Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group.

PURPOSE: To compare low-dose decitabine to best supportive care (BSC) in higher-risk patients with myelodysplastic syndrome (MDS) age 60 years or older and ineligible for intensive chemotherapy. PATIENTS AND METHODS: Two-hundred thirty-three patients (median age, 70 years; range, 60 to 90 years) were enrolled; 53% had poor-risk cytogenetics, and the median MDS duration at random assignment was 3 months. Primary end point was overall survival (OS). Decitabine (15 mg/m(2)) was given intravenously over 4 hours three times a day for 3 days in 6-week cycles. RESULTS: OS prolongation with decitabine versus BSC was not statistically significant (median OS, 10.1 v 8.5 months, respectively; hazard ratio [HR], 0.88; 95% CI, 0.66 to 1.17; two-sided, log-rank P = .38). Progression-free survival (PFS), but not acute myeloid leukemia (AML) -free survival (AMLFS), was significantly prolonged with decitabine versus BSC (median PFS, 6.6 v 3.0 months, respectively; HR, 0.68; 95% CI, 0.52 to 0.88; P = .004; median AMLFS, 8.8 v 6.1 months, respectively; HR, 0.85; 95% CI, 0.64 to 1.12; P = .24). AML transformation was significantly (P = .036) reduced at 1 year (from 33% with BSC to 22% with decitabine). Multivariate analyses indicated that patients with short MDS duration had worse outcomes. Best responses with decitabine versus BSC, respectively, were as follows: complete response (13% v 0%), partial response (6% v 0%), hematologic improvement (15% v 2%), stable disease (14% v 22%), progressive disease (29% v 68%), hypoplasia (14% v 0%), and inevaluable (8% v 8%). Grade 3 to 4 febrile neutropenia occurred in 25% of patients on decitabine versus 7% of patients on BSC; grade 3 to 4 infections occurred in 57% and 52% of patients on decitabine and BSC, respectively. Decitabine treatment was associated with improvements in patient-reported quality-of-life (QOL) parameters. CONCLUSION: Decitabine administered in 6-week cycles is active in older patients with higher-risk MDS, resulting in improvements of OS and AMLFS (nonsignificant), of PFS and AML transformation (significant), and of QOL. Short MDS duration was an independent adverse prognosticator.

Second neoplasm in children treated in EORTC 58881 trial for acute lymphoblastic malignancies: low incidence of CNS tumours.

BACKGROUND: Intensive chemotherapy has markedly improved the survival of children with acute lymphoblastic leukaemia (ALL) or lymphoblastic lymphoma (LL). Evaluation of late effects and analysis of factors contributing to their occurrence has become of major importance. Second neoplasm (SN) belongs to the most severe late events. PROCEDURE: We report the incidence of SN which occurred in patients recruited in EORTC trial 58881 for children with ALL or LL. The front-line treatment regimen was adapted from the BFM protocol, but did not include cranial radiotherapy, even in patients with initial involvement of the central nervous system. A total of 2,216 patients were recruited, of whom 2,136 achieved complete remission (CR). RESULTS: At a median follow-up of 7.5 years, 22 (1%) patients developed a SN: 20 during or after completion of front-line therapy and 2 in second CR, after relapse treatment including haematopoietic stem cell transplantation (HSCT). Ten patients developed acute myeloblastic leukaemia. Only one SN, a glioblastoma, was a brain tumour. Other SN were: two Hodgkin lymphomas, one non-Hodgkin lymphoma, two thyroid cancers, one osteosarcoma, two soft tissue sarcomas, one Ewing sarcoma, one cutaneous histiocytosis and one peritoneal carcinomatosis. The cumulative incidences of SN at 5, 8 and 13 years after registration were 0.8% (SE 0.2%), 1.0% (SE 0.2%) and 3.0% (SE 1.9%), respectively. CONCLUSION: The overall incidence rate of SN is comparable to that reported previously. In spite of short follow-up time, the low incidence of brain tumours might be related to the omission of cranial radiotherapy.

Gem-(R)CHOP versus (R)CHOP: a randomized phase II study of gemcitabine combined with (R)CHOP in untreated aggressive non-Hodgkin's lymphoma--EORTC lymphoma group protocol 20021 (EudraCT number 2004-004635-54).

BACKGROUND: Despite recent improvements, many patients with aggressive non-Hodgkin's lymphoma (NHL) ultimately succumb to their disease. Therefore, improvements in front-line chemotherapy of aggressive NHL are needed. Gemcitabine is active in lymphoma. METHODS: We performed a randomized phase II trial of the addition of gemcitabine to standard CHOP chemotherapy with or without rituximab [(R)CHOP]. The trial was also designed to determine the maximal tolerated dose (MTD) of gemcitabine in this combination. Patients with previously untreated aggressive NHL were randomized to receive either eight cycles of (R)CHOP given every 3 wk or (R)CHOP combined with gemcitabine [Gem-(R)CHOP]. RESULTS: Twenty-five patients were enrolled in the trial before early closure. Twelve were randomized to Gem-(R)CHOP and 13 to (R)CHOP. MTD of gemcitabine was 800 mg/m(2) given on days 1 and 8; dose-limiting toxicity was hematologic. Five patients (42%) treated with Gem-(R)CHOP achieved complete response in comparison with 10 (77%) treated with (R)CHOP. Median time to treatment failure was 1.5 yr for Gem-(R)CHOP and 3.1 yr for (R)CHOP. Three patients receiving Gem-(R)CHOP had serious pulmonary toxicity, when compared to none receiving (R)CHOP. One patient died of pneumonitis. CONCLUSIONS: In this group of patients, addition of gemcitabine did not seem to improve outcomes. Gem-(R)CHOP in previously untreated patients with aggressive NHL occasionally results in severe, potentially fatal, pulmonary toxicity.

Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951.

The European Organisation for Research and Treatment of Cancer 58951 trial for children with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) addressed 3 randomized questions, including the evaluation of dexamethasone (DEX) versus prednisolone (PRED) in induction and, for average-risk patients, the evaluation of vincristine and corticosteroid pulses during continuation therapy. The corticosteroid used in the pulses was that assigned at induction. Overall, 411 patients were randomly assigned: 202 initially randomly assigned to PRED (60 mg/m(2)/d), 201 to DEX (6 mg/m(2)/d), and 8 nonrandomly assigned to PRED. At a median follow-up of 6.3 years, there were 19 versus 34 events for pulses versus no pulses; 6-year disease-free survival (DFS) rate was 90.6% (standard error [SE], 2.1%) and 82.8% (SE, 2.8%), respectively (hazard ratio [HR] = 0.54; 95% confidence interval, 0.31-0.94; P = .027). The effect of pulses was similar in the PRED (HR = 0.56) and DEX groups (HR = 0.59) but more pronounced in girls (HR = 0.24) than in boys (HR = 0.71). Grade 3 to 4 hepatic toxicity was 30% versus 40% in pulses versus no pulses group and grade 2 to 3 osteonecrosis was 4.4% versus 2%. For average-risk patients treated according to Berlin-Frankfurt-Muenster-based protocols, pulses should become a standard component of therapy.

Randomized trial of two schedules of low-dose gemtuzumab ozogamicin as induction monotherapy for newly diagnosed acute myeloid leukaemia in older patients not considered candidates for intensive chemotherapy. A phase II study of the EORTC and GIMEMA leukaemia groups (AML-19).

This study compared two schedules of low-dose gemtuzumab ozogamicin (GO) as induction monotherapy for untreated acute myeloid leukaemia in older patients unfit for intensive chemotherapy, to identify the more promising regimen for further study. Patients were randomized to receive either best supportive care or a course of GO according to one of two schedules: 3 mg/m(2) on days 1, 3 and 5 (arm A), or GO 6 mg/m(2) on day 1 and 3 mg/m(2) on day 8 (arm B). Primary endpoint was the rate of disease non-progression (DnP), defined as the proportion of patients either achieving a response or maintaining a stable disease following GO induction in each arm. Fifty-six patients were randomized in the two GO arms (A, n = 29; B, n = 27). The rate of DnP was 38% [90% confidence interval (CI), 23-55] in arm A, and 63% (90% CI, 45-78) in arm B. Peripheral cytopenias were the most common adverse events for both regimens. The all-cause early mortality rate was 14% in arm A and 11% in arm B. The day 1 + 8 schedule, which was associated with the highest rate of DnP, met the statistical criteria to be selected as the preferred regimen for phase III comparison with best supportive care.

Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10.

PURPOSE: To compare the antitumor efficacy of three different anthracyclines in combination with cytarabine and etoposide in adult patients with newly diagnosed acute myeloid leukemia (AML). PATIENTS AND METHODS: We randomly assigned 2,157 patients (age range, 15 to 60 years) to receive intensive induction-consolidation chemotherapy containing either daunorubicin, idarubicin, or mitoxantrone. After achieving complete remission (CR), patients were assigned to undergo either allogeneic or autologous stem-cell transplantation (SCT), depending on the availability of a sibling donor. RESULTS: The overall CR rate (69%) was similar in the three groups. Autologous SCT was performed in 37% of cases in the daunorubicin arm versus only 29% and 31% in mitoxantrone and idarubicin, respectively (P < .001). However, the disease-free survival (DFS) and survival from CR were significantly shorter in the daunorubicin arm: the 5-year DFS was 29% versus 37% and 37% in mitoxantrone and idarubicin, respectively. The proportion of patients who underwent allogeneic SCT (22%) was equivalent in the three treatment groups, and the outcome was similar as well. The [corrected] 5-year overall survival rates were 31%, 34%, and 34%, [corrected] respectively. CONCLUSION: In adult patients with AML who do not receive an allogeneic SCT, the use of mitoxantrone or idarubicin instead of daunorubicin enhances the long-term efficacy of chemotherapy.

Treatment of childhood T-cell lymphoblastic lymphoma according to the strategy for acute lymphoblastic leukaemia, without radiotherapy: long term results of the EORTC CLG 58881 trial.

From June 1989 through to November 1998, 121 children with newly diagnosed T-cell lymphoblastic lymphoma (T-LBL) were included in the EORTC 58881 trial conducted by the Children's Leukaemia Group. The therapy regimen was based on a Berlin-Frankfurt-Munster protocol, for a total duration of 24 months. Cranial irradiation, prophylactic cranial and local, was omitted, even for patients with central nervous involvement at diagnosis. In total, 119 patients were evaluable. The median follow-up was 6.7 years. The overall event-free survival (EFS) rate at 6 years was 77.5% (standard error (SE)=4%). Median time of relapse was 1 year after complete remission (range 0.2-5.9 years). Only two (1.8%) patients had an isolated central nervous system relapse. For patients with complete response (n=16) to the 7-day prephase, the EFS rate at 6 years was 100% versus 14% (P<0.001) for patients with no response (n=7). Overall survival rate at 6 years was 86% (SE=3%). An intensive acute lymphoblastic leukaemia type chemotherapy regimen without irradiation leads to a high cure and survival rate in childhood T-LBL without an increased CNS recurrence. This suggests that prophylactic cranial irradiation can safely be omitted. Response to the prephase appeared to be a strong prognostic factor for EFS.

Adjuvant regional chemotherapy and systemic chemotherapy versus systemic chemotherapy alone in patients with stage II-III colorectal cancer: a multicentre randomised controlled phase III trial.

BACKGROUND: Systemic adjuvant chemotherapy can improve overall survival and reduce the incidence of distant metastases for patients with advanced colon cancer. This study aimed to investigate whether regional chemotherapy (given by intraperitoneal or intraportal methods) combined with systemic chemotherapy was more effective than was systemic chemotherapy alone in terms of survival and recurrence for patients with stage II-III colorectal cancer. The study also compared systemic chemotherapy with fluorouracil and folinic acid with that of fluorouracil and levamisole. METHODS: During surgery, 753 patients with stage II-III colorectal cancer were randomly assigned to systemic chemotherapy alone (379 with fluorouracil and folinic acid, and 374 with fluorouracil and levamisole), and 748 to postoperative regional chemotherapy with fluorouracil followed by systemic chemotherapy with fluorouracil and folinic acid (n=368) or with fluorouracil and levamisole (n=380). Regional chemotherapy was given intraperitoneally (n=415) or intraportally (n=235) according to institution. The primary endpoint was 5-year overall survival. Secondary endpoints were 5-year disease-free survival and toxic effects. Analyses were by intention to treat. FINDINGS: Median follow-up was 6.8 years (range 0.0-10.1). 5-year overall survival was 72.3% (95% CI 69.0-75.6) for patients assigned regional and systemic chemotherapy, compared with 72.0% (68.7-75.3) for those assigned systemic chemotherapy alone (hazard ratio [HR] 0.97 [0.81-1.15], p=0.69). 5-year overall survival for all patients assigned fluorouracil and levamisole was 72.0% (68.7-75.2) compared with 72.3% (69.0-75.6) for all those assigned fluorouracil and folinic acid (HR 0.98 [0.82-1.17], p=0.81). The hazard ratios for 5-year disease-free survival were 0.94 (0.80-1.10) for regional versus non-regional treatment, and 0.92 (0.79-1.08) for all fluorouracil and levamisole versus fluorouracil and folinic acid. Grade 3-4 toxic effects were low in all groups. INTERPRETATION: Fluorouracil-based regional chemotherapy adds no further benefit to that obtained with systemic chemotherapy alone in patients with advanced colorectal cancer.