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 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 -related cardiac toxicity and is High-dose (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- ,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-; 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. of the cycles developed DLT. No intrapatient escalation or Two consecutive cycles were administered with a 4 week dose reductions were allowed. interval. In order to receive the second cycle, patients should have recovered from any non-hematological grade III and IV toxicities, ANC should be above 1.5 ϫ 109/l, Results platelets over 100 ϫ 109/l and performance status had to be 0 or 1. If patients had not recovered from the first cycle, Patient characteristics 2 additional weeks were allowed for observation. Patients not recovered after that period were not to receive the Thirty-one patients were treated between September 1994 second cycle. and June 1996. Median age was 44 years (range 18–64). Patients were admitted to the hospital for chemotherapy Sixteen had high-risk breast cancer; 10 had metastatic administration for 36 to 48 h. Pre-hydration consisted of breast cancer (MBC); four had advanced ovarian cancer;

Bone Marrow Transplantation High-dose mitoxantrone and cyclophosphamide with G-CSF JL Pe´rez-Gracia et al 119 and one had metastatic Ewing sarcoma. Additional charac- Hematological toxicity teristics are described in Table 1. Grade IV neutropenia (ANC Ͻ0.5 ϫ 109/l) was universal with a median duration of 6 days. Neutropenia below Treatment administration 100/mm3 developed in 54 cycles (87%) and lasted a median period of 4 days when it was present. Platelet count All patients received the planned treatment. The median dropped below 20 ϫ 109/l in 30 cycles (48%), with a interval between the two cycles was 32 days (range 21–55). median recovery period of 4 days. Blood counts were per- Follow-up after each cycle was carried out in an outpatient formed 2 to 3 months after completing therapy. Twenty- setting, and only patients developing febrile neutropenia nine out of 30 patients showed WBC above 2.5 ϫ 109/l required additional hospital admission. There were no and 25 ANC of 1.5 ϫ 109/l or greater. Platelets were over toxic deaths. 100 ϫ 109/l in all patients. Hematological toxicity is described in Table 3. Platelet transfusions were required in 29 cycles (47%) Results of dose escalation and PRC were administered in 15 cycles (24%). Globally, Escalation proceeded up to the fourth level in which we some kind of transfusional therapy was performed in 21 found an unacceptable toxicity according to the established patients (68%): 19 (61%) received platelet transfusions, 12 criteria. Therefore, we chose the third level (MTZ 25 (39%) received PRC, and 10 patients (32%) required both mg/m2 and CTX 4000 mg/m2) as the MTD. The main DLT kinds of blood products. G-CSF was administered for a was hematological, especially ANC below 0.5 ϫ 109/l last- median period of 13 days (range 10–16). More information ing more than 7 days and platelets below 20 ϫ 109/l requir- is displayed in Table 4. ing more than one platelet transfusion. Non-hematological Febrile neutropenia occurred in 18 cycles (29%). Surpris- DLT included grade III emesis, asthenia and mucositis. ingly, the greatest incidence occurred at the first level More information is displayed in Table 2. which harbored half of the total number of episodes. Distri- bution of febrile neutropenia by levels was: level 1: nine episodes; level 2: one episode; level 3: five episodes; and level 4: three episodes. One patient, treated at the third Table 1 Patient characteristics level, developed a bacterial pneumonia shortly after receiv- ing the second cycle. She underwent a long-term grade IV Variable No. of % X Range neutropenia lasting 16 days and prolonged thrombopenia, patients requiring several platelet transfusions. She also had a mild renal failure with severe hypokalemia, probably due to Total patient number 31 — — — Age, years — — 44 18–64 nephrotoxic drugs. She finally recovered completely with- Diagnosis out requiring intensive care unit admission. In the rest of High-risk breast cancer 16 52 — — the patients, febrile neutropenia was uncomplicated. Nodes involved — — 7 2–15 Nodes disected — — 16 3–25 Receptor status Non-hematological toxicity Positive 9 56 — — Negative 7 44 — — Ten patients (16%) had grade III emesis. Overall, some Metastatic breast cancer 10 32 — — grade of emesis was present in 41 of the 61 cycles adminis- Previous response Partial 8 80 — — tered (66%). Grade III mucositis happened in six cycles Complete 1 10 — — (10%) and grade I or II mucositis in 11 cycles (18%). Mild IV NED 1 10 — — was frequently reported although there were only Receptor status five cases (9%) of grade III asthenia. No grade IV non- Positive 7 70 — — Negative 2 20 — — hematological toxicities were observed. Less frequent Unknown 1 10 — — adverse effects that could be attributed to chemotherapy Sites of metastasis were: diarrhea (one patient grade III and one grade II); Solitary 8 80 — — grade II hyperbilirubinemia (one episode) and hand–foot Lung 3 38 — — syndrome (one episode). Bone 2 25 — — Liver 1 13 — — There was no acute cardiac toxicity. LVEF data are avail- Nodal 1 13 — — able from 27 patients before and after treatment. Twenty- Bone five patients had both measurements done. Median LVEF Marrow 1 13 — — was 60% before treatment (range 50–67%) and median Multiple 2 20 — — Ovarian cancer 4 13 — — decrease of LVEF was 2.4%. There were two patients with Ewing sarcoma 1 3 — — a 12% decrease in LVEF, two with 9% and one with 8%. Prior 4-epirubicin 27 87 — — Median dose (mg/m2) — — 365 300–480 Long-term toxicity Doxorubicin 3 10 — — Median dose (mg/m2) — — 275 275–300 One patient, treated at the first level, developed congestive None 1 3 — — heart failure 2 years after treatment. She had received 450 mg/m2 of 4-epirubicin before high-dose therapy and she

Bone Marrow Transplantation High-dose mitoxantrone and cyclophosphamide with G-CSF JL Pe´rez-Gracia et al 120 Table 2 DLT distribution by dose levels

MTZ dose CTX dose No. No. NPa TPb Emesis Mucositis Asthenia Diarrhea Total Cycles with (mg/m2) (mg/m2) patients cycles (grade III) (grade III) (grade III) (grade III) No. DLT (%) DLT

Level 1 20 3000 9 18 — — 2 2 1 — 5 4 (22) Level 2 20 4000 7 14 2 — 1 — 1 — 4 4 (29) Level 3 25 4000 8 16 2 4 4311157(44) Level 4 30 4000 7 14 7 3 3 1 2 — 16 9 (64)

aGrade III neutropenia lasting more than 7 days. bPlatelets below 20 × 109/l requiring two or more platelet transfusions.

Table 3 Hematological toxicity and recovery One patient was diagnosed with myelodysplastic syn- drome 33 months after treatment. She was treated at the Variable Cycle No. of Median Range first level and developed a refractory anemia with excess episodes of blasts with translocation (1:3) and deletion of 6p and (%) 13q. The diagnosis was pursued after the development of moderate neutropenia and thrombopenia. She received a Nadir (day) 1 — 8.5 6–12 2 — 8.2 6–12 bone marrow transplant from her matched brother and is Overall — 8.3 6–12 currently asymptomatic. There were no other long-term Nadir 1 — 40 toxicities found, despite a minimum follow-up of 3 years (3 patients ANC = 0) for all the patients except one. (ANC × 109/l) 2 — 28 (6 patients ANC = 0) Overall — 33 (8 patients ANC = 0) Discussion No. days ANC 1 31 (100) 5.7 3–11 Ͻ0.5 × 109/l 2 31 (100) 6.3 3–16 The use of HDC for solid tumors, especially breast cancer, Overall 62 (100) 6.0 3–16 has been a matter of interest during the past years. The Day of recovery 1 — 12.4 11–17 results of the prospective trials released to date, have none- ANC Ͼ0.5 × 109/l 2 — 12.9 10–20 theless prompted the necessity of exploring variations in Overall — 12.6 10–20 the current design of HDC combinations, and several No. days ANC 1 24 (79) 3.7 1–7 9 a suggestions have been raised to increase their efficacy. The Ͻ0.1 × 10 /l 2 30 (97) 4.2 1–13 15 Overall 54 (87) 4.0 1–13 first is to select more adequately the drugs used, since this selection is too often based upon toxicity profiles rather Day of recovery 1 — 13.1 10–20 ANC Ͼ1.0 × 109/l 2 — 15.4 11–38 than on anti-tumoral activity. Indeed, many of the com- Overall — 14.3 10–38 monly used HDC schemes employ drugs that are not among No. days platelets 1 25 (81) 5.2 1–14 the most active ones at standard doses for the treatment Ͻ50 × 109/la 2 29 (94) 7.4 2–30 of breast cancer, such as , , BCNU or Overall 54 (87) 6.4 1–30 .6–11 In the second place, the possibility of disease Day of recovery 1 — 13.4 11–18 relapse due to reinfusion of hematological products con- platelets Ͼ50 × 109/l 2 — 18.2 12–40 taminated by neoplastic cells is another point of concern. Overall — 15.8 11–40 It is known that tumor cells may contaminate bone marrow No. days platelets 1 11 (35) 3.4 2–7 harvests as well as blood stem cell collections from breast Ͻ20 × 109/la 2 19 (61) 4.2 1–17 Overall 30 (48) 3.9 1–17 cancer patients, although the clinical relevance of this fact Day of recovery 1 — 13.7 12–17 is conflicting: some authors have not found an increased platelets Ͼ20 × 109/l 2 — 15 10–23 risk of relapse when there is tumor contamination of Overall — 14 10–23 grafts,29 while others have, at least for some patient sub- sets.30,31 Nonetheless, tumor contamination of reinfused aOnly includes data from cycles in which patients experienced this toxicity hematopoietic products has been correlated with disease (n = number of cycles). relapse in hematological as well as in solid tumors32,33 and may also have a role in breast cancer. The strategies to had a 50% LVEF before treatment. Although her LVEF avoid this potential contamination are either to purge the remained stable immediately after chemotherapy (51%) her reinfusion products or, as we did, to eliminate the use of latest measures ranged from 34 to 43%. We collected data hematological cell support. Finally, some authors have on LVEF from 14 patients carried out 1 year or later after hypothesized that a single cycle of HDC may be unable to treatment. Only three were below 50% (including the eradicate all cancer cells,34,35 based on tumor cell growth patient mentioned above and one who later received HDC considerations, and tandem cycles of HDC have been with hematopoietic support). Two of the patients who proposed. developed the greatest decreases in LVEF after treatment We have developed a regimen using high doses of MTZ (8% and 12%), showed normal results. and CTX that can be safely delivered in two consecutive

Bone Marrow Transplantation High-dose mitoxantrone and cyclophosphamide with G-CSF JL Pe´rez-Gracia et al 121 Table 4 Hematological support support. Seventy-four patients received the standard-dose treatment and 76 were randomized to the high-dose arm. Blood Cycle No. patients Median No. Range After a median follow-up of 5 years there was a significant product (%) units a disease-free survival improvement for the HDC arm (19% transfused vs 49%, P = 0.02) and a trend towards improved overall survival (OS) (40% vs 52%, P = 0.13) in very high-risk Platelets 1 11 (36) 1.2 1–2 у 10 2 18 (58) 1.8 1–10 patients ( 15 axillary nodes involved). Lotz et al ran- Overall 29 (47) 1.6 1–10 domized patients with MBC after four to six courses of conventional anthracycline-based chemotherapy to either Red cells 1 5 (16) 2.4 2–4 continue the same therapy or to receive high doses of MTZ 2 10 (32) 2.3 2–4 (45 mg/m2), CTX (120 mg/kg) and melphalan (140 mg/m2) Overall 15 (24) 2.3 2–4 with G-CSF and stem cell support. Twenty-nine patients received conventional treatment and 32 intensive therapy. The relapse rates at 2 years were lower for HDC (52% vs G-CSF Cycle Duration Range 27%) and median progression-free survival was also improved (15.7 vs 26.9 months, P = 0.04). Even though 1 12.6 10–16 2 12.9 10–16 OS was not statistically different, there was a trend favoring Overall 12.7 10–16 the intensive group (15.7 vs 36.1 months, P = 0.08). In an update of the results, relapse rates at 3 years still favored aCalculated over the number of cycles in which transfusions were required. the intensive group (50.8% vs 79.3%) and, although relapse rates at 5 years were nearly identical (90.8% vs 90.7%), the OS rate at that time still showed a similar trend favoring cycles without the use of hematopoietic stem cells. The HDC (18.5% vs 29.8%).42 Based on these results, it seems MTD achieved was MTZ 25 mg/m2 and CTX 4000 mg/m2. that intensification regimens containing high-dose MTZ These doses are higher than those previously reported using and CTX might be more active than those including just the same drugs with G-CSF support,36–38 and in fact they alkylating agents or drugs which are not very active at are very similar to the doses used in conventional HDC conventional doses. with hematopoietic cell support. Our regimen took place Long-term toxicity is frequently not reported in HDC mainly in an outpatient setting, representing a remarkable trials. In our study, after a minimum follow-up of 3 years advantage over the majority of the HDC programs. Patients we observed one episode of cardiac failure and one case were seen every 2 to 4 days and this provided a convenient of myelodysplasia. MTZ may cause decreases in the LVEF, control of both hematologic and non-hematologic toxicities. especially in patients treated with prior anthracyclines. The There were no episodes of bleeding related to thrombopenia patient developing cardiac failure had received 450 mg/m2 and, when required, blood and platetelet transfusions were of 4-epirubicin. This suggests that the level of prior anthra- performed at the day hospital. cycline exposure should be limited before treatment with Other investigators have reported HDC regimens that do high-dose MTZ. Myelodysplasia and other clonal hemato- not use hematological cell support, although the toxicity logical diseases such as acute leukemias have been was substantially higher than in our combination. Herzig et described following intensified chemotherapy for breast al39 employed high doses of CTX and , but tox- cancer. Although the reported 4-year probability in large icity was severe, with prolonged hematologic recovery per- series has been less than 2%,43,44 oncologists must be con- iods and a 6% treatment-related mortality rate, indicating cerned with the possibility of this complication when evalu- that the use of stem cell support could be warranted. Mor- ating the real efficacy of HDC and in the follow-up of gan et al40 delivered two cycles of high-dose CTX along these patients. with doxorubicin escalation, achieving a recommended In summary, we have been able to deliver two cycles of phase II dose of 150 mg/m2. Febrile neutropenia rates were high doses of MTZ and CTX with G-CSF after conven- around 70%, and all patients required long-term admissions tional chemotherapy, without requiring hematopoietic cell (median 23 days) and aggressive supportive care, including support. Acute toxicity was predictable and non-life- total parenteral nutrition in many cases. This indicates that, threatening, and treatment took place mainly in an out- although doxorubicin is one the most active single agents patient setting. This regimen avoids some potential draw- for breast cancer, its toxicity profile precludes it from being backs of HDC regimens currently employed. The combi- a good candidate for HDC. Finally, in a phase II trial nation is being further explored in a phase II trial directed reported by Neidhart et al,41 51 patients with refractory to obtain more data on toxicity as well as on efficacy. malignancies were treated with high doses of CTX, eto- poside and cisplatin with CSF support, and there were six non-disease-related deaths within 30 days after completing treatment. Some randomized trials have tested combinations includ- Acknowledgements ing high-dose MTZ for breast cancer treatment. Namer et al37 compared conventional therapy with CTX and doxoru- bicin vs MTZ 23 mg/m2 and CTX 600 mg/m2 in high-risk This research was funded in part by Wyeth-Lederle. The authors breast cancer patients (у10 involved nodes), with G-CSF wish to thank Dr JL Tisaire for his help.

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