Background: Breast cancer, with 2.3 million new cases and 0.7 million deaths every year, represents a great medical challenge worldwide. These numbers confirm that approx. 30% of BC patients will develop an incurable disease requiring life-long, palliative systemic treatment. Endocrine treatment and chemotherapy administered in a sequential fashion are the basic treatment options in advanced ER+/HER2- BC, which is the most common BC type. The palliative, long-term treatment of advanced BC should not only be highly active but also minimally toxic to allow long-term survival with the optimal quality of life. A combination of metronomic chemotherapy (MC) with endocrine treatment (ET) in patients who failed earlier lines of ET represents an interesting and promising option. Methods: The methodology includes retrospective data analyses of pretreated, metastatic ER+/HER2- BC (mBC) patients who were treated with the FulVEC regimen combining fulvestrant and MC (cyclophosphamide, vinorelbine, and capecitabine). Results: Thirty-nine previously treated (median 2 lines 1–9) mBC patients received FulVEC. The median PFS and OS were 8.4 and 21.5 months, respectively. Biochemical responses (CA-15.3 serum marker decline ≥50%) were observed in 48.7%, and any increase in CA-15.3 was observed in 23.1% of patients. The activity of FulVEC was independent of previous treatments with fulvestrant of cytotoxic components of the FulVEC regimen. The treatment was safe and well tolerated. Conclusions: Metronomic chemo-endocrine therapy with FulVEC regimen represents an interesting option and compares favorably with other approaches in patients’ refractory to endocrine treatments. A phase II randomized trial is warranted.
Patients with advanced ovarian cancer (OC) have a detrimental prognosis. The options for systemic treatment of advanced OC in later lines of treatment are limited by the availability of active therapies and their applicability to often fragile, exhausted patients with poor performance status. Metronomic chemotherapy (MC) is a concept of a continuous administration of cytotoxic drugs, which is characterized by multidirectional activity (anti-proliferative, anti-angiogenic, and anti-immunosuppressive) and low toxicity. We have performed a retrospective analysis of consecutive, advanced, chemo-refractory OC patients treated with MC based on single-agent topotecan (1 mg p.o. q2d) or on a topotecan (1 mg q2d) and cyclophosphamide (50 mg p.o. qd) combination (CyTo). Metronomic chemotherapy demonstrated promising activity, with 72% and 86% of patients achieving biochemical or objective disease control and 18% and 27% of patients achieving a biochemical or objective response, respectively. The median PFS in the whole population was 3.65 months, but the median PFS in patients with a biochemical response to MC (18.2% of patients) reached 10.7 months. The study also suggested that overweight or obese patients had significantly better outcomes on MC than patients with BMI <25 kg/m2. This article is the first report in the literature on metronomic chemotherapy based on a topotecan + cyclophosphamide combination (CyTo). The CyTo regimen demonstrated safety, clinical activity, and potential broad clinical applicability in advanced OC patients and will be evaluated in a forthcoming clinical trial.
Introduction: The development of resistance to endocrine treatment (HTH) can result from various biological mechanisms not only related to ER function but also to activation of multiple signaling pathways, which make HTH insufficient to control cancer cells. The combination of HTH with CDK4/6 inhibitors, which largely resemble phase-specific antiproliferative cytotoxic agents, demonstrated a striking clinical activity and became a standard treatment in ER+ breast cancer. Therefore, we have hypothesized that combining HTH (ER degraded) with metronomic polychemotherapy might improve clinical outcomes in advanced, endocrine-resistant ER+ breast cancer patients. Material and methods: The treatment (FulVEC) combined fulvestrant (500 mg i.m. d 1, 14, 28, and q4w thereafter) with a VEC regimen (vinorelbine 40 mg p.o. 3x/week, capecitabine 500 mg p.o. tid, cyclophosphamide 50 mg p.o. qd). After local ethical committee approval, this treatment was initially offered as a salvage therapy for advanced ER+ BC patients who exhausted available treatment options, and latter also for patients who refused or were ineligible for standard intravenous chemotherapy. All patients were previously treated with at least 1 line of palliative systemic therapy (47% received 3+ lines and 21% 5+ lines). Most (53%) have previously failed fulvestrant, and 34%, 32%, and 29% have previously failed palliative treatment with capecitabine, vinorelbine, and cyclophosphamide, respectively. Almost half of the patients (47%) received CDK4/6i previously. Most patients presented with bone (82%) and liver (66%) metastases. Three patients (8%) had OUN metastases, and 5% showed only locally advanced disease. Results: Between 2017-2022 – 38 patients (median age 49.1 years) received the FulVEC regimen, and all data was prospectively collected. In the ITT administration of FulVEC led to at least disease stabilization in 87% of patients and was associated with median PFS and OS of 8.5 months and 21.5 months, respectively. Previous treatment with capecitabine and vinorelbine was associated with non-significantly shorter PFS of 6.5 and 6.3 months, respectively. However, previous utilization with fulvestrant or cyclophosphamide had no impact on patient outcomes. Surprisingly, previous treatment with CDK4/6 inhibitors did not impact either PFS or OS (8.5 and 20.8 months, respectively). Patients with liver metastases had a higher (non-significant) risk of progression or death compared to other locations of metastases. Three patients with symptomatic OUN metastases (2 with leptomeningeal dissemination) treated with FulVEC responded to the treatment with median PFS and OS of 11.6 and 25.8 months, respectively. FulVEC regimen was generally well tolerated with no toxicity-related treatment cessation and temporary treatment interruption in 18% of patients due to G3-4 myelotoxicity, mainly neutropenia. Dose reduction, required in 47% of patients, was due to myelotoxicity, capecitabine-induced hand-foot-syndrome, and cyclophosphamide-induced cystitis. Conclusion: Chemo-endocrine therapy (FulVEC) comprising fulvestrant and metronomic polychemotherapy demonstrated surprisingly high activity in pretreated, endocrine-refractory breast cancer patients. Besides its significant antitumor activity and good safety profile, one of the most critical aspects of this therapy is its cost. FulVEC regimen consists of old, widely available, and inexpensive drugs and thus costs at least a level of magnitude less than any novel, targeted therapies considered for advanced ER+ BC. FulVEC and similar affordable strategies are critical for patients from low and middle-income countries. The activity of FulVEC proves that combining chemo- and hormone therapy in a palliative setting cannot be assumed as a no-go strategy. A phase III trial comparing FulVEC with physician treatment of choice in advanced BC patients who failed first-line HTH+CDK4/6i is warranted. Citation Format: Anna Buda-Nowak, Lukasz Kwinta, Pawel Potocki, Joanna Streb, Piotr Wysocki. Metronomic chemo-endocrine treatment (FulVEC) for patients with advanced hormone-refractory ER+ breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-01-08.
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