Metronomic chemotherapy from rationale to clinical studies: A dream or reality?

Gaspar, António; Silvestris, Nicola; Licchetta, Antonella; Santini, Daniele; Scartozzi, Mario; Ria, Roberto; Pisconti, Salvatore; Petrelli, Fausto; Vacca, Angelo; Lorusso, Vito

doi:10.1016/j.critrevonc.2015.01.008

Cited by 69 publications

(53 citation statements)

References 115 publications

(99 reference statements)

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“…This therapeutic modality refers to the administration of low and equally spaced doses of chemotherapeutic drugs without long rest periods in between. Concomitantly, interest has also been focused on new therapeutic schedules using conventional drugs in combination with a metronomic‐like approach focused on activating immune responses to potentiate tumor regression and avoid tumor regrowth . For instance, cyclophosphamide (CPA) metronomic therapy, used with GL261 GBM tumors growing subcutaneously in immunocompetent mice, has been shown to activate antitumor CD8 + T‐cell response, and also to induce specific long‐term T‐cell tumor memory .…”

Section: Introductionsupporting

confidence: 78%

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Metronomic treatment in immunocompetent preclinical GL261 glioblastoma: effects of cyclophosphamide and temozolomide

et al. 2017

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Glioblastoma (GBM) causes poor survival in patients even when applying aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment, but resistance always ensues. In previous years, efforts have focused on new therapeutic regimens with conventional drugs to activate immune responses that may enhance tumor regression and prevent regrowth, for example the "metronomic" approaches. In metronomic scheduling studies, cyclophosphamide (CPA) in GL261 GBM growing subcutaneously in C57BL/6 mice was shown not only to activate antitumor CD8 T-cell response, but also to induce long-term specific T-cell tumor memory. Accordingly, we have evaluated whether metronomic CPA or TMZ administration could increase survival in orthotopic GL261 in C57BL/6 mice, an immunocompetent model. Longitudinal in vivo studies with CPA (140 mg/kg) or TMZ (range 140-240 mg/kg) metronomic administration (every 6 days) were performed in tumor-bearing mice. Tumor evolution was monitored at 7 T with MRI (T -weighted, diffusion-weighted imaging) and MRSI-based nosological images of response to therapy. Obtained results demonstrated that both treatments resulted in increased survival (38.6 ± 21.0 days, n = 30) compared with control (19.4 ± 2.4 days, n = 18). Best results were obtained with 140 mg/kg TMZ (treated, 44.9 ± 29.0 days, n = 12, versus control, 19.3 ± 2.3 days, n = 12), achieving a longer survival rate than previous group work using three cycles of TMZ therapy at 60 mg/kg (33.9 ± 11.7 days, n = 38). Additional interesting findings were, first, clear edema appearance during chemotherapeutic treatment, second, the ability to apply the semi-supervised source analysis previously developed in our group for non-invasive TMZ therapy response monitoring to detect CPA-induced response, and third, the necropsy findings in mice cured from GBM after high TMZ cumulative dosage (980-1400 mg/kg), which demonstrated lymphoma incidence. In summary, every 6 day administration schedule of TMZ or CPA improves survival in orthotopic GL261 GBM with respect to controls or non-metronomic therapy, in partial agreement with previous work on subcutaneous GL261.

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Section: Introductionsupporting

confidence: 78%

“…Among the different strategies trying to improve this, several studies have described drug administration schemes named “metronomic” . This therapeutic modality refers to the administration of low and equally spaced doses of chemotherapeutic drugs without long rest periods in between.…”

Section: Introductionmentioning

confidence: 99%

Metronomic treatment in immunocompetent preclinical GL261 glioblastoma: effects of cyclophosphamide and temozolomide

et al. 2017

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“…Additional purported mechanisms by which dose-dense chemotherapy may impact the tumor microenvironment are suppression of HIF-1α, reduction of T regulatory cells, maturation of dendritic cells and inhibition of tumor cell extravasation. 23 However, in the ACRIN 6695 cohort, approximately 91% of patients received bevacizumab starting at cycle 2, so it was not possible to evaluate whether dose-dense or every-3-week paclitaxel with bevacizumab vs. without the agent had effects on PFS or OS as in the parent trial. In addition, changes of CTP biomarkers from T0 to T1, unlike those from T0 to T2, were not associated with overall response, PFS-6, PFS or OS.…”

Section: Discussionmentioning

confidence: 99%

CT Perfusion as an Early Biomarker of Treatment Efficacy in Advanced Ovarian Cancer: An ACRIN and GOG Study

Zhang

Lee

et al. 2017

Clinical Cancer Research

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PURPOSE ACRIN 6695 was a feasibility study investigating whether CT perfusion (CTP) biomarkers are associated with progression-free survival at 6 months (PFS-6) in patients with advanced ovarian cancer who were treated with carboplatin and either dose-dense (weekly) or conventional (3-weekly) paclitaxel, with optional bevacizumab in the prospective phase III GOG-0262 trial. PATIENTS AND METHODS ACRIN 6695 recruited participants with residual disease after primary cytoreductive surgery or planned interval cytoreduction following neoadjuvant therapy, to undergo CTP studies before (T0), 3-weeks (T1) and 4-weeks (T2) after chemotherapy initiation. Tumor blood flow (BF) and blood volume (BV) were derived with commercial software. Fisher’s exact tests assessed the associations of CTP biomarkers changes from T0 to T2 dichotomized at zero with PFS-6 and overall radiographic response rate, while Cox regression assessed the associations between CTP biomarkers changes and progression-free survival (PFS) and overall survival (OS). Bonferroni correction was used to account for multiple comparisons. RESULTS 76 of 120 enrolled patients from 19 centers were evaluable with a median age of 61 years. BV increase was significantly associated with lower chance of PFS-6 (p=0.028), while BF achieves borderline significance (p=0.053). In addition, BF increase was associated with shorter PFS (HR 2.9, 95% CI 1.3–6.4, p=0.008) and remained significant after adjusting for age, change in tumor volume and surgery status (p=0.007). Neither BF nor BV changes were significantly associated with treatment response rate or OS. CONCLUSION Early CTP biomarkers measurement may provide early prognostic information for PFS in newly-diagnosed ovarian cancer.

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“…Traditionally, maximum cell death was obtained directly through maximum dose density of chemotherapy limited only by concern for fatal toxicity. An alternative approach is the “metronomic” strategy (17), which administers lower doses of therapy but more frequently. This has the benefit of reducing toxicity, permitting higher total drug administration, and increasing tumor cell death by inhibiting angiogenesis.…”

Section: Evolutionary Dynamics Of Cancer Therapymentioning

confidence: 99%

Application of Evolutionary Principles to Cancer Therapy

2015

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The dynamic cancer ecosystem, with its rich temporal and spatial diversity in environmental conditions and heritable cell phenotypes, is remarkably robust to therapeutic perturbations. Even when response to therapy is clinically complete, adaptive tumor strategies almost inevitably emerge and the tumor returns. Although evolution of resistance remains the proximate cause of death in most cancer patients, a recent analysis (1) found that evolutionary terms were included in less than 1% of manuscripts on the cancer treatment outcomes and this has not changed in 30 years. Here we review treatment methods that attempt to understand and exploit intratumoral evolution to prolong response to therapy. In general, we find that treating metastatic (i.e. non-curable) cancers using the traditional strategy aimed at killing the maximum number of tumor cells is evolutionarily unsound because, by eliminating all treatment-sensitive cells, it enables rapid proliferation of resistant populations – a well-known evolutionary phenomenon termed “competitive release (2, 3).” Alternative strategies such as adaptive therapy (4, 5), “ersatzdroges (6),” and double bind treatments (7) shift focus from eliminating tumor cells to evolution-based methods that suppress growth of resistant populations to maintain long term control.

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Metronomic chemotherapy from rationale to clinical studies: A dream or reality?

Cited by 69 publications

References 115 publications

Metronomic treatment in immunocompetent preclinical GL261 glioblastoma: effects of cyclophosphamide and temozolomide

Metronomic treatment in immunocompetent preclinical GL261 glioblastoma: effects of cyclophosphamide and temozolomide

CT Perfusion as an Early Biomarker of Treatment Efficacy in Advanced Ovarian Cancer: An ACRIN and GOG Study

Application of Evolutionary Principles to Cancer Therapy

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