. 2015 Aug 3;33(28):3105–3115. doi: 10.1200/JCO.2014.60.3654

Table 5.

Summary of Studies Reporting CVD and CVAs After Chemotherapy for TC

Study	Study Type	No. of Patients With TC Given Chemotherapy^a			Calendar Years of Diagnosis	Type of Antecedent Chemotherapy	Time Period Evaluated After TC Diagnosis	CVD (total)		CVAs
Study	Study Type	Total	NS	S	Calendar Years of Diagnosis	Type of Antecedent Chemotherapy	Time Period Evaluated After TC Diagnosis	No. of Patients	Overall Risk (95% CI)	No. of Patients	Overall Risk (95% CI)
Current article,^b 2014	Retrospective population-based cohort	6,909	6,909	0	1980-2010	Not available^c	Entire time period, stratified into intervals	54^d	SMR: 1.36 (1.03 to 1.78)	10	SMR: 2.40 (1.15 to 4.42)
Haugnes et al,⁶ 2010	Multi-institutional retrospective cohort	364^e	NA	NA	1980-1994	PVB, BEP	> 2 years	27^f	HR: 2.60^g (1.10 to 5.90)	6^h	Not reportedⁱ
Dieckmann et al,¹¹ 2010	Multi-institutional retrospective survey^j	8,233	6,586	1,647	1996-2008	BEP, VIP	During or within 6 weeks of chemotherapy	25^k	Not reported	3	Not reported
Van den Belt-Dusebout et al,⁹ 2007	Multi-institutional retrospective cohort	710	614	96	1965-1995	PVB, BEP, carboplatin, ifosfamide, and dactinomycin	≥ 5 years	49^l	SIR: 1.30^m (1.00 to 1.80)	Not reported	Not reported
Van den Belt-Dusebout et al,¹⁰ 2006	Multi-institutional retrospective cohort	664	572	92	1965-1995	PVB, BEP, carboplatin, ifosfamide, and dactinomycin	≥ 5 years	36ⁿ	SIR: 1.16^m (0.81 to 1.61)	Not reported^o	HR: 0.80^p (0.40 to 1.70)
Huddart et al,⁷ 2003	Single institution	390^q	329	46	1982-1992	BEP, carboplatin, etoposide, bleomycin, or others	Entire time period taken together^r	26^s	RR: 2.59^t (1.15 to 5.84)	Not reported	Not reported
Meinardi et al,⁸ 2000	Single-institution cross-sectional	87^e	NA	NA	Before 1987	PVB, BEP, VIP	≥ 10 years	5^u	SIR: 7.10^v (1.90 to 18.30)	Not reported	Not reported

Abbreviations: BEP, bleomycin, cisplatin, and etoposide; CVA, cerebrovascular accidents; CVD, cardiovascular disease; HR, hazard ratio; NA, not applicable; NS, nonseminoma; PVB, cisplatin, vinblastine, and bleomycin; RR, relative risk; S, seminoma; SIR, standardized incidence ratio; SMR, standardized mortality ratio; TC, testicular cancer; VIP, etoposide, ifosfamide, and cisplatin.

^{^a}

This table lists the number of patients with TC given chemotherapy in each study.

^{^b}

Two thousand five hundred twenty-nine (36.6%) of the patients with NS in the current study who were treated with chemotherapy in the Surveillance, Epidemiology, and End Results program (1980 to 1999) were included in a prior international registry-based study (1943 to 2002; Fossa SD, et al: J Natl Cancer Inst 99:533-544, 2007).

^{^c}

Likely cisplatin-based chemotherapy (refer to text of article).

^{^d}

CVD is defined as diseases of the heart, cerebrovascular diseases, and other diseases of arteries, arterioles, and capillaries (see text).

^{^e}

Numbers of patients with S and NS were not reported.

^{^f}

CVD consisted of all atherosclerotic diseases, including myocardial infarction, angina, stroke, transient ischemic attack, carotid stenosis, aneurysm of aorta/renal artery, and intermittent claudication.

^{^g}

HR compared patients treated with chemotherapy with patients managed with surgery only. In addition, the HR of CVD for patients who received BEP chemotherapy compared with patients managed with surgery only was 5.7 (95% CI, 1.9 to 17.1).

^{^h}

Included patients who had cerebrovascular diseases diagnosed more than 2 years after testicular cancer diagnosis; two patients had stroke, three patients had transient ischemic attacks, and one patient had carotid stenosis.

^ⁱ

HR of cerebrovascular disease after chemotherapy compared with control group was not reported in article; however, it was noted that the HR was not statistically significantly different.

^{^j}

In this study, a questionnaire was sent to 355 institutions in Germany inquiring whether cardiovascular events occurred during or within 6 weeks of chemotherapy among survivors of TC treated during 1996 to 2008. Reporting was voluntary without validation of responses, and the survey response rate was 79%. The total number of patients with TC undergoing chemotherapy in the participating institutions was estimated to be 8,233 based on the total number of patients with TC in the national database of the Robert Koch Institute, Berlin (n = 47,651). The following methods and assumptions were used to estimate the total number of patients with TC undergoing chemotherapy, and a reduction of 10% was made to obtain the number of germ cell tumors: the relative proportion of patients requiring chemotherapy was assumed to be approximately 40% and 10% for NS and S, respectively. A further correction was made with respect to the response rate of the survey (ie, 79%), and the authors noted that a proportion of 2% was added to account for relapses requiring chemotherapy.

^{^k}

CVD consisted of 20 patients with myocardial infarction, three patients with cerebral stroke, and two patients with arterial thrombosis.

^{^l}

^.CVD was defined as myocardial infarction, angina pectoris, and congestive heart failure diagnosed at least 5 years after testicular cancer diagnosis. This study included patients in the prior report from van den Belt-Dusebout et al¹⁰ in 2006.

^{^m}

SIR of CVD compared with the age-specific, sex-specific, and calendar year–specific incidence rates of CVD in the general male population.

^ⁿ

^.CVD defined as myocardial infarction and angina pectoris diagnosed at least 5 years after testicular cancer diagnosis.

^{^o}

The number of cerebrovascular events was not reported for the chemotherapy cohort. However, 50 cerebrovascular events were reported for all patients with TC taken together.

^{^p}

HR compared patients with TC given chemotherapy with patients managed with surgery only and adjusted for recent smoking status, age at diagnosis, and treatment period.

^{^q}

An additional 15 patients with unspecified histology were included in the analysis.

^{^r}

Median follow-up time was 9.7 years (range, 0 to 19.8 years) since TC diagnosis.

^{^s}

Events were restricted to coronary artery disease (defined as myocardial infarction, angina, or sudden cardiac death) based on medical records or general practitioner communication.

^{^t}

Relative risk by age-adjusted regression analysis compared chemotherapy-treated patients with those managed with surveillance (no chemotherapy or radiation) in the same cohort.

^{^u}

CVD defined as myocardial infarction or angina with proven myocardial ischemia.

^{^v}

Represents SIR of CVD compared with the general male Dutch population.