To be eligible for this study, the patients were required to have a histologically confirmed diagnosis of carcinoma of the breast, as well as at least one measurable lesion. All the metastatic breast cancer patients were aged ≥18 yr and required to have failed with prior docetaxel-based or paclitaxel-based chemotherapy. Only the patients with an Eastern Cooperative Oncology Group (ECOG) performance status of grade 0-2 were enrolled in this study. Adequate bone marrow function (an absolute neutrophil count [ANC] ≥1,500×10³/µL and a platelet count ≥100,000×10³/µL), adequate renal function (a serum creatinine level ≤1.5 mg/dL), and adequate hepatic function (aspartate aminotransferase and alanine aminotransferase levels ≤3×upper limit of normal and a total bilirubin level ≤1.5×upper limit of normal) were required for the enrolled patients. A minimum interval of 4 weeks following completion of adjuvant chemotherapy or chemotherapy for metastatic disease was required. The patients with active infections, serious or uncontrolled concurrent medical illness, brain metastasis and previous history of other malignancies were excluded from the present study. The local ethics committee approved this study, and informed consent was obtained from all the patients prior to entry into the study.

Primary resistance was defined as progressive disease that occurred during or within 6 months after the completion of treatment in an adjuvant setting, as well as the absence of a documented tumor response in a metastatic setting.

Secondary resistance was defined as disease progression after a documented clinical response during chemotherapy, or disease progression 6 months after the completion of treatment for metastatic disease.

Chemotherapy was administered via a chemoport placed in the subclavian vein or it was directly administered into a peripheral vein. The patients were administered 25 mg/m² vinorelbine (over a 15-min infusion) on days 1 and 8, and they were administered 2,000 mg/m² ifosfamide (over a 2-hr infusion) on days 1-3. Mesna (Uromitexan) was administered IV at a dose of 2,000 mg/m² per day, and this was divided into 4 doses of 500 mg/m² each, which were administered at the time of ifosfamide infusion and at 3 hr, 6 hr, and 9 hr later. The cycles were repeated every 3 weeks until disease progression if the patient's blood count had returned to acceptable levels (WBC: 3,000×10³/µL; platelets: 70,000×10³/µL), and the non-hematological toxic effects had resolved to the normal status. The dosage of the subsequent cycles was adjusted according to the toxic effects that developed during the preceding cycle. If the hematological values were not achieved by the date of the scheduled drug administeration, then therapy was delayed in weekly intervals, and if the hematological criteria were not fulfilled after a delay of two weeks, the patient was dropped out from the study. The dosages of vinorelbine and ifosfamide were reduced by 25% during the subsequent cycles if the neutrophil and platelet count nadirs were <500×10³/µL and <50,000×10³/µL, respectively, or if neutropenic fever developed. In addition, on day 8 of chemotherapy, a complete blood count was conducted prior to vinorelbine treatment. The administration of vinorelbine was omitted for the cases of grade 4 hematological toxicity on day 8. The primary endpoint of this study was the tumor response rate, and the secondary endpoints included the time to progression (TTP), overall survival (OS) and the toxicities. TTP and OS were defined as time from the first day of treatment until the first date of disease progression or death, respectively.

Antiemetic therapy with administering 5-HT3 receptor antagonists (ondansetron) was applied in all cases. A follow-up history taking and physical examinations, tumor measurements and toxicity assessments were conducted prior to each 3-week cycle of therapy. Toxicity was evaluated using the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), Version 3.0.

Patients who had received at least two cycles of therapy were assessable for response; all patients who received treatment were assessable for toxicity. A physical examination, complete blood counts, blood chemistry and chest X-rays were acquired after each cycle of chemotherapy. Computed tomography scans were repeated every three cycles or earlier for the cases with clinical deterioration.

The responses were assessed by using WHO criteria. Complete response (CR) is defined as the disappearance of all evidence of disease for at least 1 month and the development of no new lesions. Partial response (PR) indicates a decrease of 50% or greater (compared with pretreatment measurements) in the sum of the products of the two largest perpendicular diameters of all measurable lesions and no concomitant growth of new lesions for at least 1 month. Stable disease (SD) indicates a decrease of less than 50% or an increase in tumor size less than 25% over the original measurements. Progressive disease (PD) was defined as any of the following: 1) an increase of 25% or greater over the original measurements in the sum of the products of the two largest perpendicular diameters of any measurable lesions, 2) the appearance of any new lesion, or 3) the reappearance of any lesion that had previously disappeared.

This trial was designed to detect a response rate of 30% as compared to a minimal, clinically meaningful response rate of 10%. The two-stage optimal design proposed by Simon was adopted, with a statistical power of 80% to accept the hypothesis and 5% significance to reject the hypothesis. Allowing for a follow-up loss rate of up to 20%, the total required sample size was 35 patients with measurable disease. The TTP and the OS were calculated from the initiation of treatment to the initial observation of disease progression or death, respectively. All the data was analyzed with SPSS software (version 12.0; SPSS Inc., Chicago, USA). The prognostic factors for OS, TTP and the response rate (RR) were analyzed using Fisher's exact test, Kaplan-Meier and Cox regression analyses.

Between June 2001 and August 2007, 35 patients who were resistant to taxanes (docetaxel or paclitaxel) were assigned to be treated at the Dong-A University Medical Center, Busan, South Korea. The characteristics of the 35 patients enrolled in this study are described in Table 1. Their median age was 50 yr (age range, 38-72 yr). The performance status (ECOG) was grade 0-1 in the majority of the patients; six patients (17.1%) were grade 2. All of the enrolled patients (n=35) had received prior anthracycline and taxane combination chemotherapy. Primary resistance to taxane was noted in 17 patients (48.6%), and secondary resistance to taxane was detected in 18 patients (51.4%). In 25 patients (71.4%), the hemoglobin level was in excess of 12 g/dL. The tumor marker CA 15-3 was elevated in 13 patients (37.1%). For the hormonal receptor status, the expression of estrogen receptor (ER) and/or progesterone receptor (PR) was positive in 19 patients (54.3%); HER2 was positive in 10 patients (28.6%). All of the 19 patients with hormone receptor positive tumors had received adjuvant hormonal therapy, but only six of the 19 patients (31.5%) had received prior palliative hormonal therapy. A total of 32 patients (91.4%) had received prior palliative chemotherapy of more than one regimen and a total of 17 patients (48.6%) had received prior palliative chemotherapy of more than two regimens. For metastasis, one organ was involved in 10 patients (28.6%), two organs were involved in 13 patients (37.1%) and three or more organs were involved in 12 patients (34.3%). The lung was the most common metastatic site (23 patients, 65.7%), and the lymph nodes (22 patients, 62.8%), bone (16 patients, 45.7%), liver (10 patients, 28.5%) and the skin and soft tissue (10 patients, 28.5%) were involved in a combined fashion.

Of the 35 patients who were assessed for their response, a partial response (PR) was noted in 14 patients (40%; 95% confidence interval [CI], 23-57%), stable disease (SD) was detected in 9 patients (25.7%; 95% CI, 10-41%) and progressive disease (PD) was observed in 12 patients (34.3%; 95% CI, 18-51%) (Table 2). The median follow-up duration was 32.9 months. The median TTP was 4.5 months (95% CI, 3.5-5.4 months) (Figure 1). The median OS was 18.3 months (95% CI, 12.9-23.6 months) (Figure 2).

The poor prognostic factors for OS were a serum hemoglobin level below 12 g/dL (p=0.048; 95% CI, 1.101-6.680) and visceral dominant metastasis (p=0.020; 95% CI, 1.254-14.046) on the multivariate Cox regression analysis. Other variations of the patient characteristics were not shown to be significant prognostic factors for the TTP and the OS (Table 3).

A total of 190 treatment cycles were administered to 35 patients with a median number of five cycles (range, 2-12 cycles). The number of dose reduced cycles was 74 (38.9%) among the 190 cycles. The reasons for dose reduction were neutropenia and/or febrile neutropenia. The relative dose intensities were 15 mg/m²/week (90.57%) for vinorelbine and 1,811 mg/m²/week (90.57%) for ifosfamide (Table 2).

An analysis of side effects demonstrated that the toxicities were generally manageable and anemia (grade 1 or 2 in 61.0% of the cycles or 116 of 190 cycles) was the most frequently observed. Grade 3 or 4 neutropenia was observed in 29.3% of the cycles or 56 cycles, but only six episodes of non-fatal neutropenic fever were noted. Grade 1 or 2 vomiting was noted in 8 patients (22.8%), and grade 1 or 2 peripheral sensory neuropathy was observed in 5 patients (14.2%). No treatment-related hepatotoxicity or nephrotoxicity was observed. There was no episode of hemorrhagic cystitis. No treatment-related deaths occurred during the study (Table 4).