BACKGROUND Topotecan, a topoisomerase I inhibitor, acts by stabilizing the topoisomerase DNA cleavage complex. Etoposide, a topoisomerase II inhibitor, mediates antitumor activity by stabilizing cleavage complex formed between topoisomerase II and DNA. These two agents have therapeutic activity in non‐Hodgkin lymphoma. The authors report Phase I data of topotecan and etoposide combination for patients with recurrent or refractory non‐Hodgkin lymphoma and correlation of topoisomerase–DNA complex formation to clinical response. METHODS Twenty‐two patients with recurrent or refractory aggressive non‐Hodgkin lymphoma were treated at four dose levels of topotecan (1 mg/m2/day to 2.5 mg/m2/day). Topotecan was given at a 30‐minute infusion daily with etoposide 150 mg/m2/day, both for 5 days. Topoisomerase–DNA covalent complex formation was measured using in vivo link assay, whereas topoisomerase I, IIα, and IIβ in RNA expression levels were determined by reverse transcription–polymerase chain reaction in blood samples. The relation of these levels to clinical response was studied. RESULTS The maximum tolerated dose of topotecan was 2.0 mg/m2/day for 5 days. Oropharyngeal mucositis was dose‐limiting. Of 21 examinable patients, 3 patients achieved complete remission, and 5 patients achieved partial remission. Of six untreated patients who experienced a recurrence, three had complete remission, and the other three had partial remission. Drug‐induced topoisomerase–DNA complex formation was observed throughout the treatment in blood samples of all the patients who responded. However, only 4 of 13 patients, who did not respond, formed covalent complex at all time points. This was statistically significant (P = 0.024). In all patients, expression levels of topoisomerase I and IIβ mRNA remained similar to pretreatment levels, whereas topoisomerase IIα mRNA levels decreased dramatically by the third day. CONCLUSION The recommended Phase II dose of topotecan with etoposide of 150 mg/m2/day for 5 days was 2.0 mg/m2/day for 5 days. Topoisomerase–DNA complex formation correlated with response to treatment. Cancer 2001;91:463–71. © 2001 American Cancer Society.
BACKGROUNDMalignant astrocytomas are among the most resistant tumors to curative treatments. Mean survival without treatment is measured in weeks, and even with maximal surgery and radiation, the mean reported survival is < 1 year. The advent of supportive treatments and newer agents has resulted in benefits for many patients with cancer. The authors investigated the safety and effect on survival of a high‐dose thiotepa and carboplatin regimen with autologous stem cell transplantation (ASCT) in patients with malignant astrocytomas who were enrolled in a prospective trial approved by an institutional review board (IRB).METHODSTwenty‐one patients were enrolled in an IRB‐approved, prospective trial. After baseline testing was completed, patients underwent peripheral stem cell mobilization with cyclophosphamide (4 g/m2) and etoposide (450 mg/m2) followed by granulocyte–colony‐stimulating factor (10 μg/kg). Peripheral stem cells were harvested when leukocyte counts recovered. Patients received 2 cycles of thiotepa (750 mg/m2) and carboplatin (1600 mg/m2) followed by infusion of the preserved stem cells. The cycles were administered 6–10 weeks apart. Primary outcome measures were patient survival (Kaplan–Meier analysis) and treatment toxicity (using National Cancer Institute common toxicity criteria).RESULTSAutologous stem cells were harvested effectively and transfused in all patients. Kaplan–Meier survival analysis demonstrated a survival time of 34.3 ± 5.5 months (range, 9–94 months). Despite significant myelosuppression, only three patients experienced Grade 4 complications and eight experienced Grade 3 complications.CONCLUSIONSHigh‐dose chemotherapy with thiotepa and carboplatin with concomitant ASCT was used safely to treat patients with malignant astrocytomas and may provide a survival advantage. Cancer 2004. © 2004 American Cancer Society.
Summary:Forty-five patients with metastatic breast cancer without clinically evident disease were treated with thiotepa 750 mg/m 2 , mitoxantrone 40 mg/m 2 and carboplatin 1000 mg/m 2 followed by stem cell transplantation to determine the safety and efficacy of CD34 + selection of peripheral blood stem cells. Of these, 15 patients' (group I) stem cells were processed through Baxter Isolex 300 device for CD34 + selection, whereas 30 patients (group II) received unmanipulated stem cells. Toxicity, progression-free survival and survival were compared between these two groups. There was no difference in transfusion requirements, white cell count and platelet recovery and non-hematologic toxicity between the two groups. The survival of patients in group I was 27 months compared to 38 months in group II (P = 0.8). The progression-free survival was 12 months and 13.5 months for group I and group II patients, respectively (P = 0.6). Our results indicate that while there is no adverse effect, there is also no significant advantage of CD34 + selection in terms of progression-free survival and survival in patients with metastatic breast cancer without clinically evident disease. Bone Marrow Transplantation (2000) 25, 1041-1045. Keywords: CD34 + selection; PBSC transplantation; metastatic breast cancer High-dose chemotherapy (HDC) with peripheral blood stem cell (PBSC) transplantation has been shown to be effective in patients with metastatic carcinoma of the breast. [1][2][3][4] In patients who achieve a complete remission with chemotherapy, long-term disease-free survival can be obtained by a variety of different HDC regimens. 1,2,5,6 The use of high-dose chemotherapy with stem cell rescue has allowed dose-intensity to be maximized and morbidity and mortality to be reduced. In fact, in most series, peri-transplant mortality now is below 5%. 4,7 This has allowed wide- [12][13][14] In order to reduce the risk of relapse due to tumor cells in the PBSC preparation, a variety of techniques has been applied. Negative selection techniques using chemotherapeutic agents or monoclonal antibodies have been shown to deplete tumor cells by 3 logs. 15,16 Selection techniques that enrich the preparation with CD34 + cells and deplete tumor cells in the PBSC preparation have also been used. [17][18][19] We investigated the use of CD34 + selection in patients with metastatic breast cancer undergoing HDC with PBSC, and compared the results to those noted in other patients with metastatic breast cancer undergoing identical conditioning and post-transplant care whose stem cell product was not CD34 + selected. Materials and methods Patient selectionForty-five consecutive patients with metastatic breast cancer that had been rendered free of clinically evident disease by using chemotherapy only or in combination with surgery, radiation or hormonal manipulations were eligible for PBSC transplantation following dose-intensive therapy.Patients were required to have histological documentation of breast cancer, age over 18 years, performance status...
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