UC Davis Comprehensive Cancer Center Sacramento, CA

Advances in treatment and supportive care have resulted in substantial improvements in cancer survival and a growing number of cancer survivors in the United States. These survivors, however, are at an increased risk of developing a second cancer due to genetic factors, the carcinogenic effects of cancer treatment, common exposures (eg, tobacco), and other as yet unknown factors. The risk of developing a second cancer also varies by age, with those diagnosed with their first cancer during childhood having the highest risk. The burden of second cancers in survivors of adolescent and young adult (AYA) cancers (15-39 years) is also high; they have a higher risk of developing a second cancer than older cancer survivors and have the highest absolute excess risk of a second cancer, or excess cancers per 10,000 person-years, among all age groups.

A number of studies have noted the increased late mortality after specific second cancers among young cancer survivors, but no studies have systematically assessed whether second cancers have a similar detrimental impact on survival for children, AYAs, and older adults. As progress in improving the survival of AYA patients with cancer has lagged behind that of younger and older cancer patients, it is important to determine whether the impact of second cancers on survival is disproportionate in the AYA population.

Our study, based on an analysis of more than 1 million patients with cancer of all ages from throughout the United States, compared survival by age after a second cancer to survival of the same cancer that occurs as a first cancer. We identified all patients diagnosed with only 1 or a first and second cancer during 1992 through 2008 using Surveillance, Epidemiology and End Results program data from 13 cancer registries (Figure). We collected data on the 14 most common cancer types that affect AYAs: female breast, thyroid, testicular, Hodgkin lymphoma, non-Hodgkin lymphoma, acute lymphoblastic leukemia, acute myeloid leukemia, soft tissue sarcoma, bone sarcoma, colorectal, central nervous system, cervical, melanoma, and ovarian.

In this large population-based study published in JAMA Oncology, the impact of a second cancer on survival was most pronounced in AYAs and the relatively few second cancers that occurred in children compared with older adults. We found that survival after almost all types of cancers is much higher when the cancer occurs as a first cancer than if it is a second cancer, and that for the most common second cancers in AYAs, the absolute differences in survival were substantial. Overall, children and AYAs had an 80% chance of surviving 5 years after a diagnosis of a first cancer. However, if the same cancer occurred as a second cancer, 5-year survival dropped to 47% for children and 60% for the AYA population. The differences in survival were not nearly as marked in the older adult population, who had a 70% chance of surviving 5 years overall for a first cancer and 61% for a new, second cancer.

When we looked at 5-year survival by age and individual cancer type, we found striking differences depending on whether it was a first or second cancer in all but 2 of the 14 cancer types: testes and melanoma. For the most common second cancers in AYAs, the absolute difference in 5-year survival was 42% lower for second non-Hodgkin lymphoma, 19% lower for second breast cancer, 15% lower for second thyroid cancer, and 13% lower for second soft tissue sarcoma.

In multivariable survival models, almost every cancer conferred a higher risk of death than that of the same first cancer, and the impact on survival was significantly greater in younger patients compared with older patients. What struck us was that the second cancer caused such an increased risk of death. For example, second Hodgkin lymphoma and thyroid cancer had a more than 3-fold greater risk and second breast, testicular, soft tissue sarcoma, and bone sarcoma had a more than 2-fold greater risk of cancer-specific death than each cancer occurring as a first cancer.

Worse survival after second cancers may result from the second cancers being more biologically aggressive or patients with a second cancer having a worse response to treatment, limitations on the types or doses of treatments that they can receive as a result of their prior cancer treatment, or impaired physiologic reserves that impact their ability to tolerate treatment for their second cancer.

Why younger patients tend to fare worse than older patients with the same second cancers is not fully understood or an aspect we could specifically address in this study. We next plan to examine how the time between getting a first and second cancer affects survival and whether the types of treatments for the first cancer influence the outcome of a second cancer. We hope these findings help guide clinicians in providing age-specific recommendations on cancer prevention, screening, treatment, and survivorship, especially among the AYA population for whom survival rates have not improved to the same extent as they have for children and older adults.

Keegan THM, Bleyer A, Rosenberg AS, et al. Second primary malignant neoplasms and survival in adolescent and young adult cancer survivors [published online April 20, 2017]. 

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Advances in treatment and supportive care have resulted in substantial improvements in cancer survival and a growing number of cancer survivors in the United States.

Theresa Keegan, PhD, MS

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Second Cancers Can Wield Greater Impact on Adolescent and Young Adult Survivors