Treatment of children with metastatic soft tissue sarcoma with oral maintenance compared to high dose chemotherapy: report of the HD CWS-96 trial. Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Sequential high-dose chemotherapy for children with metastatic rhabdomyosarcoma.
We prospectively studied the efficacy of high dose therapy (HDT) versus an oral maintenance treatment (OMT) in patients with stage IV soft tissue sarcoma (STS).
                Both groups were pretreated with the CEVAIE combination consisting of carboplatin, etoposide, vincristine, actinomycin D, ifosfamide, and epirubicin. HDT consisted of a tandem cycle of thiotepa (600 mg/m(2)) plus cyclophosphamide (4,500 mg/m(2)) and melphalan (120 mg/m(2)) plus etoposide (1,800 mg/m(2)). This treatment was compared with OMT, consisting of four cycles trofosfamide (10 days 2 x 75 mg/m(2)/day) plus etoposide (10 days 2 x 25 mg/m(2)/day), and 4 cycles trofosfamide (10 days 2 x 75 mg/m(2)/day) plus idarubicin (10 days 4 x 5 mg/m(2)). Eligibility criteria were: diagnosis confirmed by reference pathology, primary stage IV, below 22 years of age, and having completed the study therapy.
                From 96 patients 45 were treated with HDT and 51 with OMT. The main risk parameters were equally distributed in both arms. After a median follow-up of 57.4 months, 11/45 (24.4%) patients in the HDT-arm and 26/51 (57.8%) patients in OMT-arm were alive. Kaplan-Meier analysis demonstrated an overall survival for the whole group of 0.27 (OMT group: 0.52, HDT group 0.27, log rank P = 0.03). The proportional hazard analysis for patients with rhabdomyosarcoma (RMS) or "RMS-like" tumors (77.1% of all patients) demonstrated an independent benefit of OMT on outcome.
                Oral maintenance therapy seems to be a promising option for patients with RMS-like stage IV tumors.
                (c) 2008 Wiley-Liss, Inc. In this randomized multicenter study of 136 patients, 6 courses of CHOP (cyclo-phosphamide/doxorubicin/vincristine/prednisone) followed by rituximab (CHOP-R) were compared with rituximab-supplemented high-dose sequential chemotherapy with autografting (R-HDS) to assess the value of intensified chemo-therapy as a first-line treatment for high-risk follicular lymphoma (FL) after the introduction of monoclonal antibodies. The analysis was intention to treat with event-free survival (EFS) as the primary endpoint. Complete remission (CR) was 62% with CHOP-R and 85% with R-HDS (P < .001). At a median follow-up (MFU) of 51 months, the 4-year EFS was 28% and 61%, respectively (P < .001), with no difference in overall survival (OS). Molecular remission (MR) was achieved in 44% of CHOP-R and 80% of R-HDS patients (P < .001), and was the strongest independent outcome predictor. Patients relapsing after CHOP-R underwent salvage R-HDS in 71% of cases. Salvage R-HDS had an 85% CR rate and a 68% 3-year EFS (MFU, 30 months). We conclude that (1) achieving MR is critical for effective disease control, regardless of which treatment is used; (2) R-HDS ensures superior disease control and molecular outcome than CHOP-R, but no OS improvement; and (3) CHOP-R failures have a good outcome after salvage R-HDS, suggesting that relapsed/refractory FL could be the most appropriate setting for R-HDS-like treatments. This trial was registered at www.clinicaltrials.gov as no. NCT00435955. The RMS4.99 study was designed to explore the role of multiple sequential high-dose chemotherapy cycles administered early in the treatment of children with metastatic rhabdomyosarcoma.
                Seventy patients were enrolled and received three cycles of initial standard chemotherapy, followed by a course of cyclophosphamide and etoposide to obtain peripheral blood stem cells (PBSC), then three consecutive high-dose combinations followed by PBSC rescue. This was followed by surgery and/or radiotherapy, after which a final maintenance treatment with six courses of vincristine, actinomycin D and cyclophosphamide was administered.
                Sixty-two patients underwent the high-dose chemotherapy phase. The 3-year overall survival (OS) and progression free survival (PFS) rates for the 70 patients were 42.3% (95% confidence interval [CI] 39.5-53.6) and 35.3% (95% CI, 24.3-46.5), respectively. By multivariate analysis survival correlated strongly with age > 10 years. In a subset of patients with only one or no unfavourable prognostic factors (age > 10 years, unfavourable site of primary tumour, bone or bone marrow involvement and number of metastatic sites >2) the PFS was significantly higher, i.e. 60.5% at 3 years.
                Our study confirms that patients with favourable prognostic characteristics have a better survival. The use of sequential cycles of high-dose chemotherapy did not appear of benefit for patients with metastatic rhabdomyosarcoma.
Overall, the results of this review do not justify the use of HDC with SCR as a standard therapy for children with metastatic rhabdomyosarcoma. However, all reported studies were possibly subject to significant bias, especially selection bias. This might have underestimated the measured effect of HDC. As a result, a clinically important excess of adverse risk patients in the HDC arms may explain the non-beneficial effect of HDC. Only a large prospective RCT will be able to answer the question of whether HDC with SCR adds to survival or not definitively.