Single High-dose Chemotherapy Research Articles

Passive immunotherapy experience in patients with high-risk neuroblastoma

Introduction. Despite great achievements in treatment of neuroblastoma (NB) for the last decades, the outcome for high-risk patients remains adverse: 5-year overall survival does not exceed 30 %. The purpose of the study. Demonstration of anti-GD2 monoclonal antibodies immunotherapy and assessment of its toxicity in patients treated at the N.N. Petrov National Medical Research Center of Oncology. Material and methods . Anti-GD2 antibodies have been used as post consolidation in 8 high-risk NB patients aged from 1.8 to 10 years old since 2018 to present. After completion of induction chemotherapy according to NB-2004protocol, all patients underwent local tumor control with surgery and additional local radiotherapy in 3 cases. Four patients were received a single high-dose chemotherapy with autologous bone marrow transplant; one patient was received high-dose chemotherapy with haploidentical stem cell transplantation. Tree patients were received the tandem high-dose chemotherapy with autologous stem-cell transplantation. Two (25 %) patients had a primary resistant NB, and remission was achieved only after three lines of chemotherapy. One (12.5 %) child was diagnosed with a recurrence of NB of a solitary lesion in the right frontal lobe of the brain 8 months after the completion of the treatment according to the NB-2004protocol. Thus, 3 people from the study group received anti-GD2 antibodies after applying several lines of chemotherapy. All children at the start ofanti-GD2 antibody therapy were no progressive disease. Results. A total of 21 courses of immunotherapy were conducted. No progressive disease was the main condition of anti-GD2 antibodies immunotherapy, such patients were excluded from the research. The antibodies were administered as a continuous infusion during 10 days (240 hours) in a daily dose of 10 mg/m2. When using the antibodies, the following adverse events were noted: hematotoxicity in 90.4 % cases, fever in 71.4 %, diarrhea in 23.8 %, capillary leak syndrome in 19 % patients, neuropathy and cytokine release syndrome were detected in 14.9 % cases, pain — in 9.5 % patients. All complications were tolerable and cured, dose reduction was not required. Now 7patients are in remission, in one patient after the first cycle of immunotherapy progressive disease was revealed. Conclusions. The immunotherapy monoclonal anti-GD2 antibodies are well tolerable and safe procedure with adequate maintenance therapy. According to international experience the efficiency does not raise her doubts.

Incidence of secondary malignancies (SM) in patients (pts) with germ cell tumors (GCT) who received high-dose chemotherapy (HDCT): A retrospective study from the European Society for Blood and Marrow Transplantation (EBMT) database.

4549 Background: Little is still known about the incidence of SM in young adult pts with GCT after HDCT, owing to the rarity of the disease, and the need for registries with long term follow-up (FUP) data. In Europe, the EBMT may provide a suitable platform for such retrospective analyses. Methods: Criteria for patient selection included diagnosis of GCT, adult male gender, ≥2yr of FUP after the administration of HDCT. Summary statistics were used to describe pt characteristics and outcomes. χ2 tests were used to compare groups according to the length of FUP. Kaplan-Meier estimates were used to estimate overall survival (OS). Univariable Cox regression analyses examined clinical factors potentially associated with OS. Survival times were calculated from the HDCT administration date. To estimate the probability of developing SM, the cumulative incidence of SM was calculated for all pts. Results: From 1981 to 2014, 9,153 autografts, accounting for 5,100 pts, have been registered. Of them, 1,855 had ≥2yr of FUP. Among the latter, a total of 56 cases of SM were identified (3.0%). 28 (50%) had solid SM, 22 (39.3%) hematologic (hem) SM (5 had uncoded SM). Median age at first HDCT was 34 years (IQR: 30-42), median age at development of SM was 42 (37-51). 26 pts (46.4%) received single HDCT cycle, 22 (39.3%) multiple HDCT cycles (8 unknown). 31 pts had ≥5 yr FUP, 25 pts 2-5 yr FUP. The median latency of SM was 3.3yrs (IQR: 1.8-6.1) for hem SM and 5.6yrs (IQR: 1.2-10.8) for solid SM. Median FUP was 6.4yrs. Univariably, the type of SM (solid vs. hem) was significantly associated with OS. Hem vs solid SM: HR: 2.17 (95%CI: 1.19-4.97, p = 0.020). Median OS of pts who developed solid SM was 13.3yrs compared to 4.1yrs of those with hem SM. The retrospective nature of the data is the major limitation. Conclusions: In the largest European database of SM in GCT pts, we observed different trends for SM development according to the SM type. This information may be important for FUP guidelines of these pts. Dataset implementation is ongoing and we will compare the SM incidence from EBMT database with SM rates in the general EU population.

Incidence of secondary malignancies (SM) in patients (pts) with germ cell tumors (GCT) who received high-dose chemotherapy (HDCT): A retrospective study from the European Society for Blood and Marrow Transplantation (EBMT) database.

409 Background: Little is still known about the incidence of SM in young adult pts with GCT after HDCT, owing to the rarity of the disease, and the need for long term follow-up (FUP) data registries. In Europe, the EBMT systematically collect relevant data and may provide a suitable platform for retrospective analyses. Methods: Criteria for patient selection included diagnosis of GCT, adult male gender, ≥ 2yr of FUP after the administration of HDCT. Summary statistics were used to describe pt characteristics and outcomes. χ2 tests were used to compare groups according to the length of FUP. Kaplan-Meier estimates were used to estimate overall survival (OS) since the diagnosis of SM. Log-rank test was used to compare OS in pt subgroups. Univariable Cox regression analyses examined clinical factors potentially associated with OS following SM diagnosis. Results: From 1981 to 2014, 9,153 autografts, accounting for 5,100 pts, have been registered. Of them, 1,855 had ≥ 2yr of FUP. Among the latter, a total of 56 cases of SM were identified (3.0%). 28 (50%) had solid SM, 22 (39.3%) hematologic SM (5 had uncoded SM). Median age at first HDCT was 34 years (IQR: 30-42), median age at development of SM was 42 (37-51). 26 pts (46.4%) received single HDCT cycle, 22 (39.3%) multiple HDCT cycles (8 unknown). 31 pts had ≥ 5 yr FUP, 25 pts 2-5 yr FUP. Solid SM were developed more frequently in those with longer FUP ( ≥ 5 yrs) compared to hematologic SM (p = 0.008). Median follow-up (FUP) was 76.9 months. Univariably, the type of SM (solid vs. hematologic) was significantly associated with OS. Hematologic vs solid SM: HR: 3.49 (95%CI: 2.09-10.47, p < 0.001). Median OS of pts who developed solid SM was 32.8 months compared to 7 months of those with hematologic SM. The retrospective nature of the data is the major limitation. Conclusions: The incidence of SM in GCT pts who have received HDCT is a concern. During the FUP, there seems to be a non-overlapping risk of developing solid or hematologic SM, with a significantly different prognostic impact. These data may be important to improve patient counselling and the planning of post-HDCT FUP.

A 2-Stage Phase II Study of Panobinostat Consolidation in Multiple Myeloma (MM) Patients with < CR Following Single High-Dose Chemotherapy (HDT) Conditioned Autologous Stem Cell Transplantation (ASCT) As Part of First Line Therapy

IntroductionPanobinostat is a pan-deacetylase inhibitor with activity against all class I, II, and IV histone deacetylase enzymes, including those implicated as potential targets in MM. Panobinostat increases acetylation of histones 2, 3 and 4 (H2, H3 and H4) and proteins involved in multiple oncogenic pathways, including the aggresome protein degradation pathway.Panobinostat has not been systematically evaluated as a single agent in patients with MM, however activity was demonstrated in patients with advanced MM in phase I and II trials. This, coupled with preclinical data, favorable toxicity profile and oral formulation strongly support its evaluation in a post-ASCT consolidation context.AimTo determine rate of conversion to CR/VGPR, to evaluate safety, toxicity and to document PFS/OS in MM patients treated with panobinostat consolidation post-ASCT.To identify a pharmacodynamic biomarker that can be utilised to select patients most likely to benefit from panobinostat by assessing changes in acetylation of lysine residues in H2A, H2B, H3 and H4.MethodsPhase II, open label, single arm study. Newly diagnosed MM patients commenced panobinostat (45mg 3x per week, alternate weeks: 1 cycle = 4/52) 8-12 weeks (median 11) after a single MEL200 ASCT. Panobinostat continued until toxicity/relapse/progression. After 6 cycles (6C), patients were restaged and only continued if depth of response improved (conversion to CR/VGPR).Acetylation studies: PBMCs were collected at 3 time points - POST-ASCT, end of cycle 3 (EOC3) and end of cycle 6 (EOC6). CD3+ lymphocytes were assessed for changes in histone and tubulin acetylation in lysine (K) residues (H2A K5, H2B K5, H3 K9, H3 K14, H3 K18, H3 K27, H3 K56, H4 K5, H4 K8, H4 K12, H4 K16 and tubulin) by flow cytometry using mean fluorescence intensity (MFI) of the geometric mean. The MFI from a sample was normalized to the respective POST-ASCT sample and expressed as a fold difference.Results24 patients (F=12, M=12), median age 58yrs (44-69), commenced panobinostat. Diagnosis ISS stage: I/II: 16, III: 8. 20/24 had diagnostic cytogenetics/FISH: 5 were poor risk (t(4;14), t(14;16), +1q21).After a median of 24m following panobinostat initiation (6-43m), 6 patients remain on therapy. Discontinuation was due to failure to improve depth of response (8), progression (6), non-compliance (2) and toxicity (2). 11 patients progressed, 2 died. Estimated 2 year PFS 65% (median PFS 25m, median OS NR).22/24 patients completed at least 6C of therapy. 12/24 improved depth of response: VGPRàCR: 4, PRàVGPR: 7, PRàCR: 1; 4 patients within 0-3C, 8 patients within 3-6C. Two patients (one each from 0-3C and 3-6C groups) demonstrated a further reduction in tumour burden with maximal response occurring after EOC11 and EOC29. Median time to maximal response after was 4.6m after commencing panobinostat (1.2-29m). One patient who discontinued after EOC6 (failed to improve depth of response) had a further reduction in paraprotein from 5g/L to trace at 6m post EOC6 (sustained for 5m).All grade haematological toxicity: thrombocytopenia: 9/24 (grade 3/4 = 6), neutropenia: 7/24 (grade3 = 6), anaemia: 1/24. Principal non-haematological toxicities were GI [nausea: 22/24 (grade 3 = 3), diarrhoea: 22/24 (grade 3=4)], fatigue: 18/22 and infection: 15/22 (grade 3=9). Only 5/24 patients tolerated dosing as per protocol. The median tolerated dose was 25mg.Changes in histone acetylation were assessed for 11 responders and 5 non-responders. Responders demonstrated increasing levels of acetylation at EOC3 and EOC6: At EOC3, this was most marked for H2B K5, H3 K9, H3 K14, H3 K56, H4 K8, H4 K12, H4 K16 at EOC3, while at EOC6, all histone acetylation lysine residues tested were significantly increased compared to POST-ASCT. In contrast, there were no differences in the levels of acetylation for either EOC3 or EOC6 compared to POST-ASCT for the non-responders. The differences in observed changes in histone acetylation seen at EO6 in responders compared to non-responders were significant.ConclusionSingle agent panobinostat consolidation post-ASCT improves depth of response in a non-favourable group of patients, and in some patients, induces a further reduction in tumour burden beyond 12m post-ASCTAssessment of histone acetylation changes represents a pharmacodynamic biomarker of clinical benefit, with a strong correlation between the levels of acetylation and response of the patient to panobinostat. DisclosuresQuach:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Outcome of Patients with Multiple Myeloma and CKS1B Gene Amplification after Autologous Hematopoietic Stem Cell Transplantation

The gain/amplification of the CKS1B gene on chromosome 1q21 region is associated with a poor outcome in patients with multiple myeloma (MM). However, there are limited data on the outcome of patients with CKS1B amplification after a single high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT). We retrospectively evaluated the outcome of patients with CKS1B amplification who received an auto-HCT between June 2012 and July 2014 at our institution. We identified 58 patients with MM and CKS1B gene amplification detected by fluorescent in situ hybridization (FISH). We compared their outcomes with a propensity score–matched control group of 58 patients without CKS1B amplification who were treated at approximately the same time. The primary objective was to compare the progression-free (PFS) and overall survival (OS) between the CKS1B and the control groups. Stratified log-rank test with the matched pairs as strata and double robust estimation under the Cox model were used to assess the effect of CKS1B gene amplification on PFS or OS in the matched cohort. Patients in the CKS1B and control groups were well matched for age, gender, disease status, year of auto-HCT, response to pretransplantation therapy, and baseline hemoglobin level. In both groups, 57% patients were in first remission and 43% had relapsed disease at auto-HCT. Twenty-seven (47%) patients with CKS1B amplification had concurrent monosomy 13 or 13q deletion; 6 (10%) by conventional cytogenetics only, 16 (28%) by FISH only, and 5 (9%) by both. Median follow-up after auto-HCT was 25.4 months. The median PFS of the CKS1B and the control groups were 15.0 months and 33.0 months (P = .002), respectively. The median OS have not been reached yet. The 2-year OS rates in the CKS1B and the control groups were 62% and 91% (P = .02), respectively. In conclusion, Patients with CKS1B amplification are more likely to have additional high-risk cytogenetic abnormalities and a shorter PFS and OS after an auto-HCT.

First-line tandem high-dose chemotherapy and autologous stem cell transplantation versus single high-dose chemotherapy and autologous stem cell transplantation in multiple myeloma, a systematic review of controlled studies

Several clinical studies have compared single with tandem (also called double) autologous stem cell transplantation (ASCT) as first-line treatment in patients with symptomatic multiple myeloma (MM), one of the leading indications for ASCT worldwide. The present Cochrane Review compares tandem autologous stem cell transplantation (TASCT) with single autologous stem cell transplantation (SASCT) as first-line treatment in patients with symptomatic MM with respect to overall survival (OS), event-free survival (EFS), quality of life (QoL) and treatment- or transplantation-related mortality. We systematically identified controlled trials published between January 1995 and May 2011 in two bibliographic databases (MEDLINE and CENTRAL) and in clinical trial registries. One researcher screened references for controlled trials to determine eligibility for the systematic review (SR) according to pre-specified inclusion and exclusion criteria, reflecting characteristics of disease and the interventions. We required a minimal set of details to be reported for observational studies for the studies to be included. We critically evaluated eligible trials with respect to quality of design and actual performance. One researcher extracted individual trial results, which were checked by another researcher. We recapitulated the results of the individual trials in a standardised way for the SR in order to allow a systematic assessment of potential sources of bias. Overall, we identified 14 controlled studies. One registered randomised controlled trial (RCT) is still recruiting patients at the time of this review and no clinical results have been published. Two registered RCTs have remained unpublished despite their termination. Publications on one RCT had been retracted. We excluded five observational studies since neither patients nor treatment regimens were sufficiently characterised to allow an assessment of potential confounding by indication. We conducted a SR of study designs, definition of endpoints, treatment regimens and baseline characteristics of patients in the five included RCTs (two full-text publications, three conference presentations) enrolling1506 patients in total. Because we identified substantial clinical and methodological heterogeneity, we refrained from conducting a formal meta-analysis.While we included only previously untreated, symptomatic patients with MM the treatment regimens differed notably with respect to acute toxicity, between trials and also between study arms. Compared to state of the art treatment standards, the treatment regimens applied in all trials have to be considered as below standard from a contemporary perspective in at least one component.Three trials were likely to have the potential of being highly biased while two RCTs had a moderate potential for bias. The observed treatment effects in the set of included trials may have been influenced by a steep decrease in compliance with the second ASCT and the concomitant selection of patients. In addition, OS data were confounded by the treatment subsequent to first-line therapy.OS was statistically significantly improved in one trial only. While EFS was prolonged in four of the five trials, the median prolongation ranged between three to 12 months, with an uncertain direction of bias in the individual trials. QoL was not reported in any study. Results concerning treatment- or transplantation-related mortality could not be adequately assessed due to substantial differences in definitions between trials and low reporting quality. We did not consider any study to be sufficiently informative for contemporary treatment decisions concerning the question single versus tandem ASCT in view of inherent biases. In addition, none of the trials integrated the so-called "novel agents" which are now considered standard treatment for MM. To improve the quality of future studies, sample size calculations should consider the potentially steep decrease in compliance with the second ASCT. Reporting of results of treatment- or transplantation-related mortality should clearly specify the type and number of events (the numerator) in a well-defined population (the denominator).

Quality of life and late toxicities in germ-cell cancer patients after high-dose chemotherapy.

4600 Background: The number of long term survivors after treatment for relapsed/refractory germ cell cancer (GCC) is increasing but little is known about quality of life (QOL) and late toxicities (LT). Methods: We assessed LT and QOL in GCC patients (pts), treated in a prospective, randomized, multicenter, phase III trial comparing single versus sequential high-dose chemotherapy (HDCT) (Lorch 2007). All 216 pts were asked to complete the European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) prior to HDCT, 6 weeks after and yearly thereafter. Results were analyzed according to standard methods (Fayers 2001). In addition pts were contacted at a median of 76 months (range 45-109) after HDCT to obtain information about current social and professional activities as well as LT. Results: Among 216 pts, 92/216 (42%) were alive and without evidence of disease one year after randomization. Median age of pts was 34 years (range 15-56). A median of 4 conventional-dose cisplatin-based treatment cycles had been given prior to HDCT. Questionnaires and response to the survey were evaluable in 86/92 (93%) pts overall and in 59/86 (69%) pts more than 3 years after HDCT. Values for global health status, role functioning and emotional functioning declined during the first year after HDCT, increased in the following years, but did not reach the reference values from large samples of the general population in Norway (Hjermstad 1998). Pts after sequential HDCT scored better in a number of items (e.g. emotional-, cognitive-, social-functioning, fatigue and dyspnoea) in comparison to single HDCT including high-dose cyclophosphamide. Persisting polyneuropathy was reported in 59%, ototoxicity or tinnitus in 56%, erectile dysfunction in 24%, hypertension in 23%, hypercholesterinemia in 17%, diabetes mellitus in 6%, nephrotoxicity in 6%, myocardial infraction in 2% and second cancers in 1% of pts. Overall 82 % of pts were employed, 30% exercised regularly. Conclusions: HDCT has a negative impact on QOL, including social and professional life. Most common late toxicities were ototoxicity and polyneuropathy. Sequential HDCT without cyclophosphamide seems to result in a better outcome in respect to QOL.

Sequential Versus Single High-Dose Chemotherapy in Patients With Relapsed or Refractory Germ Cell Tumors: Long-Term Results of a Prospective Randomized Trial

To evaluate the long-term survival rates in patients with relapsed or refractory germ cell tumors (GCTs) after single or sequential high-dose chemotherapy (HDCT). Between November 1999 and November 2004, 211 patients with relapsed or refractory GCT were randomly assigned to treatment with either one cycle of cisplatin 100 mg/m(2), etoposide 375 mg/m(2), and ifosfamide 6 g/m(2) (VIP) plus three cycles of high-dose carboplatin 1,500 mg/m(2) and etoposide 1,500 mg/m(2) (CE, arm A) or three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m(2), etoposide 1,800 mg/m(2), and cyclophosphamide 6,400 mg/m(2) (CEC, arm B) followed by autologous stem-cell reinfusion. Long-term progression-free survival (PFS) and overall survival (OS) 6 years after random assignment of the last patient were compared by using the log-rank test. Overall, 108 and 103 patients were randomly assigned to arms A and B, respectivelyl. The study was stopped prematurely because of excess treatment-related mortality in arm B (14%) compared with that in arm A (4%; P = .01). As of December 2010, nine (5%) of 211 patients were lost to follow-up; 94 (45%) of 211 are alive and 88 (94%) of 94 patients are progression free. Five-year PFS is 47% (95% CI, 37% to 56%) in arm A and 45% (95% CI, 35% to 55%) in arm B (hazard ratio [HR], 1.16; 95% CI, 0.79 to 1.70; P = .454). Five-year OS is 49% (95% CI, 40% to 59%) in arm A and 39% (95% CI, 30% to 49%) in arm B (HR, 1.42; 95% CI, 0.99 to 2.05; P = .057). Patients with relapsed or refractory GCT achieve durable long-term survival after single as well as sequential HDCT. Fewer early deaths related to toxicity translated into superior long-term OS after sequential HDCT.

Superior survival after sequential high-dose chemotherapy (HDCT) as compared to single HDCT in patients with relapsed or refractory germ cell tumors (GCT): Six-year long-term follow-up of a prospective, randomized phase II trial.

4507 Background: Sequential and single high-dose chemotherapy (HDCT) can both be curative in patients (pts) with relapsed or refractory germ-cell tumors (GCT). The long-term efficacy of either moda...

Imaging findings in relapsing multiple myeloma

We present the case of a 59-year-old woman with Bence Jones (kappa type) multiple myeloma, first diagnosed in October 2005. After initial induction treatment followed by single highdose chemotherapy with melphalan, a very good partial remission was reached and lasted for more than 2 years. At this stage (October 2007), residual medullary involvement of the right humeral diaphysis was documented on a computed tomography (CT) scan (left). Three months later in January 2008, serum levels of free kappa light chains had increased, from 286 to 1770 mg/l. At this time the CT scan identified relapsing myeloma with infiltration of the medulla of the humeral diaphysis (centre). As disease progression was not clinically relevant at this point, the patient remained under close follow-up. Six months later, further disease progression was documented with progressive proteinuria, impaired renal function and a free kappa light chain level of 17 240 mg/l. CT scan revealed an increase in extent and attenuation of the medullary myelomatous infiltrate, which correlated with the clinical course (right). Consequently, treatment with bortezomib and dexamethasone was initiated.

Long-term outcome of salvage high-dose chemotherapy in patients with germ cell tumor with poor prognostic features

Objective High-dose chemotherapy (HDCT) represents an option as salvage treatment for patients with resistant/refractory germ cell tumor (GCT). The objective of this retrospective analysis was to evaluate the long-term results of a single-center experience with salvage HDCT for GCT patients, and to validate the prognostic model proposed by Einhorn and colleagues [9]. Materials and methods Between 1986 and 2003, 100 GCT patients received salvage HDCT consisting of high-doses of carboplatin, etoposide ± cyclophosphamide, or ifosfamide. Twenty-four patients underwent a second HDCT cycle, and in 1 case, a third cycle was given with a median interval time of 6 weeks (range, 5–10). Results With a median follow-up of 8 years (range, 3–17); 6 of 32 (19%) patients with resistant GCT and 1 of 19 (5%) patients with cisplatin-refractory disease have been continuously disease-free, while none of the 16 patients with absolutely cisplatin-refractory GCT were alive at 1 year from HDCT treatment. In the PBPC era, HDCT appeared to be inapplicable in 32% of patients, mainly due to progressive disease during the induction/mobilizing phase. The prognostic model by Einhorn et al. for tandem HDCT did categorize our patients treated with a single HDCT cycle or low-dose intensity regimens in a very similar manner, but with inferior overall results. Conclusions Long-term results with a single HDCT cycle or a low dose-intensity multicycle HDCT regimen remained poor in patients with adverse prognostic features. The tandem HDCT regimen represents a major option for refractory GCTs and relapsed tumors in third-line or later therapy, while a single course of HDCT should be abandoned for these patients.

Single Versus Sequential High-Dose Chemotherapy in Patients With Relapsed or Refractory Germ Cell Tumors: A Prospective Randomized Multicenter Trial of the German Testicular Cancer Study Group

To compare single versus sequential high-dose chemotherapy (HDCT) as first or subsequent salvage treatment in patients with relapsed or refractory germ cell tumors (GCTs). Between November 1999 and November 2004, 230 patients were planned to be recruited in a prospective, randomized, multicenter trial comparing one cycle of cisplatin 100 mg/m2, etoposide 375 mg/m2, and ifosfamide 6 g/m2 (VIP) plus three cycles of high-dose carboplatin 1,500 mg/m2 and etoposide 1,500 mg/m2 (CE; arm A) versus three cycles of VIP plus one cycle of high-dose carboplatin 2,200 mg/m2, etoposide 1,800 mg/m2, and cyclophosphamide 6,400 mg/m2 (CEC; arm B). The study was stopped prematurely after recruitment of 216 patients as a result of excess treatment-related mortality in arm B. One hundred eleven (51%) of 216 patients were randomly assigned to sequential HDCT, and 105 (47%) of 216 patients were randomly assigned to single HDCT. Five (2%) of 216 patients had to be excluded because of non-GCT histologies at review. With a median follow-up time of 36 months, 109 (52%) of 211 patients were alive, and 91 (43%) of 211 patients were progression free. At 1 year, event-free, progression-free, and overall survival rates were 40%, 53%, and 80%, respectively, in arm A compared with 37%, 49%, and 61%, respectively, in arm B (P > .05 for all comparisons). Treatment-related deaths, mainly as a result of sepsis and cardiac toxicity, were less frequent in arm A (four of 108 patients, 4%) compared with arm B (16 of 103 patients, 16%; P < .01). We found no difference in survival probabilities between single HDCT using CE and sequential HDCT using CEC. Sequential HDCT was better tolerated and resulted in fewer treatment-related deaths.

Outcome in 41 patients with late relapse germ cell tumors (GCT) treated with high-dose chemotherapy (HDCT)

5086 Background: The management of patients (pts) with late-relapse GCT and unresectable tumors or very high tumor markers is controversial. Methods: A total of 41 late-relapse pts were identified among a group of 216 pts with refractory or relapsed GCT who were treated in an open, prospective, randomized, multicenter phase III trial. Late relapse was defined as any relapse occurring more than 2 years after completion of initial chemotherapy for GCT. Treatment consisted of either one cycle cisplatin 100 mg/m2, etoposide 375 mg/m2 and ifosfamide 6 g/m2 (VIP) plus three cycles of high-dose carboplatin 1,500 mg/m2 and etoposide 1,500 mg/m2 (CE, arm A) or of three cycles of VIP plus one cycle high-dose carboplatin 2,200 mg/m2, etoposide 1,800 mg/m2 and cyclophosphamide 6,400 mg/m2 (CEC, arm B). Each HDCT was followed by reinfusion of autologous peripheral blood progenitor cells. Results: Overall 20 pts with late-relapse GCT received sequential HDCT and 21 pts single HDCT when the study was stopped due to excess treatment-related mortality in arm B; median time to late relapse in 41 pts was 5.4 years (range 2–18 years); 8/41 (20%) pts had seminomatous GCT, 32/41 (78%) pts had nonseminomatous GCT with or without teratoma; one pt (2%) had unknown GCT histology. No non-GCT histologies were included. The retroperitonum was most commonly involved in 30/41 (73%) pts. 29 of 41 (71%) pts had unresectable, multifocal disease and 20/41 (49%) pts also had very high markers. A complete remission to chemotherapy alone was achieved in 4/41 (10%) pts, 16/41 (39%) pts achieved a partial remission with negative tumor markers. The remaining 21/41 (51%) either had a transient or no response despite HDCT. Residual tumor resections were performed in 17/41 (41%) pts. Residual tumor histology was viable cancer in 8/17 (47%) pts, teratoma in 4/17 (24%) pts and necrosis in 5/17 (25%) pts. With a minimum follow-up of 1 year and a median follow-up of 3 years the estimated Kaplan-Meier rates are 17%, 20% and 32% for event-free, progression-free and overall survival. Conclusion: Treatment outcome after HDCT was inferior in late-relapse pts compared to the group of pts who relapsed within less than 2 years. Despite an overall poor prognosis, HDCT can still result in long-term remissions in selected late-relapse GCT pts. No significant financial relationships to disclose.

High‐dose chemotherapy and autologous stem cell rescue in children with newly diagnosed high‐risk or relapsed medulloblastoma or supratentorial primitive neuroectodermal tumor

Single or tandem double high-dose chemotherapy (HDCT) was used to treat children with newly diagnosed high-risk or relapsed medulloblastoma and supratentorial primitive neuroectodermal tumor (MB/sPNET) in order to defer or avoid radiotherapy in young children. Thirty-seven HDCTs were given to 25 children with newly diagnosed high-risk or relapsed MB/sPNET. Tandem double HDCT was used for 12 of 15 patients initially intended to receive double HDCT. Three-year EFS (+/-SE) in 6 newly diagnosed high-risk (>3 years old), 8 newly diagnosed (<3 years old), and 11 relapsed MB/sPNET was 83.3 +/- 15.2%, 62.5 +/- 20.5%, and 29.1 +/- 15.7%, respectively. Three-year EFS for patients in CR or PR and in less than PR at first HDCT was 67.4 +/- 11.0% and 16.7 +/- 15.2%, respectively (P = 0.001). Three-year EFS in patients initially intended to receive double HDCT and single HDCT was 66.0 +/- 12.4% and 40.0 +/- 15.5%, respectively. For 19 patients in CR or PR at first HDCT, 3-year EFS was 88.9 +/- 10.5% in tandem double HDCT group, and 44.4 +/- 16.6% in single HDCT group, respectively (P = 0.037). Although four treatment-related mortalities (TRMs) occurred during 25 first HDCTs, no TRM occurred during 12 second HDCTs. In four of eight young children, craniospinal radiotherapy was successfully withheld without subsequent relapse. High-dose chemotherapy may improve the survival of children with newly diagnosed high-risk MB/sPNET, and, to some extent, the survival of those with relapsed MB/sPNET. Further study is necessary to elucidate the efficacy of tandem double HDCT.

Randomized Trial of Single Compared With Tandem High-Dose Chemotherapy Followed by Autologous Stem-Cell Transplantation in Patients With Chemotherapy-Sensitive Metastatic Breast Cancer

To compare progression-free survival between single and tandem high-dose chemotherapy (HDT) followed by autologous stem-cell transplantation in chemotherapy-sensitive metastatic breast cancer patients. Between February 1997 and June 2001, 187 patients with complete and partial remission were randomly assigned to receive either one or two cycles of HDT, consisting of thiotepa (125 mg/m2/d for 4 days), cyclophosphamide (1,500 mg/m2/d for 4 days), and carboplatin (200 mg/m2/d for 4 days), followed by autologous stem-cell transplantation. One hundred seventy one of 187 randomly assigned patients completed first HDT, but only 52 of 85 completed the second HDT cycle in the tandem HDT arm. The rate of complete remission on an intent-to-treat-basis was 33% in the single-dose HDT arm and 37% in the tandem HDT arm (P = .48). The median progression-free survival times in single and tandem HDT arms were 9.4 and 11.2 months, respectively (one-sided P = .06; two one-sided P = .12), whereas median overall survival time tended to be greater after single versus tandem HDT (29 v 23.5 months, respectively; P = .4). In a multivariate analysis for progression-free survival, tandem HDT (hazard ratio [HR] = 0.71; 95% CI, 0.52 to 0.98; P = .03) and achievement of complete remission after induction chemotherapy (HR = 0.59; 95% CI, 0.37 to 0.96; P = .03) were factors for a better progression-free survival, whereas the factor of three or more sites of metastases (HR = 1.66; 95% CI, 1.12 to 2.47; P = .01) was associated with a worse progression-free survival. Despite a trend of improved progression-free survival, tandem HDT cannot be recommended for patients with chemotherapy-sensitive metastatic breast cancer because of a trend for shorter overall survival and higher toxicity compared with single HDT.

Single versus sequential high-dose chemotherapy (HDCT) in patients with relapsed or refractory germ-cell tumors (GCT)

4511 Background: Patients (pts) with relapsed or refractory GCT may be cured by HDCT. It is unknown whether single or sequential HDCT is superior. Methods: Between 11/99 and 11/04, 216 pts with relapsed or refractory GTC were treated in a prospective, randomized, multicenter phase III trial with either one cycle of cisplatin 100 mg/m2, etoposide 375 mg/m2 and ifosfamide 6 g/m2 (VIP) plus three cycles of high-dose carboplatin 1500 mg/m2 and etoposide 1500 mg/m2 (CE, arm A) or three cycles of VIP plus one cycle of high-dose carboplatin 2200 mg/m2, etoposide 1800 mg/m2 and cyclophosphamide 6400 mg/m2 (CEC, arm B) followed by reinfusion of autologous peripheral blood progenitor cells. Primary study endpoint was the event-free survival (EFS) one year after randomization. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicities. An event was defined as any deviation from the planned treatment, relapse, progression or death from any cause. The planned study size was 230 pts to detect a difference of 15% with an alpha error of 5% and a power of 80%. Results: The study was stopped after recruitment of 216 pts due to excess treatment-related mortality in arm B: 111 pts were randomized in arm A and 105 pts in arm B. Due to non-GCT histologies at review 5/216 pts had to be excluded from further analysis. With a median follow-up of 36 months, 109/211 (52%) evaluable pts are still alive and 91/211 (43%) are progression-free. At one year EFS; PFS and OS are 40%, 55% and 80% in arm A as compared to 37%, 49% and 61% in arm B. Treatment-related deaths mainly due to sepsis and cardiac toxicity were less frequent in arm A (4/111 pts, 4%) as compared to arm B (15/105 pts, 14%) (p = 0.01). Severe non-hematologic organ toxicities were also less frequent in arm A. Conclusions: Treatment with sequential high-dose carboplatin and etoposide is at least as effective but less toxic than single HDCT with carboplatin, etoposide and cyclophosphamide. No significant financial relationships to disclose.

Adding a single high-dose chemotherapy cycle to three cycles of standard salvage chemotherapy for relapsed germ-cell tumours does not improve clinical outcomes

Adding a single high-dose chemotherapy cycle to three cycles of standard salvage chemotherapy for relapsed germ-cell tumours does not improve clinical outcomes

Comparison of Interferon Versus Thalidomide Versus RIC Allotransplant for Maintenance /Consolidation Therapy after Autologous Stem Cell Transplantation in Patients with Multiple Myeloma: A Single Center Experience.

High dose chemotherapy (HDT) with autologous stem cell transplantation has improved response rates and survival of patients with multiple myeloma. However the majority of patients suffer from relapse. Therefore, in this retrospective study we evaluated the impact of maintenance therapy with either thalidomide or interferon on the progression-free survival (PFS) after HDT and compared these results with a planned allogeneic transplant with reduced intensity conditioning (RIC) as consolidation therapy after HDT.We analysed 95 patients with a median age of 55 years who were treated at our institution in 2001–2005 with the diagnosis of stage III myeloma. Melphalan 200 mg/m2 was used as conditioning regimen followed by autologous stem cell transplantation. Interferon was given at a dose of 1.0 to 4.5 million U three times a week and the daily dose of thalidomide was 100 to 400 mg according to the individual tolerance of side effects. Allotransplants were performed with HLA-identical sibling donors after fludarabin 90 mg/m2 and TBI (2Gy) conditioning. In median 3.8 months after single HDT patients received either a RIC allotransplant (n=14) or maintenance therapy with thalidomide (n=39) or interferon (n=30) or no maintenance therapy (n=12). Prognostic factors such as cytogenetic abnormalities, beta-2 microglobulin, chemosensitive disease before HDT or remission status after HDT were equally distributed in all treatment groups.After a median follow-up of 33 months (range: 8–60) PFS from the start of treatment did not differ between patients after allotransplant (median not yet reached) and patients receiving thalidomide (median 50 months, p=0.8) but was significantly improved in comparison to patients who received interferon or no maintenance therapy (median 24 months, p<0.0001). Most patients who received interferon or no maintenance therapy were treated with thalidomide at the time of relapse. Therefore, we also compared the combined PFS of patients treated with interferon maintenance followed by thalidomide in first relapse with the PFS of patients treated with immediate thalidomide maintenance therapy. Most interestingly, PFS of these two treatment schedules was not different (median 50 months in both groups; p=0.9), but the time of thalidomide exposure was in median 13 months shorter for patients in the interferon treatment arm. This is important, as to date most novel therapies hold the risk of polyneuropathy and thus pre-existing polyneuropathy due to prior thalidomide therapy limits the therapeutical options during the course of disease.Analysis of overall survival showed no differences between patients in the thalidomide or the interferon treatment arm (median not reached in both groups, p=0.5), but survival was inferior with RIC allotransplant (median 44 months, p=0.02). In conclusion, thalidomide is an effective maintenance therapy which prolongs PFS after single HDT. Interferon is less effective but the treatment schedule interferon maintenance therapy followed by thalidomide at the time of relapse is equal to upfront thalidomide maintenance therapy in terms of cumulative PFS and may be less toxic. RIC allotransplant is not superior to other treatment options and thus still has to be considered an experimental treatment option.

Tandem Autotransplants' Peripheral Blood Stem Cells Following Sequent High-Dose CHEOP Chemotherapy for Aggressive Lymphoma.

The majority of poor-risk lymphoma patients are not cured with conventional chemotherapy. There is evidence for superiority of single high-dose chemotherapy in such patients, but many still die from recurrent disease. Strategies to improve survival in these poor-risk patients include dose-intensification with high-dose chemotherapy and PBSC support autologous transplantation. These more aggressive strategies are feasible and tolerable. Whether tandem transplantation will prove more effective than current single high-dose therapy in appropriately selected patients remains to be determined. The purpose of this study was to evaluate the effectivity and safety of mobilization regimen, and the effectivity and tolerance of sequential chemotherapy combined with tandem autotransplant in aggressive lymphoma. In this study, the clinical data of 5 patients with recurrent, aggressive lymphoma treated with of sequential chemotherapy combined with tandem autotransplant were analysed respectively. The group included 1 HD and 4 NHL. Mobilization regimen was CHOEP combined with G-CSF (5ug•kg−1•d−1). The conditioning regimen for the tandem transplantation was high-dose CHEOP. The interval of the two autotransplantation was 9(5~31)weeks. In tandem autotransplant, the cell number of MNC which was transfused was 3.05 (ranged from 1.91~4.14) ×108 •kg−1 and 3.55 (ranged from 2.23~6.0) ×108•kg−1; CD34+ was 4.11 (ranged from 2.59~4.94) ×106•kg−1 and 5.70 (ranged from 2.77~10.6) ×106•kg−1; CFU-GM was 2.96 (ranged from 2.01~4.54) ×105•kg−1 and 2.44 (ranged from 1.78~2.9) ×105•kg−1 respectively (P>0.05). All patients reached prompt and sustained hemotopoietic reconstitution. The interval of ANC ≥0.5×109/L was 10 days (ranged from 8~12) and 10.5 days (ranged from 9~12); Pt ≥2.0×109/L was 11 days (ranged from 10~14) and 12.5 days (ranged from 10~15) respectively (P>0.05). Four patients were alive while 3 was in disease-free with median 46 (range 9~88) months. The overall survival was 80%, and the disease-free survival was 60%. In the conclusion, the method of sequential high-dose CHEOP chemotherapy combined with tandem autotransplant of peripheral blood stem cells for aggressive lymphoma is safe and effective.

P90 Tandem versus single high dose chemotherapy (HDC)with haematopoietic stem cell support in patients with chemosensitive metastatic breast cancer (MBC): outcome parameters - results from a randomised multicenter phase III trial

P90 Tandem versus single high dose chemotherapy (HDC)with haematopoietic stem cell support in patients with chemosensitive metastatic breast cancer (MBC): outcome parameters - results from a randomised multicenter phase III trial