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.
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 previously reported a dose-finding and phase II trial of the TI-CE regimen (paclitaxel [T] plus ifosfamide [I] followed by high-dose carboplatin [C] plus etoposide [E] with stem-cell support) in germ cell tumor (GCT) patients predicted to have a poor prognosis with conventional-dose salvage therapy. We now report the efficacy of TI-CE with prognostic factors for disease-free survival (DFS) and overall survival (OS) in our full data set of 107 patients.
Patients and Methods
Eligible patients had advanced GCTs with progressive disease following chemotherapy and unfavorable prognostic features (extragonadal primary site, incomplete response [IR] to first-line therapy, or relapse/IR to ifosfamide-cisplatin–based conventional-dose salvage). Univariate and multivariate analyses (MVAs) of prognostic factors were performed. The predictive ability of the Einhorn and Beyer prognostic models was assessed.
Most patients were platinum refractory and had an IR to first-line chemotherapy. There were 54 (5%) complete and eight (8%) partial responses with negative markers; 5-year DFS was 47% and OS was 52% (median follow-up, 61 months). No relapses occurred after 2 years. Five (24%) of 21 primary mediastinal nonseminomatous GCTs are continuously disease free. On MVA, primary mediastinal site (P < .001), two or more lines of prior therapy (P < .001), baseline human chorionic gonadotropin ≥ 1,000 U/L (P = .01), and lung metastases (P = .02) significantly predicted adverse DFS. Poor-risk patients did worse than good- or intermediate-risk patients according to both Beyer (P < .002) and Einhorn (P < .05) models.
TI-CE is effective salvage therapy for GCT patients with poor prognostic features. Mediastinal primary site and two or more lines of prior therapy were most predictive of adverse DFS. Beyer and Einhorn models can assist in predicting outcome.
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 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
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
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
Background and Objectives
Several trials have generated conflicting results about the results of high-dose chemotherapy followed by autologous stem cell transplantation (HDCT) for primary breast cancer. This meta-analysis summarizes the available evidence from all suitable studies.
Design and Methods
Prospective, randomized trials with HDCT as a first-line therapy for primary breast cancer were included in this meta-analysis. The primary outcome of interest for our analysis was survival (disease-free survival and overall survival); secondary endpoints included treatment-related mortality (TRM) and second (non-breast) cancers. We used a median age of 47, a PR positive rate of 50% and a premenopausal rate of 70% as cutoff values to complete the subgroup analyses, which were pre-planned according to the prepared protocol.
Fourteen trials with 5747 patients were eligible for the meta-analysis. Compared with non-HDCT, non-significant second (non-breast) cancers (RR = 1.28; 95% CI = 0.82–1.98) and higher TRM (RR = 3.42; 95% CI = 1.32–8.86) were associated with HDCT for primary breast cancer. A significant DFS benefit of HDCT was documented (HR = 0.89; 95% CI = 0.79–0.99). No difference in OS (overall survival) was found when the studies were pooled (HR = 0.91; 95% CI = 0.82–1.00, p = 0.062). In subgroup analysis, age and hormone receptor status had a significant interaction with prolonged DFS and OS.
HDCT has a benefit on DFS and OS compared to SDC in some special patients with high-risk primary breast cancer.
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
This pilot study evaluates the degree of side effects during high-dose chemotherapy (HD-VIC) plus autologous bone marrow transplant (HDCT) and its possible prevention by the cytoprotective thiol-derivate amifostine. Additionally, the in-patient medical costs of both treatment arms were compared. 40 patients with solid tumours were randomized to receive HD-VIC chemotherapy with or without amifostine (910 mg/m2 at day 1–3) given as a short infusion prior to carboplatin and ifosfamide. Patients were stratified according to pretreatment. HDCT consisted of an 18 h infusion of carboplatin (500 mg/m2/d over 18 h), ifosfamide (4 g/m2/d over 4 h) and etoposide (500 mg/m2/d) all given for 3 consecutive days. All patients received prophylactic application of G-CSF (5 μg kg−1 subcutaneously) to ameliorate neutropenia after treatment. Patients were monitored for nephrotoxicity, gastrointestinal side effects, haematopoietic recovery, as well as frequency of fever and infections. The median fall of the glomerular filtration rate (GFR) was 10% from baseline in the amifostine group (105 to 95 ml min−1) and 37% in the control patient group (107 to 67 ml min−1) (P< 0.01). Amifostine-treated patients revealed a less pronounced increase in albumine and low molecular weight protein urinary excretion. Stomatitis grade III/IV occurred in 25% without versus 0% of patients with amifostine (P = 0.01). Acute nausea/vomiting was frequently observed immediately during or after the application of amifostine despite intensive antiemetic prophylaxis consisting of 5-HT3-receptor antagonists/dexamethasone/trifluorpromazine. However, delayed emesis occurred more often in the control patients. Engraftment of neutrophil (> 500 μl−1) and thrombocytes (> 25 000 μl−1)were observed at days 9 versus 10 and 10 versus 12, respectively, both slightly in favour of the amifostine arm. In addition, a lower number of days with fever and a shortened duration of hospital stay were observed in the amifostine arm. The reduction of acute toxicity observed in the amifostine arm resulted in 30% savings in costs for supportive care (Euro 4396 versus Euro 3153 per patient). Taking into account the drug costs of amifostine, calculation of in-patient treatment costs from the start of chemotherapy to discharge revealed additional costs of Euro 540 per patient in the amifostine arm. This randomized pilot study indicates that both organ and haematotoxicity of HD-VIC chemotherapy can be ameliorated by the use of amifostine. Additionally, a nearly complete preservation of GFR was observed in amifostine-treated patients which may be advantageous if repetitive cycles of HDCT are planned. Larger randomized trials evaluating amifostine cytoprotection during high-dose chemotherapy are warranted. © 2001 Cancer Research Campaign http://www.bjcancer.com
toxicity; high-dose chemotherapy; PBSC transplantation; cytoprotection; amifostine; pharmacoeconomics
We present retrospectively our experience in the use of high-dose chemotherapy and haematopoietic stem cell support (HSCS) for refractory gestational trophoblastic neoplasia (GTN) in the largest series so far reported. In all, 11 patients have been treated at three Trophoblast Centres between 1993 and 2004. The conditioning regimens comprised either Carbop-EC-T (carboplatin, etoposide, cyclophosphamide, paclitaxel and prednisolone) or CEM (carboplatin, etoposide and melphalan) or ICE (ifosfamide, carboplatin, etoposide). Two patients had complete human chorionic gonadotrophin responses, one for 4 and the other for 12 months. Three patients had partial tumour marker responses for 1–2 months. High-dose chemotherapy and HSCS for GTN is still unproven. Further studies are needed, perhaps in high-risk patients who fail their first salvage treatment.
high-dose chemotherapy; gestational trophoblastic neoplasia
For patients with relapsed Hodgkin Lymphoma, high dose chemotherapy with stem cell rescue may improve survival over chemotherapy alone. We assessed outcomes of HDCT-SCT in 37 consecutive adolescent and young adult patients with relapsed HL whose malignancy was categorized based on sensitivity to chemotherapy. We determined whether current outcomes supported the use of HDCT-SCT in all of our patients or just those patients with lower risk characteristics such as chemosensitivity. With a median follow up of 6.5 years, the 2 year overall survival was 89% (95% CI: 62%–97%) for the chemo-sensitive patients (n=21). Whereas for patients with resistant disease (n=16) OS was 53% (95%CI: 25%–74%). Both autologous and allogeneic transplants were well tolerated, with 100 day treatment related mortality under 10%. Our data show encouraging outcomes for patients with chemosensitive relapsed HL who receives HSCT and supports the value of the procedure even when the disease is chemoresistant.
Hodgkin’s Lymphoma; Stem Cell Transplant; Salvage Therapy
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.
Anthracyclines (A) and taxanes (T) are standard first-line chemotherapy agents for patients with advanced breast cancer. Platinum analogues have also shown activity in the triple-negative breast cancer (TNBC) histology, but clinical data are limited. Here we report the long-term follow-up of a phase II study on TNBC treated with a combined modality therapy, including induction with AT, cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with concurrent radiation therapy, and a dose-dense consolidation chemotherapy (HDCT) with carboplatin (CBDCA), ifosfamide (IFX), etoposide (VP-16). Patients' median age was 44 years, with 73% premenopausal. Epirubicin 75 mg/m2 and docetaxel 75 mg/m2 were administered to 70 patients with TNBC: as neoadjuvant and adjuvant therapy to 12 and 58 patients, respectively. Postoperative radiation therapy, 5000 cGy, was delivered, synchronous with triweekly CMF. After radiation therapy, two courses of HDCT with CBDCA, IFX, VP-16, were given, with hematological growth factors. After a median follow-up of 81 months, all patients were evaluable for toxicity and response. Most important toxicity were grade 3 skin reaction and grade 4 hematological in 3% and 31% of patients, respectively. Pathological complete response was observed in 25% of patients receiving preoperative chemotherapy. Treatment failures were as follows: eight visceral, four contralateral breast cancer, four locoregional, and one leukemia. Five-year progression-free survival and overall survival rate were 78% and 91%, respectively. Induction chemotherapy, followed by chemoradiation therapy and HDCT, provides a prolonged disease-free period and a significant increase in overall survival in TNBC, with an acceptable toxicity profile.
Concurrent chemotherapy and radiation therapy; high-dose chemotherapy; platinum analogues; triple-negative breast cancer
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.
Neuroblastoma; High-dose chemotherapy; Allogeneic stem cell transplantation
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
Atypical teratoid rhabdoid tumors (ATRTs) are recently defined highly aggressive embryonal central nervous system tumors with a poor prognosis and no definitive guidelines for treatment. We report on the importance of an initial correct diagnosis and disease-specific therapy on outcome in 22 consecutive patients and propose a new treatment strategy. From 1992 to 2012, nine patients initially diagnosed correctly as ATRT (cohort A, median age 24 months) were treated according to an intensive multimodal regimen (MUV-ATRT) consisting of three 9-week courses of a dose-dense regimen including doxorubicin, cyclophosphamide, vincristine, ifosfamide, cisplatin, etoposide, and methotrexate augmented with intrathecal therapy, followed by high-dose chemotherapy (HDCT) and completed with local radiotherapy. Thirteen patients were treated differently (cohort B, median age 30 months) most of whom according to protocols in use for their respective diagnoses. As of July 2013, 5-year overall survival (OS) and event-free survival (EFS) for all 22 consecutive patients was 56.3 ± 11.3% and 52.9 ± 11.0%, respectively. For MUV-ATRT regimen-treated patients (cohort A) 5-year OS was 100% and EFS was 88.9 ± 10.5%. For patients treated differently (cohort B) 5-year OS and EFS were 28.8 ± 13.1%. All nine MUV-ATRT regimen-treated patients are alive for a median of 76 months (range: 16–197), eight in first complete remission. Our results compare favorably to previously published data. The drug combination and sequence used in the proposed MUV-ATRT regimen appear to be efficacious in preventing early relapses also in young children with M1–M3 stage disease allowing postponement of radiotherapy until after HDCT.
ATRT; delayed local radiotherapy; high-dose chemotherapy; improved survival; multimodal therapy
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
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
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.
In this study, we investigated the clinical characteristics and treatment results of osteosarcoma during the past 7 years, and evaluated the role of high dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT).
Materials and Methods
We retrospectively analyzed the clinical data of patients who were diagnosed as osteosarcoma at our center from January, 2000 to December, 2007.
The 5-year overall survival and event-free survival of the patients were 72.6% and 55.9%, respectively. Seventeen (41.5%) patients showed disease progression during treatment or relapse after the end of treatment. The patients who had metastasis at diagnosis or who had a lower grade of necrosis after neoadjuvant chemotherapy showed decreased overall and event-free survival. Four patients received ASCT after HDCT, and 3 of them are alive without disease.
The patients who relapsed or had refractory osteosarcoma or who had metastasis at diagnosis or a lower grade of necrosis after neoadjuvant chemotherapy showed poor prognosis. HDCT with ASCT could be an alternative treatment option for these patients.
Osteosarcoma; Autologous stem cell transplantation; High dose chemotherapy; Pediatrics
Salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT) is the standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL). Salvage regimens have never been compared; their efficacy in the rituximab era is unknown.
Patients and Methods
Patients with CD20+ DLBCL in first relapse or who were refractory after first-line therapy were randomly assigned to either rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) or rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP). Responding patients received high-dose chemotherapy and ASCT.
The median age of the 396 patients enrolled (R-ICE, n = 202; R-DHAP, n = 194) was 55 years. Similar response rates were observed after three cycles of R-ICE (63.5%; 95% CI, 56% to 70%) and R-DHAP (62.8%; 95 CI, 55% to 69%). Factors affecting response rates (P < .001) were refractory disease/relapse less than versus more than 12 months after diagnosis (46% v 88%, respectively), International Prognostic Index (IPI) of more than 1 versus 0 to 1 (52% v 71%, respectively), and prior rituximab treatment versus no prior rituximab (51% v 83%, respectively). There was no significant difference between R-ICE and R-DHAP for 3-year event-free survival (EFS) or overall survival. Three-year EFS was affected by prior rituximab treatment versus no rituximab (21% v 47%, respectively), relapse less than versus more than 12 months after diagnosis (20% v 45%, respectively), and IPI of 2 to 3 versus 0 to 1 (18% v 40%, respectively). In the Cox model, these parameters were significant (P < .001).
In patients who experience relapse more than 12 months after diagnosis, prior rituximab treatment does not affect EFS. Patients with early relapses after rituximab-containing first-line therapy have a poor prognosis, with no difference between the effects of R-ICE and R-DHAP.
First-line sequential high dose chemotherapy is under investigation in patients with ‘poor prognosis’ metastatic germ cell tumours in order to improve survival. Despite the use of autologous peripheral blood stem cell transplantation and granulocyte colony stimulating factor chemotherapy dose intensification is associated with severe haematotoxicity including anaemia, which may significantly affect quality of life and tolerability of chemotherapy. This study investigates the frequency and degree of anaemia in patients receiving first-line sequential high dose chemotherapy for metastatic testicular cancer and the impact of anaemia on treatment outcome. A total of 101 newly diagnosed patients with ‘poor prognosis’ metastatic nonseminomatous germ cell tumours were treated with one cycle of standard VIP followed by three cycles of HD-VIP-chemotherapy (etoposide, ifosfamide, cisplatin) within a large phase I/II study. Differential blood cell counts were taken prior, during and after every cycle of chemotherapy. Additionally, the numbers of red blood cell and platelet transfusions were recorded. Kaplan–Meier analyses were performed to correlate pre-treatment and post-treatment haemoglobin values to response and overall survival. Forty-eight per cent of the patients were classified anaemic (haemoglobin <12 g dl−1) prior to the start of chemotherapy. The application of sequential HD-VIP resulted in median haemoglobin nadirs between 7.8 g dl−1 (range 5.5–11.1 g dl−1) in the first cycle and 7.6 g dl−1 (range 6.0–11.4 g dl−1) in the third cycle despite the frequent use of red blood cell transfusions. Almost all patients (99%) had haemoglobin levels <10 g dl−1 at some timepoint during first-line sequential high dose chemotherapy. Overall, 97 patients received red blood cell transfusions with a median of 10 units (range 2–25) per patient during the four consecutive cycles of therapy. The time to first transfusion was shortest in patients with the lowest initial haemoglobin values. While there was no prediction of response or outcome by baseline haemoglobin-levels, a significant survival difference in favour of patients with a haemoglobin value >10.5 g dl−1 after completion of four cycles of therapy (at leukocyte recovery after the last cycle) compared to those with haemoglobin values <10.5 g dl−1 was found with 3-year overall survival rates of 87% vs 68%, respectively (P<0.05). Severe anaemia is a very frequent side effect of sequential dose intensive therapy in patients with germ cell cancer, with almost all patients becoming transfusion dependent. Despite the frequent use of red blood cell transfusions, median haemoglobin nadirs remained about 7.5–8 g dl−1 during therapy. A correlation of haemoglobin-values after completion of therapy to overall treatment outcome was found.
British Journal of Cancer (2002) 87, 1066–1071. doi:10.1038/sj.bjc.6600629 www.bjcancer.com
© 2002 Cancer Research UK
germ cell tumour; anaemia; prognostic factors; autologous blood stem cell transplantation; chemotherapy; cisplatin
We report a case of AML-M1 with 5q aberration at diagnosis. The patient was treated with high-dose chemotherapy (HDCT). After remission induction, he received allogenic peripheral blood stem cell transplantation (PBSCT) from an HLA-match donor brother. The successive follow-up conventional cytogenetics investigations in remission after HDCT and PBSCT revealed cytogenetic remission. The most interesting observation in this case is that relapsed marrow revealed the emergence of an entirely new, highly aberrant, unrelated clone with unusual translocations t(6;17)(p23;p11.2),+8,der(8)dup inv(8)(q23qter), t(10;19)(q26;q13.3) 4½ months after PBSCT. Our findings suggest the possibility of a mutagenic effect of HDCT and myeloablative intense chemotherapy before PBSCT that could have induced a genetic lesion in the recipient's genetically unstable stem cells in an environment of immunosuppression. The highly complex nature of the clone and the rapid clonal evolution indicates the possibility of selective pressure with proliferative advantage.
Acute myeloid leukemia; emergence; intense chemotherapy; mutagenic effects; peripheral blood stem cell transplantation; unusual aberrant clone