Four-step high-dose sequential chemotherapy with hematopoietic progenitor-cell support as induction treatment for patients with solid tumors

Summary:Ten patients with refractory (n ‫؍‬ 8) or early relapsing (n ‫؍‬ 2) aggressive non-Hodgkin's lymphoma were enrolled in a pilot study evaluating a high-dose sequential chemotherapy regimen with peripheral blood stem cell (PBSC) support. Five treatment phases were scheduled: phase I (cyclophosphamide ؉ etoposide followed by lenograstim (G-CSF), and a PBSC harvest); phase II (cisplatinum ؉ cytarabine ؉ etoposide followed by lenograstim); phases III and IV (cyclophosphamide ؉ cytarabine ؉ etoposide followed by autologous PBSC infusion and lenograstim); and phase V (carmustine ؉ cytarabine ؉ etoposide ؉ melphalan followed by autologous PBSC infusion and lenograstim). Ten, nine, eight, six and four of the 10 patients received one, two, three, four and five of the five scheduled phases of treatment, respectively. Four patients were withdrawn from the study due to progressive disease and two due to thrombotic microangiopathy (TM). Moreover, in the four patients who completed all treatment phases, an additional case of TM was seen. In all three patients with TM, laboratory studies showed evidence of Coombs negative hemolytic anemia, thrombocytopenia, renal dysfunction and in addition cardiac failure in two patients. TM may be a new dose-limiting toxicity of high-dose sequential chemotherapy followed by repeated PBSC transplantation. Bone Marrow Transplantation (2001) 27, 531-536. Keywords: thrombotic microangiopathy; lymphoma; chemotherapy The role of high-dose chemotherapy (HDC) with autologous stem cell support in relapsed non-Hodgkin's lymphoma (NHL) has been clearly demonstrated in patients with chemosensitive relapse. 1,2 However, NHL patients who do not achieve a first complete remission or experience early relapse still have a very poor prognosis even when HDC

Section: Discussioncontrasting

confidence: 60%

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confidence: 99%

Thrombotic microangiopathy: a new dose-limiting toxicity of high-dose sequential chemotherapy

Vantelon

Bourhis

et al. 2001

“…Peripheral blood stem cell (PBSC) support can ameliorate the hematopoietic toxicity of intensive chemotherapy and allow maximal dose intensification. [3][4][5] PBSC can be mobilized with granulocyte colony-stimulating factor (G-CSF) following multi-agent chemotherapy and reinfused as a stem-cell rescue following severely myelosuppressive therapy. However, since metastic sarcomas often have marrow involvement, tumor contamination in PBSC collections may contribute to relapse.…”

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confidence: 99%

RT-PCR evaluation of peripheral blood, bone marrow and peripheral blood stem cells in children and adolescents undergoing VACIME chemotherapy for Ewing’s sarcoma and alveolar rhabdomyosarcoma

Thomson

Hawkins

Felgenhauer

et al. 1999

Summary:Peripheral blood stem cell support allows dose intensification of multiple cycle chemotherapy for metastatic tumors, including pediatric sarcomas. The VACIME protocol (vincristine, adriamycin, cyclophosphamide, ifosfamide, mesna and etoposide) utilizes peripheral blood stem cells (PBSC) collected following the treatment cycle as support for subsequent dose-and timeintensive chemotherapy. A critical assumption is that PBSC collected in this manner will be purged of residual tumor cells in vivo. We tested this assumption using sensitive reverse-transcriptase polymerase chain reaction (RT-PCR) to assess the presence of the characteristic translocations of the Ewing's sarcoma family of tumors (ESFT) and alveolar rhabdomyosarcoma (ARMS), t(11;22), and t(2;13), respectively. We used RT-PCR to evaluate 122 samples of peripheral blood (PB), bone marrow (BM) and PBSC collected from 12 pediatric patients with metastatic ESFT and ARMS. The samples included pre-therapy BM and PB, as well as BM, PB, and PBSC collections at various times in the VACIME treatment course. Molecular evidence of tumor contamination was detected in 1/40 PBSC collections from 12 patients. In all patients, we documented clearance of disease by RT-PCR in peripheral blood and bone marrow by week 9 of the VACIME protocol. In vivo purging in combination with the intensive VAC-IME regime appears to be effective in removing tumor cells from PBSC, bone marrow, and peripheral blood as detected by RT-PCR.

“…The most commonly used drugs in published repetitive high-dose therapy regimens have been the alkylating agents, carboplatin and the anthracyclines. Although the results of studies utilizing doseescalated anthracyclines are promising, [19][20][21][22] our protocol did not incorporate these agents as we predicted that the population of patients considered for such therapies were likely to have previously failed an anthracycline-based regimen. This was the case with 72% having received a prior anthracycline.…”

Section: Discussionmentioning

confidence: 99%

Repetitive high-dose therapy with cyclophosphamide, thiotepa and docetaxel with peripheral blood progenitor cell and filgrastim support for metastatic and locally advanced breast cancer: results of a phase I study

Prince

Rischin

Toner

et al. 2000

Summary:This phase I study was designed to determine the optimal dosages of a novel repetitive high-dose therapy regimen for patients with metastatic breast cancer (MBC). The planned treatment was three cycles of high-dose cyclophosphamide, thiotepa and docetaxel delivered every 35 days with progressive dose-escalation in successive cohorts. Each cycle was supported by peripheral blood progenitor cells (PBPC) and filgrastim. Eighteen patients were entered into this trial. Of the planned 54 treatment cycles, 44 were delivered and 11 patients completed all three cycles. The dose-limiting toxicities were interstitial pneumonitis and mucositis with moderately severe diarrhea (n = 3) and rash (n = 3). There were no treatment-related deaths. Of the 17 patients with evaluable disease, 16 patients responded with six patients achieving a complete remission and an additional four patients achieving no detectable disease (negative restaging including PET scan) but a persistently abnormal bone scan. At a median follow-up of 12 months, median progression-free survival was 11 months with the median overall survival not reached. must still be considered investigational. 6-8 Nonetheless, one approach considered worthy of further investigation is the use of repeated cycles of HDT. 6 We have been interested in developing protocols utilizing repetitive cycles of HDT for patients with MBC, based on administering three cycles of HDT, with each cycle supported by PBPCs.9-11 The primary objective of this study was to develop a suitable regimen that could be delivered largely on an out-patient basis (ie not requiring parenteral nutrition or opiate analgesia for gastrointestinal toxicity) that could subsequently be tested in a randomized trial in patients with MBC.We have previously reported our results of repetitive cycles of HDT using a combination of ifosfamide, thiotepa and paclitaxel (ITP). 9 However, in that study, two patients developed grade 3 renal tubular acidosis (RTA) and we later recognized a further case of RTA in the subsequent phase II study of this regimen.12 Consequently, it was considered that this ifosfamide-related side-effect was unacceptable and in the current study we substituted cyclophosphamide for ifosfamide. Furthermore, as the planned randomized study was to utilize docetaxel in the conventionaldose therapy (CDT) arm, we have substituted docetaxel for paclitaxel in this high-dose therapy regimen. Materials and methods Eligibility criteriaPatients with histologically proven metastatic or locally advanced breast cancer were eligible for entry into this prospective trial. Sufficient PBPCs to support these three cycles of HDT were collected prior to the initiation of HDT (see below). Patients were ineligible if they had a history of prior docetaxel therapy, ventricular arrhythmia, myocardial infarction within 6 months of enrolment, congestive heart failure, hypersensitivity to any of the study drugs, were pregnant or lactating, had an ECOG performance status Ͼ2, life expectancy of less than 2 months, absolute ne...