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Whether low-dose metronomic oral cyclophosphamide improves the response to docetaxel in first-line treatment of non-triple-negative metastatic breast cancer.

ABSTRACT: Oral metronomic chemotherapy may target tumor cells indirectly via antiangiogenic activity, restoration of anticancer immune response, or induction of tumor dormancy. We initiated the single-center, randomized, open-label, phase II study to determine whether the addition of metronomic cyclophosphamide to docetaxel (T) (w/o trastuzumab) improves overall response rate (ORR) as first-line treatment among patients with non-triple-negative metastatic breast cancer (MBC). Eligible patients with previously untreated non-triple-negative MBC were randomly assigned (1:1) to receive 3-weekly cycles of Metro-TC (T 75mg/m2, d1 plus oral cyclophosphamide 50 mg daily) or T alone. All patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was ORR. Finally, 35 patients were randomized to Metro-TC group while 31 to T group. Median treatment cycles of T for both groups were 8. ORR was not improved by addition of metronomic cyclophosphamide to T (71.4% vs. 51.6%; P = 0.09). There was no statistically significant difference with regard to progression free survival (median 18.5 vs. 11.7 months; P = 0.07) or overall survival (median 33.7 vs. 33.6 months; P = 0.84) between the two group. Grade 3/4 adverse events (eg. neutropenia [100% vs. 100%], febrile neutropenia [29% vs. 29%], and neurotoxicity [6% vs. 3%]) were also comparable. There were no treatment-related deaths. We conclude that concomitant administration of metronomic cyclophosphamide and T does not appear to be a significantly active schedule for first-line treatment of non-triple-negative MBC.

SUBMITTER: Zhang J

PROVIDER: S-EPMC5668065 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Whether low-dose metronomic oral cyclophosphamide improves the response to docetaxel in first-line treatment of non-triple-negative metastatic breast cancer.

Zhang Jian J Wang Leiping L Wang Zhonghua Z Wang Biyun B Cao Jun J Lv Fangfang F Zhang Sheng S Shao Zhimin Z Hu Xichun X

Oncotarget 20170616 45

Oral metronomic chemotherapy may target tumor cells indirectly via antiangiogenic activity, restoration of anticancer immune response, or induction of tumor dormancy. We initiated the single-center, randomized, open-label, phase II study to determine whether the addition of metronomic cyclophosphamide to docetaxel (T) (w/o trastuzumab) improves overall response rate (ORR) as first-line treatment among patients with non-triple-negative metastatic breast cancer (MBC). Eligible patients with previo ...[more]

PMID: 29108332

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Project description:BackgroundTargeting tumor vasculature is a strategy with great promise in the treatment of many cancers. However, anti-angiogenic reagents that target VEGF/VEGFR2 signaling have met with variable results clinically. Among the possible reasons for this may be heterogeneous expression of the target protein.MethodsDouble immunofluorescent staining was performed on formalin-fixed paraffin embedded sections of treated and control SW480 (colorectal) and WM239 (melanoma) xenografts, and tissue microarrays of human colorectal carcinoma and melanoma. Xenografts were developed using RAG1-/- mice by injection with WM239 or SW480 cells and mice were treated with 20 mg/kg/day of cyclophosphamide in their drinking water for up to 18 days. Treated and control tissues were characterized by double immunofluorescence using the mural cell marker ?-SMA and CD31, while the ratio of desmin/CD31 was also determined by western blot. Hypoxia in treated and control tissues were quantified using both western blotting for HIF-1? and immunohistochemistry of CA-IX.ResultsVEGFR2 is heterogeneously expressed in tumor vasculature in both malignant melanoma and colorectal carcinoma. We observed a significant decrease in microvascular density (MVD) in response to low dose metronomic cyclophosphamide chemotherapy in both malignant melanoma (with higher proportion VEGFR2 positive blood vessels; 93%) and colorectal carcinoma (with lower proportion VEGFR2 positive blood vessels; 60%) xenografts. This reduction in MVD occurred in the absence of a significant anti-tumor effect. We also observed less hypoxia in treated melanoma xenografts, despite successful anti-angiogenic blockade, but no change in hypoxia of colorectal xenografts, suggesting that decreases in tumor hypoxia reflect a complex relationship with vascular density. Based on ?-SMA staining and the ratio of desmin to CD31 expression as markers of tumor blood vessel functionality, we found evidence for increased stabilization of colorectal microvessels, but no such change in melanoma vessels.ConclusionsOverall, our study suggests that while heterogeneous expression of VEGFR2 is a feature of human tumors, it may not affect response to low dose metronomic cyclophosphamide treatment and possibly other anti-angiogenic approaches. It remains to be seen whether this heterogeneity is partly responsible for the variable clinical success seen to date with targeted anti-VEGFR2 therapy.

Project description:For patients with metastatic renal cell cancer (mRCC) who progressed on vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to prolong progression free survival. Intriguingly, inhibition of mTOR also promotes expansion of immunosuppressive regulatory T cells (Tregs) that can inhibit anti-tumor immune responses in a clinically relevant way in various tumor types including RCC. This study intends to investigate whether the antitumor efficacy of everolimus can be increased by preventing the detrimental everolimus induced expansion of Tregs using a metronomic schedule of cyclophosphamide.This phase I-II trial is a national multi-center study of different doses and schedules of low-dose oral cyclophosphamide in combination with a fixed dose of everolimus in patients with mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the phase I part of the study the optimal Treg-depleting dose and schedule of metronomic oral cyclophosphamide when given in combination with everolimus will be determined. In the phase II part of the study we will evaluate whether the percentage of patients progression free at 4 months of everolimus treatment can be increased from 50% to 70% by adding metronomic cyclophosphamide (in the dose and schedule determined in the phase I part). In addition to efficacy, we will perform extensive immune monitoring with a focus on the number, phenotype and function of Tregs, evaluate the safety and feasibility of the combination of everolimus and cyclophosphamide, perform monitoring of selected angiogenesis parameters and analyze everolimus and cyclophosphamide drug levels.This phase I-II study is designed to determine whether metronomic cyclophosphamide can be used to counter the mTOR inhibitor everolimus induced Treg expansion in patients with metastatic renal cell carcinoma and increase the antitumor efficacy of everolimus.ClinicalTrials.gov Identifier NCT01462214, EudraCT number 2010-024515-13, Netherlands Trial Register number NTR3085.

Project description:There is no standard third-line or further systemic treatment for patients with inoperable locoregionally advanced recurrent or metastatic nasopharyngeal carcinoma (NPC). Metronomic oral cyclophosphamide provides an acceptable and cheap option for these heavily pretreated patients who had limited choices. We conducted a prospective phase II single-arm open-label study of metronomic oral cyclophosphamide. Patients with locoregionally advanced recurrent inoperable (rT3/T4, rN2-N3b) or metastatic (rM1) NPC who had Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0-2) and had progressed after at least 2 lines of palliative systemic chemotherapy were eligible. They received oral cyclophosphamide between 50 and 150 mg once daily until progressive disease or unacceptable toxicity. Objective response rate (ORR), disease control rate (DCR), biochemical response (two consecutive declines of plasma EBV DNA after treatment), progression-free survival (PFS), overall survival (OS), and safety profiles were evaluated. A total of 56 patients were recruited. Thirty-three, 13, 6, 3, and 1 patients received cyclophosphamide as 3rd, 4th, 5th, 6th, and 7th line of therapy respectively. After a median follow-up of 9.95 months (range 1.76-59.51 months), the ORR was 8.9% and the DCR was 57.1%. The median PFS and OS were 4.47 and 9.20 months, respectively. Those with PS 1 had longer median PFS (5.49 months) compared to those with PS 2 (3.75 months, P = .011). Besides, those who had locoregionally recurrent disease had better PFS (8.97 months, 95% CI, 0.53-17.41 months) compared to those who had distant metastases (4.14 months, 95% CI, 2.53-5.75 months, P = .020). Multivariable analysis revealed that PS 1 (vs 2) (P = .020) and locoregional recurrence (vs metastasis) (P = .029) were the only significant independent prognostic factors of PFS. Around 16 (28.6%) patients developed grade ≥3 adverse events, including malaise (5.4%), hematological (8.9%), gastrointestinal (3.6%), feverish (3.6%), and hemorrhagic (1.8%) events. The median cost of the whole drug treatment was 51.65 US dollars (USD) (range 4.15-142.75 USD) (1 USD = 7.8 HK dollars [HKD]). Metronomic oral cyclophosphamide is an acceptable third-line or beyond systemic therapy for locoregionally advanced recurrent or metastatic NPC with acceptable toxicity and limited financial burden.

Dataset Information

Whether low-dose metronomic oral cyclophosphamide improves the response to docetaxel in first-line treatment of non-triple-negative metastatic breast cancer.

Publications

Whether low-dose metronomic oral cyclophosphamide improves the response to docetaxel in first-line treatment of non-triple-negative metastatic breast cancer.

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