University of Groningen
Survivorship care after testicular cancer
Boer, Hindrik
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Boer, H. (2019). Survivorship care after testicular cancer: New insights in late effects of treatment and approaches to shared-care follow-up. Rijksuniversiteit Groningen.
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Vascular fingerprint and vascular damage
markers associated with vascular events
in testicular cancer patients during and
after chemotherapy
Chapter 5
5
S. Lubberts1, H. Boer1, R. Altena1, C. Meijer1, A.M. van Roon2, N. Zwart1, S.F. Oosting1,P.W. Kamphuisen2, J. Nuver1, A.J. Smit2, A.B. Mulder3, J.D. Lefrandt2, J.A. Gietema1 Author affi liations:
Departments of 1Medical Oncology, 2Vascular Medicine and 3Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
90
Abstract Background
Metastatic testicular cancer (TC) can be cured with bleomycin, etoposide and cisplatin (BEP) chemotherapy. This comes at the price of an increased cardiovascular disease risk, not only years afterwards, but also during and shortly after chemotherapy. To prevent cardiovascular events, high-risk patients should be identified. Aim of this study was to assess BEP-chemotherapy induced vascular damage and to find risk factors for early vascular events.
Patients and methods
A prospective cohort study was performed in (B)EP treated TC patients. Development of venous and arterial vascular events was assessed. Vascular damage markers (vWF, FVIII, IMT) and cardiovascular risk factors were assessed before and until 1 year after chemotherapy. Before start of chemotherapy a vascular fingerprint was estimated. Presence of ≥3 risk factors was defined as
high-risk vascular fingerprint: BMI>25 kg/m2, current smoking, blood pressure>140/90 mmHg,
total cholesterol>5.1 and/or LDL>2.5 mmol/L or glucose≥7 mmol/L. Results
Seventy-three patients were included. Eight (11%) developed vascular events (4 arterial events, 4 pulmonary embolisms). VWF and FVIII increased during chemotherapy, especially in patients with vascular events. Sixteen patients (22%) had a high-risk vascular fingerprint before start of chemotherapy. These patients had arterial events more often (3/16(19%) vs. 1/57(2%);p=0.031) and higher vWF levels and IMT.
Conclusions
Endothelial activation and upregulation of procoagulant activity seem important mechanisms involved in early (B)EP-chemotherapy-induced vascular events. Before chemotherapy, a quarter already had cardiovascular risk factors. A vascular fingerprint could identify patients at risk for arterial events. This vascular fingerprint, when validated, can be used as a tool to select patients who may benefit from preventive strategies.
Introduction
Since the introduction of platinum-based chemotherapy in 1977, the prognosis of metastatic
testicular cancer (TC) improved remarkably, with survival rates of 80-90%.1 Treatment consists of
orchidectomy followed by bleomycin, etoposide and cisplatin (BEP) combination chemotherapy.2
However, cure rates are compromised by the increased risk of cardiovascular disease (CVD) both
during or shortly after treatment (acute onset)3,4 as well as years after treatment (late onset).5,6
The pathophysiology is not fully understood, and probably differs between acute and late CVD onset. One of the contributing factors for both types appears to be occurrence of endothelial
dysfunction7, which can occur either as a direct chemotherapy effect or can be mediated by
development of cardiovascular risk factors; TC survivorship is generally associated with an
unfavorable cardiovascular risk profile.8,9
That early onset CVD is a source of serious treatment-induced morbidity and mortality was recently
confirmed by Fung et al10. If high-risk patients could be identified before start of chemotherapy,
preventive strategies for this group can be explored to prevent early cardiovascular events. Therefore, the aim of this study was to assess BEP-chemotherapy-induced (subclinical) vascular damage and to find clues to identify patients at risk for early vascular events. To assess vascular damage we prospectively measured different markers for subclinical vascular damage and cardiovascular risk factors. We looked into the relationship of these markers and risk factors with development of both arterial and venous vascular events.
Methods
Patients
We performed a prospective cohort study in metastatic TC patients, aged 18-50 years, treated with first-line (B)EP chemotherapy in the University Medical Center of Groningen, the Netherlands. Exclusion criteria were previous chemo-/radiotherapy, previous vascular events, erythropoietin use or glomerular filtration rate <60 mL/min. The ethics committee approved this study. All participants gave written informed consent. Patients received three or four (B)EP
courses (etoposide 100 mg/m2, days 1-5, cisplatin 20 mg/m2, days 1-5, with/without bleomycin
30 USP, days 2, 8, 15) every three weeks and were during the first 6 days of every course hydrated with 4L saline per 24h. They received dexamethasone and ondansetron as antiemetics. Vascular events of both arterial and venous origin (WHO ICD-10 I1-I99) were included as possible events. Symptomatic as well as asymptomatic vascular events (discovered on staging CT scans) which developed after start of chemotherapy until two years afterwards were taken into account.
The Khorana score, risk prediction model for venous thrombosis18, was assessed for every patient
before start of chemotherapy.
92
Plasma biomarkers
Von Willebrand Factor (vWF) was measured in citrated plasma as described earlier.4 Coagulation
factor VIII (FVIII) was measured in stored citrated plasma (-80 oC) using an automatic hemostasis
testing system (ACL TOP 500, IL, the Netherlands), measuring APTT and using FVIII deficient plasma (SynthASil kit, IL, the Netherlands). Plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA) were measured in citrated plasma as described previously [4]. Growth differentiation factor 15 (GDF-15; Human GDF-15 Quantikine ELISA kit (R&D Systems, USA)) and high sensitive C-reactive protein (hs-CRP; BNII Nephelometer (Siemens Healthcare Diagnostics BV,
the Netherlands)) were measured in stored EDTA plasma (-20 oC).
Intima media thickness (IMT)
Posterior wall IMT of the right common carotid artery was measured using an ultrasound device,
as described earlier.4 The highest value from three measurements was recorded; maximal IMT
best reflects atherosclerotic burden and cardiovascular risk.11,12 High IMT was defined as >97.5th
age-specific percentile of healthy males.13
Oxidative stress memory: advanced glycation end products (AGEs)
AGEs were determined in triplicate by measuring skin autofluorescence at the right lower arm
with the AGE-reader (DiagnOptics Technology BV, the Netherlands).14 Measurements with a
variation coefficient >12% or low reflection (R<0.07) were excluded.
Cardiovascular risk factors and the vascular fingerprint
Weight, height, waist/hip circumference and blood pressure (sphygmomanometer) were measured. Current smoking behavior was recorded. In fasting blood samples, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, total cholesterol and glucose levels
were measured. Metabolic syndrome was defined according to the NCEP.15 Cardiovascular risk was
calculated using the European standard model (SCORE).16 However, the SCORE model was not an
useful instrument: because of their young age, every patient had the same low 10-year CVD risk. Therefore, we explored which risk factors were needed to modify the SCORE model in our aim to identify high-risk patients, and compiled a vascular fingerprint of five risk factors prevalent in
TC patients/survivors9,17: overweight, smoking, hypertension, dyslipidemia and impaired fasting
glucose. We used generally accepted cut-off values: BMI >25 kg/m2, current smoking, blood
pressure >140/90 mmHg (or using antihypertensive drugs), dyslipidemia (total cholesterol >5.1 mmol/L, LDL >2.5 mmol/L or using lipid lowering drugs), fasting glucose ≥7 mmol/L (or using blood glucose lowering drugs). A high-risk vascular fingerprint was defined as ≥3 risk factors before start of chemotherapy.
Timing of study-related investigations
IMT, AGEs and cardiovascular risk factors were measured before start, one month after completion and one year after start of chemotherapy. Plasma biomarkers were measured at the same time points and additionally 1-2 weeks after start of the third chemotherapy course.
Statistics
Data are presented as medians with ranges. Wilcoxon signed-rank tests were used for paired measurements. For comparisons between groups a Mann-Whitney U or Chi- Square test (expected counts <5: Fisher Exact test) was applied, as appropriate. Two- sided P-values <0.05 were considered significant. Statistical analyses were performed in SPSS Statistics 22.0 (IBM SPSS inc, USA). With the 73 patients, 85% power (α=0.05) was reached to detect an IMT difference of
180 μm (SD:160 μm)13 between patients with (n=8) and without events (n=65).
Figure 1. Patient accrual. Between May 2006 and June 2012, 78 consecutive patients
were included of which 73 were eligible for analysis.
Results
Patients
Seventy-three consecutive patients were available for analysis (Figure 1). Characteristics are described in Table 1. Eight patients (11%) developed vascular events (4 arterial, 4 venous) (Supplementary table 1). Arterial events were a stroke, renal infarction, splenic infarction and one patient had both a stroke and renal infarction. All venous events were pulmonary embolisms, three were asymptomatic and discovered on CT-scans. Patients with vascular events were older (median 38 vs. 30 years (Table 2)). The known risk factors an elevated lactate dehydrogenase
(LDH) level as well as the Khorana score18,19 did not differ between patients with and without
events (data not shown).
94
Table 1. Patient characteristics (n=73)
Chapter 5
Tables chapter 5
Table 1. Patient characteristics (n=73).
n/median %/range
Age at start of chemotherapy, years 30 18 – 46 Histological diagnosis Non-seminoma 59 81 Seminoma 14 19 Disease stage Stage II 57 78 Stage III 7 10 Stage IV 9 12
IGCCCG prognosis group
Good 61 84 Intermediate 11 15 Poor 1 1 Chemotherapy regimen 3 cycles BEP 53 73 4 cycles BEP 13 18 4 cycles EP 3 4
4 cycles BEP/EP combination 4 5 RPLND
Before (B)EP 1 1
After (B)EP 34 47
Follow-up duration, months 33 5 – 89 Oncological status at last follow-up
No evidence of testicular cancer 67 92
Refractory on (B)EP* 1 1
Death due to testicular cancer 1 1 Recurrent testicular cancer * 4 6 IGCCCG: international germ cell cancer collaborative group; RPLND: retroperitoneal lymph node dissection; BEP: bleomycin, etoposide and cisplatin containing chemotherapy; EP: etoposide and cisplatin containing chemotherapy.
* These patients received TIP-chemotherapy (paclitaxel, iphosphamide and cisplatin) as second-line treatment.
IGCCCG: international germ cell cancer collaborative group; RPLND: retroperitoneal lymph node dissection; BEP: bleomycin, etoposide and cisplatin containing chemotherapy; EP: etoposide and cisplatin containing chemotherapy.
* These patients received TIP-chemotherapy (paclitaxel, iphosphamide and cisplatin) as second-line treatment.
Table 2 . Differences in vascular damage markers and cardiovascular risk factors in patients with versus
patients without vascular events
vWF: von Willebrand Factor; FVIII: coagulation factor VIII; IMT: intima glycation end products; BMI: body mass index.
*Mann Whitney U test / Fisher exact test. *** significance disappeared after correction for age. ¶ IMT above the 97.5th percentile of an age-matched male reference group from literature13. ^ Hypertension is defined as a systolic blood pressure >140 mmHg and/ or a diastolic blood pressure >90 mmHg or use of antihypertensive drugs. ** Dyslipidemia is defined as a fasting total cholesterol >5.1 mmol/L, LDL >2.5 mmol/L, HDL < 1.04 mmol/L, ratio total cholesterol/HDL >5 and/or triglycerides >4.5 mmol/L or use of lipid lowering medication.
96
Diabetes mellitus is defined as a fasting glucose ≥7.0 mmol/L or use of blood glucose lowering medication. Metabolic syndrome is defined according to the NCEP ATP III definition update in 2005 in which three or more of the following factors have to be present: waist circumference ≥102 cm, triglycerides ≥1.7 mmol/L, HDL cholesterol <1.03 mmol/L or use of lipid lowering medication, blood pressure ≥130/85 mmHg or use of antihypertensive drugs, fasting glucose ≥5.6 mmol/L or use of blood glucose lowering medication. Patients with a BMI >30 kg/m2 with an unknown waist circumference were considered to have abdominal obesity and therefore scored as one point for increased waist circumference.
Plasma biomarkers
Patterns of biomarker levels are shown in Table 3.
Before chemotherapy, 12% had a high vWF level (>150%). Pre-chemotherapy high vWF did not predict for vascular events. Patients with vascular events had higher vWF levels during chemotherapy and one month afterwards compared to patients without vascular events (Figure 2, Table 2).
Six patients had an elevated FVIII level (>150%) (n=6/71, 8%) before chemotherapy of whom three (n=3/6, 50%) developed vascular events versus five patients (n=5/65, 8%) with FVIII ≤150% (p=0.017). Patients with vascular events had higher FVIII levels pre-chemotherapy, during chemotherapy and one month afterwards compared to patients without vascular events (Figure 2, Table 2).
PAI-1, t-PA, PAI-1/t-PA ratio, GDF-15, and hs-CRP were not associated with the observed vascular events.
IMT
In five out of the 73 patients (7%) no successful IMT measurement was performed before start of chemotherapy due to logistic or technical reasons. Of these 68 evaluable patients, 21 (31%) had a high IMT at start of chemotherapy. Three of the 21 (14%) developed arterial events, compared to none in the remaining 47 patients (p=0.027). Overall, IMT did not change in the first year after chemotherapy (Table 4). Absolute IMT and IMT changes were, after correction for age, not different in patients who developed vascular events (Table 2).
AGEs
The amount of AGEs did not change during the first year after treatment (Table 3). There were no differences in patients with vascular events compared to those without vascular events (Table 2). Chapter 5
Ta bl e 3. V as cu la r m ar ke rs b efo re , d ur in g an d aft er c he m ot he ra py . vW F: vo n W ill eb ra nd F ac to r; FV III : c oa gu la tio n fa cto r V III ; P A I-1: p la sm in og en a ct iv at or inh ib ito r 1; t-PA : t iss ue p la sm in og en a ct iva to r; G D F-15 : g ro w th d iffe re nti ati on fa cto r 1 5; hs -CR P: h ig h-se ns iti vi ty C -re ac tiv e pro te in ; I M T: in tima me di a th ic kn es s; A G Es : a dv an ce d gl yc at io n en d pro du ct s; BM I: bo dy ma ss in de x. *: si gn ifi ca nt ly d iff er en t fr om m ea su re m en t b efo re s ta rt o f c he m ot he ra py . Be fo re s ta rt o f ch em ot he ra py Du rin g 3t h c ou rs e of ch em ot he ra py On e m on th a ft er ch em ot he ra py O ne ye ar a ft er ch em ot he ra py me di an /n ra ng e/ % me di an /n ra ng e/ % me di an /n ra ng e/ % me di an /n ra ng e/ % Pl as m a bi om ar ke rs vW F, % 98 42 -297 160* 51 -379 124* 54 -249 111* 44 -237 FV III , % 100 49 -162 152* 55 -342 118* 73 -192 123* 34 -197 PA I-1, µ g/ l 28 2-143 14* 5-48 27 6-126 21* 8-66 t-PA , µ g/ l 8 4-19 7* 3-16 9* 4-28 9* 4-20 PA I-1/ t-PA ra tio 3. 7 1. 0-12. 5 2. 0* 0. 8-7. 5 3. 3* 0. 6-12. 6 2. 6* 0. 7-5. 9 GD F-15, p g/ m l 394 187 -193 5 5342 * 1439 -18 959 865* 299 -473 7 382* 247 -981 hs -CR P, m g/ L 1. 3 0. 2-50. 4 0. 5* 0. 2-132 .0 2. 2 0. 3-29. 1 1. 5 0. 2-15. 1 IM T, µ m 586 435 -109 7 586 420 -106 5 600 400 -103 7 AG Es , AU 1. 60 1. 03 -2. 70 1. 56 0. 99 -2. 28 1. 59 1. 17 -2. 51 Ca rd io va sc ul ar ri sk fa ct or s Cu rre nt s m ok er 20/ 73 27 10/ 70 14 16/ 65 25 Ov er w ei gh t ( BM I > 25 k g/ m 2) 41/ 73 56 43/ 69 62 36/ 66 55 Obe si ty (B M I > 30 k g/ m 2) 14/ 73 19 17/ 69 25 13/ 67 19 Hyp er te ns io n ^ 14/ 60 23 7/ 66* 11 7/ 65 11 Dy sl ipi de m ia ** 57/ 70 81 59/ 71 83 54/ 65 83 Di abe te s m el lit us ‡ 2/ 68 3 3/ 71 4 2/ 61 3 Me ta bo lic sy nd ro m e □ 14/ 62 23 18/ 69 26 11/ 65 17 Table 3. Vascular mark ers b efor e, during and a fter chemother ap y vWF : v on Willebr and Fact or ; FVIII: coagulation fact or VIII; PAI-1: plasminogen activ at or inhibit or 1; t-P A: di ffer entiation fact or 15; hs -CRP : high-sensitivit y C-r eactiv e pr ot ein; IM T:
intima media thick
ness; A
GEs: mass index.
tissue plasminogen activ
at or ; GDF -15: gr owth adv anc ed gly cation end pr
oducts; BMI: body
*: signi fic antly di ffer ent fr om measur ement befor e star t of chemother ap y. ^ H yper tension is de fined as a syst olic blood pr essur e >140 mmHg and/or a diast olic blood pr essur e >90 mmHg or use of antihyper tensiv e drugs . ** D yslipidemia is de fined as a fasting total cholest er ol >5.1 mmol/L, LDL >2.5 mmol/L, HDL < 1.04 mmol/L, ratio total cholest er ol/HDL >5 and/or trigly cerides >4.5 mmol/L or use of lipid lo w ering medic ation. ‡ D iabet es mellitus is de fined as a fasting gluc ose ≥ 7.0 mmol/L or use of blood gluc ose lo w ering medic ation. Metabolic syndr ome is de fined ac cor ding to the NCEP ATP III de finition updat e in 2005 in which thr ee or mor e of the follo wing fact ors hav e to be pr esent: w aist cir cumfer enc e ≥ 102 cm, trigly cerides ≥ 1.7 mmol/L, HDL cholest er ol <1.03 mmol/L or use of lipid lo w ering medic ation, blood pr essur e ≥ 130/85 mmHg or use of antihyper tensiv e drugs , f asting gluc ose ≥ 5.6 mmol/L or use of blood gluc ose lo w ering medic ation. Patients with a BMI >30 k g/m2 with an unk no wn w aist cir cumfer enc e w er e c onsider ed t o hav e abdominal obesit y and ther efor e sc or
ed as one point for incr
eased w
aist cir
cumfer
enc
98
Cardiovascular risk factors and the vascular fingerprint
Before start of chemotherapy, the most common risk factors were dyslipidemia (81%) and overweight (56%). Twenty-three percent had the metabolic syndrome (Table 3). Separate risk factors and the metabolic syndrome were equally present in patients with and without vascular events (Table 2). Sixteen patients (22%) had a high-risk vascular fingerprint, these patients developed arterial events more often (n=3/16 (19%) vs. 1/57 (2%); p=0.031) (Table 4). Prevalence of risk factors did not change in the first year after chemotherapy, except for a decreased prevalence of hypertension (p=0.021) (Table 3). Detected risk factors at start of chemotherapy were not treated.
The 16 patients with a high-risk vascular fingerprint had a higher IMT, higher vWF levels, FVIII levels more often >150% and higher AGEs before chemotherapy (Figure 2, Table 4). Adding pre-chemotherapy FVIII >150% as risk factor to the vascular fingerprint, defining presence of ≥3 out of 6 risk factors as high-risk, led to detection of all arterial events: 18 patients (n=18/71, 25%) had a high-risk vascular fingerprint with FVIII added, of whom 4 (n=4/18, 22%) developed arterial events, compared to no arterial events in the 53 patients without high-risk vascular fingerprint (p=0.003).
Persistently high vWF and FVIII
After one year, 29% still had high vWF and/or FVIII (>150%). These patients already had higher vWF and FVIII levels pre-chemotherapy (vWF: median 136% (range:84-219) vs. 82% (range:42-297); p<.001 and FVIII: median 123% (range:56-162) vs. 93% (range:49-152); p=0.001) and during chemotherapy and were older (Supplementary table 2).
Figur e2. vWF and FVIII lev els in patients with versus without high-risk vascular fingerprint. The red lines repr esent patients with ar terial vascular ev ents , the blue lines repr esent patients with venous vascular ev ents . Numb ers corr esp ond with the numb ers in the lef t c olumn of Supplementar y Table 1. The gr ey ar ea repr esents refer enc es values . Err or bars repr esent medians with int er qu ar tile ranges . vWF , v on W illebr and fac tor ; FVIII, coagulation fac tor VIII; BEP , bleom ycin, et op
100
Supplementary table 2. Patients with persistently high vWF and/or FVIII after one year versus patients with normalized
vWF and FVIII after one year (n=65 patients with measured plasma biomarkers after one year).
vWF and/or FVIII >150% after one year
n=19
Normalized vWF and VIII after one year
n=46
median/n range/% median/n range/% p*
Age at start of chemotherapy, years 36 25-45 30 18-46 .011
Cisplatin dose, mg/m2 300 300-700 300 300-400 .895
Biomarkers during 3th course
vWF, % 203 144-379 142 51-276 <.001 FVIII, % 173 79-249 143 55-277 .004 PAI-1, µg/l 16 7-37 13 6-48 .416 t-PA, µg/l 9 5-16 7 3-16 .066 PAI-1/t-PA ratio 2.0 0.8-6.9 2.1 0.8-7.5 .493 GDF-15, pg/ml 5500 2475-14400 5235 3060-18959 .880 Hs-CRP, mg/L 0.7 0.2-132.0 0.4 0.2-9.6 .110
IMT change between start and one year
after chemotherapy, µm 83 -31-300 3 -300-317 .181
Pre-chemotherapy high-risk vascular
fingerprint 5 26 9 20 .418
vWF: von Willebrand Factor; FVIII: coagulation factor VIII; CT: chemotherapy; PAI-1: plasminogen activator inhibitor 1; t-PA: tissue plasminogen activator; GDF-15: growth differentiation factor 15; hs-CRP: high-sensitivity C-reactive protein; IMT: intima media thickness.
*Mann Whitney U test / Fisher exact test.
Table 4 . Patients with versus patients without high-risk vascular fingerprint before start of chemotherapy
vWF: von Willebrand Factor; FVIII: coagulation advanced glycation end products. *Mann Whitney U test / Fisher exact test.
Discussion
This study shows that (B)EP chemotherapy for metastatic TC induces endothelial activation and procoagulant activity. Both mechanisms were related to development of early vascular events. It also turned out that about a quarter of the TC patients already carries cardiovascular risk factors at start of chemotherapy. The vascular fingerprint combines these risk factors. Metastatic TC patients with a high-risk vascular fingerprint before start of (B)EP chemotherapy developed arterial vascular events more often (19% vs. 2%).
During chemotherapy a clear upregulation of endothelial activation (vWF) and a procoagulant effect (FVIII, PAI-1/t-PA ratio) was seen. The PAI-1/t-PA ratio decrease indicates a tumor-related pro-thrombotic state before start and fibrinolysis during chemotherapy. GDF-15 levels increased
13-fold during treatment, which is partly explained by GDF-15 being an apoptosis marker20, but the
pattern does not suggest a relationship with cancer activity. GDF-15 is also known to participate
in vascular pathological processes.21 In a preclinical model for chemotherapy-induced endothelial
damage its genes were highly upregulated22. GDF-15 thus seems to reflect endothelial activation
during chemotherapy. However, since all patients showed an increase, its distinguishing value is limited. Hs-CRP levels fell during treatment, correlating with dexamethasone administration. Chapter 5
VWF and FVIII levels were higher in patients with vascular events, strongly suggesting that endothelial activation and procoagulant activity are part of underlying mechanisms behind early onset vascular disease. The only pre-chemotherapy biomarker related to vascular events was FVIII>150%. During and one month after chemotherapy, both vWF and FVIII were higher in patients with vascular events. The course of VWF and FVIII therefore can also be helpful in detecting
high-risk patients. VWF is a known predictor for arterial events in the general population23 and
FVIII has earlier been shown to be related to venous events in cancer patients.24 Both vWF and
FVIII were not associated with venous events only in this TC cohort. Venous events probably have a different pathophysiology. Known risk factors are venous access devices, retroperitoneal tumor
mass size, high lactate dehydrogenase (LDH) levels, and a high Khorana score.18, 19, 25 In our study,
none of the patients with vascular events had venous access devices. Retroperitoneal masses, if any, were of limited size . LDH levels were not different in patients with or without vascular events. The Khorana score was not different between patients with or without vascular events.
IMT did not change in the first year after chemotherapy. In the male general population an increase
of 5.2 μm/year is estimated.13 As inter-measurement variability is 5-10% [26], one year seems too
short to observe IMT changes. A remarkable finding was that 31% had at start of chemotherapy a high IMT compared to age-matched peers from the healthy male group of a large Dutch
cohort (n=1993).13 These patients developed more often arterial vascular events. Furthermore,
a large part of the patients had cardiovascular risk factors before start of chemotherapy. Not only TC survivorship is thus associated with an unfavorable cardiovascular risk profile: at start of chemotherapy about a quarter of the patients seem already prone to development of CVD. Presence of cardiovascular risk factors did not change within the first year after chemotherapy, except for blood pressure. The higher blood pressure before start of chemotherapy is consistent
with earlier findings4 and is probably related to stress of the recent cancer diagnosis and oncology
ward admission.
The recent study of Fung et al. shows excess CVD deaths in the first year after chemotherapy for
TC10. This underlines the importance of identifying high-risk patients before start of treatment, as
standard application of prevention strategies also carries risk. We provide the vascular fingerprint as an easy tool to identify high-risk patients. The vascular fingerprint consists of traditional cardiovascular risk factors: overweight, smoking, hypertension, dyslipidemia and impaired fasting glucose. Patients with ≥3 risk factors were considered to have a high-risk vascular fingerprint (n=16, 22%). Adding pre-chemotherapy FVIII>150% as risk factor to the vascular fingerprint led to detection of all arterial events. Main differences with the metabolic syndrome –which was not associated with early onset vascular events– are the addition of smoking behavior and a more rigorous cut-off for overweight. The TC population is relatively young, it is assumable that a BMI of
25-30 kg/m2 is an additional risk factor.
The vascular fingerprint appears to pinpoint TC patients at increased risk for early onset arterial vascular events. The metabolic syndrome is more likely involved in late onset atherosclerotic Vascular damage markers in testicular cancer patients during and after chemotherapy
102
CVD, because its definition is based on insulin resistance eventually leading to atherosclerosis.27
Although results are statistically significant and the vascular fingerprint is supported by known vascular damage markers (vWF, FVIII, IMT and AGEs), the current data especially are hypothesis-generating. Therefore a validation study is needed to test the performance of this selection tool in an independent larger cohort with newly diagnosed disseminated TC patients requiring cisplatin combination chemotherapy (validation study: Clinicaltrials.gov NCT02573584). When validated, intervention trials should be initiated in which TC patients with a high-risk vascular fingerprint before start of chemotherapy are randomized for a prophylactic intervention, for example with LMWHs.
One year after chemotherapy, 29% had a high vWF and/or FVIII level. These patients also had higher vWF and FVIII levels before start and during chemotherapy. This persistent vascular activation status possibly contributes to late onset CVD, in which the accelerated atherosclerotic phenotype plays a role. However, longer follow-up is needed to determine this effect. When this is done and the data available, possible intervention strategies could be explored but for now, these patients should be monitored closely during follow-up.
In conclusion, endothelial activation and increased procoagulant activity are important underlying mechanisms involved in the development of vascular events during and shortly after chemotherapy. Before start of chemotherapy, about a quarter of the TC patients already has an increased CVD risk, as demonstrated by presence of cardiovascular risk factors and a high IMT. Traditional cardiovascular risk factors were clustered in a pre-chemotherapy vascular fingerprint. This vascular fingerprint, when validated, can be used as a tool to select patients who may benefit from preventive strategies.
Funding
This work was supported by the Dutch Cancer Society (grant 2009-4365). The funding source had no role in study design, collection, analysis and interpretation of data and also no role in writing this manuscript.
Disclosures
AJS is founder and shareholder of Diagnoptics Technologies, The Netherlands, the company which developed the AGE reader. JG received institutional grants from Roche, AbbVie and Siemens. The other authors have no disclosures to report.
Acknowledgements
We like to acknowledge Anne van Gessel, Annet Possel-Nicolai, Margreet Teune-Weesjes, Marianne Bruin and Wietze Kuipers for performing the IMT and AGE measurements. We thank Gerrie Steursma for her administrative support.
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Supplementary tables and figures Supplementa ry table 1. Char ac teristic s of patients with v ascular ev ents (n=8) CT -sc an: c omput ed t omogr aphy sc anner ; BEP : bleomy cin, et
oposide and cisplatin c
ontaining chemother
ap
y; EP
: et
oposide and cisplatin c
ontaining chemother ap y. *: diagnosed on e valuating CT -sc an. Su pp le m en ta ry ta bl e 1. Ch ar ac te ris tic s of p at ie nt s w ith v as cu la r e ve nt s (n = 8) Ag e Ev en t Sym pt om s Ri sk fa ct or s in vas cu lar fin ge rp ri nt Ax ia l Ø la rg es t re tr op eri to ne al m as s on CT -sc an Ti m in g Tr ea tm en t Ou tc om e 1 29 Is ch em ic str ok e Ye s Ov er w ei gh t Sm ok er Dy sl ipi de m ia No v is ib le m as se s 1 ye ar afte r B EP Thr om bo ly sis , a nt ic oa gu la tio n Mi ld a ph asi a 2 45 Is ch em ic str ok e Ye s Ov er w ei gh t Sm ok er Dy sl ipi de m ia No v is ib le m as se s Du rin g 4t h BE P Thr om bo ly sis , a nt ic oa gu la tio n, ch an ge o f r eg im en : a bs ta in ed fr om la st 2 bl eo m yc in g ifts Di ed fr om pr og re ss iv e di se as e 8 m on th s af te r sta rt of ch em ot he ra py 3 43 Is ch em ic str ok e, re na l in fa rc tio n Ye s Ov er w ei gh t Hyp er te ns io n Dy sl ipi de m ia No v is ib le m as se s, ce rv ica l l ym ph n od e on ly Du rin g 4t h BE P An tic oa gu la tio n Fu ll re co ve ry 4 45 Sp le ni c in fa rc tio n No * Ov er w ei gh t Dy sl ipi de m ia 4. 0 cm 1 m on th afte r B EP An tic oa gu la tio n Fu ll re co ve ry 5 39 Pu lm on ar y em bo lis m No * Dy sl ipi de m ia 1. 2 cm 1 m on th afte r E P An tic oa gu la tio n Fu ll re co ve ry 6 36 Pu lm on ar y em bo lis m No * Ov er w ei gh t Hyp er te ns io n Dy sl ipi de m ia 3. 4 cm 1 m on th afte r B EP An tic oa gu la tio n Fu ll re co ve ry 7 35 Pu lm on ar y em bo lis m Ye s Ov er w ei gh t Dy sl ipi de m ia 2. 1 cm Du rin g 2n d BE P An tic oa gu la tio n, c ha ng e of re gi m en : in ste ad o f 3 th B EP , 2 E P Fu ll re co ve ry 8 27 Pu lm on ar y em bo lis m No * Ov er w ei gh t Dy sl ipi de m ia 3. 2 cm Du rin g 4t h BE P An tic oa gu la tio n Fu ll re co ve ry CT -s ca n: c om pu te d to m og ra ph y sc an ne r; BE P: b le om yc in , e to po si de a nd c isp la tin c on ta in in g ch em ot he ra py ; E P: e to po si de a nd c is pl at in c on ta in in g c he m ot he ra py . * : d ia gn os ed o n eva lu at in g CT -sc an .
106
Supplementary table 2. Patients with persistently high vWF and/or FVIII after one year versus patients with
normalized vWF and FVIII after one year (n=65 patients with measured plasma biomarkers after one year)
vWF: von Willebrand Factor; FVIII: coagulation factor VIII; CT: chemotherapy; PAI-1: plasminogen activator inhibitor 1; t-PA: tissue plasminogen activator; GDF-15: growth differentiation factor 15; hs-CRP: high-sensitivity C-reactive protein; IMT: intima media thickness.
*Mann Whitney U test / Fisher exact test.
Supplementary table 2. Patients with persistently high vWF and/or FVIII after one year versus patients with normalized
vWF and FVIII after one year (n=65 patients with measured plasma biomarkers after one year).
vWF and/or FVIII >150% after one year
n=19
Normalized vWF and VIII after one year
n=46
median/n range/% median/n range/% p*
Age at start of chemotherapy, years 36 25-45 30 18-46 .011
Cisplatin dose, mg/m2 300 300-700 300 300-400 .895
Biomarkers during 3th course
vWF, % 203 144-379 142 51-276 <.001 FVIII, % 173 79-249 143 55-277 .004 PAI-1, µg/l 16 7-37 13 6-48 .416 t-PA, µg/l 9 5-16 7 3-16 .066 PAI-1/t-PA ratio 2.0 0.8-6.9 2.1 0.8-7.5 .493 GDF-15, pg/ml 5500 2475-14400 5235 3060-18959 .880 Hs-CRP, mg/L 0.7 0.2-132.0 0.4 0.2-9.6 .110
IMT change between start and one year
after chemotherapy, µm 83 -31-300 3 -300-317 .181
Pre-chemotherapy high-risk vascular
fingerprint 5 26 9 20 .418
vWF: von Willebrand Factor; FVIII: coagulation factor VIII; CT: chemotherapy; PAI-1: plasminogen activator inhibitor 1; t-PA: tissue plasminogen activator; GDF-15: growth differentiation factor 15; hs-CRP: high-sensitivity C-reactive protein; IMT: intima media thickness.
*Mann Whitney U test / Fisher exact test. Chapter 5
