High-dose mitoxantrone and cyclophosphamide without stem cell support in high-risk and advanced solid tumors: a phase I trial

Abstract

Summary:This phase I study was designed to develop a high-dose combination of two cycles of mitoxantrone and cyclophosphamide in patients with solid tumors, as an alternative to single-cycle high-dose regimens that use only alkylating agents. Treatment was delivered with granulocyte colony-stimulating factor (G-CSF), but without stem cell support, in order to avoid potential tumor cell reinfusion. Thirty-one patients with advanced solid tumors received two cycles of high-dose mitoxantrone (20-30 mg/m 2 ) plus high-dose cyclophosphamide (3000-4000 mg/m 2 ). All patients received G-CSF until hematologic recovery. Dose-escalation was performed when less than 50% of cycles per level had dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) achieved was mitoxantrone 25 mg/m 2 and cyclophosphamide 4000 mg/m 2 . Main dose-limiting toxicities (DLTs) were hematological: grade IV neutropenia lasting more than 7 days and thrombopenia below 20 × 10 9 /l requiring more than one platelet transfusion. Non-hematological DLT consisted predominantly of grade III emesis and asthenia. Follow-up after each cycle was performed in an outpatient setting and there were no toxic deaths. In conclusion, the administration of two cycles of high-dose mitoxantrone and cyclophosphamide with G-CSF support is safe and feasible. MTD was mitoxantrone 25 mg/m 2 and cyclophosphamide 4000 mg/m 2 . Evaluation of this regimen is being done in a phase II trial. Bone Marrow Transplantation (2001) 27, 117-123. Keywords: breast cancer; ovarian cancer; colony-stimulating factors; dose intensification High-dose chemotherapy (HDC) has been widely employed during the last years for the treatment of solid tumors, especially breast cancer. 1 Its use was based on preclinical 2,3 and phase II clinical studies. 4,5 However, several randomized trials have not found significant benefits for this strategy either in the adjuvant or in the metastatic setting [6][7][8][9][10][11] and moreover, the author of the trials that more consistently showed a benefit for HDC 12,13 has been recently discredited due to scientific misconduct. 14 Nonetheless, the interpretation of some of the negative reports has raised a number of issues such as the insufficient number of patients and shortness of follow-up preventing detection of significant differences between the compared treatments, as well as the inadequacy of some of the control arms. 15 In addition, HDC has proved its value in other neoplastic diseases such as lymphomas, 16,17 multiple myeloma 18 and possibly germ cell tumors, 19-21 whenever the procedure and the indications have been adequately established. Therefore, while the currently available data does not recommend the use of HDC in common clinical practice, the validation in the context of controlled clinical trials of alternative approaches that may improve its results is clearly warranted. 15,22 Different methods have been suggested in order to improve the efficacy of currently employed HDC regimens, such as using drugs other than just alkylating agents, avo...

High‐dose mitoxantrone and cyclophosphamide without stem cell support in patients with high‐risk and advanced breast carcinoma

“…An important concern for the clinical use of MTZ is its potential association with hematologic neoplasms, especially acute myelocytic leukemias. Even though no episodes were observed in the current study, one of the patients who was included in the previous Phase I trial developed a myelodisplastic syndrome 19. A recent retrospective review reported a significantly increased risk of acute leukemia for patients who were treated in the adjuvant setting with cumulative doses of MTZ > 13 mg/m 2 , although, in fact, most patients developing leukemia had received doses > 56 mg/m 2 17, 47.…”

“…In a previous Phase I trial, we developed a combination of two cycles of high‐dose mitoxantrone (MTZ) and cyclophosphamide (CTX) delivered with granulocyte‐colony stimulating factor (G‐CSF) but without stem cell support 19. The rationale for developing this combination was to select drugs for HDC based on their clinical efficacy at standard doses rather than just on their toxicity profile; to eliminate the use of hematopoietic cell support to avoid the risks of reinfusion of grafts contaminated by neoplastic cells and to make the procedure less complicated and less expensive; and to deliver two cycles of HDC rather than just one cycle.…”

Mitoxantrone Mediates Demethylation and Re-Expression of Cyclin D2, Estrogen Receptor 14.3.3 Sigma In Breast Cancer Cells

“…[1][2][3] Mitoxantrone is classified as a topoisomerase II inhibitor due to its ability to intercalate into DNA and interfere with strand breakage and rejoining, resulting in double strand breaks. 4 In addition, mitoxantrone can also be activated by formaldehyde in cell-free systems to bind covalently to DNA, 5 specifically at CpG and CpA sequences in DNA, producing labile drug-DNA adducts which can be detected as 'virtual' interstrand crosslinks.…”