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ANTICANCER RESEARCH 27: 1009-1014 (2007)

Dosage of and Combination Therapy in Patients with Metastatic

SHINJI OHNO1, SHOSHU MITSUYAMA2, KAZUO TAMURA3, REIKI NISHIMURA4, MAKI TANAKA5, YUZO HAMADA6, SHOJI KUROKI7 and THE KYUSHU BREAST CANCER STUDY GROUP

1Department of Breast Oncology, National Kyushu Cancer Center Hospital, 3-1-1 Notame, Minami-ku, Fukuoka 811-1395; 2Department of Surgery, Kitakyushu Municipal Medical Center, 2-1-1 Bashaku, Kokurakita-ku, Kitakyushu City, Fukuoka 802-0077; 3First Department of Internal Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0818; 4Department of Breast and Endocrine Surgery, Kumamoto City Hospital, 1-1-60 Kotoh Kumamoto City, Kumamoto 862-8505; 5Department of Surgery, Social Insurance Kurume Daiichi Hospital, 21 Kushihara-machi, Kurume City, Fukuoka 830-0013; 6Department of Breast Surgery, Hirose Hospital, 1-12-12 Watanabedouri Chuo-ku, Fukuoka 810-0004; 7Department of Surgery and Oncology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

Abstract. Background: Capecitabine is a highly effective and therapy is distressing for women and can lead patients well-tolerated treatment for metastatic breast cancer (MBC) and to consider stopping therapy (1). Intense nausea associated extends survival when combined with . Capecitabine with -based therapy also adversely affects and cyclophosphamide are orally administered and have patients' quality of life (2). Therefore a preclinical synergy and non-overlapping toxicities. Patients and regimen that minimises these effects is likely to be attractive Methods: Sixteen pretreated MBC patients received escalating to patients. Another important consideration with taxane- doses of oral capecitabine 628 to 829 mg/m2 twice daily (bid) and anthracycline-based therapies is the need for regular plus oral cyclophosphamide 33 to 50 mg/m2 bid, on days 1 to 14 clinic visits or hospitalisations for intravenous administration every 21 days. Results: Among the ten patients receiving of chemotherapy, which are inconvenient and disruptive. The capecitabine/cyclophosphamide 829/33 mg/m2 bid on days 1 to majority of patients prefer oral to intravenous chemotherapy, 14, two experienced dose-limiting toxicities (DLT, treatment delay providing efficacy is not compromised (3-5). In patients with >1 week due to grade 2 leukopenia). Because neither patient a strong preference for oral therapy or a fear of needles, developed further grade >1 toxicity and none of the patients patients in whom venous access is problematic, or those who experienced grade 3/4 toxicities or further DLTs, this dose level have difficulty in regularly attending a cancer centre for is the recommended regimen, producing partial responses in two intravenous therapy, active oral therapy is appealing. The of five evaluable patients. Conclusion: The recommended all oral combination of capecitabine and cyclophosphamide capecitabine/cyclophosphamide combination regimen is well potentially provides an attractive, all oral alternative, giving tolerated and active in MBC, and is being evaluated in a phase II patients more freedom and a sense of control over their study in anthracycline-pretreated MBC. treatment. Both cyclophosphamide and capecitabine have Anthracycline- or taxane-based regimens are standard demonstrated efficacy in breast cancer in a range of settings. for metastatic breast cancer (MBC). Cyclophosphamide is typically used as a component of However, associated with both anthracycline and combination regimens, such as AC ( and cyclophosphamide) and fluoropyrimidine-based combination regimens including CMF (cyclophosphamide, and 5- (5-FU)). Capecitabine monotherapy has Correspondence to: Shinji Ohno, Department of Breast Oncology, shown excellent efficacy and safety in pretreated MBC (6-9) National Kyushu Cancer Center Hospital, 3-1-1 Notame, Minami- and as first-line monotherapy (10). The high single-agent ku, Fukuoka 811-1395, Japan. Tel: +81 92 541 3231, Fax: +81 92 activity and unique safety profile of capecitabine, including a 542 8503, e-mail: [email protected] particularly low incidence of myelosuppression and absence Key Words: Metastatic breast cancer, cyclophosphamide, of alopecia, provide a strong rationale for incorporating capecitabine, oral chemotherapy, phase I trial. capecitabine into combination regimens. In addition, the

0250-7005/2007 $2.00+.40 1009 ANTICANCER RESEARCH 27: 1009-1014 (2007) crucial role of intratumoral (TP) in The maximum tolerated dose (MTD) was determined by the activation of capecitabine to 5-FU (11) makes assessing safety during the first two cycles. In the event of safety capecitabine a logical combination partner for therapies that concerns at dose level 1, patients would be enrolled at dose level -1 (capecitabine/cyclophosphamide: 502/33 mg/m2 bid). If no up-regulate TP. Several chemotherapeutic agents, including DLTs occurred in the first three patients, the dose would be cyclophosphamide, docetaxel and , up-regulate increased to the next level. If only one of the three patients intratumoral TP and have demonstrated synergistic experienced a DLT, three additional patients would be treated at antitumour activity in combination with capecitabine, that dose level, and in the absence of further DLTs the dose providing a clear rationale for these combinations in the would be escalated to the next level. If DLTs occurred in two or clinical setting (12, 13). Randomised clinical trials have more of a cohort of six patients, this dose would be considered already demonstrated that the addition of capecitabine to the MTD. If only three patients had been treated at the preceding dose level, three additional patients would be treated at the docetaxel significantly improves response rate, time to preceding dose level to confirm the recommended dose (RD). If progression and overall survival compared with docetaxel the MTD was not reached at dose level 3, level 3 would be alone in anthracycline-pretreated patients (14) and considered the RD. compared with sequential docetaxel followed by capecitabine as first-line therapy (15). Dose modifications. From cycle 3 onwards, capecitabine and Based on the good tolerability, low incidence of alopecia cyclophosphamide treatment would be interrupted if patients and oral administration of cyclophosphamide and experienced haematological or non-haematological toxicity (excluding hand-foot syndrome (HFS) grade >2) or grade 3 HFS. capecitabine, together with their preclinical synergy, a In patients experiencing a grade 2 adverse event, treatment would dosage study was conducted to evaluate the safety and be withdrawn and resumed at the same dose only when symptoms efficacy of an all oral combination of capecitabine and resolved to grade 0 or 1. If a grade 3 toxicity occurred, treatment cyclophosphamide in patients with MBC and to determine would be interrupted until symptoms resolved to grade 0-1 and the optimum dosing schedule. then treatment would be resumed at 75% of the previous dose. If a grade 4 toxicity occurred, treatment would be discontinued Patients and Methods permanently. If treatment was interrupted for >3 weeks, the patient would be withdrawn from the study. Eligibility. Eligibility criteria included: histologically or cytologically confirmed MBC; age 20 to 74 years; ECOG Performance Status 0 Study assessments. The following tests were conducted within two to 2; at least one prior in the adjuvant or weeks prior to the start of chemotherapy and every week during metastatic setting; resolution of all toxicities from prior therapy; the first two treatment cycles: general haematology, blood adequate vital organ functions (serum haemoglobin concentration chemistry and physical examination for other subjective and ≥9.0 g/dl, neutrophil count ≥2,000/mm3, platelet count objective symptoms/clinical findings. During cycles 3 to 6, these ≥100,000/mm3, aspartate aminotransferase (AST) and alanine tests were conducted immediately before each treatment cycle aminotransferase (ALT) <1.5 x upper normal limit (UNL) of range and at the study end. The performance status was evaluated set by the institution (in cases of hepatic metastasis, ≤3 x UNL, before starting each treatment cycle and at the study end. alkaline phosphatase ≤2.5 x UNL, serum creatinine <1.5 x UNL, Adverse events were monitored and recorded throughout the serum total bilirubin <1.25 x UNL, and normal electrocardiogram)); treatment (NCI CTC). The tumour status was monitored four creatinine clearance >50 ml/min; life expectancy ≥3 months; no weeks prior to the start of treatment, before the start of cycles 3 symptomatic central nervous system metastases and no infectious and 5, and at the end of treatment, using chest X-ray, computed complications. All patients provided written informed consent. tomography (CT) and magnetic resonance imaging (MRI), evaluation of serum tumour markers, and relevant ultrasound Treatment plan. Patients received up to six 3-week cycles of examination and bone scintography (if possible). The tumour capecitabine and cyclophosphamide administered orally twice daily response was determined using the Response Evaluation Criteria (bid) on days 1 to 14, followed by a drug-free interval from day 15 in Solid Tumors (RECIST) (17). to day 21. Three escalating dose levels were planned: level 1 (capecitabine/cyclophosphamide: 628/33 mg/m2 bid); level 2 Results (capecitabine/cyclophosphamide: 829/33 mg/m2 bid); level 3 (capecitabine/cyclophosphamide: 829/50 mg/m2 bid). Patient characteristics. Between August 2003 and February Adverse events were graded according to National Cancer 2004, nine patients (six at dose level 1, three at dose level Institute Common Toxicity Criteria (NCI CTC), version 2.0 (16). 2) were enrolled. To confirm the tolerability of dose level 2, Dose-limiting toxicities (DLT) were defined as any of the following seven additional patients were enrolled between August during the first two cycles of therapy: grade 4 lasting 2004 and February 2005. Thus, a total of 16 patients ≥7 days; platelet count <25,000/mm3; fever ≥38ÆC lasting ≥72 participated in the phase II study to determine the RD. hours; grade 3 neutropenia with mucositis or diarrhoea grade ≥2; grade 3 or 4 non-haematological toxicity (excluding alopecia, nausea Table I shows patient characteristics. All patients had and vomiting, unless nausea and/or vomiting made oral feeding performance status 0. The median age was 55 years (range: impossible for ≥4 days, necessitating fluid infusion) and any event 43 to 70). The major metastatic sites were lymph nodes, leading to a >7-day delay in administration of the next cycle. lungs and liver. The majority of patients had received two

1010 Ohno et al: Oral Capecitabine/Cyclophosphamide Combination in MBC

Table I. Patient characteristics. Table II. Adverse events (no. of patients).

Level 1 Level 2 Additional Total Grade Level 1 Level 2 Additional (n=6) (n=3) level 2 (n=16) level 2 (n=7) Cycles All Cycles All Cycles All Age (years) 1-2 cycles 1-2 cycles 1-2 cycles Median (range) 63 (44-70) 53 (47-65) 52 (43-58) 55 (43-70) Prior chemotherapy Haematological events 1 regimen 0 1 3 4 Leukopenia 1 1 1 2 regimens 2 0 3 5 2423312 ≥3 regimens 4 2 1 7 32 Anthracycline 4 1 7 12 Neutropenia 2 1 1 Taxane 6 2 1 9 311 5-Fluorouracil 5 2 5 12 Non-haematological events Prior radiotherapy for Hand-foot syndrome 1 1 1 1 2 advanced disease 4 2 3 9 Stomatitis 1 1 1 1 1 Tumour sites Nausea 1 1 12013Anorexia 1 1 1 22136Diarrhoea 1 1 1 1 1 ≥3 2 2 3 7 Alopecia 1 1 1 1 Raised ALT 1 1 1 1 1 Raised AST 1 1 1 Raised alkaline phosphatase 1 1 1 or more prior chemotherapy regimens; six out of the nine ALT, alanine aminotransferase; AST, aspartate aminotransferase. patients treated in the dose-escalation phase had received three or more prior regimens.

DLTs. Cycle 2 was delayed by one week in two out of the Safety. Table II lists toxicities by dose level. There were no six patients treated at dose level 1 due to grade 2 grade 2, 3 or 4 non-haematological events at any of the dose leukopenia. However, no DLTs occurred in any of these levels. During the early cycles, the neutrophil count fell to patients. Two out of the three patients treated at dose level nearly 1,500/mm3, but then remained stable, indicating that 2 developed DLTs. Treatment was interrupted for >1 week continued therapy did not exacerbate toxicity. Excluding the for each of the patients because of grade 2 leukopenia, two patients with DLTs, seven out of the eight patients which did not resolve to grade 0-1 within seven days. Both treated at the RD completed all six treatment cycles. The patients had been heavily pretreated (three or more prior remaining patient withdrew consent after only one cycle. No regimens). Only one of these patients experienced grade further treatment interruptions were required and there were ≥3 haematological toxicity (grade 3 neutropenia) and no dose reductions. All patients were treated as out-patients. neither developed any grade >1 non-haematological toxicity. Based on these findings, the Data and Safety Efficacy. Two out of the eight evaluable patients achieved Monitoring Committee agreed that dose level 2 should not partial responses. Both of these patients were treated at dose be defined as the MTD and recommended protocol level 2, giving a response rate of 40% in the five evaluable modification. Consequently treatment was delayed only if patients treated at the RD. Both of these patients received patients had a neutrophil count ≥1,500/mm3, a platelet capecitabine/cyclophosphamide as first-line chemotherapy. count ≥75,000/mm3, or haemoglobin ≥8.0g/dl. Dose level 2 Disease progression was recorded at the end of the sixth was expanded to confirm its tolerability. cycle in both patients. Previous treatment in all five Seven additional subjects were enrolled at dose level 2. evaluable patients treated at the RD is shown in Table III. Two patients were excluded because safety evaluation was not possible (one withdrew consent and data were missing Discussion for the other). No DLTs occurred during the first two cycles in any of these five subjects, and none developed any grade This study identified dose level 2 (capecitabine 829 mg/m2 bid ≥3 haematological toxicity or grade ≥2 non-haematological plus cyclophosphamide 33 mg/m2 bid on days 1 to 14 of each toxicity. Consequently dose level 2 (capecitabine 829 mg/m2 3-week cycle) as the RD. As expected given the relatively low bid plus cyclophosphamide 33 mg/m2 bid) was confirmed as dose of capecitabine in this study, the incidence of HFS was well tolerated. low. Only one patient experienced grade 1 HFS during the

1011 ANTICANCER RESEARCH 27: 1009-1014 (2007)

Table III. Prior treatment in five evaluable patients treated at the recommended dose level.

Patient no. Adjuvant therapy Treatment for MBC Response to oral capecitabine/ cyclophosphamide

2-2 CMF + toremifene Radiation → anastrozole → radiation → Partial response medroxyprogesterone acetate

F-2* Primary breast cancer: None Partial response tamoxifen → Contralateral breast cancer: EC

F-1 Tamoxifen + Radiation → → toremifene → Stable disease fadrozole → anastrozole → radiation → exemestane → medroxyprogesterone acetate

F-3 CAF → UFT + cyclophosphamide None Stable disease

F-4 EC → toremifene Anastrozole Stable disease

*Patient had metachronous cancers of contralateral breasts. CAF, doxorubicin, cyclophosphamide, 5-fluorouracil; CMF, cyclophosphamide, methotrexate, 5-fluorouracil; EC, , cyclophosphamide; MBC, metastatic breast cancer; UFT, uracil, tegafur.

first two cycles, with an additional case occurring during a (22). In the present study, replacing with subsequent cycle. There were no grade ≥2 non- capecitabine as a combination partner for cyclophosphamide haematological toxicities, only one patient experienced AST appeared to improve tolerability. Particularly noteworthy was elevation (grade 1) and there were no bilirubin elevations. the lack of non-haematological toxicities of grade >1 severity. This contrasts with the safety profile of capecitabine Two out of the five evaluable patients treated at the RD monotherapy observed in two phase II studies in breast cancer achieved a partial response. Therefore further evaluation is conducted in Japan. In both studies, capecitabine 828 mg/m2 warranted, particularly as a pharmacokinetic study has was given twice daily, days 1 to 21 of each 4-week cycle (18, demonstrated that the 5'-deoxy-5-fluorouridine (5'-DFUR) 19). Grade 3/4 bilirubin elevations were reported in 8% of area under the blood concentration curve was 2.4-fold greater patients in one study and 22% in the other. for capecitabine 828 mg/m2 twice daily than for doxifluridine In a phase I study investigating capecitabine/ 400 mg three times daily (23). It is plausible that cyclophosphamide combination therapy in patients with capecitabine/cyclophosphamide may improve the efficacy of advanced cancer (20), grade 3 diarrhoea and grade 4 cyclophosphamide/fluoropyrimidine therapy as well as the vomiting were dose limiting. This marked difference in the tolerability compared with doxifluridine/ cyclophosphamide. safety profile of the combination is probably attributable to This study suggests that the all oral regimen of the different dosing schedule used by Findlay et al. (20), capecitabine 829 mg/m2 twice daily plus cyclophosphamide with capecitabine administered every day without 33 mg/m2 twice daily, both administered on days 1 to 14 every interruption and cyclophosphamide administered on days 1 three weeks, is feasible, active and extremely well tolerated. to 14 every four weeks. Therefore the dose intensity of both drugs was substantially higher than in the present study. Acknowledgements Interestingly, cyclophosphamide has been evaluated in This study was supported by the Clinical Haematology Oncology combination with doxifluridine, an intermediate metabolite Treatment Study Group. of capecitabine, in a phase II study in patients with MBC (21). The overall response rate was 60% and the median time References to progression and overall survival were 11.7 and 40.3 months, respectively. Grade 3/4 haematological toxicity 1 Love RR, Leventhal H, Easterling DV and Nerenz DR: Side occurred in 22% and non-haematological toxicity occurred in effects and emotional distress during cancer chemotherapy. Cancer 63: 604-612, 1989. 5% of patients. In a phase III trial in the adjuvant setting, the 2 Boehmke MM and Dickerson SS: Symptom, symptom addition of cyclophosphamide to doxifluridine significantly experiences, and symptom distress encountered by women with improved disease-free survival compared with doxifluridine breast cancer undergoing current treatment modalities. Cancer alone, but resulted in a significantly higher rate of toxicity Nurs 28: 382-389, 2005.

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