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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Cover of Holland-Frei Cancer Medicine

Holland-Frei Cancer Medicine. 5th edition.

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Chapter 156Secondary Cancers: Incidence, Risk Factors, and Management

, MD, , MD, PhD, and , MD.

Second primary cancers have become an increasingly important concern in oncology during the last two decades, as they now comprise the sixth most common group of malignancies after skin, colorectal, lung, breast, and prostate cancers.1,2 In this chapter, we discuss the etiologic factors responsible for secondary cancers and suggest methods of long-term surveillance for individuals at high risk of developing multiple malignant neoplasms.

What was formerly a problem primarily in pediatric cancer survivors and for the survivors of the more curable adult cancers has become a more universal problem in the present-day practice of oncology. Survivors of all cancers are living for longer periods, partly because of the more frequent use of radiation and chemotherapy.3 The formerly unacceptable toxicities of these modalities are more readily controlled with better supportive care. These therapies, as well as underlying predisposition, have been implicated in the etiology of second neoplasms. Other reasons for an increase in multiple cancers include fewer competing causes of mortality and consequently more naturally occurring cancers in an increasingly aging population.

When reviewing data on second malignant neoplasms, consideration must be given to the definition. One can readily appreciate a “second cancer” as such when the second neoplasm differs histologically, or molecularly, from the primary neoplasm. But when considering incidence, how should one regard a second, histologically identical, cancer in a paired organ? Reports and analyses of data have emphasized the importance of ruling out metastatic disease when a new tumor arises, but traditionally many registries consider tumors of the same histologic type in the second of paired organs to be “second cancers.” Reports of multiple primaries should clearly state whether second cancers include or exclude nonmetastatic neoplasms in paired organs.

The frequency with which second cancers occur may be expressed as an actuarial risk within a given cohort, as a relative risk when compared with a standard population, or as an attributable risk, with the latter reflecting the additional cases associated with a specific exposure or other etiology. Each of these methods has inherent limitations when attempting to ascribe causation, especially when several factors are implicated.

We will first discuss the role that shared environmental risk factors play in the etiology of second cancers and how they can increase the risk of a second cancer developing in a patient already at high risk. Lifestyle factors, such as smoking, alcohol, exercise, and diet, clearly play a role in a long list of cancers, such as those of the head and neck, bladder, and gastrointestinal tract, which are often seen following treatment for the primary neoplasm.

Another at-risk group consists of individuals with a genetic predisposition to multiple neoplasms. More than 30 genes have been cloned whose mutations are known to increase cancer susceptibility.4 The first of these, retinoblastoma, was described many years before the mutated gene was cloned, but others, including the phakomatoses, multiple endocrine neoplasias, and the DNA repair disorders, such as hereditary nonpolyposis colon cancer (HNPCC), are also related to multiple neoplasms. Studies of these mutations and their resultant disruption of cellular signaling pathways have provided insight into tumorigenesis, both in its hereditary and sporadic forms.

Another potentially critical category of etiologic factors that cannot yet be evaluated is polymorphism for metabolizing enzymes. For example, cytochrome P-450 and GST variants may be important determinants of whether or not exposure to a specific environmental agent, radiation, or chemotherapy is associated with an increased likelihood of developing a second malignant neoplasm.

Second cancers have also been known to result from the radiation and chemotherapy used to treat a primary cancer. Studies of pediatric cancer survivors have provided much information concerning the relationship of therapy to second neoplasms because of the young age at diagnosis and the high cure rates following successful therapy. As therapy becomes more intensive for adults as well as children and cure rates increase, we may expect a resultant increase in toxicity, including second cancers. It should be emphasized, however, that most second cancers occur naturally and randomly in cancer survivors, and so are a sign of improved survival following the first cancer diagnosis. Fear of a second primary should not outweigh the use of curative therapy for the first cancer.

Registries that record information about patients with second cancers, including therapy received and family history, are valuable resources for the analysis of risk factors and for providing genetic material to laboratory scientists. As knowledge concerning risk factors for secondary cancers increases, it will be possible to provide more focused surveillance in the follow-up of long-term survivors. Such knowledge is also useful for planning clinical trials with the objective of reducing long-term morbidity while concomitantly maintaining a similar cure rate.

Incidence of Secondary Cancer

Overall, cancer is the second leading cause of death in the United States exceeded only by heart disease.4a That ranking is only likely to become higher as competing causes of mortality, such as coronary artery disease, decline.3 If cancer were a disease with no associated mortality and evenly distributed throughout the population, and, assuming a lifetime cumulative incidence of approximately 33%, one would expect that 1 in 9 people would develop two primary cancers in his or her lifetime. Taking this a step further, 1 in 27 would develop three primary cancers, and so on. Although chance or random distribution probably plays the most important role in second malignancies, a statistically elevated association between two tumor types may point to a specific etiology. Later in this chapter, we discuss therapy-related effects and genetic factors. However, while those may seem most dramatic, shared risk factors probably play the greatest role in the development of second cancers.

Analyses from the U.S. National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program indicate that multiple primary neoplasms comprised 13.1% of cancers in men and 13.7% of cancers in women, a proportion that had doubled over the previous 20 years.1,2 This refers to the proportion of secondary cancers among all cancers, but when one compares cancer survivors with the general population, the incidence rate of second malignancies appears to be almost twice the rate of initial primary cancers. Stated in a different way, any survivor of cancer has twice the probability of developing a new primary cancer than a cancer-free individual of the same age and sex. One critical factor determining the increased risk of developing second neoplasms is the probability of surviving a first neoplasm. Another potential factor is detection bias. During the work-up of an initial symptomatic cancer, otherwise clinically unrecognized malignancies may be detected. Thus, most experts distinguish between malignancies discovered or diagnosed simultaneously and those that are metachronous or develop subsequently. Detection bias is also seen with the enhanced long-term surveillance for second malignancies in cancer survivors.

Although case reports and case series describe certain pairs or clusters of cancers in individuals, the establishment of a true pair-wise association requires a more systematic and controlled approach. Cancer may be common, but individual types of cancer are relatively rare. For example, breast cancer and prostate cancer occur in 1 to 2 per 1,000 individuals per year at the age adults are at the highest risk for these cancers. Thus, a large number of cancer survivors are needed with initial cancers of one type in order to determine whether the development of certain secondary cancers are due to chance or are true associations.5

As a result, the most valuable information concerning the incidence of second malignancies has come from population-based registries rather than hospital-based series. In addition to providing follow-up on large numbers of cancer survivors, cancer registries also provide sufficient information to calculate the expected rates of second malignancies. A comparison of the observed incidence with expected incidence of second malignancies (O/E) provides the standardized incidence ratio (SIR), an estimate of the risk of developing a second malignancy in a given cancer survivor. For example, an SIR of 2.0 would indicate that an individual diagnosed with a given malignancy is at twice the risk of developing a second malignancy of a given type, compared with a similarly aged member of the general population of the same sex. Such rates and ratios generally exclude the initial 3 to 6 months after diagnosis in order to eliminate synchronous malignancies. Furthermore, estimates are made for different time intervals following the initial cancer in order to evaluate the effects of enhanced surveillance on the observed incidence of second malignancies.5–8

The most important contribution in this area, to date, is a systematic analysis of all major cancers as second malignancies, published as a National Cancer Institute monograph in 1985.6 This analysis utilized data from the Connecticut Tumor Registry, the oldest extant systematic population-based registry available, and similar data from the Danish Cancer Registry, another long ongoing population-based cancer registry. More recently, multiple studies have utilized data from the SEER program, which comprises population-based registries encompassing approximately 10 to 11% of the United States population. The SEER program has amassed data on 1.8 million new cancer cases diagnosed from 1973 to 1992. We have recently published a systematic analysis of pair-wise risk for selected cancers using this data set, to which the interested reader is referred.7 In Table 156.1, we include some data from the analyses of SEER data for illustrative and discussion purposes.

Table 156.1. Risk of Secondary Cancers for Selected Cancers, Based on Data from SEER, 1973–1994.

Table 156.1

Risk of Secondary Cancers for Selected Cancers, Based on Data from SEER, 1973–1994.

An excellent illustration of the bias which occurs in the detection of second malignancies that stem from enhanced utilization of diagnostic tools at the time of initial work-up or for subsequent surveillance of a cancer patient is the interrelationship between colorectal cancer and prostate cancer in men. Studies have shown that following the diagnosis of colorectal cancer in men, there is an enhanced diagnosis of prostate cancer secondary to increased screening for prostate cancer. However, men diagnosed with prostate cancer do not have an elevated incidence of colorectal cancer, presumably because there is not as much clinically occult colorectal cancer waiting to be diagnosed under these circumstances.6,7,9

The above illustrates an important principle, that is, one can utilize the directionality of the pair-wise association as a means for investigating the etiology of the association. For example, a therapy-related second malignancy should occur at increased incidence following a specific initial primary cancer, for example, leukemia following Hodgkin’s disease. The association should be, and in fact is, unidirectional, that is, there is no enhanced risk of Hodgkin’s disease following leukemia.6,7,9,10 When shared environmental exposures play a major role in the elevation of risk, one expects to see a bi-directional association, that is, each member of the pair should occur at elevated risk following the other primary malignancy.

Another illustration of this phenomenon is bilateral disease, or development of the same malignancy in the second of paired organs. For almost all cancers, there is an elevated risk of the malignancy in both the paired organs, for example, bilateral breast cancer or bilateral ovarian cancer. Whether these are diagnosed synchronously or metachronously, it seems likely that this is due to shared factors, whether environmental or genetic. Other portions of the same organ may also be affected, as in multiple primary cancers of the colon.6,11

Clinical Characteristics

One question that arises concerning second malignancies is how they differ clinically from their de novo equivalents. On the one hand, some second malignancies are diagnosed earlier and thus have a better outcome due to increased surveillance and better overall medical care of the cancer survivor. On the other hand, once cancer has been treated, many physicians focus on the primary neoplasm and neglect routine surveillance for second cancers.12,13 Women who have survived cancer should at least have routine mammography screening, Pap smears, and colorectal cancer screening, using the guidelines that would apply to any other woman in the general population. Counseling of survivors should include instructions for primary and secondary prevention of new malignancies.

Some second malignancies appear to be less amenable to treatment than primary tumors of the same histologic type. The best example of this is therapy-related acute myelocytic leukemia (t-AML) where the prognosis is much worse than for de novo AML.14,15 Presumably this reflects enhanced mutations and other molecular genetic abnormalities stemming from exposure to chemotherapy or radiation. Treatment for a second cancer must also take into account the toxicity from the initial therapy. Robinson and co-workers have explored the characteristics and stage distributions, as well as survival characteristics, of malignancies occurring as second primaries. For the most part, stage for stage, there do not appear to be major differences between second malignancies and their de novo counterparts.12,13,16–18

Shared Environmental Risk Factors

Tobacco

The best known environmental risk factor for cancer is tobacco use or cigarette smoking. It has been estimated that one-third of cancers can be attributed to this lifestyle factor19 and multiple cancers may occur in those who smoke or use chewing tobacco or snuff. The greatest risk following tobacco use is development of cancers of the upper aerodigestive tract (UADT). It is not surprising that a survivor of one such malignancy is at elevated risk of having a second malignancy in the same exposed area. Thus, it is well recognized that one must carefully monitor a survivor of a UADT malignancy for the development of another cancer within the upper aerodigestive tract.20–25 In fact, when such a malignancy presents in the head and neck area, it is recommended that the patient undergo triple endoscopy: bronchoscopy, nasopharyngoscopy, and esophagoscopy. Some have attributed the occurrence of these malignancies to a so-called field cancerization effect, which has also been described for the urinary bladder and the oral cavity. Large areas in the involved tissue may be affected by tobacco carcinogens before rising to the stage of actual invasive cancer. Hence, the initial neoplasm that is diagnosed represents only the first portion of the field to reach a malignant level and the rest of the field remains at elevated risk for progressing to invasive cancer.23,26–28 More recent work by Sidransky and others have suggested that there is more monoclonality within these fields, that is, the upper aerodigestive tract squamous epithelium or the urinary bladder epithelium, than had been previously appreciated, and that these field effects may represent the migration of an early malignant clone throughout the epithelium.29,30

Second malignancies associated with tobacco are not limited to the upper aerodigestive tract. Bladder cancer,31 renal cancer,31 and pancreatic cancer,32 among others, are observed at higher rates in association with head and neck or upper aerodigestive tract cancers.

Diet and Hormones

Although studies of geographic variation suggest that dietary risk factors contribute greatly to cancer etiology, the exact relationships and risk factors involved remain controversial.33 For example, the Japanese tend to have much lower rates of colorectal cancer, breast cancer, and endometrial cancer than Western nations and also have major differences in dietary habits. It is not known, however, whether these differences reflect the intake of dietary carcinogens, such as fats, the absence of certain protective factors, such as vitamins, the caloric content of specific types of food, or overall differences in hormone levels.33 However, there is considerable interplay between diet, obesity, physical activity, and hormones, especially female reproductive hormones.34

Using population-based data as discussed above, associations between colorectal cancer, ovarian cancer, endometrial cancer, and breast cancer have been demonstrated for decades.5–7,9,35 Although advances in our understanding of molecular genetics and other risk factors have led to an explanation for some of these associations, familial syndromes, such as BRCA1 and -2, on the observed association between breast and ovarian cancers do not appear to be responsible for the majority of the population-based association between these two malignancies.36,37 Dietary habits that result in high caloric intake and thus obesity can change the estrogen milieu of a given individual and enhance the occurrence of several malignancies, most notably colorectal cancer, endometrial cancer, and breast cancer, all of which have been associated with obesity. Part of the risk may derive from elevations in estrogen levels, and this is likely to become a greater problem as hormone replacement therapy becomes more common in postmenopausal women. The fact that these cancer types vary as a group in their international incidence lends credence to their shared risk factors.

The associations among breast, ovarian, colorectal, and endometrial cancers are lower than those observed for the tobacco-related neoplasms. Nonetheless, since these are fairly common cancers that are usually amenable to early detection and effective treatment at early stages, patients with one of these cancer types need to be monitored closely by their oncologists, who can provide the appropriate medical care and surveillance.

Other Shared Risk Factors

Other shared risk factors also play a role in the occurrence of specific multiple primary cancer associations. For example, certain malignancies have been recognized as occurring in association with human immunodeficiency virus (HIV). Two of the most common are Kaposi’s sarcoma (KS) and non–Hodgkin’s lymphomas of the central nervous system (CNS). Recent investigations have suggested that CNS lymphoma and KS tend to occur in the same individual.38

The co-occurrence of malignancies may serve as clues to as yet undiscovered or under-appreciated risk factors for specific malignancies. For example, adenocarcinomas of the small bowel are rare, and little is known regarding their etiology other than the elevated risk associated with Crohn’s disease. Neugut and Santos have recently described a bi-directional association between small bowel adenocarcinoma and large bowel adenocarcinoma.39 This has led to work suggesting a similar pattern of molecular genetic abnormalities in the two different forms of cancer.40 Epidemiologic and clinicopathologic correlations between the two suggest that research into why adenocarcinoma of the small bowel is rare, while it is a common malignancy in the large bowel, should be pursued as a potential future prevention strategy for colorectal cancer.40,41

Genetic Risk Factors

Cancer arises when a gene mutation leads to an abnormal cell and results in clonal proliferation, aggressive spread, or prevention of apoptosis. The vast majority of these mutations occur after birth and are found only in the cancer cells themselves. However, about 5% of cancers are thought to arise in the context of a known hereditary cancer syndrome. Studies of these mutations and their resultant disruption of cellular signaling pathways provide insight into tumorigenesis, both in its hereditary and spontaneous forms. These genes are often predisposing for more than one tumor type, and hence, multiple cancers may occur in individuals who carry them. In addition, somatic cells may sustain transforming mutations following treatment with radiation and certain chemotherapeutic agents and lead to secondary cancers. This will be discussed in the next section. Research into the types and functions of genes associated with familial cancer syndromes that lead to one or more malignancies has provided valuable insight into the cellular pathways necessary for normal cell growth and propagation processes that when subverted lead to malignancy and metastases. A better understanding of these hereditary cancer syndromes and their genetic basis helps elucidate the pathways involved in carcinogenesis (Table 156.2).

Table 156.2. Summary of Selected Inherited Cancer Syndromes.

Table 156.2

Summary of Selected Inherited Cancer Syndromes.

Hereditary cancer syndromes are identified by families in which multiple generations have a consistent pattern of malignancy or when individuals develop multiple cancers during their lifetime, starting at an unexpectedly young age. Familial predisposition to cancer may be associated with a germline mutation leading to inactivation of a tumor suppressor gene, activation of a proto-oncogene, or inactivation of a DNA mismatch repair gene.42

More than 30 cancer predisposing genes have been cloned that involve loss-of-function mutations in tumor suppressor genes, gain-of-function mutations in oncogenes, or mutations of genes which encode DNA repair.4 Due to incomplete penetrance, only some individuals who carry a mutant allele of an inherited cancer gene will develop a primary malignancy and fewer still will develop more than one. The gene phenotype is not 100% penetrant and suggests that a single mutation is not a sufficient condition for cancer. Interaction with modifier genes, exposure to exogenous agents, or lifestyle choices may also be operative.

In this section, we will discuss the best known hereditary cancer syndromes associated with germline mutations that can predispose to tumors in more than one tissue or in both members of paired organs.

Retinoblastoma

Retinoblastoma (RB), although affecting only 1 child in 20,000, is the prototype of inheritable cancers. Multiple cancers, tumors in both eyes and in other organs, are also characteristic features of this syndrome. In 1986, the retinoblastoma gene, rb1, on chromosome 13 became the first tumor suppressor gene to be cloned.43 As Knudson had hypothesized in 1971, if both copies of rb1 in a single retinoblast are lost or mutated, cancer develops.44 In 40% of affected children, one copy of rb1 is mutated prior to birth and is present in all cells of the body. This germline mutation results in retinoblastoma in young children (average age 10 months) and tends to be multi-focal or bilateral.

In an extensive review of second cancers in patients treated for primary RB, Wong et al.45 found the cumulative incidence of a second cancer at 50 years to be 51% for the hereditary form of retinoblastoma, but only 5% for those individuals with the sporadic, nonhereditary form. The most common second malignancies were bone and soft tissue sarcomas occurring primarily, but not exclusively, within the radiation field. Patients with retinoblastoma are also at an increased risk for melanoma, brain tumors, and histiocytosis X.46 An increase in the relative risk of a second malignancy for each incremental increase in radiation dose received was noted as well, and parallels the risk in those not genetically predisposed. Although radiation therapy is a risk factor for second malignancies, genetic predisposition in hereditary RB significantly heightens that risk. Survivors of childhood retinoblastoma, even if never treated with radiation or chemotherapy, must be monitored long term for the development of sarcomas, adult carcinomas, and other neoplasms.

Neurofibromatosis

Neurofibromatosis type 1 (NF1) occurs in 1 in 3,000 individuals, is dominantly inherited, and predisposes carriers to both benign and malignant tumors. Approximately 50% of cases result from a new germline mutation with the other 50% being inherited from an affected parent. The nf1 gene on chromosome 17 functions as a classic tumor suppressor gene. Mutations of the gene associated with neurofibromatosis type 2 (NF2), nf2, on chromosome 22 has also been identified as a tumor suppressor gene, but it predisposes the carrier to a different spectrum of neoplasms.

NF1 manifests itself clinically, usually by the age of 5 years, as multiple café-au-lait spots, cutaneous neurofibromas, and developmental abnormalities or delay. Early neoplastic manifestations include optic pathway tumors, the majority of which are benign but can, nevertheless, grow and impair normal function.47 Neurofibrosarcomas, pheochromocytomas, rhabdomyosarcomas, and juvenile myelomonocytic leukemias are also associated with NF1.

The more rare NF2 patients have a distinct clinical presentation, with over 85% developing vestibular schwannomas.48 They may also have café-au-lait spots and cutaneous neurofibromas, but the average age of presentation is in the third decade. Other more malignant CNS tumors occur with time, including meningiomas, astrocytomas, and ependymomas.

Mutations in both NF genes appear to predispose to multiple neoplasms, especially following therapy with radiation. For this reason, children with NF who have had one neoplasm should be followed up closely for the development of secondary cancer.

Li-Fraumeni Syndrome

The Li-Fraumeni syndrome was originally described in 1969 and characterized by individuals with an increased risk of breast cancer, sarcomas, leukemia, and CNS tumors.49 In the 1990s a mutation in the p53 tumor suppressor gene located on chromosome 17 was found to be associated with this syndrome, with over 70% of Li-Fraumeni families having a mutation in p53.50 A Li-Fraumeni–like syndrome in which individuals do not carry a mutant p53 but in whom a similar spectrum of multiple tumors is seen has also been described.51

The risk of developing a second malignancy in patients with Li-Fraumeni syndrome is 50% at 30 years. It has been suggested that the predisposition for cancer in these individuals is exacerbated by an increased susceptibility to DNA-damaging agents and ionizing radiation received as treatment of a first cancer.52

Syndromes of Inherited Colon Cancer

Two major dominantly inherited syndromes that predispose carriers to colon cancer as well as other neoplasms are known.53 Familial adenomatous polyposis (FAP) affects approximately 1 in 7,000 individuals in the United States and is known to be due to a germline mutation of the tumor suppressor gene, apc. During the second decade of life multiple adenomatous polyps in the colon become evident and, if untreated, colon cancer develops by the fourth to fifth decades. Other malignant tumors associated with FAP include small bowel adenocarcinoma, hepatoblastoma, desmoid tumors, and thyroid carcinoma. A variant of FAP, Turcot’s syndrome, has an increased association of colorectal cancer with tumors of the central nervous system.53

Hereditary nonpolyposis colon cancer (HNPCC) is associated with mutations in several DNA mismatch repair genes. It is primarily manifested as multi-focal colorectal cancer but is also associated with gastric, pancreatic, endometrial, ovarian, uterine, and urinary tract tumors. HNPCC confers up to an 80% lifetime risk of colorectal cancer, primarily by the age of 50 years, and is felt to account for 1 to 5% of all colorectal cancers.54 Individuals diagnosed with any of these neoplasms need to be studied for a germline mutation and followed up expectantly so that they might benefit from early diagnosis of the associated tumors.

Familial Breast Cancer

Mutation of the genes BRCA1 and BRCA2 have been linked to breast cancer susceptibility. Although both genes appear to function in the same cellular signaling pathway, mutations of each are associated with a different constellation of tumors.55 Women with BRCA1 mutations develop breast and ovarian cancer but carriers also have an increased risk of developing colon and prostate cancer. BRCA2 mutations are associated with breast cancer in men and women, as well as pancreatic adenocarcinoma and ovarian cancer. Women of Ashkenazi Jewish descent are more likely to carry a BRCA1 or BRCA2 mutation and account for over a third of the women developing breast cancer before the age of 40 years.

Multiple Endocrine Neoplasia

Two clinically distinct multiple endocrine neoplasia (MEN) syndromes with autosomal dominant inheritance patterns are known.56,57 MEN I affects the anterior pituitary, the pancreas, and the parathyroid gland; the gene has been mapped to chromosome 11. MEN II involves tumors of the thyroid, the adrenal medulla, and the autonomic nervous system and has been divided into MEN IIA—thyroid, parathyroid, and pancreas—and MEN IIB—thyroid, adrenal, and ganglion cells. MEN II results from a mutation of the ret oncogene on chromosome 10. The diagnosis of neoplasms in any of these sites and especially two or more of these sites should alert the clinician to the possibility of a relevant mutation.

Other Syndromes Associated with Cancer Susceptibility

Ataxia telangiectasia is a rare disorder associated with neurologic, immunologic, and developmental defects in which homozygotes are at increased risk for lymphoid malignancies, cancer of the stomach, and perhaps other tumors.58 These individuals also have an increased sensitivity to the effects of radiation and are, therefore, more prone to the development of secondary cancer. It has also been suggested that heterozygotes are at increased risk of breast cancer.

Individuals affected with xeroderma pigmentosum develop multiple skin cancers at an early age, as they are extremely sensitive to the carcinogenic effects of ultraviolet radiation. Bloom syndrome is characterized by growth deficiency, erythematous skin eruption, abnormal facies, and immunodeficiency. All affected individuals develop cancer before the age of 30 years. Although there seems to be a predominance of lymphocytic leukemia and lymphoma, all cancers types are seen in this condition.58

Therapy-Related Secondary Cancers

Ionizing Radiation

Radiation has long been associated with the development of primary cancers and, when used as treatment, imparts a risk for the development of a second cancer. Typically, these tumors occur within or at the margin of the radiated field. Bone and soft tissue sarcomas are the most frequent second neoplasms following radiation therapy, but skin, brain, thyroid, and breast cancer also can occur.52,59–61 In the Late Effects Study Group, the median time to developing a second neoplasm was 10 years following radiation, but second neoplasms were seen as late as 34 years following exposure.46 Radiogenic leukemias appear earlier with a latency period of 4 to 8 years and radiation-related solid tumors usually appear 10 to 40 years following radiation exposure.52,62

For many postradiation malignancies, the risk of a second malignancy is higher, if the radiation exposure occurs earlier in life or during periods of rapid growth of a tissue, such as bone sarcomas during adolescence. This is also seen with thyroid, breast, skin, brain, and stomach cancers, as well as in acute leukemia. Adolescent girls receiving mediastinal radiation therapy for Hodgkin’s disease develop breast cancer more often than do their adult counterparts.61 Cells that have matured and are no longer proliferating appear to be less susceptible to the effects of radiation, although lung cancer has been observed after chest irradiation and bladder cancer after pelvic irradiation.63–66 More recently an association between radiation and esophageal cancer has been observed.67

Dose–response relationships have been found between radiation dose and sarcomas. A 40-fold increase in risk of bone sarcomas was observed following 60 Gy or more.60 Ten-fold increases in soft-tissue sarcoma risk were seen in RB patients receiving 60 Gy or more, but even 5 Gy increased the risk two-fold for this genetically predisposed group.45 High-dose radiation appears not to increase the risk for leukemia and thyroid cancer. This may be due to cell killing and inactivation, with cells losing their ability to proliferate, and therefore, they are unable to sustain a malignant transformation. Another observation has been that, as for other sources of radiation exposure, radiation therapy and cigarette smoking may act in a synergistic fashion.68

Chemotherapy

Leukemia as a secondary cancer can occur following treatment with chemotherapy. Although acute myelogenous leukemia (AML) is the most common type of therapy-related leukemia, acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome have also been reported.14,69,70 Chemotherapy-induced myeloid leukemias are relatively resistant to subsequent therapy and have a cure rate of only 10 to 20%, stressing the importance of primary prevention.14,15,70

Evidence is accumulating concerning the mechanisms of DNA topoisomerase-II inhibitors and alkylating agent–induced leukemias.14,70Table 156.3 summarizes the features of these chemotherapy-related leukemias. Alkylating agents include cyclophosphamide, ifosfamide, cisplatin, carboplatin, busulfan, melphalan, nitrogen mustard, and procarbazine. Treatment-related myelodysplasia or secondary leukemia following alkylator therapy has a latency period of 4 to 7 years. These leukemias demonstrate deletions on chromosomes 5 or 7. Topoisomerase-II inhibitors include the epipodophyllotoxins, etoposide, and teniposide, as well as the anthracycline doxorubicin. Leukemia following epipodophyllotoxin therapy has a shorter latency period (1 to 3 years) and is primarily associated with translocation of the mll gene at chromosome band 11q23.

Table 156.3. Characteristics of Therapy-Related Acute Myelogenous Leukemia.

Table 156.3

Characteristics of Therapy-Related Acute Myelogenous Leukemia.

In children treated for solid tumors, such as Hodgkin’s disease, Ewing’s sarcoma, and rhabdomyosarcoma, a dose–response relationship has been demonstrated for alkylators and the risk of leukemia. Alkylating agents increase the risk of a second leukemia almost five-fold, but that risk increases to almost 24-fold in patients receiving the highest doses.69 Doxorubicin together with high-dose alkylating agents has been shown to increase that risk further.69 A similar increase in risk of secondary leukemia is noted with increasing dose of epipodophyllotxins. t-AML is reported in fewer than 3% of germ cell tumor patients receiving doses of etoposide less than 2 g/m2. This risk increases to more than 11% in patients receiving more than 2 g/m2.62 Using more recent data from the Cancer Therapy Evaluation Program (CTEP), Smith et al. did not find a dose–response relationship for epipodophyllotoxin in solid tumors and secondary AML, with no increased risk in patients who received up to 5 g/m2 of etoposide.71

Alkylating agents may also potentiate the risk of secondary bone cancers when used with radiation therapy.60 The relative risk of secondary bone sarcomas following radiation therapy was 2.7, but when alkylating agents were used as well, the relative risk rose to 4.7.

Hodgkin’s Disease

Patients with Hodgkin’s disease treated with chemotherapy, radiation therapy, or a combination have a relative risk of 2 to 4 of developing a second cancer.10,59,72,73 The overall cumulative incidence of developing a second malignancy, the majority of which are solid neoplasms, after being treated for childhood Hodgkin’s disease is 20% in 20 years.

Thyroid cancer is the most common postradiation cancer noted in Hodgkin’s disease survivors. Breast cancer is seen in females, with those over the age of 10 years being at greatest risk. There is also an increased risk of skin cancer within the radiation field. Recently, many pediatric centers have altered their therapy and treat Hodgkin’s disease to reflect differences in second cancer and gonadal toxicity in girls and boys.

The chemotherapy used to treat Hodgkin’s disease has also been associated with the development of secondary leukemia. As many as 25% of second malignancies following treatment for Hodgkin’s disease are secondary leukemia or lymphoma.10,59,72,73 MOPP regimens that contain nitrogen mustard and procarbazine have the greatest risk for secondary leukemia compared with treatment with cyclophosphamide.73 Higher doses and multiple alkylating agents also increase that risk, but radiation therapy does not appear to do so.

Retinoblastoma

As discussed above, RB patients are at very high risk of developing a second malignancy, primarily because of their genetic predisposition. An interaction with radiation has also been shown. In the largest study of RB survivors, Wong reported 190 second cancers for a relative risk (RR) of 30, compared with age-matched controls.45 The cumulative incidence of second cancers for patients with hereditary RB was 51% at 50 years, compared with 5% in 50 years for the nongenetic form of RB. Two-thirds of the second cancers were osteogenic or soft tissue sarcomas, and a radiation dose–response relationship was noted for all soft tissue sarcomas with as little as 5 Gy, increasing the risk of second malignancy two-fold. For those patients receiving over 60 Gy, there was a 10-fold increase in risk.

Acute Lymphocytic Leukemia

Patients with ALL, the most common first malignancy of childhood, who received 24 Gy cranial or craniospinal radiation therapy as CNS prophylaxis, have a 22-fold increase in the RR of CNS tumors. Children less than 5 years of age at the time of radiation had the highest risk.74 A review of secondary brain tumors at the St. Jude Children’s Research Hospital found a cumulative incidence of 1.4% in children with primary ALL. There was a statistically significant increase in risk with increasing cranial radiation dose, with patients receiving > 30 Gy having a 3.23% cumulative incidence of brain tumors at 20 years.75 Fortunately, in more recent protocols, cranial radiation has been replaced by more intensive intrathecal chemotherapy for children under the age of 10 years who have no evidence of CNS disease at diagnosis.

The risk for t-AML in patients treated for ALL varies with the original protocol used and the dose and schedule of epipodophyllotoxins. Children receiving weekly or twice weekly epipodophyllotoxins had a cumulative incidence of 12% of developing secondary AML.76

Wilms’ Tumor

The data from the National Wilms’ Tumor Study Group (NTWTS) found an eight-fold increase in second malignancies in children treated for Wilms’ tumor between 1969 and 1991.77 There was an excess of leukemia as well as lymphomas and solid tumors. The secondary leukemias were primarily t-AML and were diagnosed 1 to 6 years from original therapy. Similar latency periods were seen for lymphomas. Secondary solid tumors following treatment for Wilms’ tumor had a much longer latent period of 3 to 21 years. The solid tumors were primarily sarcomas and carcinomas (breast, thyroid, colon, hepatocellular, parotid), but there was also an increased incidence of brain tumors. Patients who had received abdominal radiation had twice the risk of second cancers, compared with those who did not. The study also suggested that doxorubicin potentiated the radiation effect. In the United Kingdom, the 20-year cumulative incidence of developing a second malignant neoplasm after Wilms’ tumor was 3 to 6%.78

Upper Aerodigestive Tract Cancers

The increase in esophageal cancer, which occurs following lung cancer, has been found to be enhanced by treatment of the initial lung cancer with radiation, strongly suggesting a carcinogenic effect of radiation in its etiology. Nonetheless, the risk of esophageal carcinoma is elevated following lung cancer even in the absence of radiation therapy.25,52,66,67

Schottenfeld and his colleagues, as well as others, have demonstrated that tobacco cessation following the diagnosis of the initial primary cancer leads to a reduction in subsequent risk for other tobacco-related malignancies, and thus, in most instances, it remains a reasonable strategy to decrease risk.22,26

It is essential to perform a work-up for multiple primaries at presentation, particularly for an initial head and neck cancer, including malignancies of the oropharynx, tongue, and larynx. If a lung nodule or nodules in the other areas of the head and neck appear, it is essential to rule out the possibility that this represents a second malignancy. If a lung nodule is a recurrence or metastasis from an initial oropharyngeal primary, then the prognosis is poor. However, if a lung nodule represents a second primary lung cancer and is operable, cure is still a possibility. Every effort should be made to make this distinction. New molecular genetic approaches may play a role in the future in making this distinction.

Breast Cancer

Breast cancer is the most common malignancy diagnosed in women in the United States. Women with an initial breast cancer are at significantly elevated risk for cancer in the contralateral breast. It has been shown that antiestrogens and breast cancer screening can reduce the incidence of second malignancies as well as improve survival.79 Breast cancer survivors are also at elevated risk for cancers of the ovary, endometrium, and colon/rectum, independent of the treatment administered for the breast cancer.6,7,9,80 This suggests that these organs share risk factors with cancer of the breast, including obesity, diet, and reproductive hormonal status. New discoveries in breast cancer genetics also implicate mutations in BRCA1 and BRCA2 as risk factors for ovarian as well as breast cancer. Screening for ovarian and endometrial cancer as well as colorectal cancer should be done regularly in women with a history of breast cancer.81,82

The treatment utilized for breast cancer may also impact on the subsequent risk of second malignancies. Studies have shown that postmastectomy radiation can elevate the subsequent risk of lung cancer, particularly in smokers.63,64,68 If alkylating agents are used as adjuvant therapy, the risk of acute leukemia will also be increased, particularly if patients have also received postmastectomy radiation.55,83 Postirradiation sarcomas may also occur.84 While tamoxifen acts as an antiestrogen with regard to breast cancer and significantly reduces the occurrence of contralateral breast cancer, it acts as a proestrogenic agent elsewhere, raising the risk for endometrial cancer.80 Thus, patients who have received long-term adjuvant hormonal therapy should have regular endometrial screening by a gynecologist. Radiation therapy for an initial breast cancer does not appear to elevate the risk for contralateral breast cancer.80

Prostate Cancer

It has recently been reported that radiotherapy for prostate cancer elevates the long-term risk for bladder cancer.65 Nonetheless, the risk does not appear to be excessive and does not occur for some years following the radiotherapy. As described earlier, an association between prostate cancer and other malignancies has occasionally been found, for example, lung cancer or colorectal cancer, but these have usually been unidirectional, and thus probably represent detection bias rather than some shared risk factor.

Testicular Cancer

Testicular cancer is one of the most curable solid tumors whether it occurs unilaterally or bilaterally.31,85 Since etoposide has been utilized as a major treatment modality in this disease, and this chemotherapeutic agent has been associated with acute leukemia, there may be some elevation in risk of leukemia following successful therapy.31,70 Furthermore, when radiation therapy is used in the primary management of testicular cancer, there may be elevated risks for other neoplasms in the pelvis.

Pancreas/Gastric Cancer

Since both pancreatic and gastric cancer have a poor outlook with few long-term survivors, it is difficult to know what second malignancies would be associated with these neoplasms. Both are associated with cigarette smoking, however, and thus, one could speculate that when successful treatments are developed, other tobacco-related malignancies might be observed. Pancreatic cancer has occurred as a second malignancy in individuals with other smoking-related neoplasms.32

Colorectal Cancer

Survivors of colorectal cancer are at elevated risk for second malignancies within the colon and rectum, as well as in the breast, uterus, and ovary.82 In those with HNPCC, there is an elevated risk of small bowel and endometrial cancers.

Endometrial/Ovarian Cancer

Survivors of endometrial cancer are at elevated risk for ovarian and colorectal cancers as well as breast cancer.6,7,9,82,86 As a result, appropriate surveillance and screening should be performed in women with any of these neoplasms. If appropriate, bilateral oophorectomy should be considered at the time of hysterectomy in order to reduce the subsequent risk for ovarian cancer.

Skin Cancer

It has long been recognized that basal cell carcinomas and squamous cell carcinomas (nonmelanotic skin cancer) tend to occur in the same individuals.87 This represents the impact of sun exposure, a shared risk factor. Thus, those who have nonmelanotic skin cancer should undergo regular surveillance for further skin malignancies and should avoid further sun exposure. Individuals with dysplastic nevi may develop multiple cutaneous melanomas and should undergo regular evaluations by experienced clinicians.88

Conclusion

Therapeutic options for secondary cancers are often compromised by the therapy for the first neoplasm, but early diagnosis can often lead to successful treatment of most second cancers. Identifying those who are at greater risk for multiple neoplasms can help medical providers better monitor for second neoplasms and advise patients on ways of reducing risks.

Many groups of high-risk individuals are already known, and several ways of reducing the incidence of second cancers are already underway. The knowledge that certain agents and regimens increase the risk of a second malignancy has prompted pediatric oncologists to modify therapy. For example, knowing that patients with the hereditary form of RB are at high risk of developing sarcomas in the radiation field has led to studies testing the effectiveness of neoadjuvant chemotherapy and an emphasis on local treatment methods other than radiation therapy.

For adult neoplasms, research that focuses on the avoidance of known environmental carcinogens offers the hope that some neoplasms in multiple sites can be prevented. Survivors of childhood cancer are an excellent population in which to study the effectiveness of educational intervention techniques. And finally, study of the genetic changes in cancer in families with many affected members and of individuals with more than one primary tumor can increase our knowledge of the nature of the changes leading to transformation of a normal cell to malignancy. This may lead to the identification of susceptible individuals and to the development of appropriate methods of surveillance and counseling.

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