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Second Malignant Neoplasms
Summary of Key Points
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Subsequent malignancies after successful treatment for cancer occur in a meaningful minority of persons.
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The etiology is often multifactorial and includes known hereditary conditions, unrecognized genetic predisposition, primary cancer, therapeutic exposures, age, and lifestyle practices.
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Guidelines for screening are available for some but not all situations; health care providers and patients should be aware of such guidelines.
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Further research is needed to identify persons at highest risk so more useful preventive strategies can be developed.
The American Cancer Society estimated that in 2017, there would be an estimated 1,688,780 new cancer cases diagnosed and 600,920 cancer deaths in the United States. Because of the rising incidence of and survival from cancer, as of January 2016, it is estimated that there are 15.5 million cancer survivors in the United States, representing 4.8% of the population. The number of cancer survivors is projected to increase by 31%, to 20.3 million by 2026 and to 26.1 million by 2040.
With a growing cohort of cancer survivors now living, efforts have focused on decreasing the risk for adverse long-term health-related outcomes, the most significant of which are subsequent malignant neoplasms (SMNs). In an analysis of 2,116,163 patients 18 years of age or older who were diagnosed with a primary malignancy from the 10 most common cancer sites (prostate, breast, lung, colon, rectum, bladder, uterus, kidney, melanoma, and non-Hodgkin lymphoma) between 1992 and 2008 using Surveillance, Epidemiology, and End Results (SEER) data, 170,865 (8.1%) developed a second primary malignancy. In multivariable analysis, a history of non-Hodgkin lymphoma (hazard ratios [HRs] of 2.7 and 2.9, respectively, for men and women) and bladder cancer (HRs of 1.9 and 1.7, respectively, for men and women) predicted the highest risk of developing a second cancer. For patients with two incident cancers, 13% died of their initial cancer, but more than half (55%) died of their second primary malignancy.
The most recent monograph from the National Cancer Institute on subsequent malignancies, published in 2006, does not reflect the current percentage because it reports on the period from 1973 to 2000. However, this monograph still represents the largest overview of subsequent malignancies that includes data on both adult and pediatric cancers. In this report, among 2 million patients with cancer who survived at least 2 months with close to 11 million person-years at risk, cancer survivors had a 14% higher risk of having a new malignancy than would have been expected in the general SEER population (observed/expected = 1.14), with an excess absolute risk (EAR) of 21 per 10,000 person-years. However, the risk of SMN compared with the general population was highly dependent on the age of the patient at first cancer diagnosis because risk for cancer rises with increased attained age in the general population. For example, for persons younger than 18 years at initial diagnosis, the relative risk (RR) was 6.13, and the EAR was 15 per 10,000 person-years. The RR and EAR for persons 70 to 79 years at initial diagnosis dropped to their lowest values, 1.02 and 4, respectively. The highest EARs of 32 to 39 were noted in young to middle-age adults ages 30 to 59 years at initial cancer diagnosis.
Gender also influenced risk, with a slightly increased risk for females (RR = 1.17) compared with males (RR = 1.11), a pattern that remained even when gender-specific malignancies were excluded from the analyses. Blacks also had elevated RR and EAR (1.31 and 46, respectively) compared with whites (1.12 and 20, respectively). Although RRs were highest in the first 5 years from diagnosis, cumulative incidence increased by years of follow-up: 5.0%, 8.4%, 10.8%, and 13.7% at 5, 10, 15, and 25 years, respectively.
More than 80% of multiple primary cancers reported arose in separate or independent organ systems. New malignancies that occurred in the same site or organ as the first primary cancer accounted for 13.2%, with the most common sites being the female breast, colon, lung, and skin (melanoma). Table 50.1 shows the significant relative and excess absolute risks by primary cancer site. It should be noted that the EAR for cancers occurring at tobacco- or alcohol-related sites, such as the oral cavity, pharynx, esophagus, larynx, and lung, was 114 cases per 10,000 person-years and overall accounted for 10,000 excess subsequent cancers.
Table 50.1
Risk Factors for Subsequent Malignancy in the United States by Site
Modified from National Cancer Institute. New malignancies among cancer survivors: SEER cancer registries, 1973-2000, http://seer.cancer.gov/publications/mpmono/ ; 2013.
| Primary Cancer | Observed Versus Expected | Excess Absolute Risk/10,000 Person Years |
|---|---|---|
| Lip | 1.16 | 34 |
| Oral cavity | 2.45 | 231 |
| Nasopharynx | 1.49 | 47 |
| Salivary gland | 1.25 | 644 |
| Colon | 1.07 | 13 |
| Anal | 1.24 | 36 |
| Lung | 1.36 | 65 |
| Larynx | 1.71 | 150 |
| Nasal | 1.44 | 68 |
| Breast | 1.18 | 23 |
| Cervix | 1.32 | 24 |
| Vulva | 1.12 | 16 |
| Ovary | 1.18 | 15 |
| Testis | 1.62 | 21 |
| Bladder | 1.17 | 34 |
| Kidney | 1.13 | 23 |
| Renal pelvis or ureter | 1.29 | 55 |
| Bone sarcoma | 1.24 | 13 |
| Soft tissue sarcoma | 1.19 | 20 |
| Melanoma of skin | 1.24 | 27 |
| Ocular melanoma | 1.16 | 24 |
| Other ocular (nonretinoblastoma) | 1.35 | 51 |
| Brain and central nervous system | 1.11 | 4 |
| Thyroid | 1.11 | 8 |
| Hodgkin lymphoma | 2.22 | 49 |
| Non-Hodgkin lymphoma | 1.14 | 14 |
| Chronic lymphocytic leukemia | 1.19 | 38 |
| Chronic myeloid leukemia | 1.16 | 19 |
| Acute lymphocytic leukemia | 1.55 | 5 |
| Childhood cancer | 6.07 | 15 |
| Retinoblastoma | 14.71 | 24 |
| Ewing sarcoma | 14.84 | 44 |
| Hodgkin lymphoma | 9.55 | 39 |
| Central nervous system peripheral neuroectodermal | 12.54 | 26 |
The etiology of SMNs is multifactorial. Host and environmental factors clearly play a role, but defining these contributions can be difficult. Superimposed on this general population risk for second and subsequent primary cancers are treatment-associated malignancies, in which chemotherapy and RT for the primary cancer can increase risk for a subsequent cancer. This risk is then modified by host and environmental factors that affect risk of primary cancer, such as lifestyle (e.g., use of tobacco and alcohol, sun exposure, and diet), workplace and home exposures to carcinogens, viruses, age, gender, genetics, infection, immune function, hormone levels, and interactions of all of these factors. Table 50.2 summarizes common risk factors for SMNs in these general categories, but categories are not fully exclusive of one another.
Table 50.2
Potential Risk Factors for Subsequent Malignancy
| Risk Factor | Examples |
|---|---|
| Genetic syndromes |
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| Potential genetic modifying factors |
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| Disease and treatment |
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| Lifestyle-modifying factors |
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| Infection |
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Genetic Risks for Subsequent Malignancy
When considering the risk of SMNs associated with genetic predisposition, one must consider genetic disorders with high risk for both primary and subsequent malignancy, as well as less well-defined gene–environment interactions. The former category, which accounts for a small minority of SMNs, includes hereditary breast cancer (BRCA1/BRCA2) , heritable retinoblastoma, neurofibromatosis, nevoid basal cell carcinoma (BCC), Li-Fraumeni syndrome, hereditary nonpolyposis colorectal cancer (Lynch syndrome), multiple endocrine neoplasia, Bloom syndrome, xeroderma pigmentosum, and similar syndromes. Table 50.3 summarizes these syndromes and common sites for primary and subsequent neoplasms; in addition, several are discussed here.
Table 50.3
Common Hereditary Cancer Syndromes
| Syndrome | Common Mutations or Pathways | Cancer Risks |
|---|---|---|
| Hereditary breast cancer | BRCA1 | Breast, ovarian |
| BRCA2 | Breast, ovarian, prostate, pancreatic, gallbladder and bile duct, stomach, malignant melanoma | |
| Hereditary nonpolyposis colorectal cancer | DNA mismatch repair | Colon, endometrium, stomach, small intestine, hepatobiliary, kidney, ureter, ovary |
| Neurofibromatosis | NF1 | Leukemia, central nervous system, peripheral nerve sheath |
| Retinoblastoma | RB1 | Sarcoma, leukemia, melanoma, breast, lung |
| Li-Fraumeni syndrome | TP53 | Breast, sarcoma, leukemia, central nervous system, adrenocortical carcinoma gonadal germ cell |
| Nevoid basal cell carcinoma | PTCH1 | Medulloblastoma, basal cell carcinoma |
| Bloom syndrome Xeroderma pigmentosum Ataxia telangiectasia |
DNA repair | Lymphoma, leukemia, skin, soft tissue, epithelial |
Mutations in BRCA1 and BRCA2 are associated with high risk for secondary breast cancer. In a study of 810 women with a stage I or II primary breast cancer in the setting of BRCA1 or BRCA2 , a contralateral breast cancer developed in 149 participants (18.4%), with a 15-year actuarial risk of 36.1% and 28.5%, respectively, for women with a BRCA1 or BRCA2 mutation. Younger age (<50 years) at primary breast cancer diagnosis and having two or more first-degree relatives with breast cancer also increased risk. A reduction of risk was noted with oophorectomy (RR = 0.47). Among 396 women with stage I or stage II primary breast cancer in the setting of a BRCA1 or BRCA2 mutation, the 5-year actuarial risk of ipsilateral breast cancer was 5.8%, and the 10-year risk was 12.9%. Receipt of chemotherapy and RT both reduced risk (RR = 0.45 and 0.28, respectively). Oophorectomy was associated with a significant risk reduction (RR = 0.33). With increases in oophorectomy in patients with a BRCA mutations, data are emerging on occult and subsequent malignancies. In a cohort that included 148 BRCA1 , 98 BRCA2 , 6 BRCA not otherwise specified (NOS), and 5 BRCA1 and 2 mutation carriers at the time of risk-reducing salpingo-oophorectomy (RRSO), occult carcinoma was seen in 14 or 257 (5.4%) of patients. Three patients with negative pathology at RRSO subsequently developed primary peritoneal serous carcinoma (PPSC), and two patients (22%) with serous tubal intraepithelial carcinoma at time of RRSO subsequently developed pelvic serous carcinoma. A total of 110 women (43%) were diagnosed with breast cancer before RRSO, and 14 of the remaining 147 (9.5%) developed breast cancer after RRSO. Patients with BRCA2 also have an increased risk for prostate cancer, pancreatic cancer, gallbladder and bile duct cancer, stomach cancer, and malignant melanoma.
Mutations in mismatch repair genes in persons with hereditary nonpolyposis colorectal cancer can lead to the more site-specific colorectal cancer syndrome associated with other gastrointestinal (GI) cancers (Lynch syndrome type I) or the family cancer syndrome, in which early-onset endometrial and stomach cancers are seen in addition to colorectal cancer (Lynch syndrome type II).
Neurofibromatosis type 1 (NF1), which results from a mutation in the NF1 gene at chromosome 11q12, is not associated with malignancy in the majority of patients with this syndrome. However, patients (and particularly children) with NF1 have an increased risk for leukemias, central nervous system (CNS) tumors, and peripheral nerve sheath tumors.
Retinoblastoma, which is associated with germline mutation of the tumor suppressor RB1 gene at chromosome 13q14, is the most common hereditary syndrome associated with SMN after childhood cancer, with significantly increased risk of sarcomas both inside and outside the RT field, along with leukemia, melanoma, and epithelial tumors such as breast and lung cancers. This risk is further increased with RT, significantly lower, but not absent, in survivors of nonheritable disease.
In a cohort of 1604 patients treated from 1914 to 1984, the cumulative incidences of SMN were 51% and 5% at 50 years for heritable and nonheritable retinoblastoma survivors, respectively. A follow-up 9 years later found 50-year cumulative incidences to be 36% and 5.7%, with standardized incidence ratios (SIRs) of 19 and 1.2, respectively, for those with heritable disease versus nonheritable disease. RT increased SMN risk in heritable patients another 3.1-fold. The cumulative probability of death from SMN was 25.5% for bilateral disease survivors and extended beyond 40 years after retinoblastoma diagnosis. In another cohort, association of RB1 genotype and SMN was evaluated in 44 patients, with a significantly increased risk reported among carriers of one of the 11 recurrent CGA>TGA nonsense RB1 mutations and significantly lower risk with low penetrance mutations.
As a result of the high risk of SMN, therapy has changed dramatically over the past 2 decades, with avoidance of RT, but more use of systemic and intraarterial chemotherapy. When RT is needed, proton beam is recommended because of the lower risk for SMN. Several small studies have evaluated SMN risk in patients treated with systemic chemotherapy. In a review by Gombos, 15 cases of therapy-related acute myeloblastic leukemia were identified, 8 of whom had received etoposide. In a cohort of 187 patients with heritable retinoblastoma treated with carboplatin, etoposide, and vincristine without RT, 4% developed SMNs at a mean of 11 years of follow-up, with one reported etoposide-related leukemia. There were no SMNs among the 58 patients with nonheritable retinoblastoma.
Li-Fraumeni syndrome, which is associated with germline mutation in the TP53 gene at chromosome 17q13, is characterized by increased risk for breast cancer, sarcoma, leukemia, brain tumors, adrenocortical carcinoma, and gonadal germ cell tumors. Several small studies have reported an excess of multiple primary tumors in patients with Li-Fraumeni syndrome, but this phenomenon has not been systematically studied.
Nevoid BCC syndrome associated with mutation of the PTCH1 gene on chromosome 9 is associated with BCC and medulloblastoma, and many BCCs can develop during a patient's lifetime. Although multiple BCCs are reported in survivors of childhood cancer, it is likely that persons who experience these along the track of RT within a very short latency may have this genetic predisposition.
Bloom syndrome, xeroderma pigmentosum, and ataxia telangiectasia are all rare disorders of DNA repair that can lead to multiple primary cancers, including leukemia and lymphoma, skin cancer, soft tissue sarcomas, and epithelial tumors. However, these syndromes have well-recognized phenotypes and thus are not an occult cause of SMN.
Treatment-Associated Risks for Subsequent Malignancies
Radiation Therapy
Data on the carcinogenic potential of ionizing radiation exposure from cancer treatment, other disease treatment, and environmental causes have been available for several decades. These data have shown that organs differ in their sensitivity for SMN and the dose needed to induce malignancy and that latency and age at time of exposure remain important risk factors. Risk of SMN from radiation therapy (RT) appears to be proportional to the number of premalignant stem cells created and the number of cells that survive RT, which in turn are related to cellular killing, cellular repopulation occurring between fractions and after the last fraction, and the ratio of proliferation rate for premalignant to normal cells. Furthermore, the type and energy of radiation and the time course during which exposure occurs all affect risk for SMNs. Low-linear-energy transfer radiation, such as x-rays and gamma rays, is sparsely ionizing and is generally less efficient in tumor induction than densely ionizing high-linear-energy transfer radiation (e.g., α particles and neutrons), for which the carcinogenic effectiveness is not diminished at high doses and may be increased with fractionation and protraction.
The risk of SMN after treatment with RT is related to age at treatment; generally, younger age is associated with increased risk, total dose, and mode of RT delivery. Latency periods are long, and risk appears to rise without a clear plateau for decades after RT is conducted.
Many of the data on SMN in childhood cancer come from the Childhood Cancer Survivor Study (CCSS), which evaluates long-term outcomes in childhood cancer survivors treated between 1970 and 1987 who survived at least 5 years after the initial diagnosis. In this cohort, risk for SMN was examined with respect to therapeutic exposures, which were well documented through chart abstraction for each participant. In addition, radiation dosimetry was evaluated for some in-depth analyses of radiation risk. In a report on subsequent neoplasms from the CCSS, among 14,359 survivors, 1402 individuals had a total of 2703 subsequent neoplasms, which included 802 second malignant neoplasms, 159 nonmalignant meningiomas, 169 benign or in situ neoplasms, and 1574 nonmelanoma skin cancers. In multivariable analysis, risk of any subsequent neoplasm was increased 2.7-fold with RT exposure. Risk related to RT for malignant neoplasms other than nonmelanoma skin cancer was increased 2.6-fold, risk of meningioma was increased 16.6-fold, and risk of nonmelanoma skin cancer was increased 4.4-fold. Dose–response relationships also appear to differ between organs with respect to risk of SMN in childhood cancer survivors.
Among 116 survivors with a subsequent CNS neoplasm, compared with control participants who did not have a subsequent CNS neoplasm, RT was associated with an increased risk for any subsequent CNS malignant neoplasm and specifically for subsequent glioma (odds ratio [OR] = 6.78) and meningioma (OR = 9.94). Furthermore, linear dose–response relationships between radiation dose and secondary glioma and meningioma were identified. The excess RRs per Gy, equal to the dose of the linear response function, were 0.33 per Gy for glioma and 1.06 per Gy for meningioma. With increasing length of follow-up, the number of new glioma cases declined, but the incidence of meningioma continued to increase with longer length of follow-up.
In analyses of secondary thyroid cancer, risk increased with radiation dose to the thyroid gland for doses as high as 29 Gy and decreased for doses greater than 30 Gy, with this linear exponential dose most pronounced in persons younger than 10 years at the time of exposure.
The risk of breast cancer after chest RT is now well established with a dose–response relationship. Among 1230 female childhood cancer survivors treated with chest irradiation who were participants in the CCSS, those treated with lower doses of radiation (median, 14 Gy) to a large volume (whole-lung field) had a high risk of breast cancer (SIR = 43.6) as did survivors treated with high doses of delivered radiation (median, 40 Gy) to the mantle field (SIR = 24.2). The cumulative incidence of breast cancer by age 50 years was 30%, and breast cancer-specific mortality rates at 5 and 10 years were 12% and 19%, respectively.
The risk of SMN related to RT among adults treated for cancer clearly differs from that among children. In a report from SEER, in patients 20 years of age or older who were diagnosed with a primary cancer between 1973 and 2002, an analysis compared risk for SMN among those treated with or without RT. In this group of 647,672 patients with cancer, a second solid organ malignancy developed in 60,271 (9%). For each of the first cancer sites, the RR of developing an SMN associated with RT was elevated and was highest for organs that typically received more than 5 Gy. As seen in studies of childhood cancer survivors, risk decreased with increasing age at diagnosis and increased with time since diagnosis. It was estimated that 3266 excess solid organ SMNs could be related to RT, and by 15 years after diagnosis, there were five excess cancers per 1000 patients treated with RT.
However, survivors of adult-onset malignancies who were treated with RT are clearly at some increased risk for SMN, as evidenced by several large population-based studies of SMNs.
Travis and colleagues identified 2285 second solid cancers in 40,576 1+-year survivors of testicular cancer who were treated between 1943 and 2001. Statistically significant increased risks of solid cancers were observed among patients treated with RT alone (RR = 2.0) or in combination with chemotherapy (RR = 2.9). Among 104,760 1-year survivors of cervical cancer, 12,496 SMNs were found overall (SIR = 1.33). Compared with the general population, patients with cervical cancer who were treated with RT, but not patients who did not receive RT, were at increased risk for all second cancers, particularly at the sites of the colon, rectum or anus, urinary bladder, ovary, and genitalia. The association of RT with second cancer risk was modified by age at cervical cancer diagnosis for the rectum or anus, genital sites, and urinary bladder, with higher HRs for second cancer at younger ages of diagnosis of cervical cancer.
In a cohort of 32,941 patients treated for Hodgkin lymphoma between 1935 and 1994, SMNs occurred in 2153, and the risk for solid tumors was elevated 2.3-fold in patients who were treated with radiation alone, 1.7-fold in those treated with chemotherapy alone, and 3.1-fold with combined modality therapy. In an analysis of treatment in a more contemporary era, 8807 patients diagnosed with stage I–II classic Hodgkin lymphoma (cHL) between 1988 and 2009 who received RT were selected from the SEER database. A total of 523 (6%) patients developed a second malignancy. Median latency to second malignancy was 5.8 years (range, 0.1–21.5). Of the 523 patients who developed a second malignancy, 228 (44%) occurred in the first 5 years, 139 (27%) were diagnosed between years 5 to 10, and 156 (30%) occurred beyond 10 years. Treatment between 2000 and 2009 was associated with an HR for second malignancy of 0.77 compared with the treatment between 1988 and 1999.
Prostate cancer is another important adult-onset cancer to consider risk for SMS, with its current 10-year relative survival rate of 99.7%. Among 441,504 men who were diagnosed with prostate cancer between 1992 and 2010 identified from SEER, it was noted that survivors had a lower risk of being diagnosed with another cancer overall compared with the US population (SIR = 0.60). The risks of leukemia and cancers of the oral cavity and pharynx, esophagus, stomach, colon and rectum, liver, gallbladder, pancreas, lung and bronchus, and larynx were significantly lower. Conversely, these patients had a greater risk of bladder, kidney, and endocrine and soft tissue cancers.
Treatment with RT increased risk for bladder cancer (SIR = 1.4) and rectal cancer (SIR = 1.7) compared with no radiation (SIRbladder = 0.76; SIRrectal = 0.74). In a meta-analysis, of 13 studies comprising 762,468 breast cancer patients, 5 years or more after diagnosis, RT was significantly associated with an increased risk of second non–breast cancer with a RR of 1.12. The risk increased over time and was highest 15 or more years after breast cancer diagnosis, for second lung and esophagus cancer.
The most common second cancers associated with RT exposure are shown in Table 50.4 , together with the most common primary cancers for which the RT was administered.
Table 50.4
Common Radiotherapy-Associated Cancers
| Radiation Field | Common Primary Malignancy Treated | Common Subsequent Malignancies |
|---|---|---|
| Brain | Central nervous system, leukemia | Central nervous system |
| Neck | Hodgkin lymphoma | Thyroid |
| Thoracic | Hodgkin lymphoma, Wilms tumor, sarcoma, breast | Breast, lung |
| Abdomen | Sarcoma, Wilms, Hodgkin, gastrointestinal | Colon |
| Pelvis | Gonadal | Gonadal |
| Soft tissue | Sarcoma | Sarcoma |
| Bone | Sarcoma, retinoblastoma | Sarcoma |
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