A Pilot, Phase II, Randomized, Open-Label Clinical Trial Comparing the Neurotoxicity of Three Dose Regimens of Nab-Paclitaxel to That of Solvent-Based Paclitaxel as the First-Line Treatment for Patients with Human Epidermal Growth Factor Receptor Type 2-Negative Metastatic Breast Cancer

Abstract

Background This study aimed to characterize the neurotoxicity of three different regimens of nab‐paclitaxel compared with a standard regimen of solvent‐based (sb) paclitaxel for the first‐line treatment of HER2‐negative metastatic breast cancer based on the Total Neurotoxicity Score (TNS), a tool specifically developed to assess chemotherapy‐induced neurotoxicity. Materials and Methods This was a randomized, open‐label study testing 4‐week cycles of 80 mg/m2 sb‐paclitaxel (PACL80/w) on days 1, 8, and 15; 100 mg/m2 nab‐paclitaxel on days 1, 8, and 15 (NAB100/w); 150 mg/m2 nab‐paclitaxel on days 1, 8, and 15 (NAB150/w); and 150 mg/m2 nab‐paclitaxel on days 1 and 15 (NAB150/2w). In addition to the TNS, neuropathy was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI‐CTCAE). Tumor response and quality of life were also evaluated. Results Neurotoxicity, as evaluated by the TNS, did not significantly differ between the sb‐paclitaxel group and any of the nab‐paclitaxel groups. The frequency of (any grade) polyneuropathy, as measured by the NCI‐CTCAE, was lower in the PACL80/w (n = 7, 50%) and NAB150/2w (n = 10, 62.5%) groups than in the NAB100/w (n = 13, 81.3%) or NAB150/w (n = 11, 78.6%) group. Although the differences were not statistically significant, compared with the other groups, in the NAB150/w group, the time to occurrence of grade ≥2 polyneuropathy was shorter, and the median time to recovery from grade ≥2 polyneuropathy was longer. Dose delays and reductions due to neurotoxicity and impact of neurotoxicity on the patients’ experience of symptoms and functional limitations was greater with NAB150/w. Among the seven polymorphisms selected for genotyping, the variant alleles of EPHA5‐rs7349683, EPHA6‐rs301927, and EPHA8‐rs209709 were associated with an increased risk of paclitaxel‐induced neuropathy. Conclusion The results of this exploratory study showed that, regardless of the dose, nab‐paclitaxel did not differ from sb‐paclitaxel in terms of neurotoxicity as evaluated with the TNS. However, results from NCI‐CTCAE, dose delays and reductions, and functional tools consistently indicate that NAB150/w regimen is associated with a greater risk of chemotherapy‐induced neuropathy. Thus, our results question the superiority of the TNS over NCI‐CTCAE for evaluating chemotherapy‐induced neuropathy and guiding treatment decisions in this context. The selection of the nab‐paclitaxel regimen should be individualized based on the clinical context and potentially supported by pharmacogenetic analysis. Registry: EudraCT, 2012‐002361‐36; NCT01763710 Implications for Practice The results of this study call into question the superiority of the Total Neurotoxicity Score over the National Cancer Institute Common Terminology Criteria for Adverse Events for evaluating chemotherapy‐induced neuropathy and guiding treatment decisions in this context and suggest that a regimen of 150 mg/m2 nab‐paclitaxel administered on days 1, 8, and 15 is associated with a greater risk of chemot...

A systematic review and meta-analysis of nab-paclitaxel mono-chemotherapy for metastatic breast cancer

“…Furthermore, in the xed weekly or triweekly nab-paclitaxel monotherapy, the incidence of grade 3/4 peripheral sensory neuropathy increased if nab-paclitaxel dosage increased. This was in accordance with the results of Ciruelos E as they found the grade 3 peripheral neuropathy was deemed to be taxanes-related, which is known to be cumulative [35].…”

“…We ultimately identi ed 22 independent studies published between March 2005 and March 2020 [9,10,12,13,16,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. A ow chart representing selection of studies is shown in Figure 1.…”

Chemotherapy-induced peripheral neuropathy: part 1—current state of knowledge and perspectives for pharmacotherapy

“…In addition to age, a number of other potential risk factors for CIPN development have been identified. These include the cumulative dose of a chemotherapeutic agent, genetic factors, a history of neuropathy before the start of chemotherapy (e.g., painful diabetic neuropathy or neuropathy due to viral infections), impaired renal function with reduced creatinine clearance, and smoking history [9,15,17,[28][29][30][31][32].…”

A Systematic Review and Meta-Analysis of Nab-Paclitaxel Mono-Chemotherapy for Metastatic Breast Cancer.

“…We ultimately identified 22 independent studies published between March 2005 and March 2020 [9,10,12,13,16,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37]. A flow chart representing selection of studies is shown in Figure 1 Table 1.…”

“…the results of Ciruelos E as they found the grade 3 peripheral neuropathy was deemed to be taxanes-related, which is known to be cumulative[35].Concerning to the efficacy outcomes, our analysis showed nab-paclitaxel monotherapy could provide a 40% ORR, a 60% CBR, a median PFS of 7.64 months and a median OS of 24.51 months for the overall population of patients with MBC who received various doses, schedules, and regimens of nab-paclitaxel across all lines of therapy. Still, in MBC patients who received nab-paclitaxel monotherapy in the first line treatment, the nab-paclitaxel efficacy outcomes could be more encouraging with a 48.2% ORR, a 68.7% CBR, a median PFS of 8.01 months and a median OS of 24.41 months.…”