Comprehensive Characterization of the Vascular Effects of Cisplatin-Based Chemotherapy in Patients With Testicular Cancer

Abstract

Background: Cisplatin-based chemotherapy increases the risk of cardiovascular and renal disease.

Objectives: We aimed to define the time course, pathophysiology, and approaches to prevent cardiovascular disease associated with cisplatin-based chemotherapy.

Methods: Two cohorts of patients with a history of testicular cancer (n = 53) were recruited. Cohort 1 consisted of 27 men undergoing treatment with: 1) surveillance; 2) 1 to 2 cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy (low-intensity cisplatin); or 3) 3 to 4 cycles of BEP (high-intensity cisplatin). Endothelial function (percentage flow-mediated dilatation) and cardiovascular biomarkers were assessed at 6 visits over 9 months. Cohort 2 consisted of 26 men previously treated 1 to 7 years ago with surveillance or 3 to 4 cycles BEP. Vasomotor and fibrinolytic responses to bradykinin, acetylcholine, and sodium nitroprusside were evaluated using forearm venous occlusion plethysmography.

Results: In cohort 1, the percentage flow-mediated dilatation decreased 24 h after the first cisplatin dose in patients managed with 3 to 4 cycles BEP (10.9 ± 0.9 vs. 16.7 ± 1.6; p < 0.01) but was unchanged from baseline thereafter. Six weeks after starting 3 to 4 cycles BEP, there were increased serum cholesterol levels (7.2 ± 0.5 mmol/l vs. 5.5 ± 0.2 mmol/l; p = 0.01), hemoglobin A1c (41.8 ± 2.0 mmol/l vs. 35.5 ± 1.2 mmol/l; p < 0.001), von Willebrand factor antigen (62.4 ± 5.4 mmol/l vs. 45.2 ± 2.8 mmol/l; p = 0.048) and cystatin C (0.91 ± 0.07 mmol/l vs. 0.65 ± 0.09 mmol/l; p < 0.01). In cohort 2, intra-arterial bradykinin, acetylcholine, and sodium nitroprusside caused dose-dependent vasodilation (p < 0.0001). Vasomotor responses, endogenous fibrinolytic factor release, and cardiovascular biomarkers were not different in patients managed with 3 to 4 cycles of BEP versus surveillance.

Conclusions: Cisplatin-based chemotherapy induces acute and transient endothelial dysfunction, dyslipidemia, hyperglycemia, and nephrotoxicity in the early phases of treatment. Cardiovascular and renal protective strategies should target the early perichemotherapy period. (Clinical Characterisation of the Vascular Effects of Cis-platinum Based Chemotherapy in Patients With Testicular Cancer [VECTOR], NCT03557177; Intermediate and Long Term Vascular Effects of Cisplatin in Patients With Testicular Cancer [INTELLECT], NCT03557164).

Keywords: 0FMD, flow-mediated dilatation; ACh, acetylcholine; BEP, bleomycin, etoposide and cisplatin; BK, bradykinin; FBF, forearm blood flow; ICAM, intracellular adhesion molecule; PAI, plasminogen activator inhibitor; SNP, sodium nitroprusside; germ cell tumors; platinum therapy; t-PA, tissue plasminogen activator; testicular cancer; thrombosis; vWF, von Willebrand factor.

© 2020 The Authors.

Figures

Graphical abstract

Figure 1

Cancer Management Regimes and Assessments in Cohort 1 (Early Effects Study) Patients with a recent diagnosis of testicular/retroperitoneal germ cell cancer and orchidectomy ≤8 weeks prior scheduled for cisplatin-based chemotherapy or active surveillance were recruited. Participants were stratified into 3 groups by management: 1) active surveillance for stage 1 low-risk disease; 2) 1 to 2 cycles of adjuvant bleomycin, etoposide, and cisplatin (BEP) chemotherapy for stage 1 high-risk disease; or 3) 3 to 4 cycles BEP chemotherapy for metastatic disease. Red circles illustrate study assessments.

Figure 2

Cohort 1 (Early Effects Study): %FMD Score Changes in %FMD among patients managed with surveillance (dark blue line), 1 to 2 cycles bleomycin, etoposide, and cisplatin (BEP) (light blue line), and 3 to 4 cycles BEP (red line). The blue and red shaded rectangles refer to duration of chemotherapy treatment (solid blue = 1 cycle, light blue = 2 cycles; solid red = 3 cycles, light red = 4 cycles). Shaded areas indicate chemotherapy. ∗∗p < 0.01. BL = baseline; FMD = flow-mediated dilatation; m = month; W = week.

Figure 3

Cohort 1 (Early Effects Study): Renal Biomarkers Changes in renal biomarkers among patients managed with surveillance (purple line), 1 to 2 cycles BEP (blue line), and 3 to 4 cycles BEP (red line): (A) Log urine ACR; (B) eGFR; (C) serum cystatin C; (D) log urine IL-18 per urine creatinine. Shaded areas indicate chemotherapy. The p values represent 2-way analysis of variance with correction for multiple comparisons. ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001. ACR = albumin to creatinine ratio; Cr = creatinine; eGFR = estimated glomerular filtration rate; IL = interleukin; other abbreviations as in Figure 2.

Figure 4

Cohort 2 (Medium-Term Effects Study): Absolute Forearm Blood Flow Changes in absolute forearm blood flow among patients managed 1 to 7 years previously with orchidectomy plus 3 to 4 cycles BEP (red line) versus orchidectomy alone (blue line): (A) bradykinin 100, 300, and 1,000 pmol/min; (B) acetylcholine 5, 10, and 20 μg/min; (C) sodium nitroprusside 2, 4, and 8 μg/min. The p values represent 2-way analysis of variance with correction for multiple comparisons. ACh = acetylcholine; BK = bradykinin; SNP = sodium nitroprusside; other abbreviations as in Figure 2.

Figure 5

In Vitro Effects From Cisplatin on Stress Kinase Signaling and Thrombotic Pathways in Human Aortic Endothelial Cells Effects from cisplatin on phosphorylation of Akt (A) and ERK1/2 (B), and mRNA expression of t-PA (C) and PAI-1 (D). The p values represent 1-way analysis of variance with correction for multiple comparisons (Western Blot analyses) or unpaired Student’s t-test (mRNA expression). ∗p < 0.05. 5ʹ = 5 min; 15ʹ = 15 min; (1) = cisplatin 1 μg/ml; (3) = cisplatin 3 μg/ml; (15) = cisplatin 15 μg/ml; Cis = cisplatin; CTR = control; PAI = plasminogen activator inhibitor; t-PA = tissue plasminogen activator.

Central Illustration

Effects of Cisplatin-Based Chemotherapy on Endothelial Function Patients with testicular cancer managed with cisplatin-based chemotherapy or surveillance were enrolled. Endothelial function was assessed by % flow-mediated dilatation over 9 months in patients with a recent diagnosis, or venous occlusion plethysmography in patients managed 1 to 7 years previously. Acute and transient endothelial dysfunction was observed 24 h after cisplatin-based chemotherapy, and endothelial function was not impaired 1 to 7 years after treatment. In the left panel, the blue and red shaded rectangles refer to duration of chemotherapy treatment (solid blue = 1 cycle, light blue = 2 cycles; solid red = 3 cycles, light red 4 = cycles). Shaded areas indicate chemotherapy. ∗∗p < 0.01.