Toxicity Of High-dose Chemotherapy Research Articles

High dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HPSCT) with subsequent immunotherapy in metastatic breast cancer (MBC): Final results of a phase I stud

726 Introduction: This phase-I study prospectively analysed the efficacy and toxicity of HDCT, HPSCT and subsequent immunotherapy with T–cell reinfusion in chemotherapy-sensitive patients with MBC. Patients and methods: After leukapheresis and cryopreservation of T-cells, patients received 2 cycles of standard chemotherapy ET (epirubicin/paclitaxel) and 1 cycle of EI (epirubicin/ifosfamide) followed by G-CSF and stem cell harvest. After a third cycle of ET, responders (CR/PR) underwent HDCT (thiotepa 600 mg/m2/melphalan 140–180 mg/m2) and HPSCT. Once hematopoietic reconstitution was achieved, T-cells were reinfused followed by application of bispecific antibodies against HER-2/neu and EpCAM. Results: Thirty-three patients were recruited on study, and nineteen pts who had responded to initial standard chemotherapy (4 CR, 15 PR, OR = 58%) underwent HDCT and HPSCT. Subsequently, another 6 patients achieved a CR after HDCT resulting in an overall CR rate of 10/33 pts (30%). Two early deaths were observed (one toxic, one PD). T-cell reinfusion and bispecific antibodies were given to 17 patients. The main side effects during HDCT were severe (grade 3 / 4) hematotoxicity, mucositis, gastrointestinal toxicity. Elevated liver enzymes (grade 2 / 3) were seen in all patients. The intravenous application of bispecific antibodies resulted in intermittent fever and chills. Within a follow-up period of 54.7 to 79.1 months, all patients relapsed, and two patients are still alive. The median progression-free survival was 10.6 months (range: 2.1–31.2) and the median overall survival was 22.7 months (range: 1.8–79.1+). Conclusion: Despite a high complete remission rate and despite a novel immunotherapeutic approach including bispecific antibodies and T-cell reinfusion, HDCT and subsequent HPSCT failed to induce a major improvement of survival in chemosensitive patients with metastatic breast cancer. No significant financial relationships to disclose.

Thiotepa-Based High-Dose Chemotherapy With Autologous Stem-Cell Rescue in Patients With Recurrent or Progressive CNS Germ Cell Tumors

To evaluate the efficacy and toxicity of high-dose chemotherapy (HDC) followed by autologous stem-cell rescue (ASCR) in patients with relapsed or progressive CNS germ cell tumors (GCTs). Twenty-one patients with CNS GCTs who experienced relapse or progression despite having received initial chemotherapy and/or radiotherapy were treated with thiotepa-based HDC regimens followed by ASCR. Estimated overall survival (OS) and event-free survival (EFS) rates for the entire group 4 years after HDC were 57% +/- 12% and 52% +/- 14%, respectively. Seven of nine (78%) patients with germinoma survived disease-free after HDC with a median survival of 48 months. One patient died as a result of progressive disease (PD) 39 months after HDC, and another died as a result of pulmonary fibrosis unrelated to HDC 78 months after ASCR without assessable disease. However, only four of 12 patients (33%) with nongerminomatous germ cell tumors (NGGCTs) survived without evidence of disease, with a median survival of 35 months. Eight patients with NGGCTs died as a result of PD, with a median survival of 4 months after HDC (range, 2 to 17 months). Patients with germinoma fared better than those with NGGCTs (P =.016 and.014 for OS and EFS, respectively). Patients with complete response to HDC also had significantly better outcome (P <.001 for OS and EFS) compared with patients with only a partial response or stable disease. There were no toxic deaths because of HDC. Dose escalation of chemotherapy followed by ASCR is effective therapy for patients with recurrent CNS germinomas and might be effective in patients with recurrent NGGCTs with a low tumor burden.

Adjuvant treatment of high-risk stage II breast cancer with doxorubicin followed by high-dose chemotherapy and autologous stem-cell transplantation: a single-institution experience with 132 consecutive patients.

Several studies have shown conflicting results with the use of intensive consolidation chemotherapy for breast cancer. The aim of the present study was to investigate the efficacy, feasibility and toxicity of high-dose chemotherapy with stem cell support in patients with high-risk stage II breast cancer. From February 1994 to November 1998, 132 consecutive patients with multinode positive breast cancer were entered to the study. In total, 86 patients had >or=10 positive axillary lymph nodes, and 46 had 4-9 positive axillary lymph nodes with at least two additional predetermined risk factors at diagnosis. All patients were offered adjuvant chemotherapy (doxorubicin, 75 mg/m(2) x 4) followed by high-dose chemotherapy (cyclophosphamide 6000 mg/m(2), carboplatin 800 mg/m(2) and thio-tepa 500 mg/m(2)) and autologous stem cell support with growth factor. In all, 131 patients also received local radiation therapy and tamoxifen based on receptor status. After a median follow-up of 51 months (range 27-87), the disease-free and overall survival rates were 72 and 81%, respectively. There was no difference in the outcome for high-risk patients with > or < than 10 positive axillary lymph nodes. On Cox regression analysis only progesterone receptor status was predictive of disease-free, but not overall survival. There were no treatment-related deaths; grades III-IV toxicity was relatively low. This combined approach of doxorubicin followed by high-dose chemotherapy and stem-cell support, followed by locoregional radiotherapy, was safe and seems to be effective in patients with multinode positive stage II breast cancer. In previous trials of adjuvant high-dose therapy in this patient population, treatment-related morbidity and mortality markedly influenced the outcome. For this high-risk patient population, further testing of intensive chemotherapy regimens with a lower toxicity profile is warranted.

P.41 Efficacy of glutamine vs whole protein supplementson gastrointestinal toxicity of high dose chemotherapy in autologous hemopoietic transplant

P.41 Efficacy of glutamine vs whole protein supplementson gastrointestinal toxicity of high dose chemotherapy in autologous hemopoietic transplant

Incidence and prevention of nonhaematological toxicity of high-dose chemotherapy.

The introduction of the haematopoietic growth factors (HGFs), together with the evolution of techniques to harvest haematopoietic stem cells from the peripheral blood, have greatly facilitated the use of high-dose chemotherapy (HDC). While haematological toxicity of HDC is no longer dose-limiting, damage to other tissues has become more pronounced. In fact, nonhaematological toxicity (NHTOX) is now often dose-limiting in HDC regimens. NHTOX associated with HDC regimens depends on the type and dose of the drugs used, the physical condition and the characteristics of the patients treated and the given comedication. We describe the most important toxic effects of commonly used HDC programmes, such as nausea, vomiting, and mucositis, neutropaenic fever and sepsis, various major organ toxicities, catheter-associated problems and long-term complications. In addition, we discuss the possibilities of preventing these side-effects and what action to take if they occur.

Feasibility and toxicity of high-dose chemotherapy with/without BCNU for autologous bone marrow transplantation (ABMT) in breast carcinoma

Feasibility and toxicity of high-dose chemotherapy with/without BCNU for autologous bone marrow transplantation (ABMT) in breast carcinoma

High-dose chemotherapy with busulphan and cyclophosphamide and bone-marrow transplantation for drug-sensitive malignancies in adults: a preliminary report.

The technique of high-dose chemotherapy and bone-marrow transplantation takes advantage of any potential dose-response effect in the treatment of cancer and the ability of infused marrow to circumvent severe myelotoxicity. We report our initial experience of 20 high-dose chemotherapy procedures with busulphan and cyclophosphamide as the treatment regimen. Autologous (14 patients), human leukocyte antigen-matched, sibling-allogeneic (five patients) and identical-twin (one patient) transplantations were performed in patients with leukaemias (12 patients), lymphomas (seven patients) or a germ-cell tumour (one patient). One in-hospital and one late death occurred as a result of the toxicity of high-dose chemotherapy. All evaluable patients demonstrated bone-marrow engraftment and became independent of blood transfusions. Five of six patients who were treated in partial remission or relapse obtained a complete remission. Seven patients have relapsed. Eleven patients currently are alive and disease-free and nine patients have returned to their full-time occupations. High-dose chemotherapy can be undertaken with an over-all morbidity that is similar to that which is experienced during the induction chemotherapy of acute leukaemia.

Current problems and future goals in clinical bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) is associated with the cumulative toxicity of high dose chemotherapy and/or radiation therapy regimens currently in use, with acute and chronic graft vs host disease (GVHD), as well as with the consequences of delayed immunological reconstitution due to slow maturation of the immune system and drugs currently used for prevention of GVHD. Although GVHD may be overcome by T-cell depletion it leads to an increased incidence of graft rejection and relapse of the original malignancy. These too represent major problems. Autologous BMT results in high relapse rates due to lack of immune-mediated allogeneic interactions of grafted cells against tumor cells of the host. In view of the fact that experiments in animal models of human disease suggest that antileukemic effects of allogeneic marrow grafts may be partially independent of GVHD, new approaches for amplification of antitumor effects of autologous and allogeneic cells by cytokines and by lymphokine-activated cells are discussed. Evidence for antileukemia effects of IL-2 therapy in animals is presented. Beneficial effects of several cytokines in autologous and allogeneic BMT are suggested by significant facilitation of immunological and hematopoietic reconstitution following transplantation of bone marrow cells treated in vitro with cytokines (including ASTA-Z-purged marrow) and following in vivo administration of cytokines in conjunction with BMT. Overall, in view of several innovative biological interventions, it seems that significant progress in autologous and allogeneic BMT may be underway; the concept yet to be established is that successful and less risky BMT may be accomplished by replacing aggressive chemoradiotherapy regimens with sophisticated immunomanipulations and biological response modifying agents.