DISCUSSION

Docetaxel is recommended as a single agent or in combination for the treatment of breast cancer in neoadjuvant, adjuvant and metastatic settings by several guidelines.25,26 Globally several novel docetaxel formulations are being developed to overcome the toxicities related to excipients used in the conventional docetaxel formulation, among which, NDLS was approved by the Drug Controller General of India in August 2013.

NDLS was developed using the patented (worldwide [WO2008127358], Europe [2076244], Japan [5917789] and Canada [CA2666322]) “NanoAqualip” technology.27 NDLS was developed by adding docetaxel to high pressure homogenized soy phosphatidylcholine and sodium cholesteryl sulfate in sodium citrate buffer under continuous high pressure homogenization. Nanosomal lipid-based (with generally regarded as safe [GRAS] lipids by the US Food and Drug Administration) docetaxel nanoparticles (<100 nm) may infiltrate and get trapped in the damaged tumor vasculature and necrotic tumor tissue collagen material resulting in increased retention [enhanced permeability and retention (EPR) effect]. The efficacy and safety of NDLS has been demonstrated in breast, gastric, ovarian, cervical, penile, hormone refractory prostate and non-small cell lung cancers.21,28-31 Furthermore, a panel of oncology experts has recommended using NDLS in patients with metastatic disease, those at risk of hypersensitivity reactions, diabetics and those in whom steroids need to be avoided.32

The current study presents the findings of NDLS-based chemotherapy in breast cancer patients in neoadjuvant, adjuvant and metastatic settings. In neoadjuvant settings, achieving pathologic complete response (pCR) is associated with significantly reduced disease recurrence and improved survival in breast cancer patients.33 In our study, both ORR and DCR rates were 100% (CR: 50%, PR: 50%) with NDLS-based chemotherapy in the neoadjuvant setting. In this analysis, only one patient was evaluated using pathological response and achieved pCR, and remaining patients were evaluated based on overall response criteria by RECIST 1.1. Furthermore, median OS was not reached for neoadjuvant settings; 91.7% patients were alive at last follow-up (median follow-up: 21.1 months; range: 2.06–46.8 months). NDLS was most commonly used as a TCH (33.3%) regimen in the neoadjuvant setting, since 5/12 (41.7%) patients in this setting were human epidermal growth factor receptor 2 positive (HER2+).26 Previous reports on neoadjuvant treatment with taxanes, platinum agent and trastuzumab have shown ORR rates of 87.1% (n=39),34 98% (n=42)35 and 100% (n=32)36 in previous studies in patients with breast cancer treated in neoadjuvant settings. In an Indian retrospective analysis by Tiwari et al,36 TCH regimen (n=32) demonstrated an ORR of 100%. The higher response rate (100%) observed in our study in neoadjuvant treatment could be attributed to the small sample size. Kolberg et al37 showed that 94.2% patients were alive at 53.6 months follow-up with a TCH regimen.37 In our study, 91.7% patients were alive at a median follow-up of 21.1 months in the neoadjuvant setting. The above evidence shows the potential of NDLS-based regimens in managing breast cancer in neoadjuvant setting.


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Docetaxel in combination with anthracyclines and cyclophosphamide as concurrent (the TAC regimen) or sequentially (AC→T) has been evaluated for adjuvant treatment in many studies.38 In our study, NDLS was most commonly used in combination as TC, TAC and TCH regimens in adjuvant setting. The US Oncology Research Trial 9735 showed an OS of 90% with adjuvant TC regimen at a median follow-up of 5.5 years in early breast cancer patients (n=506).39 The 7-year follow-up, in this study, showed an OS rate of 87% with a TC regimen.40 The TAX316 study evaluated TAC regimen in adjuvant treatment of breast cancer and showed that 87.8% patients were alive at a median follow-up of 77 months.41 Jones et al,42 showed 98.3% alive patients at a median follow-up of 36.1 months who had received an adjuvant TCH regimen. In our study, at a median follow-up of 21.6 months (range: 3.5–49.8 months), the median OS was not reached for adjuvant setting and 90.2% (55/61) patients were still alive.

Docetaxel has been established as an effective treatment option in the treatment of MBC after failure of prior chemotherapy.43 Conventional docetaxel has reported an ORR of 30–47% in MBC at various dose levels.44,45 The efficacy and safety of NDLS was compared with conventional docetaxel in the management of MBC by Ahmad et al. NDLS monotherapy demonstrated an ORR of 35.5% (n=49) vs 26.3% (n=23) with conventional docetaxel at 75 mg/m2 in the treatment of 72 locally advanced or MBC patients. The safety was comparable between NDLS and conventional docetaxel, though patients in the NDLS group were not premedicated with corticosteroids. In our study, NDLS plus carboplatin and TCH were the most common NDLS-based regimens used in metastatic settings. In a study by Mavroudis et al,46 docetaxel plus carboplatin showed an ORR of 61% in MBC patients (n=36). The NCCTG 9932 trial showed an ORR of 58% with docetaxel plus carboplatin in 35 patients.47 The Phase III BCIRG 007 study by Valero et al48 demonstrated an ORR of 72% and median OS of 37.4 months for TCH regimen in HER2+ MBC patients (n=132).48 TCH demonstrated an ORR of 79% (n=62) in the BCIRG 101 study and 58% (n=59) in the UCLA-ORN study for the treatment of MBC.49 In our analysis, NDLS-based regimens demonstrated an ORR and DCR of 64.7% and 70.6%, respectively. At a median follow-up of 22.4 months (range: 5.1–36.9 months), the median OS was 30.4 months and 44.4% patients were still alive.

Overall, NDLS-based regimens were found to be well tolerated in breast cancer patients. GCSF was used in most of the patients and the safety profile of NDLS in this study is consistent with previous literature.20,22,50 In the TAX313 study, fluid retention (38%), thrombocytopenia (11%), neutropenia (94%), febrile neutropenia (7%), treatment-related grade III/IV infection (3%) and anemia (94%) were the most common AEs with conventional docetaxel. In our study, severe grade IV neutropenia and thrombocytopenia were reported in 2 (3.70%) patients, which resolved with supportive therapy. The most commonly reported grade III AEs were lymphopenia (5.6%), anemia, thrombocytopenia and neutropenia (3.7% each), and grade IV AEs were neutropenia and thrombocytopenia (3.7% each). The AEs of interest with conventional docetaxel formulation such as hypersensitivity reactions, fluid retention, neuropathy and nail disorders were not observed with NDLS in our study. Hyperglycemia was the most common non-hematological AE which could be attributed to the fact that 23.1% of the patients in this study had diabetes at baseline and the majority of the patients received corticosteroids as premedication. The major limitation of this study is its retrospective nature and data availability with respect to survival and safety. The progression-free survival (PFS) could not be captured in this study since being a real-world study, the data on progression and serial scans were not available for most of the patients at most of the follow-up timepoints. This is one of the major limitations of this study.

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