Metronomic Oral Cyclophosphamide in Patients with Advanced Solid Tumors

Bojko, Peter; Schimmel, G.; Bosse, Daniel; Abenhardt, Wolfgang

doi:10.1159/000336144

Cited by 8 publications

(2 citation statements)

References 11 publications

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“…Metronomic chemotherapy has been suggested to induce anti-cancer effects via multiple mechanisms, including anti-angiogenesis, anti-tumor immune response, and direct anti-cancer action [8]. Low-dose oral cyclophosphamide is one of the most commonly administered metronomic agents either alone or together with other agents such as capecitabine and methotrexate [9,10,11,12]. Because metronomic chemotherapy induces anti-cancer effects with minimal side effects, it is a good candidate for combined use with endocrine therapy.…”

Section: Introductionmentioning

confidence: 99%

Differential Involvement of Autophagy and Apoptosis in Response to Chemoendocrine and Endocrine Therapy in Breast Cancer: JBCRG-07TR

Ueno

Masuda

Kamigaki

et al. 2019

IJMS

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Endocrine therapy is an essential component in the curative treatment of hormone receptor (HR)-positive breast cancer. To improve treatment efficacy, the addition of metronomic chemotherapy has been tested and shown to improve therapeutic effects. To better understand cellular reactions to metronomic chemoendocrine therapy, we studied autophagy-related markers, beclin 1 and LC3, and apoptosis-related markers, TUNEL and M30, in pre- and post-treatment cancer tissues from a multicenter neoadjuvant trial, JBCRG-07, in which oral cyclophosphamide plus letrozole were administered to postmenopausal patients with HR-positive breast cancer. Changes in the levels of markers were compared with those following neoadjuvant endocrine therapy according to clinical response. Apoptosis, in addition to autophagy-related markers, increased following metronomic chemoendocrine therapy and such increases were associated with clinical response. By contrast, following endocrine therapy, the levels of apoptosis-related markers did not increase regardless of clinical response, whereas the levels of autophagy-related markers increased. Furthermore, levels of the apoptosis-related marker, M30, decreased in responders of endocrine therapy, suggesting that the induction of apoptosis by metronomic chemoendocrine therapy was involved in the improved clinical outcome compared with endocrine therapy. In conclusion, metronomic chemoendocrine therapy induced a different cellular reaction from that of endocrine therapy, including the induction of apoptosis, which is likely to contribute to improved efficacy compared with endocrine therapy alone.

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Section: Introductionmentioning

confidence: 99%

Differential Involvement of Autophagy and Apoptosis in Response to Chemoendocrine and Endocrine Therapy in Breast Cancer: JBCRG-07TR

Ueno

Masuda

Kamigaki

et al. 2019

IJMS

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“…It has been suggested to act via multiple mechanisms in exerting anticancer effects, including anti‐angiogenesis, antitumor immune response, and direct anticancer action . Oral cyclophosphamide is one of the most commonly used metronomic agents and is administered alone or together with other drugs such as capecitabine and methotrexate . Because metronomic chemotherapy shows anticancer effects via different mechanisms of action without overt toxic side effects, it is a good candidate in combination with endocrine therapy.…”

Section: Introductionmentioning

confidence: 99%

A multicenter phase II trial of neoadjuvant letrozole plus low‐dose cyclophosphamide in postmenopausal patients with estrogen receptor‐positive breast cancer (JBCRG‐07): therapeutic efficacy and clinical implications of circulating endothelial cells

et al. 2018

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Neoadjuvant endocrine therapy has been reported to decrease tumor size, which leads to increased breast conservation rates. To improve the clinical response, metronomic chemotherapy with endocrine therapy is a promising strategy. A multicenter phase II single‐arm neoadjuvant trial with letrozole and cyclophosphamide was conducted. Eligibility criteria included postmenopausal status, T2–4 N0–1, and estrogen receptor‐positive breast carcinoma. Letrozole (2.5 mg) plus cyclophosphamide (50 mg) was given orally once a day for 24 weeks. The primary endpoint was the clinical response rate (CRR). To investigate anti‐angiogenic effects, circulating endothelial cells (CECs) were quantified using the CellSearch system. From October 2007 to March 2010, 41 patients were enrolled. The CRR was 67.5% (52.0–80.0%), which was above the prespecified threshold (65%). The conversion rate from total mastectomy to breast‐conserving surgery was 64% (18/28). Grade 3 or greater nonhematological toxicity was not reported. Clinical response was associated with improved disease‐free survival (DFS) (P = 0.020). The increase in CEC counts at 8 weeks was observed in nonresponders (P = 0.004) but not in responders. Patients with higher CEC counts at baseline or post‐treatment showed worse DFS than those with lower counts (P < 0.001 at baseline and = 0.014 post‐treatment). Multivariate analysis showed that post‐treatment CEC counts but not pretreatment counts were independently correlated with DFS (P = 0.046). In conclusion, neoadjuvant letrozole plus cyclophosphamide showed a good clinical response for postmenopausal patients with estrogen receptor‐positive breast cancer. CEC quantification is a promising tool for treatment monitoring and prognostic stratification for metronomic therapy following validation of our results in larger studies. Clinical trial registration number: UMIN000001331 Phase II study of neoadjuvant letrozole combined with low‐dose metronomic cyclophosphamide for postmenopausal women with endocrine‐responsive breast cancer (JBCRG‐07)

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