Abstract
Although microtubule inhibitors are generally used in advanced stages, they provide the opportunity to prolong survival as an alternative when medical oncologists have difficulty finding options in their patients, who typically have a poor prognosis and most of whom are unresponsive to treatment. For this reason, we wanted to investigate the effect of ixabepilone treatment on survival in earlier metastatic lines. Our study also examined the frequency of side effects and survival differences in patients whose dose was reduced or whose treatment was discontinued. Our study includes patients diagnosed with metastatic breast cancer who received ixabepilone treatment between January 2011 and January 2021. Median overall survival (OS) in the group receiving ixabepilone on the 5th line and before was 22.0 months (95% CI: 21.0–22.9), in the group receiving ixabepilone after the 5th line was calculated as 10.0 months (95% CI: 8.9–11.0) (P < .001). Median OS (months) in the group receiving ixabepilone on the 4th line and before was 26.0 (95% CI: 23.6–28.3), in the group receiving ixabepilone after the 4th line was determined as 12.0 (95% CI: 10.5–13.4) (P < .001). Dose reduction or discontinuation of ixabepilone treatment in patients due to side effects did not affect OS and progression-free survival with ixabepilone statistically significantly. Ixabepilone treatment has side effects, similar to all other treatments used in metastatic breast cancer, however, these side effects are manageable. Additionally, since ixabepilone treatment is preferred in patients who have previously received many different chemotherapeutics and experienced cumulative toxicity, the side effects of ixabepilone may seem to be greater than they are. In our study, we showed that ixabepilone treatment has a statistically significant positive effect on survival if preferred in earlier metastatic lines. As similar studies increase in centers where ixabepilone treatment is generally given in advanced metastatic lines, treatment approaches may change in the coming years.
Keywords: efficacy and tolerability, ixabepilone, metastatic breast cancer
1. Introduction
Breast cancer is the most common malignancy in women. It is also one of the cancers that most commonly causes death.[1] Although we aim to diagnose at an early stage, some patients are diagnosed in the metastatic stage or become metastatic after recurrence or progression. For metastatic patients who are hormone receptor positive, HER2 negative, and resistant to endocrine therapy, systemic chemotherapy is recommended if there is no germline BRCA mutation. Systemic chemotherapy agents include anthracyclines, taxanes, antimetabolites such as capecitabine and gemcitabine, and microtubule inhibitors (vinorelbine, eribulin, and ixabepilone). For HER2-positive patients, HER2 targeting treatments and their combination with chemotherapy agents are recommended in the first steps, and systemic chemotherapy and microtubule inhibitors are recommended in the advanced stages in patients with progression. Ixabepilone, an analog of the natural product epothilone B, stabilizes microtubules resulting in cell cycle arrest and apoptosis. Epothilones are 16-member ring macrolides with antimicrotubule activity that share a similar mechanism of action to the taxanes but have demonstrated potent antiproliferative activity in several different multidrug-resistant and paclitaxel-resistant tumor cell lines in vitro and in vivo.[2] Side effects of ixabepilone therapy are generally similar to those of anthracyclines and taxanes. The most common side effects are myelosuppression and peripheral neuropathy. These are reversible after dose reduction or discontinuation of therapy.[3] Although microtubule inhibitors are generally used in advanced stages, they provide the opportunity to prolong survival as an alternative when medical oncologists have difficulty finding options in their patients, who typically have a poor prognosis and most of whom are unresponsive to treatment. For this reason, we wanted to investigate the effect of ixabepilone treatment on survival in earlier metastatic lines. Our study also examined the frequency of side effects and survival differences in patients whose dose was reduced or whose treatment was discontinued.
2. Materials and methods
Our study includes patients diagnosed with breast cancer who received ixabepilone treatment between January 2011 and January 2021. A total of 45 randomized patients from a single center were included in our study. The patients’ age at diagnosis, tumor histology, estrogen receptor level, progesterone receptor level, HER2 status, metastasis sites, de novo or metastasis development during follow-up, and neoadjuvant or adjuvant treatment receipt were examined. Overall survival (OS) was defined as the interval from the ixabepilone treatment start to the last recorded patient encounter or demise, while progression-free survival (PFS) was delineated as the time from the start of treatment to radiological progression. Treatments at each line in the metastatic stage were recorded and the longest PFS was determined. 18F-fluorodeoxyglucose positron emission tomography-computed tomography was used to assess treatment responses. All patients underwent imaging every 3 months after metastasis developed. Radiologic response was evaluated by response evaluation criteria in solid tumors.[4] Treatment response was accepted as the best response detected in the imaging performed throughout the treatment. Treatment response groups were determined as partial response (PR), progressive disease (PD), and stable disease (SD). Side effects (fatigue, neuropathy, neutropenia, and thrombocytopenia) and their grades were recorded. All patients were started on ixabepilone at 40 mg/m2 every 3 weeks on day 1 of a 21-day cycle. If the neutrophil count was <500 cells/mm3 for 7 days or more, febrile neutropenia, platelet count <25,000 cells/mm3, or <50,000 cells/mm3 with bleeding, the ixabepilone dose was reduced by 20%. The ixabepilone dose was also reduced by 20% in patients with prolonged grade 2 neuropathy and other grade 3 adverse effects. Treatment was stopped in patients with grade 4 side effects. We grouped the patients into those who received ixabepilone treatment at or before the 5th and 4th line and those who received it later. The study excluded individuals with incomplete data, those diagnosed with more than one primary malignancy, and patients under the age of 18. The study was approved by the local Ethics Committee and conducted in accordance with the Helsinki Declaration and ethical principles (Approval date and number: January 12, 2021, 478).
2.1. Statistical analysis
Statistical analysis “IBM SPSS Statistics for Windows. It was performed using Version 25.0 (Statistical Package for the Social Sciences, IBM Corp., Armonk, NY). Descriptive statistics are presented as n and % for categorical variables and Median (min–max) for continuous variables. Wilcoxon test was used to compare repeated measurements. The Kaplan–Meier method was used to compare OS and PFS times between various clinical parameter groups. P < .05 was considered statistically significant.
3. Results
All patients were female and the median age was 49 years. De novo metastasis was detected in 12 of the patients, and metastasis was detected in 33 patients during follow-up. The median follow-up time was 93 months. Grade 2 to 4 side effects were observed in 27 patients. Data on the patients’ characteristics and clinical features are shown in Table 1. Median PFS with ixabepilone was 6.0 months (2.0–12.0 months), and when the longest PFS was examined for all treatments received in the metastatic stage before ixabepilone in all patients, the median PFS was found to be 7.0 months (2.0–12.0 months). Median OS was determined as 12.0 months (4.0–28.0 months). Median OS (months) was statistically significant according to de novo/during follow-up metastasis groups (P = .006). Median OS (months) was determined as 10.0 (95% CI: 6.6–13.3) in the de novo group and 14.0 (95% CI: 8.3–19.6) in the follow-up metastasis group (Fig. 1).
Table 1.
Data on the patients’ characteristics and clinical features (n = 45).
| Values | N (%) |
|---|---|
| Age | |
| Median (min-max) | 49.0 (28–72) |
| Histopathology | |
| Triple-negative | 9 (20.0) |
| HER2 positive | 6 (13.3) |
| HR-positive, HER2 negative | 30 (66.7) |
| Metastasis area | |
| Bone | 7 (15.6) |
| Bone + visceral | 24 (53.3) |
| Visceral | 14 (31.1) |
| Best response to ixabepilone treatment | |
| PD | 15 (33.3) |
| PR | 18 (40.0) |
| SD | 12 (26.7) |
| Ixabepilone treatment | |
| 5th line and earlier | 18 (40.0) |
| After 5th line | 27 (50.0) |
| Ixabepilone treatment | |
| 4th line and earlier | 7 (15.6) |
| After 4th line | 38 (84.4) |
| De novo metastasis/metastasis during follow-up | |
| De Novo | 12 (26.7) |
| During follow-up | 33 (73.3) |
| Side effects | |
| Neutropenia | 5 (20.0) |
| Peripheral neuropathy | 11 (44.0) |
| Thrombocytopenia | 3 (12.0) |
| Fatigue | 6 (24.0) |
| Side effect grade | |
| 2 | 12 (44.4) |
| 3 | 9 (33.3) |
| 4 | 6 (13.3) |
| Dose reduction due to side effects | |
| No | 32 (71.1) |
| Yes | 13 (28.9) |
| Discontinuation of treatment due to side effects | |
| No | 39 (86.7) |
| Yes | 6 (13.3) |
| Mortality | |
| Live | 15 (33.3) |
| Exitus | 30 (66.7) |
| Follow-up time (month) | |
| Median (min–max) | 93.0 (22.0–160.0) |
| PFS with ixabepilone (months) | |
| Median (min–max) | 6.0 (2.0–12.0) |
HR = hormone receptor, PD = progressive disease, PFS = progression-free survival, PR = partial response, SD = stable disease.
Figure 1.
Median overall survival in de novo and during follow-up metastasis groups according to Kaplan–Meier analysis.
Median OS (months) was found to be statistically significant according to the groups in which line the patient received ixabepilone treatment after metastasis. Median OS (months) in the group receiving ixabepilone on the 5th line and before was 22.0 (95% CI: 21.0–22.9), in the group receiving ixabepilone after the 5th line was calculated as 10.0 (95% CI: 8.9–11.0) (P < .001) (Fig. 2). Median OS (months) in the group receiving ixabepilone on the 4th line and before was 26.0 (95% CI: 23.6–28.3), in the group receiving ixabepilone after the 4th line was determined as 12.0 (95% CI: 10.5–13.4) (P < .001) (Fig. 3). Our patients received ixabepilone treatment at the earliest in the metastatic 3rd line and the latest in the 11th line.
Figure 2.
Median overall survival in the 5th line and before and after 5th line groups according to Kaplan–Meier analysis.
Figure 3.
Median overall survival in the 4th line and before and after 4th line groups according to Kaplan–Meier analysis.
When all patients’ treatments received before ixabepilone were examined; 44% of the treatments in all steps were chemotherapy-based treatments (capecitabine, gemcitabine, gemcitabine + cisplatin/carboplatin, paclitaxel, doxorubicin + cyclophosphamide), 12% were microtubule inhibitors (vinorelbine, eribulin), 11% were HER-2 targeting treatments (trastuzumab + pertuzumab, trastuzumab emtansine, lapatinib), and 33% were endocrine treatments (fulvestrant, CDK 4–6 inhibitors + letrozole/fulvestrant, anastrozole/letrozole, tamoxifen + goserelin/leuprolide, exemestane + everolimus).
Median OS (months) was found to be statistically significant according to the best response groups to ixabepilone treatment (P < .001). The median OS (months) in the PD group was 10.0 (95% CI: 9.1–10.8), the median OS in the PR group (month) was determined as 21.0 (95% CI: 19.6–22.3), and in the SD group it was 12.0 (95% CI: 10.3–13.6) (Fig. 4). OS comparisons between patient groups are shown in Table 2.
Figure 4.
Median overall survival in the best response to ixabepilone treatment groups according to Kaplan–Meier analysis.
Table 2.
Overall survival comparisons between patient groups.
| OS (months) | Median (%95 CI) | P |
|---|---|---|
| General | 12.0 (9.8–14.3) | |
| De-novo/during follow-up metastasis | ||
| De novo | 10.0 (6.6–13.3) | .006 |
| During follow-up | 14.0 (8.37–19.6) | |
| Ixabepilone treatment | ||
| After 5th line | 10.0 (8.9–11.0) | <.001 |
| 5th line and earlier | 22.0 (21.0–22.9) | |
| Ixabepilone treatment | ||
| After 4th line | 12.0 (10.5–13.4) | <.001 |
| 4th line and earlier | 26.0 (23.6–28.3) | |
| The best response to ixabepilone treatment | ||
| PD | 10.0 (9.1–10.8) | <.001 |
| PR | 21.0 (19.6–22.3) | |
| SD | 12.0 (10.3–13.6) | |
| Dose reduction due to side effects | ||
| No | 12.0 (9.2–14.7) | .810 |
| Yes | 14.0 (7.6–20.3) | |
| Discontinuation of treatment due to side effects | ||
| No | 12.0 (9.7–14.2) | .789 |
| Yes | 12.0 (3.9–20.0) |
Kaplan–Meier curve, long rank test, P < .05 statistically significant.
OS = overall survival, PD = progressive disease, PR = partial response, SD = stable disease.
Median PFS (months) with ixabepilone treatment was determined as 6.0 (95% CI: 4.9–7.0). Median PFS (months) in the PD group was 4.0 (95% CI: 3.4–4.5), 7.0 (95% CI: 5.6–8.3) in the PR group, and 7.0 (95% CI: 5.6–8.3) in the SD group.
Due to side effects, drug doses were reduced in 13 patients, and treatment was discontinued in 6 patients in our study. The ixabepilone dose was reduced by 20% due to grade 2 to 3 peripheral neuropathy in 8 patients and grade 3 hematological toxicity in 5 patients. Of the 6 patients whose treatment was discontinued, 3 had grade 4 neuropathy and 3 had grade 4 hematological toxicity. Dose reduction or discontinuation of ixabepilone treatment in patients due to side effects did not affect OS and PFS with ixabepilone statistically significantly. PFS comparisons between patient groups are shown in Table 3.
Table 3.
Progression-free survival comparisons between patient groups.
| PFS (months) | Median (%95 CI) | P |
|---|---|---|
| General | 6.0 (4.9–7.0) | |
| De-novo/during follow-up metastasis | ||
| De novo | 6.0 (5.2–6.8) | .666 |
| During follow-up | 7.0 (5.4–8.5) | |
| Ixabepilone treatment | ||
| After 5th line | 4.0 (2.3–5.7) | .115 |
| 5th line and earlier | 6.0 (4.8–7.1) | |
| Ixabepilone treatment | ||
| After 4th line | 6.0 (0.8–11.1) | .185 |
| 4th line and earlier | 6.0 (4.7–7.2) | |
| The best response to ixabepilone treatment | ||
| PD | 4.0 (3.4–4.5) | <.001 |
| PR | 7.0 (5.6–8.3) | |
| SD | 7.0 (5.6–8.3) | |
| Dose reduction due to side effects | ||
| No | 6.0 (4.9–7.0) | .783 |
| Yes | 7.0 (5.8–8.1) | |
| Discontinuation of treatment due to side effects | ||
| No | 6.0 (5.0–6.9) | .906 |
| Yes | 4.0 (2.4–5.5) |
Kaplan–Meier curve, long rank test, P < .05 statistically significant.
PD = progressive disease, PFS = progression-free survival, PR = partial response, SD = stable disease.
4. Discussion
There are many treatment options for metastatic breast cancer, such as chemotherapy, immunotherapy, endocrine therapy, anti-HER2 therapy, and CDK4–6 inhibitors. For this reason and the limited number of studies, ixabepilone treatment is generally preferred in advanced lines. Ixabepilone is a semisynthetic analog of epothilone B with microtubule inhibitory activity that is approved for the treatment of metastatic breast cancer after failure of an anthracycline and a taxane. It has been shown that cancer cells that develop resistance to anthracyclines and taxanes are sensitive to epothilones, and epothilones are not affected by anthracycline/taxane resistance mechanisms.[5] Ixabepilone can be used alone or in combination with capecitabine. It has been shown in previous studies that in patients with advanced triple-negative breast cancer ixabepilone + capecitabine treatment increases PFS compared to the treatment of capecitabine alone.[6] In phase 3 studies compared the weekly paclitaxel and weekly ixabepilone effect after doxorubicin + cyclophosphamamide in patients with operable triple-negative breast cancer, disease-free survival, and 5-year OS were found similar.[7] The efficacy and safety of ixabepilone was investigated in a phase 2 study in patients with metastatic breast cancer resistant to anthracycline, taxane, and capecitabine. SD rate was 50%, and the median PFS was 3.1 months.[8] In our study, SD and PR patients constituted 60% and no patients with a complete response. This may be due to the limited number of patients in our study. Additionally, in our study, the median PFS with ixabepilone was calculated as 6 months.
In Turkey, according to reimbursement rules, patients with metastatic breast cancer who have previously received anthracycline, taxane, gemcitabine, vinorelbine, and capecitabine treatments can use ixabepilone as monotherapy and government institutions pay for it. Since the socioeconomic status and average financial income of the patients who applied to our center were generally unable to cover the treatment costs, the patient who earliest received ixabepilone treatment in our study received the treatment in the metastatic third line. We had only 1 patient who received ixabepilone treatment in the third line of metastatic disease.
In our study, we found that there was a statistically significant difference between the OS of patients who received ixabepilone treatment 4th line and before and after the 4th line (P < .001, median OS 26.0 vs 12.0 months). Due to the low number of patients who received ixabepilone treatment at metastatic 4th line and before, we also examined patients who received metastatic 5th line and before as a separate subset. We also found a statistically significant difference between the OS of patients who received ixabepilone treatment 5th line and before and after the 5th line (P < .001, median OS 22.0 vs 10.0 months). However, no statistically significant difference was observed for PFS with ixabepilone between these groups. Similar to a previous study, the median ixabepilone line is 6 in metastatic breast cancer patients in our study.[9] Based on these results, with the increase in the number of studies, it may be possible to start ixabepilone treatment earlier, especially in regions such as our country where ixabepilone treatment is given in advanced metastatic lines.
Our study observed side effects in 25 of 45 patients (55.5%). The most common side effect was peripheral neuropathy. Grades 3 and 4 side effects were observed in 15 patients (33.3%). There were 6 patients whose treatment was discontinued due to grade 4 side effects. The side effect rates observed in our patients were similar to previous studies.[10] An earlier study suggested that neurotoxicity was a positive prognostic factor in metastatic breast cancer patients receiving ixabepilone treatment in the first line.[11] In our study, no statistically significant difference was found in terms of OS and PFS between patients whose ixabepilone dose was reduced and whose ixabepilone treatment was discontinued due to side effects. Similar to our study, a review showed that dose reduction due to side effects did not negatively affect the overall efficacy and clinical outcome in patients receiving ixabepilone + capecitabine treatment for metastatic breast cancer.[12]
The data obtained from our study are generally compatible with the literature. Although the follow-up period was long, the relatively small number of patients can be seen as a limitation of our study.
In conclusion, ixabepilone treatment has side effects, similar to all other treatments used in metastatic breast cancer, however these side effects are manageable. Additionally, since ixabepilone treatment is preferred in patients who have previously received many different chemotherapeutics and experienced cumulative toxicity, the side effects of ixabepilone may seem to be greater than they are. As similar studies increase in centers where ixabepilone treatment is generally given in advanced metastatic lines, treatment approaches may change in the coming years.
Author contributions
Data curation: Mert Erciyestepe, Ömer Burak Ekinci, Şaban Seçmeler, Ahmet Emin Öztürk, Okan Aydin, Tugay Atasever, Asli Büyükkuşcu.
Investigation: Mert Erciyestepe, Ahmet Emin Öztürk, Asli Büyükkuşcu.
Methodology: Mert Erciyestepe, Oğuzhan Selvi, Ahmet Emin Öztürk, Tugay Atasever.
Resources: Okan Aydin, Tugay Atasever.
Supervision: Emir Çelik.
Writing – original draft: Mert Erciyestepe, Oğuzhan Selvi, Muhammed Mustafa Atci.
Writing – review & editing: Emir Çelik, Kayhan Ertürk, Muhammed Mustafa Atci.
Abbreviations:
- OS
- overall survival
- PD
- progressive disease
- PFS
- progression-free survival
- PR
- partial response
- SD
- stable disease
The authors have no funding and conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are publicly available.
How to cite this article: Erciyestepe M, Ekinci ÖB, Seçmeler Ş, Selvi O, Öztürk AE, Aydin O, Büyükkuşcu A, Atasever T, Çelik E, Ertürk K, Atci MM. Evaluation of ixabepilone efficacy and tolerability in metastatic breast cancer. Medicine 2024;103:47(e40649).
Contributor Information
Ömer Burak Ekinci, Email: obekinci@hotmail.com.
Şaban Seçmeler, Email: drsabansecmeler@hotmail.com.
Oğuzhan Selvi, Email: selvioguz@gmail.com.
Ahmet Emin Öztürk, Email: draeozturk@gmail.com.
Okan Aydin, Email: drokan29@gmail.com.
Asli Büyükkuşcu, Email: aslibuyukkuscu@hotmail.com.
Tugay Atasever, Email: tugay.atasever@hotmail.com.
Emir Çelik, Email: emircelikk@gmail.com.
Kayhan Ertürk, Email: kayhanerturk@gmail.com.
Muhammed Mustafa Atci, Email: dr_mmatci@hotmail.com.
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