Second Malignancy Risk Sky-High for Childhood Cancer Survivors

Findings suggest need for heightened surveillance through adulthood.

This article was first published on Tuesday, October 29, 2019 in MedPage Today.

By Pam Harrison, Contributing Writer, MedPage Today

Childhood cancer survivors have a dramatically higher risk for breast cancer and other subsequent malignancies, especially when treated with both chemotherapy and radiation, according to two studies examining the same cohort.

Among girls, the likelihood of a breast cancer diagnosis as an adult increased for every 10 Gy of radiation received (odds ratio [OR] 3.9, 95% CI 2.5-6.5) and for every 100 mg/m² of anthracycline administered (OR 1.23, 95% CI 1.09-1.39), reported Lene Veiga, PhD, of the National Cancer Institute in Bethesda, Maryland, and colleagues.

"To our knowledge, this is the largest study of treatment-related breast cancer after childhood cancer," the investigators wrote in JAMA Pediatrics. "We also provide the first evidence that the combination of anthracyclines and radiotherapy may markedly increase breast cancer risks and is greater than the sum of their individual effects, consistent with an additive interaction."

Veiga's group looked at 14,358 childhood cancer patients from the North American Childhood Cancer Survivor Study who were initially diagnosed from 1970 to 1986 in Canada and the U.S., and survived at least 5 years. In all, 271 female patients later developed breast cancer at a median age of 39 years.

Children who received a radiation dose of 10 Gy or more but no anthracycline treatment were nearly 10 times more likely to be diagnosed with breast cancer in adulthood (OR 9.6, 95% CI 4.4-20.7) compared to those who received little to no radiation (<1 Gy), which grew to nearly 20 times more likely with the addition of anthracycline therapy (OR 19.1, 95% CI 7.6-48.0).

Paradoxically, higher doses of radiation (≥15 Gy) delivered to the ovaries resulted in a lower risk of developing breast cancer as an adult and this protective effect was seen for both estrogen receptor (ER)-positive and ER-negative breast cancers. That said, most patients who received 15 Gy or more to the ovaries reported either never menstruating or going into menopause within 5 years of their first cancer diagnosis.

When looking at the effect of cumulative anthracycline doses by ER status, only ER-positive disease remained significant (OR 1.49 for every 100 mg/m², 95% CI 1.21-1.83). Interestingly, there was evidence of a dose response for doxorubicin -- the most commonly used anthracycline drug -- but not for daunorubicin.

Veiga's group noted that the dose of radiotherapy used for many childhood cancers has been dropping in the past few decades, as has the volume of tissue being irradiated.

"It is surprising therefore that there has not been clear evidence that these decreases have translated into lower breast cancer risks," they commented. "One possibility that our results suggest is that this increased breast cancer risk could be associated with the concurrent increase in the use of anthracycline therapy."

In a separate but related study published in the Journal of Clinical Oncology, investigators evaluated the effect of receiving treatment with chemotherapy alone on subsequent malignant neoplasms (SMN) in the same Childhood Cancer Survivor Study cohort.

As reported by researchers led by Lucie Turcotte, MD, of the University of Minnesota Medical School in Minneapolis, the SMN rate among childhood cancer survivors treated with chemotherapy alone was nearly three times as high as the general population (standardized incidence ratio [SIR] 2.8, 95% CI 2.5-3.2).

For their study, they looked at treatment data for 22,154 childhood cancer survivors who were diagnosed with their initial cancer at a median age of 7 years, and who had a median age of 31.9 years at last follow-up.

Of the 1,490 SMNs identified among 1,344 childhood cancer survivors, 229 of them occurred among 206 patients treated with chemotherapy only.

The increased risk from chemotherapy alone was linked to multiple subsequent cancers:

• Leukemia and lymphoma (SIR 1.9, 95% CI 1.3-2.7)
   
• Breast cancer (SIR 4.6, 95% CI 3.5-6.0)
   
• Soft-tissue sarcoma (SIR 3.4, 95% CI 1.9-5.7)
   
• Thyroid cancer (SIR 3.8, 95% CI 2.7-5.1)
   
• Melanoma (SIR 2.3, 95% CI 1.5-3.5)

Elevated risks were also associated with high cumulative exposure to alkylating agents (relative rate [RR] 1.2 per 5,000 mg/m², 95% CI 1.1-1.3) and platinums (RR 2.7 for doses greater 750 mg/m², 95% CI 1.1-6.5). A linear dose-response relationship was seen between anthracycline use and the risk of breast cancer as well (RR 1.3 per 100 mg/m², 95% CI 1.2-1.6).

"Here, in a large, well-characterized 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," the study authors noted.

The 30-year cumulative incidence rate for an SMN was 3.9% for those treated with chemotherapy alone, 9.0% for those who received chemotherapy plus radiation, and 10.8% with radiation alone, as compared with 3.4% for those who received neither for their childhood cancer.

"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," they added. "These findings inform risk-based counseling 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."

Veiga and colleagues had no financial conflicts of interest to declare.

Turcotte had no conflicts of interest to declare.