years old), RT including reduced-dose craniospinal RT (23.4 or 30.6 Gy) was administered either after two cycles of induction chemotherapy or after surgery, and tandem HDCT/auto-SCT was administered after six cycles of induction chemotherapy.
A total of 13 patients (five young and eight older) were enrolled from November 2004 to June 2012. Eight patients, including all five young patients, had metastatic disease at diagnosis. Six patients (four young and two older) experienced progression before initiation of RT, and seven were able to proceed to HDCT/auto-SCT without progression during induction treatment. Three of six patients who experienced progression during induction treatment underwent HDCT/auto-SCT as salvage treatment. All five young patients died from disease progression. However, four of the eight older patients remain progression-freewith a median follow-up period of 64 months (range, 39 to 108 months). Treatment-related late toxicities were acceptable.
The required dose of craniospinal RT might be reduced in older patients if the intensity of chemotherapy is increased. However, early administration of RT should be considered to prevent early progression in young patients.
Brain neoplasms; Chemotherapy; Hematopoietic stem cell transplantation; Radiotherapy
The purpose of this study was to evaluate in a phase I-II trial whether low doses of recombinant human interleukin 2 (rHuIL-2) over a prolonged period of time are safe and effective in eradicating or controlling minimal residual disease in children with neuroblastoma given high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). From January 1992 to July 1996, 17 consecutive patients, with either stage IV or relapsed neuroblastoma, were enrolled. Patients received rHuIL-2 after a median time interval (min-max) of 105 days (56-153) after HDCT and ASCT. The protocol consisted of 2 'priming' courses of rHuIL-2 at escalating doses administered intravenously at 72-h intervals, followed by 'maintenance' with 11 monthly and six bimonthly boosting 5-day courses administered subcutaneously on an outpatient basis. At April 1997, 7 out of the 17 patients had completed the treatment schedule, four had discontinued treatment because of toxicity and four because of relapse; the remaining two patients are still on treatment, having completed 15 courses. Expansion of T lymphocytes, together with an increase in both natural killer cells and in activated T lymphocytes was evidenced. After a median (min-max) follow-up time of 30 (16-64) months, 12 out of 17 patients are alive and well. Two patients relapsed and died 14 and 35 months after transplant. Three patients are alive after having relapsed at 41, 21 and 13 months. The actuarial 2-year event-free survival and overall survival are 67% and 92% respectively. Intermittent administration of low doses of rHuIL-2 given for a long period of time is well tolerated and seems capable of controlling minimal residual disease after HDCT and ASCT in children with high-risk neuroblastoma.
Background. Dose-dependent response makes certain pediatric brain tumors appropriate targets for high-dose chemotherapy with autologous hematopoietic stem-cell rescue (HDCT-AHSCR). Methods. The clinical outcomes and toxicities were analyzed retrospectively for 18 consecutive patients ≤19 y/o treated with HDCT-AHSCR at UCLA (1999–2009). Results. Patients' median age was 2.3 years. Fourteen had primary and 4 recurrent tumors: 12 neural/embryonal (7 medulloblastomas, 4 primitive neuroectodermal tumors, and a pineoblastoma), 3 glial/mixed, and 3 germ cell tumors. Eight patients had initial gross-total and seven subtotal resections. HDCT mostly consisted of carboplatin and/or thiotepa ± etoposide (n = 16). Nine patients underwent a single AHSCR and nine ≥3 tandems. Three-year progression-free and overall survival probabilities were 60.5% ± 16 and 69.3% ± 11.5. Ten patients with pre-AHSCR complete remissions were alive/disease-free, whereas 5 of 8 with measurable disease were deceased (median followup: 2.3 yrs). Nine of 13 survivors avoided radiation. Single AHSCR regimens had greater toxicity than ≥3 AHSCR (P < .01). Conclusion. HDCT-AHSCR has a definitive, though limited role for selected pediatric brain tumors with poor prognosis and pretransplant complete/partial remissions.