The risk of multiple primary cancers is increasing due to increasing numbers of survivors, long-term side effects of chemotherapy and/or radiation therapy, increased diagnostic sensitivity, and persisting effects of genetic and behavioral risk factors.
Abstract: The frequency of patients living after a cancer diagnosis continues to increase due to the rising incidence of cancer as well as the improved survival of cancer patients thanks to advances in cancer research and treatment. The risk of multiple primary cancers is also increasing due to increasing numbers of cancer survivors, long-term side effects of chemotherapy and/or radiation therapy, increased diagnostic sensitivity, and persisting effects of genetic and behavioral risk factors. Multiple primary cancers are defined as more than one synchronous or metachronous cancer in the same individual. Although several different definitions of multiple primaries have been proposed, the main definitions come from the Surveillance, Epidemiology, and End Results (SEER) Program and the International Association of Cancer Registries and International Agency for Research on Cancer (IACR/IARC). Depending on the definition, overall reported frequency of multiple primary cancers varies between 2.4% and 17%. Underlying causes for multiple primary cancers may include host and lifestyle-related factors, environmental and genetic factors and treatment related factors. Significant temporal changes have been found in the prevalence of cancer risk factors (ie, smoking, alcohol consumption, obesity) as well as advances in diagnostic sensitivity and improved screening programs that may affect the incidence of second or more cancers. In this review, the literature on multiple primary cancers is analyzed with a focus on clinical situations where a treating physician should take into consideration the possibility of multiple primaries.
Despite overall declining age-standardized cancer incidence rates in men and stable rates in women, growing and aging populations combined with improvements in cancer survival have led to mounting numbers of cancer survivors in the United States. More than 16.9 million US residents with a history of cancer were alive on January 1, 2019, and this number is projected to grow to more than 22.1 million by January 1, 2030. The most prevalent cancers in 2019 are prostate (3,650,030), colon and rectum (776,120), and melanoma (684,470) among males, and breast (3,861,520), uterine corpus (807,860), and colon and rectum (768,650) among females. Many cancer survivors must cope with the physical effects of cancer and its treatment, potentially leading to functional and cognitive impairments as well as other psychologic and economic sequelae. Among survivors, long-term, late effects such as subsequent cancers are of concern. Information on late and long-term complications at the population level, however, is limited.
Recognition of multiple primary cancers goes as far back as 1921, when a report showed that there were 4.7% multiple primary cancers found in 3,000 cases of malignancy. Many factors can influence the reported numbers of multiple primaries, including the definition utilized, patient population studied, and follow-up time. Depending on the definition, the overall reported frequency of multiple primary cancers varies between 2% and 17%. Registries use various rules to distinguish between cancers that are new cases and those that are an extension of an existing cancer. The two most frequently used definitions are by the SEER Program and the IACR/IARC. The SEER database takes into account histology, site, laterality, and time since initial diagnosis to identify multiple primary cancers and considers single tumors of different parts of the same organ (eg, colon) as multiple sites. The IACR/IARC rules are more exclusive; only one tumor is registered for an organ, irrespective of time, unless there are histologic differences. The SEER database recommends use of a 2-month period to distinguish between synchronous and metachronous multiple primaries, whereas IARC suggests a 6-month period.[8,9] The rules of the SEER program are used mainly by North American cancer registries while the rules of IACR and the IARC are used internationally. A summary definition of multiple primary cancers is included in the Table.
Cancer, a multistage process of initiation, promotion, malignant transformation, and progression, often involves damage to DNA. Mutations in critical areas of genes that regulate cell growth, cell death, or DNA repair may lead to the selective growth of damaged cell lines and accumulation of further genetic damage. Once enough damages accumulate in the DNA, cancer may develop. Factors associated with increased risk of developing more than one primary cancer may include genetic susceptibility and familial cancer syndromes, environmental and lifestyle exposures (eg, tobacco, alcohol use), hormonal factors, immune deficiency and infection, carcinogenic effects of prior cancer treatments, and finally, interaction among all of these factors.[5,11,12]
About 1% to 2% of all cancers are associated with hereditary cancer syndromes. Affected individuals have a heritable germline mutation in every cell, which may have arisen early in development. Many of these syndromes are autosomal dominant, with a 50% chance that someone carrying the gene will pass it on to their child. Identification of a germline mutation in a cancer survivor portends increased risk for specific second primary cancers. The most relevant cancer predisposition syndromes in routine oncology care include hereditary breast and ovarian cancer syndrome, Lynch syndrome/hereditary nonpolyposis colon cancer, multiple endocrine neoplasia type 1 and type 2, von Hippel-Lindau disease, and Li-Fraumeni syndrome. Heritable cancer syndromes should be suspected when several generations of a family are diagnosed with certain cancers at a relatively young age or when several individuals in a family develop multiple primary cancers. When a heritable cancer syndrome is suspected, genetic counseling should be discussed because this may identify mutations in known cancer susceptibility genes.
Environmental and lifestyle influences such as tobacco use, excess alcohol intake, and dietary patterns may play a significant role in the development of multiple primary cancers. Tobacco use is one of the most well-recognized causes of multiple primary cancers, with strong associations between cancers of the lung and upper aerodigestive tract (oral cavity, pharynx, larynx, and esophagus). Lung cancer survivors also demonstrate increased risks of cancers of the head and neck and bladder and second primary lung cancers. This is reflective of a phenomenon called Ã¢€Åfield cancerization,Ã¢€Â in which some of the multiple patches of transformed cells in the respiratory and urinary tract may evolve into second (or more) cancers. Other cancers related to tobacco use include stomach, liver, pancreas, kidney, uterine cervix, and myeloid leukemia. Alcohol consumption has been associated with increased risk of cancers including oral cavity and pharynx, esophagus, liver, colon, larynx, and female breast. For some cancers, the risks associated with excessive alcohol consumption and tobacco use are much higher than for either exposure alone.[17,18] Tobacco- and alcohol-related cancer sites are estimated to account for more than 35% of all subsequent malignancies. Dietary factors and being either overweight or obese are reflected in the aggregation of cancers of the breast, uterine corpus, ovary, colon, esophageas, gallbladder, kidney, pancreatic, and thyroid.[19,20]
Hormonal factors play an important role in the development of female breast cancer and several cancers of the female reproductive system. Individuals may be at increased risk of developing multiple primary cancers due to hormonal factors. Studies of multiple primary cancers have found increases in relative risks for breast, ovarian, and uterine corpus cancers, which may be attributable to common hormonal risk factors related to menstrual and pregnancy history and use of hormonal medications. This may result not only from factors related to menstrual and pregnancy history but also from use of hormonal medications and genetic susceptibility factors that increase risk for several cancers.
Some established, growing evidence supports a causal role of immunodeficiency and infections in increased risk for primary and secondary cancers. Immunodeficiency syndromes, either acquired or inherited, have been associated with an increased risk of non-Hodgkin lymphoma, Kaposi sarcoma, and squamous cell cancer on sun-exposed areas of the skin. Human papillomavirus (HPV) infections are the main cause of cancer of the uterine cervix and have been implicated in other cancers of the anogenital tract (ie, vulva, vagina, perineum, anus, penis) for which there is evidence of mutually increased risk. HPV, especially HPV-16, has been implicated in oropharyngeal cancers.  Patients infected with human immunodeficiency virus (HIV) are at increased risk of non-Hodgkin lymphoma, Kaposi sarcoma, and cervical and anal cancer. Although case reports document multiple cancers in HIV-infected individuals, the relative risk for multiple primary tumors in patients with HIV-related immunodeficiency is unknown.
The carcinogenic potential of chemotherapy and radiation therapy is well known. The association between some alkylating chemotherapy agents and risk of developing acute leukemia, which typically occurs in the first 10 years after treatment, is well-established. Other drug classes associated with increased risk of acute myeloid leukemia include topoisomerase II inhibitors, anthracyclines, and platinum-based therapies.[23,24] The second cancers associated with radiation therapy include acute leukemia, chronic myelogenous leukemia, and breast, lung, thyroid, and nonmelanoma skin cancers. Second cancers of the bone and connective (soft) tissues occur within or adjacent to the irradiated area among patients treated with high-dose radiation. Dose and type of radiation, the intrinsic susceptibility of exposed tissues, and patient characteristics influence the risk for radiation-associated cancers. The risk is generally higher when developing tissue is exposed at a younger age.
Depending on the definition, the frequency of multiple primaries is in the range of 2% to 17%. The number of patients with multiple primary cancers seems to be growing based on the National Cancer Institute SEER Program. With advances in early detection, supportive care, and effective cancer treatments and with longer follow-up, the number of multiple primaries will continue to increase. Over the past few decades, the meaningful increases in the 5-year relative survival rate for all cancers continues to be offset by the long-term late effects of cancer and its treatment. One of the most life-threatening sequelae is the diagnosis of a new cancer. Patients with a prior cancer diagnosis usually undergo several follow-up tests and examinations often over a period of several years to rule out relapse of their disease. With the increasing use of more sophisticated and sensitive imaging methods, such as PET/CT, more and more cancer survivors are now found to have new suspicious lesions in their thyroid, colon, breast, esophagus, bile duct, and head and neck that might have been missed otherwise.[27,28] Practicing oncologists should be aware of this rather not uncommon presentation in their cancer surveillance patients and watch for the clinical features that may be indicative of a second primary cancer. Late and atypical metastatic spread pattern for a given primary tumor, discordant tumor burden/tumor marker levels, isolated single new metastatic lesions, continued exposure to environmental carcinogens (eg, smoking, alcohol), and history of prior carcinogenic chemotherapy (eg, etoposide, anthracyclines) or radiation therapy may be some of the manifestations indicative of the presence of a second primary cancer.
After histologic confirmation of a second primary cancer, the decision for active treatment may be difficult in the advanced and surgically unresectable second primary presentation. The challenge is to find an anticancer therapy strategy that covers both cancer types without increased toxicity or relevant pharmacologic interactions and without negative impact on the overall outcome. There are no well-established, evidence-based guidelines in this setting. These patients are always excluded from clinical trials by the eligibility criteria unless they have been low grade/stage and were successfully treated at least 3 to 5 years ago. To reflect more of a real-life population and to enable participation of patients with a second primary cancer history in clinical trials, the exclusion criteria, especially for early-phase clinical trials, should be modified to only exclude patients who currently require active anticancer therapy. Admittedly, this may add marked complexity to assessing efficacy and progression and may therefore not be suitable for phase III clinical trials. Moreover, there is a lack of reliable safety and efficacy data for the drugÃ¢€“drug interactions of antineoplastic (ie, cytotoxic, biologic, immunotherapy) treatment options being considered for a given patient. Decisions about if and how to treat these patients should be based on multidisciplinary tumor board discussions and should be individualized.
The increased knowledge about patients with hereditary cancer and cancer survivors will hopefully allow for the development of specific management and surveillance measures. Few studies have specifically addressed the prevention of multiple primary cancers in cancer survivors. There is also a lack of specific screening guidelines in this setting. Currently, all cancer survivors are recommended to follow applicable national guidelines for cancer screening for average-risk individuals in the general population (ie, not cancer survivors) such as those provided by the American Cancer Society, American Society of Clinical Oncology, National Comprehensive Cancer Network, and the US Preventive Services Task Force.
How are multiple primaries defined?
• A cancer of a different site and histologic (microscopic composition of cells and/or tissue) type than the original cancer is considered a separate primary.
• Cancers of different histologic types in the same site are considered separate primaries regardless of whether they are diagnosed at the same or different times.
• A new cancer of the same site or with the same histology as an earlier one is considered the same primary cancer if diagnosed within 2 months or a separate primary cancer if diagnosed after 2 months, unless the medical record specifically states that it is recurrent or metastatic disease.
• If an organ is paired, each member of the pair is generally considered to be a separate site.
• Important exceptions to these general rules include most histological types of cancer in the prostate and urinary bladder, for which multiple tumors are reported as a single primary with the date of the first invasive lesion.
• A different set of rules is used to determine multiple primaries of the lymphatic and hematopoeitic (the production of blood cells) systems.
Reproduced from American Cancer Society. Cancer Facts & Figures 2009. 
Finally, it is important that patients diagnosed with cancer have information about possible late and long-term effects of treatment and their symptoms, as well as possible signs of recurrence and second tumors. A physician-guided follow-up plan should include information about recommended cancer screening, surveillance for recurrence, and the schedule on which tests and examinations should be performed. In addition to recommendations that are specific to their primary cancer, age at initial diagnosis, and potential risks related to treatment, it is important that cancer survivors follow the recommendations for cancer prevention and early detection in the general population, including tobacco avoidance or cessation, physical activity, nutrition and diet, healthy weight, and all standard cancer screenings.[30,31]
Overall, the incidence of multiple primary cancers is increasing due to increased detection of early-stage cancers and advances in cancer treatment. Different mechanisms such as family history, genetic defects, hormonal factors, alcohol, tobacco, and environmental influences have been implicated in the development of multiple primary cancers. Diagnosis and treatment for multiple cancers remains a challenge because of variable definitions of multiple primaries, lack of specific screening guidelines, and the lack of well-established treatment guidelines. Management of these patients should be individualized through a multidisciplinary approach. Further research is needed to better understand and define prevention, screening, diagnosis, treatment, and survivorship issues in this area.
Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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