Chemotherapy and risk of subsequent malignant neoplasms in the childhood cancer survivor study cohort

Lucie M. Turcotte, Qi Liu, Yutaka Yasui, Tara O. Henderson, Todd M. Gibson, Wendy Leisenring, Michael A. Arnold, Rebecca M. Howell, Daniel M. Green, Gregory T. Armstrong, Leslie L. Robison, Joseph P. Neglia

Research output: Contribution to journalArticle

Abstract

PURPOSE Therapeutic radiation in childhood cancer has decreased over time with a concomitant increase in chemotherapy. Limited data exist on chemotherapy-associated subsequent malignant neoplasm (SMN) risk. PATIENTS AND METHODS SMNs occurring . 5 years from diagnosis, excluding nonmelanoma skin cancers, were evaluated in survivors diagnosed when they were , 21 years old, from 1970 to 1999 in the Childhood Cancer Survivor Study (median age at diagnosis, 7.0 years; median age at last follow-up, 31.8 years). Thirty-year SMN cumulative incidence and standardized incidence ratios (SIRs) were estimated by treatment: Chemotherapy-only (n = 7,448), chemotherapy plus radiation (n = 10,485), radiation only (n = 2,063), or neither (n = 2,158). Multivariable models were used to assess chemotherapy-associated SMN risk, including doseresponse relationships. RESULTS Of 1,498 SMNs among 1,344 survivors, 229 occurred among 206 survivors treated with chemotherapy only. Thirty-year SMN cumulative incidence was 3.9%, 9.0%, 10.8%, and 3.4% for the chemotherapy-only, chemotherapy plus radiation, radiation-only, or neither-treatment groups, respectively. Chemotherapy-only survivors had a 2.8-fold increased SMN risk compared with the general population (95% CI, 2.5 to 3.2), with SIRs increased for subsequent leukemia/lymphoma (1.9; 95% CI, 1.3 to 2.7), breast cancer (4.6; 95% CI, 3.5 to 6.0), soft-tissue sarcoma (3.4; 95% CI, 1.9 to 5.7), thyroid cancer (3.8; 95% CI, 2.7 to 5.1), and melanoma (2.3; 95% CI, 1.5 to 3.5). SMN rate was associated with . 750 mg/m2 platinum (relative rate [RR] 2.7; 95% CI, 1.1 to 6.5), and a dose response was observed between alkylating agents and SMN rate (RR, 1.2/5,000 mg/m2; 95% CI, 1.1 to 1.3). A linear dose response was also demonstrated between anthracyclines and breast cancer rate (RR, 1.3/100 mg/m2; 95% CI, 1.2 to 1.6). CONCLUSION Childhood cancer survivors treated with chemotherapy only, particularly higher cumulative doses of platinum and alkylating agents, face increased SMN risk. Linear dose responses were seen between alkylating agents and SMN rates and between anthracyclines and breast cancer rates. Limiting cumulative doses and consideration of alternate chemotherapies may reduce SMN risk.

Original languageEnglish (US)
Pages (from-to)3310-3319
Number of pages10
JournalJournal of Clinical Oncology
Volume37
Issue number34
DOIs
StatePublished - Jan 1 2019

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Cohort Studies
Drug Therapy
Neoplasms
Radiation
Alkylating Agents
Anthracyclines
Incidence
Breast Neoplasms
Platinum
Skin Neoplasms
Thyroid Neoplasms
Sarcoma
Melanoma
Lymphoma
Leukemia
Therapeutics

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Chemotherapy and risk of subsequent malignant neoplasms in the childhood cancer survivor study cohort. / Turcotte, Lucie M.; Liu, Qi; Yasui, Yutaka; Henderson, Tara O.; Gibson, Todd M.; Leisenring, Wendy; Arnold, Michael A.; Howell, Rebecca M.; Green, Daniel M.; Armstrong, Gregory T.; Robison, Leslie L.; Neglia, Joseph P.

In: Journal of Clinical Oncology, Vol. 37, No. 34, 01.01.2019, p. 3310-3319.

Research output: Contribution to journalArticle

Turcotte, LM, Liu, Q, Yasui, Y, Henderson, TO, Gibson, TM, Leisenring, W, Arnold, MA, Howell, RM, Green, DM, Armstrong, GT, Robison, LL & Neglia, JP 2019, 'Chemotherapy and risk of subsequent malignant neoplasms in the childhood cancer survivor study cohort', Journal of Clinical Oncology, vol. 37, no. 34, pp. 3310-3319. https://doi.org/10.1200/JCO.19.00129
Turcotte, Lucie M. ; Liu, Qi ; Yasui, Yutaka ; Henderson, Tara O. ; Gibson, Todd M. ; Leisenring, Wendy ; Arnold, Michael A. ; Howell, Rebecca M. ; Green, Daniel M. ; Armstrong, Gregory T. ; Robison, Leslie L. ; Neglia, Joseph P. / Chemotherapy and risk of subsequent malignant neoplasms in the childhood cancer survivor study cohort. In: Journal of Clinical Oncology. 2019 ; Vol. 37, No. 34. pp. 3310-3319.
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title = "Chemotherapy and risk of subsequent malignant neoplasms in the childhood cancer survivor study cohort",
abstract = "PURPOSE Therapeutic radiation in childhood cancer has decreased over time with a concomitant increase in chemotherapy. Limited data exist on chemotherapy-associated subsequent malignant neoplasm (SMN) risk. PATIENTS AND METHODS SMNs occurring . 5 years from diagnosis, excluding nonmelanoma skin cancers, were evaluated in survivors diagnosed when they were , 21 years old, from 1970 to 1999 in the Childhood Cancer Survivor Study (median age at diagnosis, 7.0 years; median age at last follow-up, 31.8 years). Thirty-year SMN cumulative incidence and standardized incidence ratios (SIRs) were estimated by treatment: Chemotherapy-only (n = 7,448), chemotherapy plus radiation (n = 10,485), radiation only (n = 2,063), or neither (n = 2,158). Multivariable models were used to assess chemotherapy-associated SMN risk, including doseresponse relationships. RESULTS Of 1,498 SMNs among 1,344 survivors, 229 occurred among 206 survivors treated with chemotherapy only. Thirty-year SMN cumulative incidence was 3.9{\%}, 9.0{\%}, 10.8{\%}, and 3.4{\%} for the chemotherapy-only, chemotherapy plus radiation, radiation-only, or neither-treatment groups, respectively. Chemotherapy-only survivors had a 2.8-fold increased SMN risk compared with the general population (95{\%} CI, 2.5 to 3.2), with SIRs increased for subsequent leukemia/lymphoma (1.9; 95{\%} CI, 1.3 to 2.7), breast cancer (4.6; 95{\%} CI, 3.5 to 6.0), soft-tissue sarcoma (3.4; 95{\%} CI, 1.9 to 5.7), thyroid cancer (3.8; 95{\%} CI, 2.7 to 5.1), and melanoma (2.3; 95{\%} CI, 1.5 to 3.5). SMN rate was associated with . 750 mg/m2 platinum (relative rate [RR] 2.7; 95{\%} CI, 1.1 to 6.5), and a dose response was observed between alkylating agents and SMN rate (RR, 1.2/5,000 mg/m2; 95{\%} CI, 1.1 to 1.3). A linear dose response was also demonstrated between anthracyclines and breast cancer rate (RR, 1.3/100 mg/m2; 95{\%} CI, 1.2 to 1.6). CONCLUSION Childhood cancer survivors treated with chemotherapy only, particularly higher cumulative doses of platinum and alkylating agents, face increased SMN risk. Linear dose responses were seen between alkylating agents and SMN rates and between anthracyclines and breast cancer rates. Limiting cumulative doses and consideration of alternate chemotherapies may reduce SMN risk.",
author = "Turcotte, {Lucie M.} and Qi Liu and Yutaka Yasui and Henderson, {Tara O.} and Gibson, {Todd M.} and Wendy Leisenring and Arnold, {Michael A.} and Howell, {Rebecca M.} and Green, {Daniel M.} and Armstrong, {Gregory T.} and Robison, {Leslie L.} and Neglia, {Joseph P.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1200/JCO.19.00129",
language = "English (US)",
volume = "37",
pages = "3310--3319",
journal = "Journal of Clinical Oncology",
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publisher = "American Society of Clinical Oncology",
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TY - JOUR

T1 - Chemotherapy and risk of subsequent malignant neoplasms in the childhood cancer survivor study cohort

AU - Turcotte, Lucie M.

AU - Liu, Qi

AU - Yasui, Yutaka

AU - Henderson, Tara O.

AU - Gibson, Todd M.

AU - Leisenring, Wendy

AU - Arnold, Michael A.

AU - Howell, Rebecca M.

AU - Green, Daniel M.

AU - Armstrong, Gregory T.

AU - Robison, Leslie L.

AU - Neglia, Joseph P.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - PURPOSE Therapeutic radiation in childhood cancer has decreased over time with a concomitant increase in chemotherapy. Limited data exist on chemotherapy-associated subsequent malignant neoplasm (SMN) risk. PATIENTS AND METHODS SMNs occurring . 5 years from diagnosis, excluding nonmelanoma skin cancers, were evaluated in survivors diagnosed when they were , 21 years old, from 1970 to 1999 in the Childhood Cancer Survivor Study (median age at diagnosis, 7.0 years; median age at last follow-up, 31.8 years). Thirty-year SMN cumulative incidence and standardized incidence ratios (SIRs) were estimated by treatment: Chemotherapy-only (n = 7,448), chemotherapy plus radiation (n = 10,485), radiation only (n = 2,063), or neither (n = 2,158). Multivariable models were used to assess chemotherapy-associated SMN risk, including doseresponse relationships. RESULTS Of 1,498 SMNs among 1,344 survivors, 229 occurred among 206 survivors treated with chemotherapy only. Thirty-year SMN cumulative incidence was 3.9%, 9.0%, 10.8%, and 3.4% for the chemotherapy-only, chemotherapy plus radiation, radiation-only, or neither-treatment groups, respectively. Chemotherapy-only survivors had a 2.8-fold increased SMN risk compared with the general population (95% CI, 2.5 to 3.2), with SIRs increased for subsequent leukemia/lymphoma (1.9; 95% CI, 1.3 to 2.7), breast cancer (4.6; 95% CI, 3.5 to 6.0), soft-tissue sarcoma (3.4; 95% CI, 1.9 to 5.7), thyroid cancer (3.8; 95% CI, 2.7 to 5.1), and melanoma (2.3; 95% CI, 1.5 to 3.5). SMN rate was associated with . 750 mg/m2 platinum (relative rate [RR] 2.7; 95% CI, 1.1 to 6.5), and a dose response was observed between alkylating agents and SMN rate (RR, 1.2/5,000 mg/m2; 95% CI, 1.1 to 1.3). A linear dose response was also demonstrated between anthracyclines and breast cancer rate (RR, 1.3/100 mg/m2; 95% CI, 1.2 to 1.6). CONCLUSION Childhood cancer survivors treated with chemotherapy only, particularly higher cumulative doses of platinum and alkylating agents, face increased SMN risk. Linear dose responses were seen between alkylating agents and SMN rates and between anthracyclines and breast cancer rates. Limiting cumulative doses and consideration of alternate chemotherapies may reduce SMN risk.

AB - PURPOSE Therapeutic radiation in childhood cancer has decreased over time with a concomitant increase in chemotherapy. Limited data exist on chemotherapy-associated subsequent malignant neoplasm (SMN) risk. PATIENTS AND METHODS SMNs occurring . 5 years from diagnosis, excluding nonmelanoma skin cancers, were evaluated in survivors diagnosed when they were , 21 years old, from 1970 to 1999 in the Childhood Cancer Survivor Study (median age at diagnosis, 7.0 years; median age at last follow-up, 31.8 years). Thirty-year SMN cumulative incidence and standardized incidence ratios (SIRs) were estimated by treatment: Chemotherapy-only (n = 7,448), chemotherapy plus radiation (n = 10,485), radiation only (n = 2,063), or neither (n = 2,158). Multivariable models were used to assess chemotherapy-associated SMN risk, including doseresponse relationships. RESULTS Of 1,498 SMNs among 1,344 survivors, 229 occurred among 206 survivors treated with chemotherapy only. Thirty-year SMN cumulative incidence was 3.9%, 9.0%, 10.8%, and 3.4% for the chemotherapy-only, chemotherapy plus radiation, radiation-only, or neither-treatment groups, respectively. Chemotherapy-only survivors had a 2.8-fold increased SMN risk compared with the general population (95% CI, 2.5 to 3.2), with SIRs increased for subsequent leukemia/lymphoma (1.9; 95% CI, 1.3 to 2.7), breast cancer (4.6; 95% CI, 3.5 to 6.0), soft-tissue sarcoma (3.4; 95% CI, 1.9 to 5.7), thyroid cancer (3.8; 95% CI, 2.7 to 5.1), and melanoma (2.3; 95% CI, 1.5 to 3.5). SMN rate was associated with . 750 mg/m2 platinum (relative rate [RR] 2.7; 95% CI, 1.1 to 6.5), and a dose response was observed between alkylating agents and SMN rate (RR, 1.2/5,000 mg/m2; 95% CI, 1.1 to 1.3). A linear dose response was also demonstrated between anthracyclines and breast cancer rate (RR, 1.3/100 mg/m2; 95% CI, 1.2 to 1.6). CONCLUSION Childhood cancer survivors treated with chemotherapy only, particularly higher cumulative doses of platinum and alkylating agents, face increased SMN risk. Linear dose responses were seen between alkylating agents and SMN rates and between anthracyclines and breast cancer rates. Limiting cumulative doses and consideration of alternate chemotherapies may reduce SMN risk.

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