Table 9. Treatment Complications Observed in Hodgkin Lymphoma Survivors continued...
A number of series evaluating the incidence of subsequent neoplasms in survivors of childhood and adolescent Hodgkin lymphoma have been published.[31,32,33,34,35,36,37,38,39] Many of the patients included in these series received high-dose radiation therapy and high-dose alkylating agent chemotherapy regimens, which are no longer used.
Subsequent neoplasms comprise two distinct groups: chemotherapy-related myelodysplasia/acute myeloid leukemia (AML) and solid neoplasms that are predominately radiation related.[40,41]
Secondary hematological malignancy (most commonly AML and myelodysplasia) is related to the use of alkylating agents, anthracycline, and etoposide and exhibit a brief latency period (<3 years from the primary cancer). This excess risk is largely related to cases of myelodysplasia and secondary AML. A single-study experience suggests that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity. Clinical trials using dexrazoxane in childhood leukemia have not observed an excess risk of subsequent neoplasms.[43,44,45]
Chemotherapy-related myelodysplasia/AML are less prevalent following contemporary therapy because of the restriction of cumulative alkylating agent doses.
Solid neoplasms most often involve the skin, breast, thyroid, gastrointestinal tract, and lung with risk increasing with radiation dose.
The risk of a secondary solid tumor escalates with the passage of time after diagnosis of Hodgkin lymphoma, with a latency of 20 years or more.
Breast cancer is the most common therapy-related solid subsequent neoplasm after Hodgkin lymphoma. The absolute excess risk ranges from 18.6 to 79 per 10,000 person-years, and the cumulative incidence ranges from 12% to 26%, 25 to 30 years after radiation exposure. [37,46,47,48]
High risk of breast cancer has been found to increase as early as 8 years from radiation exposure, and it continues to increase with time from exposure. The median age at diagnosis of breast cancer is 36 years, at least 25 years earlier than what is observed in the general population.
The cumulative incidence of breast cancer by age 40 to 45 years ranges from 13% to 20%, compared with a 1% risk for women in the general population.[37,46,48,49] This risk is similar to what is observed for women with a BRCA gene mutation, where, by age 40 years, the cumulative incidence of breast cancer ranges from 10% to 19%.
The risk for breast cancer in female survivors of Hodgkin lymphoma is directly related to the dose of radiation therapy received over a range from 4 to 40 Gy. There is a 3.2-fold increase in the risk of developing breast cancer for females who received 4 Gy and an eightfold increase in risk for females who received 40 Gy. Female patients treated with both radiation therapy and alkylating agent chemotherapy have a lower RR for developing breast cancer than women receiving radiation therapy alone.[38,52] CCSS investigators also demonstrated that breast cancer risk associated with breast irradiation was sharply reduced among women who received 5 Gy or more to the ovaries. The protective effect of alkylating chemotherapy and ovarian radiation is believed to be mediated through induction of premature menopause, suggesting that hormone stimulation contributes to the development of radiation-induced breast cancer.
Female survivors of Hodgkin lymphoma who develop breast cancer have a sevenfold increase in rate of death, even when adjusted for stage, compared with patients who develop breast cancer de novo. These survivors also have a twofold increase in the rate of death from cardiac disease.
A study of women survivors who received chest radiation for Hodgkin lymphoma showed that one of the most important factors in obtaining mammograms per guidelines was recommendation from their treating physician. Standard guidelines for routine breast screening are available. The COG guidelines recommend annual screening mammograms for women beginning 8 years after treatment or at age 25 years, whichever is later.
Greenfield DM, Walters SJ, Coleman RE, et al.: Prevalence and consequences of androgen deficiency in young male cancer survivors in a controlled cross-sectional study. J Clin Endocrinol Metab 92 (9): 3476-82, 2007.
Howell SJ, Radford JA, Adams JE, et al.: The impact of mild Leydig cell dysfunction following cytotoxic chemotherapy on bone mineral density (BMD) and body composition. Clin Endocrinol (Oxf) 52 (5): 609-16, 2000.
Fitoussi, Eghbali H, Tchen N, et al.: Semen analysis and cryoconservation before treatment in Hodgkin's disease. Ann Oncol 11 (6): 679-84, 2000.
Viviani S, Ragni G, Santoro A, et al.: Testicular dysfunction in Hodgkin's disease before and after treatment. Eur J Cancer 27 (11): 1389-92, 1991.
Howell SJ, Shalet SM: Effect of cancer therapy on pituitary-testicular axis. Int J Androl 25 (5): 269-76, 2002.
Kenney LB, Laufer MR, Grant FD, et al.: High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer 91 (3): 613-21, 2001.
Rowley MJ, Leach DR, Warner GA, et al.: Effect of graded doses of ionizing radiation on the human testis. Radiat Res 59 (3): 665-78, 1974.
Hobbie WL, Ginsberg JP, Ogle SK, et al.: Fertility in males treated for Hodgkins disease with COPP/ABV hybrid. Pediatr Blood Cancer 44 (2): 193-6, 2005.
da Cunha MF, Meistrich ML, Fuller LM, et al.: Recovery of spermatogenesis after treatment for Hodgkin's disease: limiting dose of MOPP chemotherapy. J Clin Oncol 2 (6): 571-7, 1984.
Meistrich ML, Wilson G, Brown BW, et al.: Impact of cyclophosphamide on long-term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas. Cancer 70 (11): 2703-12, 1992.
Thibaud E, Ramirez M, Brauner R, et al.: Preservation of ovarian function by ovarian transposition performed before pelvic irradiation during childhood. J Pediatr 121 (6): 880-4, 1992.
Chemaitilly W, Mertens AC, Mitby P, et al.: Acute ovarian failure in the childhood cancer survivor study. J Clin Endocrinol Metab 91 (5): 1723-8, 2006.
Sklar CA, Mertens AC, Mitby P, et al.: Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 98 (13): 890-6, 2006.
van der Kaaij MA, Heutte N, Meijnders P, et al.: Premature ovarian failure and fertility in long-term survivors of Hodgkin's lymphoma: a European Organisation for Research and Treatment of Cancer Lymphoma Group and Groupe d'Etude des Lymphomes de l'Adulte Cohort Study. J Clin Oncol 30 (3): 291-9, 2012.
Constine LS, Donaldson SS, McDougall IR, et al.: Thyroid dysfunction after radiotherapy in children with Hodgkin's disease. Cancer 53 (4): 878-83, 1984.
Hancock SL, Cox RS, McDougall IR: Thyroid diseases after treatment of Hodgkin's disease. N Engl J Med 325 (9): 599-605, 1991.
Sklar C, Whitton J, Mertens A, et al.: Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 85 (9): 3227-32, 2000.
Loeffler JS, Tarbell NJ, Garber JR, et al.: The development of Graves' disease following radiation therapy in Hodgkin's disease. Int J Radiat Oncol Biol Phys 14 (1): 175-8, 1988.
Fajardo LF, Eltringham JR, Steward JR: Combined cardiotoxicity of adriamycin and x-radiation. Lab Invest 34 (1): 86-96, 1976.
Adams MJ, Lipshultz SE: Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: implications for screening and prevention. Pediatr Blood Cancer 44 (7): 600-6, 2005.
Hancock SL, Tucker MA, Hoppe RT: Factors affecting late mortality from heart disease after treatment of Hodgkin's disease. JAMA 270 (16): 1949-55, 1993.
King V, Constine LS, Clark D, et al.: Symptomatic coronary artery disease after mantle irradiation for Hodgkin's disease. Int J Radiat Oncol Biol Phys 36 (4): 881-9, 1996.
Adams MJ, Lipshultz SE, Schwartz C, et al.: Radiation-associated cardiovascular disease: manifestations and management. Semin Radiat Oncol 13 (3): 346-56, 2003.
Küpeli S, Hazirolan T, Varan A, et al.: Evaluation of coronary artery disease by computed tomography angiography in patients treated for childhood Hodgkin's lymphoma. J Clin Oncol 28 (6): 1025-30, 2010.
Trachtenberg BH, Landy DC, Franco VI, et al.: Anthracycline-associated cardiotoxicity in survivors of childhood cancer. Pediatr Cardiol 32 (3): 342-53, 2011.
van Dalen EC, van der Pal HJ, Kok WE, et al.: Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer 42 (18): 3191-8, 2006.
Krischer JP, Epstein S, Cuthbertson DD, et al.: Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J Clin Oncol 15 (4): 1544-52, 1997.
van Dalen EC, Caron HN, Dickinson HO, et al.: Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev (2): CD003917, 2008.
Silber JH, Cnaan A, Clark BJ, et al.: Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines. J Clin Oncol 22 (5): 820-8, 2004.
Lipshultz SE, Lipsitz SR, Sallan SE, et al.: Long-term enalapril therapy for left ventricular dysfunction in doxorubicin-treated survivors of childhood cancer. J Clin Oncol 20 (23): 4517-22, 2002.
Beaty O 3rd, Hudson MM, Greenwald C, et al.: Subsequent malignancies in children and adolescents after treatment for Hodgkin's disease. J Clin Oncol 13 (3): 603-9, 1995.
van Leeuwen FE, Klokman WJ, Veer MB, et al.: Long-term risk of second malignancy in survivors of Hodgkin's disease treated during adolescence or young adulthood. J Clin Oncol 18 (3): 487-97, 2000.
Green DM, Hyland A, Barcos MP, et al.: Second malignant neoplasms after treatment for Hodgkin's disease in childhood or adolescence. J Clin Oncol 18 (7): 1492-9, 2000.
Metayer C, Lynch CF, Clarke EA, et al.: Second cancers among long-term survivors of Hodgkin's disease diagnosed in childhood and adolescence. J Clin Oncol 18 (12): 2435-43, 2000.
Wolden SL, Lamborn KR, Cleary SF, et al.: Second cancers following pediatric Hodgkin's disease. J Clin Oncol 16 (2): 536-44, 1998.
Sankila R, Garwicz S, Olsen JH, et al.: Risk of subsequent malignant neoplasms among 1,641 Hodgkin's disease patients diagnosed in childhood and adolescence: a population-based cohort study in the five Nordic countries. Association of the Nordic Cancer Registries and the Nordic Society of Pediatric Hematology and Oncology. J Clin Oncol 14 (5): 1442-6, 1996.
Bhatia S, Yasui Y, Robison LL, et al.: High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: report from the Late Effects Study Group. J Clin Oncol 21 (23): 4386-94, 2003.
Constine LS, Tarbell N, Hudson MM, et al.: Subsequent malignancies in children treated for Hodgkin's disease: associations with gender and radiation dose. Int J Radiat Oncol Biol Phys 72 (1): 24-33, 2008.
Swerdlow AJ, Higgins CD, Smith P, et al.: Second cancer risk after chemotherapy for Hodgkin's lymphoma: a collaborative British cohort study. J Clin Oncol 29 (31): 4096-104, 2011.
Reulen RC, Frobisher C, Winter DL, et al.: Long-term risks of subsequent primary neoplasms among survivors of childhood cancer. JAMA 305 (22): 2311-9, 2011.
Friedman DL, Whitton J, Leisenring W, et al.: Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 102 (14): 1083-95, 2010.
Le Deley MC, Leblanc T, Shamsaldin A, et al.: Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Société Française d'Oncologie Pédiatrique. J Clin Oncol 21 (6): 1074-81, 2003.
Tebbi CK, London WB, Friedman D, et al.: Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol 25 (5): 493-500, 2007.
Lipshultz SE, Scully RE, Lipsitz SR, et al.: Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol 11 (10): 950-61, 2010.
Barry EV, Vrooman LM, Dahlberg SE, et al.: Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane. J Clin Oncol 26 (7): 1106-11, 2008.
Kenney LB, Yasui Y, Inskip PD, et al.: Breast cancer after childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Intern Med 141 (8): 590-7, 2004.
Ng AK, Bernardo MV, Weller E, et al.: Second malignancy after Hodgkin disease treated with radiation therapy with or without chemotherapy: long-term risks and risk factors. Blood 100 (6): 1989-96, 2002.
Taylor AJ, Winter DL, Stiller CA, et al.: Risk of breast cancer in female survivors of childhood Hodgkin's disease in Britain: a population-based study. Int J Cancer 120 (2): 384-91, 2007.
Henderson TO, Amsterdam A, Bhatia S, et al.: Systematic review: surveillance for breast cancer in women treated with chest radiation for childhood, adolescent, or young adult cancer. Ann Intern Med 152 (7): 444-55; W144-54, 2010.
Easton DF, Ford D, Bishop DT: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 56 (1): 265-71, 1995.
Alm El-Din MA, Hughes KS, Finkelstein DM, et al.: Breast cancer after treatment of Hodgkin's lymphoma: risk factors that really matter. Int J Radiat Oncol Biol Phys 73 (1): 69-74, 2009.
Travis LB, Hill DA, Dores GM, et al.: Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 290 (4): 465-75, 2003.
Inskip PD, Robison LL, Stovall M, et al.: Radiation dose and breast cancer risk in the childhood cancer survivor study. J Clin Oncol 27 (24): 3901-7, 2009.
De Bruin ML, Sparidans J, van't Veer MB, et al.: Breast cancer risk in female survivors of Hodgkin's lymphoma: lower risk after smaller radiation volumes. J Clin Oncol 27 (26): 4239-46, 2009.
Milano MT, Li H, Gail MH, et al.: Long-term survival among patients with Hodgkin's lymphoma who developed breast cancer: a population-based study. J Clin Oncol 28 (34): 5088-96, 2010.
Oeffinger KC, Ford JS, Moskowitz CS, et al.: Breast cancer surveillance practices among women previously treated with chest radiation for a childhood cancer. JAMA 301 (4): 404-14, 2009.
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