Summary:Cardiac toxicity is an uncommon but potentially serious complication of high-dose (HD) chemotherapy and little is known about incidence, severity and underlying mechanisms. We have systematically reviewed the literature of the last 30 years to summarize and appraise the published evidence on cardiac toxicity associated with HD chemotherapy. HD cyclophosphamide-containing regimens have been most commonly associated with cardiac toxicity, with a progressively decreasing incidence over time. Dosage, application regimens and coadministration of other chemotherapeutic agents emerged as risk factors. While cardiac toxicity has been rarely associated with other cytotoxic drugs, an unexpected incidence of severe cardiotoxicity resulted from reduced-intensity conditioning regimens containing melphalan and fludarabine. Predictive value of cardiologic examination of patients is limited, and patients with a slight depression of cardiac performance could tolerate HD chemotherapy. Clinical examination, resting electrocardiography and dosage adjustment in overweight patients remain the mainstay of prevention, with bidimensional echocardiography (2D echo) for patients with a history of anthracycline exposure. Strategies to decrease the long-term negative impact of anthracycline administration on cardiac performance are being investigated. New 2D echo-based techniques and circulating markers of cardiac function hold promise for allowing identification of patients at high risk for and early diagnosis of cardiac toxicity.
Summary:High-dose cyclophosphamide (HD-CTX) is largely employed in high-dose chemotherapy (HD-CHT) protocols. HD-CTX dose-limiting toxicity expresses itself as cardiac toxicity which is fatal in a minority of patients. The pathophysiology of HD-CTX-associated cardiotoxicity is still poorly understood. Autopsy studies in patients who died from acute HD-CTX-induced cardiac toxicity revealed hemorrhagic myocardial cell death and interstitial edema. Recently troponins, in particular troponin I (cTnI), have been found to represent a uniquely sensitive and specific marker of myocyte membrane integrity and therefore to increase in response to minimal myocardial cell damage in different settings, including doxorubicin-induced cardiotoxicity. We performed a multiparametric cardiologic monitoring in 16 consecutive breast cancer patients undergoing HD-CTX by means of serial ECG registrations and cardiac enzymes (CPK, CPK-MB and cTnI) determinations plus echocardiography in order to clarify acute cardiac events following HD-CTX administration. Neither overt cardiac toxicity nor cardiac enzymes elevation were recorded. Serial ECGs revealed in six cases little and reversible reduction of QRS voltage and/or ST abnormalities. Echo monitoring showed in four cases mild and transient increase of LV diastolic/systolic diameter/volume without decrease of FS% or EF% below normal values: in two of them abnormalities of diastolic function (E/A mitral doppler ratio) were also recorded. We conclude that our protocol of HD-CTX administration does not cause myocardial cell damage as analyzed by serum cTnI levels, thus suggesting that myocyte membrane injury may not be the first direct mechanism of HD-CTX cardiotoxicity. ECG (ie QRS voltages ) and Echo (ie E/A ratio) monitoring leads us to hypothesize that slight interstitial edema with reduction of LV diastolic compliance may be initial signs of cardiac dysfunction in this clinical setting. Bone Marrow Transplantation (2001) 28, 277-282.
Background: Breast cancer stem cells (BCSCs) have the ability to self renew and generate the full range of cells that make up a bulk tumor. Chemokine receptor 1 (CXCR1) is almost exclusively expressed in the aldehyde dehydrogenase positive (ALDH+) BCSC population compared with its expression in bulk tumor cells. CXCR1 is a receptor for CXCL8 (previously IL8), a proinflammatory chemokine implicated in the metastasis and progression of multiple malignancies, including breast cancers. CXCL8 has also been shown to stimulate self-renewal of BCSCs in vitro. Tissue damage induced by chemotherapeutic agents may induce CXCL8 as part of the injury response. This suggests that strategies aimed at interfering with the CXCL8/CXCR1 axis, activated by conventional chemotherapy (CT), may be able to target BCSCs and increase the efficacy of current therapies. Reparixin, a low molecular weight blocker of CXCL8 biological activity, reduced ALDH-1+ cells in a human breast cancer xenograft when administered alone or in combination with taxane chemotherapy, and reduced metastases. Based on these findings, a Phase Ib study to determine the safety of paclitaxel plus reparixin therapy, and to explore the effects of reparixin on BCSCs and the tumor microenvironment, was initiated. Design and Treatment: Patients will receive a three-day run-in with reparixin oral tablets 3 times/day (tid) followed by paclitaxel 80 mg/m2/week (Days 1, 8, and 15 for 28-day cycle) + reparixin oral tablets tid for 21 days. Three dose levels of 3–6 subjects will be explored in total: Dose level 1 = 400 mg oral reparixin tid; Dose level 2 = 800 mg reparixin tid; and Dose level 3 = 1200 mg reparixin tid. An additional 6 subjects will be enrolled at the highest tolerated dose. Safety will be assessed following one cycle. Treatment continues as long as clinical benefit is observed. Main Eligibility Criteria: Patients must be female aged > 18 years with HER-2 negative MBC, eligible for treatment with paclitaxel (not taxane-refractory), have had up to 3 prior CT lines for advanced breast cancer (not including neo/adjuvant chemotherapy), must have measurable disease according to RECIST criteria version 1.1, have ECOG PS of 0–1, have adequate organ function, and have no brain metastases. Objectives: Primary: To evaluate the safety and pharmacokinetic (PK) profile of the combination treatment. Secondary: 1) To evaluate tumor biopsies for the effects of reparixin on BCSC markers and tumoral microenvironment; 2) To evaluate blood samples for a) enumeration and molecular characterization of circulating tumor cells (CTCs), biomarker profiling for BCSC and epithelial-mesenchymal transition (EMT), and b) inflammatory cytokines; 3) To assess disease response for indication of efficacy. Statistical Methods: All tumor data collected will be reviewed and listed. No formal statistical analysis of this data is planned. Safety and tolerability analysis will be applied on the safety population with descriptive statistics for the safety variables. Summary statistics will be performed for each PK parameter and correlative study parameter. Accrual status: To date, four subjects have been enrolled at the first dose level. Target accrual is 15–24 subjects. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-01.
Background: Breast cancer stem cells (BCSCs) have the ability to self renew and generate the full range of cells that make up a bulk tumor. Chemokine receptor 1 (CXCR1) is almost exclusively expressed in the aldehyde dehydrogenase-1 positive (ALDH-1+) BCSC population compared with its expression in bulk tumor cells. CXCR1 is a receptor for CXCL8 (previously IL8), a proinflammatory chemokine implicated in the metastasis and progression of multiple malignancies, including breast cancers. CXCL8 has also been shown to stimulate self-renewal of BCSCs in vitro. Reparixin, a low molecular weight blocker of CXCL8 biological activity, reduced ALDH-1+ cells in a human breast cancer xenograft when administered alone or in combination with taxane chemotherapy, and reduced metastases. Based on these findings, a phase 1b study of reparixin in combination with paclitaxel in metastatic breast cancer was initiated and is completing enrolment. This small, pilot, window of opportunity study aims at exploring the safety and effects of reparixin on BCSC markers in early breast cancer. Design and Treatment: Reparixin oral tablets 1000 mg will be given 3 times daily (tid) for 21 consecutive days in the interval prior to planned surgery. Main Eligibility Criteria: Patients must be female aged > 18 years with ER-/PR-/HER-2 negative or ER+/PR+/HER-2 negative stage II and IIa operable breast cancer, with clinical tumor diameter of at least 2 cm, have had no prior surgery, radiotherapy, hormone therapy or chemotherapy, must be willing to undergo two mandatory tumor biopsies (pre- and post-therapy) that are not required for standard care. Objectives: Primary: 1) Evaluate the effects of orally administered reparixin on BCSCs in the primary tumor and the tumoral microenvironment by measuring: a) effects on BCSCs, in tissue samples by flow cytometry or RT-PCR and immunohistochemistry (IHC) b) pathway markers, Phosphatase and tensin homolog (PTEN) and CXCR1 levels in tissue samples by IHC c) Markers of inflammation in plasma samples and leukocyte subsets and study polymorphonuclear nuclear leukocyte [PMN] biology in peripheral blood samples d) Markers of angiogenesis, tumor infiltrating leukocytes, autophagy and EpCAM and EMT markers in tumor tissue samples 2) Evaluate the safety of oral reparixin administered three times daily (tid) for 21 consecutive days. Secondary: To define the pharmacokinetic (PK) profile of single agent orally administered reparixin. Statistical Methods: Comparative Analysis of pre- versus post-treatment biomarker results will be performed. In addition, exploratory correlative analyses may be carried out comparing changes in biomarker expression between selected biomarkers. Additional correlative analyses between biomarker results at specific timepoints may be investigated similarly. Safety and tolerability analysis will be applied on the safety population with descriptive statistics for the safety variables. Summary statistics will be performed for each PK parameter and correlative study parameter. Accrual status: To date, three subjects have been enrolled. Target accrual is 40 subjects. Contact for further Information: pieradelchi.ruffini@dompe.it. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-03.
Background: Breast cancer stem cells (BCSC) have the ability to self renew and generate the full range of cells that make up a bulk tumor. Experimental models and retrospective clinical observations point to BCSC as responsible for tumor recurrence and metastasis. CXCR1, one of the receptors for CXCL8, has been identified on BCSC. Reparixin, an allosteric inhibitor of CXCR1, reduced BCSC in breast cancer xenografts (Ginestier C et al., JCI 2010) both as single agent and in combination with taxane chemotherapy. In a phase Ib trial in women with metastatic HER2-negative BC, the combination of escalating doses (400 to 1200 mg three times per day) of reparixin with weekly paclitaxel resulted in a low incidence and severity of adverse reactions, a sizeable response rate and time-to-progression, with some long-term responders (Schott AF et al., SABC 2014). Trial Design: In this randomized, double-blind phase 2 trial patients will be randomized (1:1) to paclitaxel 80 mg/m2 on days 1, 8 and 15 of 28-day cycles in combination with reparixin or placebo oral tablets 1200 mg three times daily on days 1-21. Treatment continues until disease progression, unacceptable toxicity or withdrawal of consent. An independent Data Monitoring Committee has been appointed to oversee the trial. An independent Radiology Review will be performed for analysis of primary and secondary endpoints. Disease response will be assessed every 8 weeks. Patients will be followed up to 12 months after last enrolled patient completes treatment. Eligibility Criteria: Patients must be female aged ≥18 years with untreated metastatic TNBC who have relapsed >12 and >6 months after the end of a taxane- or non taxane-based (neo)adjuvant chemotherapy regimen, respectively. They must have measurable disease, ECOG PS of 0-1, adequate organ function, and no history or evidence of brain metastases (brain CT or MRI required). Tumor tissue must be available from a metastatic site or from primary tumor for confirmation of diagnosis and correlative studies. Key exclusion criteria are pre-existing peripheral neuropathy G>1 and any disease significantly affecting gastrointestinal function. Specific Aims: Primary: to evaluate progression-free survival (PFS) rate by independent assessment. Secondary: to determine median PFS, overall survival (OS), objective response rates and safety of the combination treatment. Exploratory: to determine median time to new tumor metastasis (TTM), proportion of patients progressing with new metastatic lesions, incidence and severity of peripheral neuropathy, and to evaluate BCSC in metastatic tissue Statistical Methods: The trial design provides 80% power to detect an increase in 6 month PFS from 30% to 50% with a 2-sided 5% significance level (Chi-square test). Kaplan-Meier curves will be produced for median PFS, OS outcomes and exploratory median TTM. Appropriate descriptive statistics will be provided for safety variables. Present Accrual and Target Accrual: Target accrual is 190 patients. Patients will be enrolled internationally in US and Europe. Contact Information: info@dompe.com Citation Format: Chang JC, Schott AF, Wicha MS, Cristofanilli M, Ruffini PA, McCanna S, Goldstein LJ. A randomized, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for triple-negative breast cancer (fRida). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-07.
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