Platinum exposure and cause-specific mortality among patients with testicular cancer

Harmke J. Groot; Flora E. van Leeuwen; Sjoukje Lubberts; Simon Horenblas; Ronald de Wit; J. Alfred Witjes; Gerard Groenewegen; Philip M. Poortmans; Maarten C. C. M. Hulshof; Otto W. M. Meijer; Igle J. de Jong; Hetty A. van den Berg; Tineke J. Smilde; Ben G. L. Vanneste; Maureen J. B. Aarts; Katarzyna Jozwiak; Alexandra W. van den Belt-Dusebout; Jourik A. Gietema; Michael Schaapveld

doi:10.1002/cncr.32538

Platinum exposure and cause-specific mortality among patients with testicular cancer

Harmke J. Groot, Flora E. van Leeuwen, Sjoukje Lubberts, Simon Horenblas, Ronald de Wit, J. Alfred Witjes, Gerard Groenewegen, Philip M. Poortmans, Maarten C. C. M. Hulshof, Otto W. M. Meijer, Igle J. de Jong, Hetty A. van den Berg, Tineke J. Smilde, Ben G. L. Vanneste, Maureen J. B. Aarts, Katarzyna Jozwiak, Alexandra W. van den Belt-Dusebout, Jourik A. Gietema, Michael Schaapveld^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era. Methods In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause-specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis. Results With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m(2) platinum dose administered (P-trend <.001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure. Conclusions Platinum-containing chemotherapy is associated with a dose-dependent increase in the risk of SMN mortality.

Original language	English
Pages (from-to)	628-639
Number of pages	12
Journal	Cancer
Volume	126
Issue number	3
Early online date	15 Nov 2019
DOIs	https://doi.org/10.1002/cncr.32538
Publication status	Published - 1 Feb 2020

Keywords

cause-specific mortality
cisplatin
epidemiology
platinum
survivorship
testicular cancer
GERM-CELL CANCER
LONG-TERM SURVIVORS
2ND CANCERS
CARDIOVASCULAR-DISEASE
THROMBOEMBOLIC EVENTS
MYOCARDIAL-INFARCTION
CHILDHOOD-CANCER
CHEMOTHERAPY
CISPLATIN
RISK

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Groot, H. J., van Leeuwen, F. E., Lubberts, S., Horenblas, S., de Wit, R., Witjes, J. A., Groenewegen, G., Poortmans, P. M., Hulshof, M. C. C. M., Meijer, O. W. M., de Jong, I. J., van den Berg, H. A., Smilde, T. J., Vanneste, B. G. L., Aarts, M. J. B., Jozwiak, K., van den Belt-Dusebout, A. W., Gietema, J. A., & Schaapveld, M. (2020). Platinum exposure and cause-specific mortality among patients with testicular cancer. Cancer, 126(3), 628-639. https://doi.org/10.1002/cncr.32538

@article{93b4dad25b86489e9df07b83bbf501c0,

title = "Platinum exposure and cause-specific mortality among patients with testicular cancer",

abstract = "Background Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era. Methods In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause-specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis. Results With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m(2) platinum dose administered (P-trend <.001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure. Conclusions Platinum-containing chemotherapy is associated with a dose-dependent increase in the risk of SMN mortality.",

keywords = "cause-specific mortality, cisplatin, epidemiology, platinum, survivorship, testicular cancer, GERM-CELL CANCER, LONG-TERM SURVIVORS, 2ND CANCERS, CARDIOVASCULAR-DISEASE, THROMBOEMBOLIC EVENTS, MYOCARDIAL-INFARCTION, CHILDHOOD-CANCER, CHEMOTHERAPY, CISPLATIN, RISK",

author = "Groot, {Harmke J.} and {van Leeuwen}, {Flora E.} and Sjoukje Lubberts and Simon Horenblas and {de Wit}, Ronald and Witjes, {J. Alfred} and Gerard Groenewegen and Poortmans, {Philip M.} and Hulshof, {Maarten C. C. M.} and Meijer, {Otto W. M.} and {de Jong}, {Igle J.} and {van den Berg}, {Hetty A.} and Smilde, {Tineke J.} and Vanneste, {Ben G. L.} and Aarts, {Maureen J. B.} and Katarzyna Jozwiak and {van den Belt-Dusebout}, {Alexandra W.} and Gietema, {Jourik A.} and Michael Schaapveld",

note = "Funding Information: This work was supported by the Dutch Cancer Society (grant 2011‐5209). Publisher Copyright: {\textcopyright} 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.",

year = "2020",

month = feb,

day = "1",

doi = "10.1002/cncr.32538",

language = "English",

volume = "126",

pages = "628--639",

journal = "Cancer",

issn = "0008-543X",

publisher = "Wiley",

number = "3",

}

Groot, HJ, van Leeuwen, FE, Lubberts, S, Horenblas, S, de Wit, R, Witjes, JA, Groenewegen, G, Poortmans, PM, Hulshof, MCCM, Meijer, OWM, de Jong, IJ, van den Berg, HA, Smilde, TJ, Vanneste, BGL, Aarts, MJB, Jozwiak, K, van den Belt-Dusebout, AW, Gietema, JA & Schaapveld, M 2020, 'Platinum exposure and cause-specific mortality among patients with testicular cancer', Cancer, vol. 126, no. 3, pp. 628-639. https://doi.org/10.1002/cncr.32538

TY - JOUR

T1 - Platinum exposure and cause-specific mortality among patients with testicular cancer

AU - Groot, Harmke J.

AU - van Leeuwen, Flora E.

AU - Lubberts, Sjoukje

AU - Horenblas, Simon

AU - de Wit, Ronald

AU - Witjes, J. Alfred

AU - Groenewegen, Gerard

AU - Poortmans, Philip M.

AU - Hulshof, Maarten C. C. M.

AU - Meijer, Otto W. M.

AU - de Jong, Igle J.

AU - van den Berg, Hetty A.

AU - Smilde, Tineke J.

AU - Vanneste, Ben G. L.

AU - Aarts, Maureen J. B.

AU - Jozwiak, Katarzyna

AU - van den Belt-Dusebout, Alexandra W.

AU - Gietema, Jourik A.

AU - Schaapveld, Michael

N1 - Funding Information: This work was supported by the Dutch Cancer Society (grant 2011‐5209). Publisher Copyright: © 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

PY - 2020/2/1

Y1 - 2020/2/1

N2 - Background Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era. Methods In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause-specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis. Results With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m(2) platinum dose administered (P-trend <.001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure. Conclusions Platinum-containing chemotherapy is associated with a dose-dependent increase in the risk of SMN mortality.

AB - Background Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era. Methods In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause-specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis. Results With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m(2) platinum dose administered (P-trend <.001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure. Conclusions Platinum-containing chemotherapy is associated with a dose-dependent increase in the risk of SMN mortality.

KW - cause-specific mortality

KW - cisplatin

KW - epidemiology

KW - platinum

KW - survivorship

KW - testicular cancer

KW - GERM-CELL CANCER

KW - LONG-TERM SURVIVORS

KW - 2ND CANCERS

KW - CARDIOVASCULAR-DISEASE

KW - THROMBOEMBOLIC EVENTS

KW - MYOCARDIAL-INFARCTION

KW - CHILDHOOD-CANCER

KW - CHEMOTHERAPY

KW - CISPLATIN

KW - RISK

U2 - 10.1002/cncr.32538

DO - 10.1002/cncr.32538

M3 - Article

C2 - 31730712

SN - 0008-543X

VL - 126

SP - 628

EP - 639

JO - Cancer

JF - Cancer

IS - 3

ER -