Chemotherapy, especially higher cumulative doses of the platinum and alkylating agents, is associated with an increased risk of subsequent malignancies in survivors of childhood cancer.
A 30-year follow-up of more than 22,000 participants in the Childhood Cancer Survivor Study compared outcomes in patients treated with chemotherapy alone, chemo plus radiotherapy, radiotherapy alone or neither therapy.
The study found the 30-year subsequent malignant neoplasm (SMN) risk was highest in patients treated with any radiation (9.0% for radiotherapy alone; 10.8% for chemo plus radiotherapy). SMN risk was 3.9% for patients treated with chemotherapy alone and 3.4% for patients treated without chemo or radiotherapy.
However SMN rates at 10 to 25 year time points showed the chemotherapy only group had almost twice the rate as patients who didn’t receive chemo or radiation (RR 1.9).
The SMN rate in survivors treated with chemotherapy alone was nearly three-fold greater than that of the general population (Standardised incidence ratio [SIR] 2.8).
The most frequently observed SMNs were breast, thyroid, melanoma and soft-tissue sarcoma.
“The SMN rate relative to the general population was highest among survivors of CNS tumours (SIR, 5.8), driven by subsequent, nonrecurrent CNS tumours. Rates were also elevated for survivors of sarcoma (SIR, 3.3), neuroblastoma (SIR, 3.0), and leukaemia or lymphoma (SIR, 2.4),” the study said.
“Within the group of chemotherapy-only survivors, the SMN rate was associated with female sex (RR, 1.8; 95% CI, 1.3 to 2.6), high cumulative alkylating agent exposure (CED >10,000 mg/m2; RR v no alkylating agents, 2.0; 95% CI, 1.2 to 3.3), and high cumulative platinum exposure (>750 mg/m2; RR v no platinum, 2.7; 95%, CI 1.1 to 6.5).”
“Neither anthracycline nor epipodophyllotoxin exposure at any dose level was associated with increased SMN rates among chemotherapy-only survivors.”
Anthracycline exposure >300 mg/m2 was however associated with increased subsequent breast cancer rate in a linear dose response relationship.
The study said therapeutic radiation use has declined over time because of long-term health consequences but the types and doses of chemotherapy have also changed.
“Here, in a large, well characterised cohort of childhood cancer survivors, we demonstrated that survivors treated with chemotherapy alone are at increased risk for developing an SMN compared with the general population, though risk and cumulative incidence were approximately half of what was observed in survivors exposed to radiation plus chemotherapy.”
“We also showed that survivors treated with higher cumulative doses of alkylating agents and/or platinum based drugs experienced increased rates of SMNs, and there is a linear dose-response relationship between alkylating agent cumulative dose and SMN relative rate.”
“These findings inform risk-based counselling and support the need for surveillance for early detection of SMNs among individuals treated with chemotherapy, particularly higher cumulative doses of alkylating agents and platinum and no radiotherapy.”