Secondary Malignancies: What, When, Why, in Whom?

I have to worry about a secondary cancer AND myeloma?

Article Type: Side Effects
Author: Smita Bhatia MPH MD
Publication Date: Posted 10/27/2008
Source: medscape
Source Type: online newsletter

The 5-year survival rate among patients with cancer is now 66%.^[1] For childhood cancer, progress in diagnosis and treatment has transformed a once uniformly fatal disease into a group of malignancies that are now curable in most patients. With the increasing use of risk-based high-intensity therapy and the resulting improvement in survival, the number of cancer survivors is growing rapidly^[1]; in the United States, the number of cancer survivors. has tripled since 1971 and is growing by 2% each year.^[2] In 2004, there were 10.8 million cancer survivors, and this number is projected to approach 12 million by 2010 (Figure 1). Together with this success, and the realization that the goal of curing cancer is achievable, is a heightened recognition of the need to reduce treatment-related adverse events and improve quality of life.

Figure 1. (click image to zoom)

Number of US cancer survivors in millions. Based on data from Surveillance Epidemiology and End Results.

Subsequent Malignant Neoplasms

The cumulative incidence of SMNs approaches 15% at 20 years after diagnosis of primary cancer, representing a 3- to 10-fold increased risk for cancer survivors, compared with the general population.

One of the most serious adverse events encountered in cancer survivors is the development of subsequent malignant neoplasms (SMNs). The cumulative incidence of SMNs approaches 15% at 20 years after diagnosis of primary cancer, representing a 3- to 10-fold increased risk for cancer survivors, compared with the general population.^[3-6] SMNs are a leading cause of non-relapse-related late mortality.^[7,8] Unique clinical and pathologic characteristics have resulted in a conventional classification of SMNs into 2 distinct groups: therapy-related myelodysplasia/acute myeloid leukemia (t-MDS/AML) and therapy-related solid tumors (Figure 2). Characteristics of t-MDS/AML include a short latency (typically less than 3 years from primary cancer diagnosis) and exposure to alkylating agents and/or topoisomerase II inhibitors. Therapy-related solid tumors, on the other hand, have a strong and well-defined association with radiation, and are characterized by latencies that exceed 10 years.^[4,9-11]

Figure 2. (click image to zoom)

Cumulative incidence of subsequent malignant neoplasms after Hodgkin's lymphoma. From Bhatia S, et al, with permission.^[15]

t-MDS/AML has been reported after treatment of several primary cancers, such as Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL); acute lymphoblastic lymphoma (ALL); sarcomas; and breast, ovarian, and testicular cancers.^[6,11-17] t-MDS/AML is the major cause of non-relapse-related mortality in patients with HL and NHL who had been treated with high-dose therapy followed by stem cell rescue (autologous hematopoietic cell transplantation [HCT]).^[18-23] The cumulative incidence of t-MDS/AML has ranged from 2% at 15 years after conventional therapy with alkylating agents^[11] to 8.6% at 6 years after autologous HCT.^[20] t-MDS/AML is classically associated with exposure to alkylating agents and topoisomerase II inhibitors used for treatment of the primary cancers listed above. The magnitude of risk for t-MDS/AML following radiation is considerably smaller than that observed after these agents. t-MDS/AML is a clonal hematopoietic disorder, characterized by distinct chromosomal changes.^[24-26] Two types of t-MDS/AML, classified according to therapeutic exposures, are recognized by the World Health Organization: alkylating agent/radiation-related type and topoisomerase II inhibitor-related type.^[27]

Alkylating Agent-Related t-MDS/AML

Alkylating agents associated with t-MDS/AML include cyclophosphamide, ifosfamide, mechlorethamine, melphalan, busulfan, nitrosureas, chlorambucil, dacarbazine,^[28] and platinum compounds.^[16] Mutagenicity is related to the ability of alkylating agents to form crosslinks and/or transfer alkyl groups to form DNA monoadducts. Alkylation results in inaccurate base pairing during replication and single- and double-strand breaks in the double helix as the alkylated bases are repaired. Expressed mutations involve different base substitutions, including transitions and transversions. The risk for alkylating agent-related t-MDS/AML is dose-dependent, with a latency of 3-5 years after exposure to alkylating agents.^[29] Alkylating-agent-related t-MDS/AML is associated with abnormalities involving chromosomes 5 (-5/del[5q]) and 7 (-7/del[7q]), and with a high frequency of multidrug resistance phenotype. Alkylating agent-related t-MDS/AML is generally refractory to treatment,^[30] with a median survival of 5 months.^[31]

Topoisomerase II Inhibitor-Related t-AML

Topoisomerase II catalyzes the relaxation of supercoiled DNA by covalently binding and transiently cleaving and religating both strands of the DNA helix. DNA topoisomerase II inhibitors (epipodophyllotoxins and anthracyclines) stabilize the enzyme-DNA covalent intermediate, reduce the religation rate, and cause chromosomal breakage. These events initiate apoptosis required for antineoplastic activity.^[32,33] Occasionally, repair of chromosomal damage results in chromosomal translocations, leading to leukemogenesis.^[32,34,35] Most of the translocations disrupt a breakpoint cluster region between exons 5 and 11 of the 11q23 band and fuse mixed-lineage leukemia (MLL) with a partner gene.^[36-38] In vitro studies have provided evidence that etoposide can directly induce MLL rearrangements in hematopoietic cells.^[39] Topoisomerase II inhibitor-related t-AML presents as overt leukemia, without preceding myelodysplasia,^[40,41] usually after a latency of 6 months to 3 years,^[41] and is associated with balanced translocations involving chromosome bands 11q23 or 21q22.^[41] Other translocations observed in patients with topoisomerase II-related t-AML include inv(18)(p13q22) or t(17,19)(q22;q12).^[40,42]

Therapy-Related Solid Tumors

Radiation induces solid tumors, usually within the radiation field.^{[4,10,11,15,43]} In contrast to t-MDS/AML, the latency for therapy-related solid tumors is usually longer than 10 years.^[4,10,11,15] The risk is highest when radiation exposure occurs at a younger age,^{[4,9,11,44-50]} and rises with increasing doses of radiation and with increasing follow-up from radiation.^[10,15] Radiation-associated solid tumors account for the largest burden of SMNs (~80%). Some of the well-established radiation-related solid tumors include breast cancer, thyroid cancer, brain tumors, sarcomas, and basal cell carcinomas.^{[4,9-11,15,48,51]}

Radiation-associated solid tumors account for the largest burden of SMNs (~80%).

Radiation-Related Breast Cancer

Radiation-related breast cancer is the most common subsequent solid tumor among female HL survivors, largely due to high-dose, large-field chest radiation for HL (standardized incidence ratio = 25-55).^[11,15,51] The latency is 15-20 years from HL diagnosis, and the risk is highest among patients diagnosed with HL at a young age. Female patients treated with mantle radiation before the age of 30 years are at a significantly higher risk of developing radiation-related breast cancer compared with those treated after age 30.^[15,31] For female HL patients treated with chest radiation before the age of 16 years, the cumulative incidence of secondary breast cancer approaches 20% by age 45 years (Figure 3).^[15] The risk increases with increasing doses of radiation (P value for trend < .001).^[51,52] In contrast, treatment with alkylating agents or radiation to the ovaries is associated with a reduction in risk.^[52] The large majority of these women are diagnosed with their breast cancer at a relatively young age, often before 40 years of age. Because outcome is closely linked to stage at diagnosis, early diagnosis should confer survival advantage.^[53] Mammography in isolation may not be the ideal screening tool for radiation-related breast cancers occurring in relatively young women with dense breasts, hence the recommendations by the American Cancer Society to use adjunctive screening with magnetic resonance imaging (MRI).^[54]

Figure 3. (click image to zoom)

Breast cancer after Hodgkin's lymphoma in girls receiving radiation. From Bhatia S, et al, with permission.^[15]

Radiation-Related Thyroid Cancer

Radiation-related thyroid cancer develops after radiation to the neck for HL, ALL, and after total body irradiation for HCT, with a median latency of 15 years.^{[4,9,11,14,15]} Risk increases with radiation dose up to 29 Gy, with a fall in risk at doses > 30 Gy, consistent with a cell-killing effect.^[43]

Radiation-Related Brain Tumors

Radiation-related brain tumors primarily include gliomas and meningiomas, and have been reported after cranial radiation for histologically distinct brain tumors^[10] or for management of central nervous system disease among patients with ALL or NHL.^[4,6,9] The radiation-related dose response for the excess risk for these brain tumors is linear.^[10]

Radiation-Related Sarcomas

Radiation-related sarcomas develop within the radiation field after a latency period of ~10 years, and exhibit a clear relationship with radiation dose. Radiation-associated sarcomas respond poorly to therapy.^[55,56]

Radiation-Related Basal Cell Cancers

Radiation-related basal cell cancers are the most prevalent SMN in cancer survivors. Ultraviolet and ionizing radiation are known risk factors. The large majority (> 90%) of basal cell cancers in cancer survivors develop within the radiation field.^[4,9-11,14]

Radiation-Related Lung Cancer

An increased risk for lung cancer (relative risk of 2.6- to 7.0-fold) has been observed following exposure to chest radiation, especially in patients treated for HL.^[57] Cigarette smoking seems to multiply the risk associated with therapy-related lung cancer. It is therefore critical to make every effort to counsel survivors in regard to the risks of smoking and to provide those who do smoke with information about smoking cessation programs.

Genetic Susceptibility and SMNs

Genetic predisposition may play a role in the development of SMNs, as evidenced by the increased risk for SMNs among patients with the hereditary form of retinoblastoma. Radiation further increases the risk for SMNs in patients with hereditary retinoblastoma. The cumulative incidence for developing a new cancer at 50 years after diagnosis of retinoblastoma approaches 36% for those with hereditary disease vs 5.7% for those with the nonhereditary form.^[58] Compared with the general population, survivors of retinoblastoma who carry germline mutations in RB1 (ie, hereditary retinoblastoma survivors) are at an increased risk for sarcomas, melanoma, and cancers of the brain and nasal cavities. In addition, survivors of hereditary retinoblastoma who are not exposed to high-dose radiation therapy have a high lifetime risk of developing late-onset epithelial cancers, such as lung cancer and bladder cancer.^[59] Members of families with Li-Fraumeni syndrome have been reported to be at an increased risk for multiple subsequent cancers, with the highest risk observed among survivors of childhood cancer.^[60] It therefore appears that germline mutations in tumor suppressor genes, such as those occurring in Li-Fraumeni syndrome, may interact with therapeutic exposures, resulting in an increased risk for second cancers. Patients with Fanconi's anemia show a high incidence of t-MDS/AML and certain types of solid tumors^[61-63]; cells from patients with Fanconi's anemia are characterized by chromosomal hypersensitivity to DNA crosslinking agents.^[64]

The literature clearly supports the role of chemotherapy and radiation in the development of SMNs.^[28] However, interindividual variability exists, suggesting a potential role for genetic variation in determining susceptibility to genotoxic exposures. As discussed, the risk for SMNs could potentially be elevated by mutations in vital genes that are rare but of high penetrance and lead to serious genetic diseases. However, the population attributable risk that is due to these mutations is likely to be very small because of their extremely low prevalence. The interindividual variability in treatment-related risk for SMNs may be related to common polymorphisms in low-penetrance genes. However, limited data exist with regard to the role of polymorphisms in genes that modulate susceptibility to SMNs.

Screening

The Children's Oncology Group (COG) has developed risk-based guidelines (Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers) specifically linked to therapeutic exposures and designed to direct follow-up care for patients who have completed treatment of childhood cancer.^[65] These guidelines represent a set of comprehensive screening recommendations that can be used to standardize and direct the follow-up care for this group of cancer survivors. Ongoing monitoring facilitates early identification of and intervention for treatment-related complications to reduce the morbidity related to these outcomes. Specially tailored patient education materials, known as "Health Links," accompany the guidelines, offering detailed information on guideline-specific topics to enhance health promotion in this population with specialized healthcare needs. The Guidelines and the Health Links can be downloaded from www.survivorshipguidelines.org. Because these Guidelines are exposure-based, and there is a clear relationship between chemotherapy and radiation and the development of SMNs, the COG Guidelines can be applied to all "at-risk" populations.

SMNs remain a significant threat to the health of survivors treated for cancer; therefore, vigilant screening is important for those at risk. Risk for t-MDS/AML usually manifests within 10 years following exposure. Recommendations include monitoring with annual complete blood count for 10 years after exposure to alkylating agents or topoisomerase II inhibitors. Most other subsequent malignancies are associated with radiation exposure. Screening recommendations include careful annual physical examination of the skin and soft tissues in the radiation field with radiographic or other cancer screening modalities, as indicated. Specialized recommendations for women who received radiation with potential impact to the breast before the age of 30 years (ie, radiation doses of 20 Gy or higher to the mantle, mediastinal, whole lung, and axillary fields) include monthly breast self-examination beginning at puberty, annual clinical breast examinations beginning at puberty until age 25 years, and then a clinical breast examination every 6 months, with annual mammograms and MRIs beginning 8 years after radiation or at age 25 (whichever milestone occurs first).

Screening

Future Directions

The growing population of cancer survivors carries a significant burden of morbidity, necessitating comprehensive long-term follow-up, which should ideally begin at the completion of active therapy. Documentation of therapeutic exposures will form the basis for use of recommendations within the long-term follow-up guidelines, thus ensuring standardization of care received by the survivors. However, many barriers prevent effective follow-up, the most fundamental of which are the lack of understanding by long-term survivors about their risk, as well as by the primary care physicians caring for them. Shortcomings of the healthcare system are also potential barriers to long-term follow-up, and include infrastructure issues, such as a lack of capacity within centers, training and educational deficiencies, and inadequate/ineffective communication between oncologists and primary care physicians who subsequently provide the large bulk of follow-up care.

Improvement in cancer diagnosis and treatment with the resultant growing population of survivors has also resulted in increasing emphasis on research focusing on adverse health-related outcomes, such as SMNs and identification of high-risk groups. Appropriate surveillance will facilitate timely identification and appropriate management of SMNs, and reduce the associated morbidity and mortality. However, the long-term costs and benefit of surveillance, early detection, and management need further investigation.

Attention should also be focused on development of intervention strategies, such as behavior modification (eg, smoking cessation), educational interventions (eg, importance of screening), screening for early detection of SMNs, and chemoprevention. Execution of these intervention strategies in the setting of clinical trials would allow us to understand the impact of the specific interventions on early detection, with an overall reduction in morbidity and mortality and an ultimate improvement in the overall quality of life for cancer survivors, and particularly for those who had been treated in childhood.

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