The risk of developing or dying of a new primary cancer, particularly those cancers associated with smoking and obesity, was greater among survivors of adult-onset cancers than the expected risk in the general population, according to an analysis of data from more than 1.5 million cancer survivors.1 These findings, concluded the authors of the study published in JAMA, “highlight the importance of ongoing surveillance and efforts to prevent new cancers among survivors.”
“Subsequent primary cancer accounts for a major proportion of new cancer diagnoses each year, especially for older adults, the study’s lead author, Hyuna Sung, PhD, said in an interview with The ASCO Post. “For adults older than age 65, about one in four new cancer diagnoses is not the first cancer.” Dr. Sung is Principal Scientist in Cancer Surveillance Research at the American Cancer Society, Atlanta.
Hyuna Sung, PhD
Among cancer survivors, only a few smoking- or obesity-associated subsequent primary cancers, “such as lung, urinary bladder, oral cavity/pharynx, colorectal, pancreatic, uterine corpus, and liver cancers constituted considerable proportions of the total incidence and mortality, with lung cancer alone accounting for 31% to 33% of mortality from all subsequent primary cancers,” the researchers reported.
Data From 12 SEER Registries
The retrospective cohort study included data from 12 Surveillance, Epidemiology, and End Results (SEER) registries in the United States for 1,537,101 people who had been diagnosed with first primary cancers from 1992 to 2011 and survived at least 5 years and were followed until death, age 89, or the end of 2017. Ages ranged from 20 to 84 (mean age, 60.4), and 41% were aged 65 or older at the time the first primary cancer was diagnosed. Women constituted 48.8% of the study population, and 81.5% of patients included in the study were White.
Compared with the general population, men in the study population had a statistically significantly higher risk of developing a subsequent primary cancer for 18 of the 30 first primary cancer types included in the study. In addition, for men, their risk of dying of any subsequent primary cancer was statistically significantly higher for 27 types. Women had a statistically significantly higher risk for 21 of 31 first primary cancer types; their risk of dying of any subsequent primary cancer was statistically significantly higher for 28 types, compared with risks in the general population.
Male survivors (excluding those with prostate cancer) had an 11% higher risk of developing a subsequent primary cancer and a 45% higher risk of dying of it. Women had a 10% higher risk of developing a subsequent primary cancer and a 33% higher risk of dying of it.
The highest overall standardized incidence ratio and standardized mortality ratio were estimated among survivors of laryngeal cancer (standardized incidence ratio = 1.75 for men; 2.48 for women) and gallbladder cancer among male survivors (standardized mortality ratio = 3.82 for men). “Gallbladder cancer is rare,” Dr. Sung noted, “but patients who develop that have a higher risk of developing other types of obesity-related cancers.”
Among all cancer survivors, the four subsequent primary cancers that contributed most to the total incidence of subsequent primary cancers were lung (19.1%), prostate (13.7%), urinary bladder (11.1%), and colorectal cancers (10.1%) in men; and lung (19.3%), breast (17.3%), colorectal (11.0%), and uterine corpus cancers (7.4%) in women, according to the study authors. The four subsequent primary cancers that contributed most to the total subsequent primary cancer mortality were lung (33.1% in men; 31.2% in women), colorectal (8.8% in men), pancreatic (8.5% in men; 9.4% in women), followed by non-Hodgkin lymphoma (6.0% in men,) and breast (5.8% in women), they reported.
Reflecting Changes Over Time
This study was a follow-up to the seminal report published by the National Cancer Institute in 2006, which examined cancer survivors who were diagnosed between 1973 to 2000. “Since then, things changed over time considerably in terms of the prevalence of risk factors, such as smoking, obesity, and how we treat cancers, as well as survivor outcomes,” Dr. Sung commented. “We wanted to update that seminal report using more contemporary statistics to provide more timely information to cancer survivors and health-care providers about the risk of developing and dying from subsequent primary cancer.”
The 2006 report included 16 major types of cancer, but the updated study included more than 30 different cancer types. It is also more succinct, 15 pages vs more than 200 in the previous report. “We don’t have in-depth results for each type of cancer survivor group,” Dr. Sung noted. “It it is more like a catalogue, so future researchers or cancer survivors can easily look up what type of cancer survivors are most likely to develop as a subsequent primary cancer.”
We don’t have well-established … survivorship guidelines we can provide to survivors who develop subsequent primary cancers.— Hyuna Sung, PhD
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Shared Risk Factors
“Although some of the higher-risk subsequent primary cancers among survivors may reflect genetic predisposition and treatment exposures, most of this excess risk is likely due to host factors (eg, aging, immunity) and to lifestyle risk factors (eg, smoking, obesity, alcohol, infection) shared by the first and subsequent cancers,” the researchers wrote.
The study, however, was not intended to focus on lifestyle risk factors. “This is purely an association study between first and subsequent cancers,” Dr. Sung emphasized. “We happen to have found many significant associations occurred between cancers that shared common risk factors, and most of the associations could be explained by smoking or obesity. How we relate smoking and obesity to our results is solely based on literature review, because we didn’t actually factor that risk factor information in our data,” she stated.
“There is a substantial variation in the risk estimates in terms of the strength of the association and the variety of cancers across cancer types and sex. But what is surprising is that when we combined all cancer survivors together, the large proportion of subsequent cancer burden is explained by only a few smoking or obesity-related cancers,” Dr. Sung said.
The risks of smoking-related subsequent primary cancers were higher following many types of smoking-related first primary cancers, suggesting the role of smoking as a shared risk factor, the researchers found. Four common smoking-related subsequent primary cancers—lung, urinary bladder, oral cavity/pharyngeal, and esophageal—accounted for 26% to 45% of the total incidence and mortality of subsequent primary cancers, with lung cancer alone accounting for 31% to 33% of the total mortality among those with subsequent primary cancers.
Tobacco Dependence and Smoking-Related Cancers
“In 2018, 12% of cancer survivors in the United States were current smokers,” the researchers reported, with a higher percentage among survivors of smoking-related cancers, 20% vs 11% for survivors of nonsmoking-related cancers. In comparison, in 2018, 14% of the general population smoked.2
Only 46% of cancer survivors who smoked “reported using counseling or medication when trying to quit, and less than 8% reported using both quitting aids, suggesting the majority of attempts to quit are inadequately supported,” the researchers reported. “Thus, systematic efforts are needed to increase the provision of counseling and pharmacologic interventions for tobacco dependence among survivors.”
Although lung, urinary bladder, oral cavity/pharyngeal, and esophageal cancers comprised a high proportion of the smoking-related subsequent primary cancers, cancers of the stomach, colorectum, pancreas, and liver have also been associated with smoking, as well as with obesity. Three of these cancers—colorectal, pancreatic, and liver—together with cancers of the corpus uteri, comprised 22% to 26% of the total mortality from subsequent primary cancers.
“People may not necessarily know how comprehensively smoking affects cancer risk,” Dr. Sung said. “They may know about lung cancer but not necessarily colorectal or pancreatic. As for obesity, the general public awareness of the impact of obesity on cancer risk is really low.” Media coverage of diet and nutrition issues may have increased awareness, she acknowledged, but “we don’t see a significant drop in obesity prevalence in the United States at all, and losing weight is not an easy issue, even though people might be aware of the health effects.”
Two-Thirds Overweight
“In 2018, 67% of cancer survivors in the United States were overweight or obese, and 34% of survivors reported no leisure time physical activity,” the researchers wrote. “Many cancer survivors, however, report that they have never discussed lifestyle recommendations relevant to body weight with their health-care providers, nor have they changed these behaviors. Survivorship care may require greater focus on lifestyle factors, including weight management, physical activity, and healthy eating; survivorship care guidelines recommending health promotion need wider dissemination and implementation in oncology and primary care.”
“I don’t think there is a significant difference between the general population and cancer survivors when it comes to obesity,” Dr. Sung said. “For some kinds of survivors, especially breast cancer survivors, it is so easy to gain weight, even after diagnosis. So, for some cancers associated with obesity, you could expect those cancer survivor groups may have a higher obesity prevalence than the general population, but not all cancers are like that. For survivors of stomach cancer, sometimes their weight is lower than the general population.”
Although the study did not look at the risks associated with radiation and systemic treatments, Dr. Sung acknowledged that these treatments may also have an effect on weight.
Future Analyses
Patricia A. Ganz, MD
Jacqueline N. Casillas, MD, MSHS
The study did not explore in depth certain areas, such as the effects of treatment and differences between younger and older patients. Dr. Sung agreed with a comment in an accompanying editorial by Patricia A. Ganz, MD, and Jacqueline N. Casillas, MD, MSHS, of the UCLA Jonsson Comprehensive Cancer Center, Los Angeles: Future analyses of the data may “explore in more detail the subsequent primary cancers observed in younger adults to complement the available survivorship literature in this patient population.”3
“That was one of the most critical components that our study didn’t address,” Dr. Sung said. In addition, “we didn’t conduct the analysis by race, ethnicity, geography, socioeconomic status, or insurance status,” she added. “So, these aggregated results we presented might conceal some disparities that might exist in cancer survivor groups. That is something we should address in our future research.”
Lack of Guidelines
“We don’t have well-established standard guidelines about how we treat multiple primary cancers for a patient who may have different types of cancer at the same time or sometimes one after another or survivorship guidelines we can provide to survivors who develop subsequent primary cancers,” Dr. Sung noted.
“Studies are very limited to inform treatment guidelines because clinical trials to measure the effectiveness and safety of new drugs, or the harm and benefit of screening, often exclude participants with a history of cancer, precluding the opportunity to evaluate the efficacy of the new drug to treat a particular primary cancer. Those are research gaps where we need to do better.”
DISCLOSURE: Dr. Sung and Dr. Casillas reported no conflicts of interest. Dr. Ganz serves as editor of the cancer survivorship section of Up-to-Date and Editor-in-Chief of the Journal of the National Cancer Institute and has received honorarium from Wolters-Kluwer and Oxford University Press.
REFERENCES
1. Sung H, Hyun N, Leach CR, et al: Association of first primary cancer with risk of subsequent primary cancer among survivors of adult-onset cancers in the United States. JAMA 324:2521-2535, 2020.
2. American Cancer Society: Cancer Facts and Figures 2021. Available at https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf. Accessed February 4, 2021.
3. Ganz PA, Casillas JN: Incorporating the risk for subsequent primary cancers into the care of adult cancer survivors: Moving beyond 5-year survival. JAMA 324:2493-2495, 2020.
