Bone Marrow Transplantation (2001) 27, 117–123 2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt High-dose mitoxantrone and cyclophosphamide without stem cell support in high-risk and advanced solid tumors: a phase I trial JL Pe´rez-Gracia, R Colomer, A Ruiz-Casado, A Arcediano, MV Tornamira, C Go´mez-Martı´n, V Valentin, C Mendiola, H Corte´s-Funes and J Hornedo Division of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain Summary: due to scientific misconduct.14 Nonetheless, the interpret- ation of some of the negative reports has raised a number This phase I study was designed to develop a high-dose of issues such as the insufficient number of patients and combination of two cycles of mitoxantrone and cyclo- shortness of follow-up preventing detection of significant phosphamide in patients with solid tumors, as an alter- differences between the compared treatments, as well as the native to single-cycle high-dose regimens that use only inadequacy of some of the control arms.15 In addition, HDC alkylating agents. Treatment was delivered with gra- has proved its value in other neoplastic diseases such as nulocyte colony-stimulating factor (G-CSF), but without lymphomas,16,17 multiple myeloma18 and possibly germ cell stem cell support, in order to avoid potential tumor cell tumors,19–21 whenever the procedure and the indications reinfusion. Thirty-one patients with advanced solid have been adequately established. Therefore, while the cur- tumors received two cycles of high-dose mitoxantrone rently available data does not recommend the use of HDC 2 (20–30 mg/m ) plus high-dose cyclophosphamide (3000– in common clinical practice, the validation in the context 2 4000 mg/m ). All patients received G-CSF until hemato- of controlled clinical trials of alternative approaches that logic recovery. Dose-escalation was performed when less may improve its results is clearly warranted.15,22 than 50% of cycles per level had dose-limiting toxicity Different methods have been suggested in order to (DLT). The maximum tolerated dose (MTD) achieved 2 improve the efficacy of currently employed HDC regimens, was mitoxantrone 25 mg/m and cyclophosphamide such as using drugs other than just alkylating agents, avoid- 4000 mg/m2. Main dose-limiting toxicities (DLTs) were ing the risk of reinfusion of grafts contaminated by cancer hematological: grade IV neutropenia lasting more than cells or delivering more than a single cycle of HDC. We 7 days and thrombopenia below 20 × 109/l requiring planned a phase I trial to develop a HDC scheme applying more than one platelet transfusion. Non-hematological DLT consisted predominantly of grade III emesis and this rationale. This regimen was designed to be less toxic asthenia. Follow-up after each cycle was performed in than conventional intensive regimens and to be managed an outpatient setting and there were no toxic deaths. In mainly in an outpatient setting. Such a regimen could conclusion, the administration of two cycles of high-dose gather the potential advantages of HDC while being safer, mitoxantrone and cyclophosphamide with G-CSF sup- more affordable and avoiding the potential risks of tumor port is safe and feasible. MTD was mitoxantrone 25 cell reinfusion. mg/m2 and cyclophosphamide 4000 mg/m2. Evaluation For the design of our trial, we employed a combination of this regimen is being done in a phase II trial. Bone of mitoxantrone (MTZ) and cyclophosphamide (CTX), Marrow Transplantation (2001) 27, 117–123. drugs which have shown activity at standard doses, as sin- Keywords: breast cancer; ovarian cancer; colony-stimu- gle agents or in combination, in the treatment of several lating factors; dose intensification hematological and solid tumors, including breast can- cer.23,24 MTZ is a synthetic anthracenedione that does not produce the quinone-type free radicals that probably mediate the anthracycline-related cardiac toxicity and is High-dose chemotherapy (HDC) has been widely employed therefore associated with less cardiotoxicity. Myelosuppres- during the last years for the treatment of solid tumors, sion constitutes its dose-limiting toxicity. In vitro, MTZ had 1 2,3 especially breast cancer. Its use was based on preclinical a steeper dose–response effect in breast cancer models than 4,5 and phase II clinical studies. However, several ran- doxorubicin,2 which makes it a good candidate for HDC.25 domized trials have not found significant benefits for this When given along with colony-stimulating factors (CSF), 6–11 strategy either in the adjuvant or in the metastatic setting MTZ can be safely delivered in sequential cycles at doses and moreover, the author of the trials that more consistently 2 26,27 12,13 ranging from 28 to 32 mg/m . CTX is an alkylating showed a benefit for HDC has been recently discredited agent widely used in many HDC combinations. When administered with CSF, CTX can be delivered at doses up 2 28 Correspondence: Dr R Colomer, Division of Medical Oncology, Hospital to 7 g/m without hematopoietic support. Universitario 12 de Octubre, Avda., de Co´rdoba Km 5.4, 28041, Madrid, Spain Received 3 August 2000; accepted 26 October 2000 High-dose mitoxantrone and cyclophosphamide with G-CSF JL Pe´rez-Gracia et al 118 Patients and methods 3000 cm3 of dextrose-saline given over 12 h before treat- ment. CTX was administered diluted in 2000 cm3 of 5% Patient selection dextrose over 90 min. MTZ was then given diluted in 250 cm3 5% dextrose over 15 min. Post hydration consisted of Patients were included from the following diagnostic 4000 cm3 of dextrose-saline given over 24 h. Mesna was groups: metastatic cancer in complete or partial response administered before CTX (2 g/m2 i.v.) and with the post after standard chemotherapy, or with no evidence of disease hydration (3 g/m2 i.v.). Antiemetic therapy with ondasetron after surgery or radiotherapy (stage IV NED), and high-risk and dexamethasone was provided, as well as furosemide breast cancer (five or more positive axillary nodes) after after CTX to ensure proper diuresis. conventional adjuvant treatment. Additional inclusion cri- After chemotherapy, patients were discharged and they teria were: age 18 to 60 years, ECOG performance status were followed on an outpatient basis. They all received 0 or 1, life expectancy greater than 12 weeks, absence of subcutaneous granulocyte colony-stimulating factor (G- previous cardiovascular disease or other poorly controlled CSF) 300 ␮g/24 h and antimicrobial prophylaxis with oral medical illness, adequate cardiac, renal, hepatic and hema- ciprofloxacin 500 mg/12 h from the day of discharge until tological function (left ventricular ejection fraction (LVEF) ANC was above 0.5 ϫ 109/l. у 50% measured by resting multigated nuclear scans Once the two cycles had been completed, hormonal or Ͻ Ͻ (MUGA), creatinine 1.2 mg/dl; total bilirubin 1.5 radiation therapy was administered when indicated accord- Ͼ ϫ 9 mg/dl; absolute neutrophil count (ANC) 1.5 10 /l; and ing to standard criteria. No more chemotherapy treatment Ͼ ϫ 9 platelets 100 10 /l), informed consent prior to initiating was allowed until progression. therapy and adequate access to hospital (within 1 h). Exclusion criteria were: confirmed central nervous system metastases or carcinomatous lymphangitis; treatment with Follow-up and toxicity assesment chemotherapy or radiotherapy within 3 weeks prior to study entry; more than one previous regimen of prior chemo- Patients were seen every 2 to 4 days in an outpatient setting, therapy (including adjuvant or neoadjuvant therapy); treat- starting on the 6th day after discharge. Blood counts were ment with more than 350 mg/m2 of doxorubicin or 525 performed on each visit. Platelet transfusions were adminis- ϫ 9 mg/m2 of 4-epirubicin; and previous treatment with radio- tered if platelets were below 20 10 /l and packed red therapy through a left chest port. The protocol was cells (PRC) were transfused according to common clinical reviewed by an Ethics Committee. criteria. Transfusions were performed at the day hospital. Patients developing febrile neutropenia were admitted to the hospital and received standard treatment while main- Pre-treatment evaluation taining G-CSF. Toxicity was graded according to the World Health Organization (WHO) scale. Before treatment, all patients were evaluated with medical history, physical examination, blood counts and chemistry, and LVEF measured by MUGA. In high-risk breast cancer Definition of dose-limiting toxicity, maximum tolerated patients, distant disease was excluded by chest radiograph, dose and criteria for dose escalation bone scan and abdominal ultrasound or computerized tom- ography (CT). Ovarian cancer patiens were evaluated with Dose escalation was based on the number of patients who abdominal CT and chest radiograph or CT. Tumor markers experienced dose-limiting toxicity (DLT) during each were determined when appropriate. Other tests were perfor- cycle. DLT was defined as ANC below 0.5 ϫ 109/l lasting med when required according to clinical and/or comp- more than 7 days, platelets below 20 ϫ 109/l requiring more lementary examination data. MUGA was repeated after than one platelet transfusion or grades 3–4 non-hematolo- completing treatment. gical toxicity (excluding alopecia). Four patients were to be treated with two cycles at each level. Escalation to the next level proceeded if DLT was present in less than half Treatment plan of the cycles given at the previous level. If DLT occurred Four dose levels were established: level 1: MTZ 20 mg/m2 in one patient, three or four more patients were included at and CTX 3000 mg/m2; level 2: MTZ 20 mg/m2 and CTX the same level. Maximum tolerated dose (MTD) was 4000 mg/m2; level 3: MTZ 25 mg/m2 and CTX 4000 defined as the highest dose level at which less than 50% mg/m2; and level 4: MTZ 30 mg/m2 and CTX 4000 mg/m2.